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A physical exam is one of the most common ways to diagnose depression. Within the exam your doctor will simply ask questions about your physical health. This is because in some cases depression can correlate to an underlying health issue.
For example, your doctor may order a blood test to examine your thyroid to make sure that it is functioning properly.

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One symptom of depression which can be considered as multiple is the feeling of sadness, emptiness and hopelessness. Studies have been reported that working out or weightlifting is a natural aid in fighting depression.

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The LG Health Hub features breaking medical news and straightforward advice to help individuals of all ages make healthy choices and reach their wellness goals. The blog puts articles by trusted Lancaster General Health clinical experts, good 'n healthy recipes, videos, patient stories, and health risk assessments at your fingertips.

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Strength Training: The Missing Piece in Fitness That Helps Fight Depression - Penn Medicine Lancaster General Health

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Muscle-strengthening exercise not only enhances your physical health, research shows it also has mental health benefits.

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Sports and exercise – such as Nordic walking, jogging, cycling, swimming or hiking – are often recommended for the relief or prevention of depression. Many people find that physical activity improves their mood and gives them more energy, and it has been found to help relieve depression in some people too. Research has found that it doesn't completely cure depression but it can help.

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There are various treatment options for depression. They include psychological treatments, medication and general measures such as relaxation techniques. Different treatment options are often combined.

Depression is one of the most common mental illnesses. During a depressive episode, people feel like they're in a deep, dark pit for weeks or months, and often can't see any way out. In chronic depression, the symptoms last for years. Treatment can shorten depressive episodes and relieve the symptoms.

Does depression always need to be treated?

If someone has mild depression, or it has only just started, one option is to wait and see whether the symptoms go away again without treatment. This "watchful waiting" approach doesn't mean that the symptoms are ignored and nothing is done, though. It is important to stay in touch with the doctor and have regular appointments to discuss how you're feeling and how you can cope with the situation. If the symptoms get worse or last several weeks, further treatment may be needed.

It is also important for people to be able to talk with others. Partners, friends and family play a very important role here. Support and information centers can offer help and guidance too. Sometimes it can help to talk to people who have gone through similar experiences, for example in a support group.

Particularly in moderate or severe depression, it is usually very important to get immediate treatment because the symptoms are very distressing and can last quite a while. This is also true if someone has chronic depression or is thinking of harming or killing themselves (committing suicide).

How long does treatment last?

A distinction is made between different phases of treatment, referred to as "acute," "continuation" and "maintenance" treatment (relapse prevention). Acute treatment usually lasts six to eight weeks. The aim is to

relieve symptoms enough to enable the person to cope in everyday life again, and

make the symptoms go away sooner, preventing the depression from further affecting their lives.

The next phase of treatment is called continuation treatment. This usually lasts four to nine months. The aim of continuation treatment is to

further relieve the symptoms, until they go away, and

sustain the progress made through treatment.

For people with a high risk of recurring depression, long-term treatment may be considered in order to prevent a relapse. This "relapse prevention" can sometimes last for years - for example, if the symptoms haven't disappeared completely despite acute and continuation treatment, or if the patient's personal circumstances are still very difficult. People who have chronic depression often take medication for many years too.

What are the psychological treatment options?

Psychological treatment usually involves talking about things in depth and doing behavioral exercises. The kind of psychological treatment that is most commonly used for depression is known as cognitive behavioral therapy (often called "CBT" for short). Statutory health insurance companies in Germany cover the costs of CBT as well as other outpatient treatments, including depth psychology and systemic therapy. They are often offered by specially trained therapists.

If someone is going through an acute depressive episode, the doctor will usually recommend short-term psychological support, sometimes together with medication. Then you can apply for a full course of outpatient psychological treatment.

Cognitive behavioral therapy

In depression, negative thought patterns such as self-doubt and feelings of guilt often make the problem worse. Cognitive behavioral therapy aims to break these patterns bit by bit, so that people feel better about themselves.

Cognitive behavioral therapy combines two treatment approaches:

Cognitive therapy: Cognitive therapy is based on the idea that problems are often caused less by things and situations themselves, but rather by the importance that people attach to them. So changing the way people see things can be an important step.

Behavioral therapy: Behavioral therapy is based on the assumption that behavior is learned and can also be unlearned. The goal of behavioral therapy is to identify destructive patterns of behavior, then work at them and change them.

The goal of cognitive behavioral therapy is to become more aware of your own thoughts, attitudes and expectations. This makes it possible to identify false and distressing beliefs, and then change them.

Psychoanalytic approaches

Psychoanalytic approaches include analytical psychotherapy and methods based on depth psychology. They are based on the belief that unresolved, unconscious conflicts can cause depression. The aim is to identify and work through previously unknown issues by talking to a therapist. People who have psychoanalytic therapy have to be prepared to face potentially painful past experiences. Psychoanalysis usually takes longer than approaches based on depth psychology.

Systemic therapy

Systemic therapy approaches place a lot of importance on the relationships between people - for instance, within your family, your group of friends or at work. These relationships can play a role in the development of depression. The therapy might involve trying to improve communication within the family, for instance. The aim is to reduce the symptoms of depression.

How do I find a psychotherapist?

Family doctors often recommend a particular psychotherapist. But you can also contact the private practice of a psychotherapist or psychiatrist. In Germany, the association of statutory health insurance physicians (Kassenärztliche Vereinigung) can help you get an appointment.

You can have an initial appointment in a psychotherapy practice without being referred by a doctor or sending an application to your health insurer. In urgent cases, you can also turn to psychiatric practices with an emergency service, outpatient psychotherapy clinics in hospitals, as well as psychiatric or psychosomatic hospitals.

For outpatient psychotherapy to work, it is very important to find a psychotherapist who you can trust and feel comfortable with. In Germany, the first three to five psychotherapy sessions in an outpatient setting are considered to be trial sessions, to see whether the chemistry between the client and therapist is right and whether the client is happy with the therapist's treatment approach.

When are the different medications considered?

Medication doesn't help in mild depression. There may be other good reasons to not take medication (at first). For instance, the symptoms sometimes get better without antidepressants after a short while. The possible side effects will also play a role when deciding whether or not to take antidepressants.

But the symptoms may be so bad that it makes sense to use medication. This is particularly true for people who have severe and regularly recurring depression - especially if they are thinking of harming themselves or committing suicide. Sometimes people are only capable of starting psychological treatment once their symptoms have improved a bit due to medication.

Antidepressants

Various medications and groups of drugs are classified as antidepressants. They can have a mood-lifting effect and increase motivation. Antidepressants are often used in combination with psychological treatment. But it usually takes several days or weeks for antidepressants to start working. In acute depression they have to be taken every day for several weeks or months before they start having a noticeable effect. This is often followed by continuation treatment, which lasts four to nine months. How long people take medication for will depend on factors like their symptoms and their risk of having another depressive episode. Some people take antidepressants for years to prevent further depressive episodes.

The possible side effects of antidepressants include a dry mouth, headaches and feeling faint, restlessness and a decreased sex drive. These usually arise within the first few weeks of taking antidepressants. Whether or not someone has side effects, which side effects they have, and how frequent the side effects are will depend on the specific drug and dose that is used.

Different people react a bit differently to medication too. That's why it's important to see a doctor regularly while on medication, so they can see how things are going and adjust the treatment if necessary. Towards the end of the treatment, the dose of antidepressants is gradually reduced over the course of several weeks. If someone stops taking antidepressants suddenly, they might (temporarily) have problems sleeping, feel nauseous or restless. Stopping taking the medication as soon as you start to feel better without consulting your doctor can increase the risk of depression returning.

Herbal products

The most common and best-known herbal medicines for the treatment of depression are made from St. John's wort. These products are often used to treat mild depression. Some are used to treat moderate depression too.

Some St. John's wort products for moderate depression have to be prescribed by a doctor. When considering taking prescription-free St. John's wort products (or most other herbal medicines, for that matter), it is important to be aware that there are a wide variety of products on the market, with very different doses and ingredients. Many St. John's wort products only have a small amount of the extract in them. Herbal products can have side effects and interact with other medications too, so it's important to consult a doctor before taking St. John's wort.

Are there other treatment options?

A lot of other treatments and strategies are offered to people with depression. But many of these haven't been clearly proven to help reduce the symptoms. Some can be a useful addition or alternative to other treatments in certain situations.

Relaxation techniques and yoga

There is some evidence that relaxation techniques can help relieve mild to moderate depression. These include approaches such as progressive muscle relaxation, autogenic training, music therapy and yoga. But they aren't as effective as other treatments, such as cognitive behavioral therapy. Psychotherapists sometimes teach relaxation techniques as part of the therapy, though.

Sports and exercise

Sports and exercise - such as Nordic walking, jogging, cycling, swimming or hiking - are often recommended for the relief or prevention of depression. Many people find that physical activity improves their mood and gives them more energy, and it has been found to help relieve depression in some people too. But research has also shown that physical activity doesn't generally have a very big impact in people with depression. And there is little research on whether the benefits of exercise last in the longer term. Sports and exercise can be a useful addition to other treatments, though.

It is also not clear how much people might benefit from different types of sports and exercise. Physical activity might not necessarily be suitable for all types of depression either. For instance, people who have severe depression are often not capable of being physically active. Being advised to do more exercise might make them feel even worse.

Light therapy

Light therapy, also known as phototherapy, is used in the treatment of seasonal affective disorder (SAD). This form of depression affects some people during the darker months of the year. Treatment with artificial light is an option here if the lack of natural bright daylight is thought to be affecting their mood. Light therapy involves sitting in front of a special bright light (a light therapy device) for about half an hour every morning.

Sleep deprivation therapy

This treatment involves temporarily depriving the patient of sleep. They stay awake for a whole night and only go to sleep the following night. It is thought that sleep deprivation changes the metabolism in the brain, and that this might lead to an improvement in mood. Sleep deprivation therapy only aims to improve the symptoms temporarily. It can be used in addition to other treatments.

Electroconvulsive therapy

Electroconvulsive therapy is usually carried out in a hospital, under general anesthetic. Electrodes are placed on the patient's head and a short burst of electric current is passed through the brain, inducing a seizure. The patient can't feel anything because the procedure is carried out under general anesthesia. Electroconvulsive therapy is usually only considered as a treatment option for people with severe depression if other treatments haven't helped.

Sources

Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN). S3-Leitlinie und Nationale Versorgungsleitlinie (NVL): Unipolare Depression. AWMF-Registernr.: nvl-005. March 2017.

IQWiG health information is written with the aim of helping people understand the advantages and disadvantages of the main treatment options and health care services.

Because IQWiG is a German institute, some of the information provided here is specific to the German health care system. The suitability of any of the described options in an individual case can be determined by talking to a doctor. We do not offer individual consultations.

Our information is based on the results of good-quality studies. It is written by a team of health care professionals, scientists and editors, and reviewed by external experts. You can find a detailed description of how our health information is produced and updated in our methods.

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There are various treatment options for depression. They include psychological treatments, medication and general measures such as relaxation techniques. Different treatment options are often combined. Depression is one of the most common mental illnesses. During a depressive episode, people feel like they're in a deep, dark pit for weeks or months, and often can't see any way out.

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Psychological treatment usually involves talking about things in depth and express your feelings with a professional. If someone is going through an acute depressive episode, the doctor will usually recommend short-term psychological support, sometimes together with medication. Then you can apply for a full course of outpatient psychological treatment.
People who have psychoanalytic therapy have to be prepared to face potentially painful past experiences.

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Within a psychiatric evaluation, your mental health professional will ask about your symptoms, feelings, and behavior patterns. Commonly the patient is given a questionnaire to help them answer the questions. Your mental health professional will then use the results from the questions/questionnaire and compare them to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders) to determine whether or not the patient has depression.

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A symptom of depression would thoughts of suicide. One treatment for this would be taking SSRI's which for simple terms are one kind of antidepressants.

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Overview

What is depression? A Mayo Clinic expert explains.

Learn more about depression from Craig Sawchuk, Ph.D., L.P., clinical psychologist at Mayo Clinic.

Hi, I'm Dr. Craig Sawchuk, a clinical psychologist at Mayo Clinic. And I'm here to talk with you about depression. Whether you're looking for answers for yourself, a friend, or loved one, understanding the basics of depression can help you take the next step.

What is depression?

Depression is a mood disorder that causes feelings of sadness that won't go away. Unfortunately, there's a lot of stigma around depression. Depression isn't a weakness or a character flaw. It's not about being in a bad mood, and people who experience depression can't just snap out of it. Depression is a common, serious, and treatable condition. If you're experiencing depression, you're not alone. It honestly affects people of all ages and races and biological sexes, income levels and educational backgrounds. Approximately one in six people will experience a major depressive episode at some point in their lifetime, while up to 16 million adults each year suffer from clinical depression. There are many types of symptoms that make up depression. Emotionally, you may feel sad or down or irritable or even apathetic. Physically, the body really slows down. You feel tired. Your sleep is often disrupted. It's really hard to get yourself motivated. Your thinking also changes. It can just be hard to concentrate. Your thoughts tend to be much more negative. You can be really hard on yourself, feel hopeless and helpless about things. And even in some cases, have thoughts of not wanting to live. Behaviorally, you just want to pull back and withdraw from others, activities, and day-to-day responsibilities. These symptoms all work together to keep you trapped in a cycle of depression. Symptoms of depression are different for everyone. Some symptoms may be a sign of another disorder or medical condition. That's why it's important to get an accurate diagnosis.

What causes depression?

While there's no single cause of depression, most experts believe there's a combination of biological, social, and psychological factors that contribute to depression risk. Biologically, we think about genetics or a family history of depression, health conditions such as diabetes, heart disease or thyroid disorders, and even hormonal changes that happen over the lifespan, such as pregnancy and menopause. Changes in brain chemistry, especially disruptions in neurotransmitters like serotonin, that play an important role in regulating many bodily functions, including mood, sleep, and appetite, are thought to play a particularly important role in depression. Socially stressful and traumatic life events, limited access to resources such as food, housing, and health care, and a lack of social support all contribute to depression risk. Psychologically, we think of how negative thoughts and problematic coping behaviors, such as avoidance and substance use, increase our vulnerability to depression.

The good news is that treatment helps. Effective treatments for depression exist and you do have options to see what works best for you. Lifestyle changes that improve sleep habits, exercise, and address underlying health conditions can be an important first step. Medications such as antidepressants can be helpful in alleviating depressive symptoms. Therapy, especially cognitive behavioral therapy, teaches skills to better manage negative thoughts and improve coping behaviors to help break you out of cycles of depression. Whatever the cause, remember that depression is not your fault and it can be treated.

To help diagnose depression, your health care provider may use a physical exam, lab tests, or a mental health evaluation. These results will help identify various treatment options that best fit your situation.

Help is available. You don't have to deal with depression by yourself. Take the next step and reach out. If you're hesitant to talk to a health care provider, talk to a friend or loved one about how to get help. Living with depression isn't easy and you're not alone in your struggles. Always remember that effective treatments and supports are available to help you start feeling better. Want to learn more about depression? Visit mayoclinic.org. Do take care.

Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. Also called major depressive disorder or clinical depression, it affects how you feel, think and behave and can lead to a variety of emotional and physical problems. You may have trouble doing normal day-to-day activities, and sometimes you may feel as if life isn't worth living.

More than just a bout of the blues, depression isn't a weakness and you can't simply "snap out" of it. Depression may require long-term treatment. But don't get discouraged. Most people with depression feel better with medication, psychotherapy or both.
Depression care at Mayo Clinic
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Symptoms

Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

Feelings of sadness, tearfulness, emptiness or hopelessness

Angry outbursts, irritability or frustration, even over small matters

Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports

Sleep disturbances, including insomnia or sleeping too much

Tiredness and lack of energy, so even small tasks take extra effort

Reduced appetite and weight loss or increased cravings for food and weight gain

Anxiety, agitation or restlessness

Slowed thinking, speaking or body movements

Feelings of worthlessness or guilt, fixating on past failures or self-blame

Trouble thinking, concentrating, making decisions and remembering things

Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide

Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Depression symptoms in children and teens

Common signs and symptoms of depression in children and teenagers are similar to those of adults, but there can be some differences.

In younger children, symptoms of depression may include sadness, irritability, clinginess, worry, aches and pains, refusing to go to school, or being underweight.

In teens, symptoms may include sadness, irritability, feeling negative and worthless, anger, poor performance or poor attendance at school, feeling misunderstood and extremely sensitive, using recreational drugs or alcohol, eating or sleeping too much, self-harm, loss of interest in normal activities, and avoidance of social interaction.

Depression symptoms in older adults

Depression is not a normal part of growing older, and it should never be taken lightly. Unfortunately, depression often goes undiagnosed and untreated in older adults, and they may feel reluctant to seek help. Symptoms of depression may be different or less obvious in older adults, such as:

Memory difficulties or personality changes

Physical aches or pain

Fatigue, loss of appetite, sleep problems or loss of interest in sex - not caused by a medical condition or medication

Often wanting to stay at home, rather than going out to socialize or doing new things

Suicidal thinking or feelings, especially in older men

When to see a doctor

If you feel depressed, make an appointment to see your doctor or mental health professional as soon as you can. If you're reluctant to seek treatment, talk to a friend or loved one, any health care professional, a faith leader, or someone else you trust.

When to get emergency help

If you think you may hurt yourself or attempt suicide, call 911 in the U.S. or your local emergency number immediately.

Also consider these options if you're having suicidal thoughts:

Call your doctor or mental health professional.

Contact a suicide hotline.

In the U.S., call or text 988 to reach the 988 Suicide & Crisis Lifeline, available 24 hours a day, seven days a week. Or use the Lifeline Chat. Services are free and confidential.

U.S. veterans or service members who are in crisis can call 988 and then press "1" for the Veterans Crisis Line. Or text 838255. Or chat online.

The Suicide & Crisis Lifeline in the U.S. has a Spanish language phone line at 1-888-628-9454 (toll-free).

Reach out to a close friend or loved one.

Contact a minister, spiritual leader or someone else in your faith community.

If you have a loved one who is in danger of suicide or has made a suicide attempt, make sure someone stays with that person. Call 911 or your local emergency number immediately. Or, if you think you can do so safely, take the person to the nearest hospital emergency room.

More Information

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Causes

It's not known exactly what causes depression. As with many mental disorders, a variety of factors may be involved, such as:

Biological differences. People with depression appear to have physical changes in their brains. The significance of these changes is still uncertain, but may eventually help pinpoint causes.

Brain chemistry. Neurotransmitters are naturally occurring brain chemicals that likely play a role in depression. Recent research indicates that changes in the function and effect of these neurotransmitters and how they interact with neurocircuits involved in maintaining mood stability may play a significant role in depression and its treatment.

Hormones. Changes in the body's balance of hormones may be involved in causing or triggering depression. Hormone changes can result with pregnancy and during the weeks or months after delivery (postpartum) and from thyroid problems, menopause or a number of other conditions.

Inherited traits. Depression is more common in people whose blood relatives also have this condition. Researchers are trying to find genes that may be involved in causing depression.

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment.

Factors that seem to increase the risk of developing or triggering depression include:

Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic

Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems

Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide

Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren't clearly male or female (intersex) in an unsupportive situation

History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder

Abuse of alcohol or recreational drugs

Serious or chronic illness, including cancer, stroke, chronic pain or heart disease

Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Complications

Depression is a serious disorder that can take a terrible toll on you and your family. Depression often gets worse if it isn't treated, resulting in emotional, behavioral and health problems that affect every area of your life.

Examples of complications associated with depression include:

Excess weight or obesity, which can lead to heart disease and diabetes

Pain or physical illness

Alcohol or drug misuse

Anxiety, panic disorder or social phobia

Family conflicts, relationship difficulties, and work or school problems

Social isolation

Suicidal feelings, suicide attempts or suicide

Self-mutilation, such as cutting

Premature death from medical conditions

Prevention

There's no sure way to prevent depression. However, these strategies may help.

Take steps to control stress, to increase your resilience and boost your self-esteem.

Reach out to family and friends, especially in times of crisis, to help you weather rough spells.

Get treatment at the earliest sign of a problem to help prevent depression from worsening.

Consider getting long-term maintenance treatment to help prevent a relapse of symptoms.

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Depression (major depressive disorder) - Symptoms and causes

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Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest and can interfere with your daily functioning.

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Prolonged sadness or hopelessness is defined as having a two week or longer state of sadness. This is by far the most common and earliest symptom of depression.

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National Institute of Mental Health (NIMH)

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Learn about depression, including types, signs and symptoms, risk factors, treatments and therapies, and things you can do to help during treatment.

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The anatomical depression affects/ Body System 

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The anatomical depression affects/ Body System 

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Depression can affect the body in many ways. It can affect the heart, kidney, nervous system, and immune system health.

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The anatomical structures depression affects - Brain

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The anatomical structures depression affects - Brain

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Major depressive disorder is known as a disorder of the brain. The primary anatomical structures that are affected within the brain are the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and the amygdala.

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Summary

Depression is the leading cause of disability around the world, but little is known about its pathology. Currently, the diagnosis of depression is made based on clinical manifestations, with little objective evidence. Magnetic resonance imaging (MRI) has been used to investigate the pathological changes in brain anatomy associated with this disorder. MRI can identify structural alterations in depressive patients in vivo, which could make considerable contributions to clinical diagnosis and treatment. Numerous studies that focused on gray and white matter have found significant brain region alterations in major depressive disorder patients, such as in the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala. The results are inconsistent and controversial because of the different demographic and clinical characteristics. However, some regions overlapped; thus, we think that there may be a "hub" in MDD and that an impairment in these regions contributes to disease severity. Brain connections contain both structural connections and functional connections, which reflect disease from a different view and support that MDD may be caused by the interaction of multiple brain regions. According to previous reports, significant circuits include the frontal‐subcortical circuit, the suicide circuit, and the reward circuit. As has been recognized, the pathophysiology of major depressive disorder is complex and changeable. The current review focuses on the significant alterations in the gray and white matter of patients with the depressive disorder to generate a better understanding of the circuits. Moreover, identifying the nuances of depressive disorder and finding a biomarker will make a significant contribution to the guidance of clinical diagnosis and treatment.

Keywords: Psychoradiology, diffusion MRI; magnetic resonance imaging; major depressive disorder; structure MRI

1. INTRODUCTION

Major depressive disorder (MDD) is characterized by persistent low mood, often accompanied by cognitive dysfunction, physical symptoms, and impaired social function.1 According to the World Health Organization's statistics, more than 300 million people worldwide suffer from depression. More severely, depression can cause suicide, and nearly 800 000 people die every day due to suicide. According to statistics from 2015,2 suicide is the second leading cause of death among people 15‐29 years of age, resulting in vast economic and social burdens. Based on epidemiological studies, more than 30% of patients with depression suffer from ineffective antidepressant treatments, and their lifetime prevalence rate is approximately 16.2%.3 Currently, the diagnosis of MDD relies on patients' reporting and behavioral assessments. Little is known about its precise neurobiological biomarkers. Neuroimaging studies have the advantage of being noninvasive and repeatable and might provide precise evidence to clinics for more successful individualized therapies.

In recent years, neuroimaging methods, especially magnetic resonance imaging (MRI), have been used in many studies to identify disorder‐related patterns of the brain changes associated with MDD. The MRI scan sequences that are commonly used by researchers include high‐resolution structural imaging (3D‐T1), which depicts gray matter thickness in volume and brain morphology; diffusion tensor imaging (DTI), which depicts the microstructure of the white matter; and functional magnetic resonance imaging (fMRI), which depicts the neuronal activity in target brain regions. Previous studies based on MRI found that several brain regions are significantly impaired in MDD patients. Several regional gray matter changes have been identified in the frontal lobe, parietal lobe, thalamus, caudate, pallidum, putamen, and temporal lobes (eg, the hippocampus and amygdala)4, 5, 6 by anatomical MRI studies. DTI studies have shown white matter alterations, such as decreased fractional anisotropy (FA) in the cingulum,7 hippocampus, parietal regions,8 inferior temporal gyrus, and superior frontal gyrus. These findings were confirmed by a recent meta‐analysis.9 In addition, abnormal brain activity was found in the prefrontal cortex,10 occipital lobe,11 temporal gray, caudate,12 and putamen.13 Different brain regions have connections with each other and ultimately form complex brain networks. A hub is a region that is highly connected and highly central that plays a role in global information integration14 (Figure 1 ). The impairment of hub nodes or their connections may be a leading cause of disease, such as MDD. Structural connections between cortical and subcortical areas compose several circuits, such as the frontal‐subcortical circuit,15 basal ganglic‐thalamic‐cortical circuit,16 prefrontal hippocampus circuit,17 the limbic‐cortical‐striatal‐thalamic‐cortical circuit,18 and the limbic‐cortical‐striatal‐pallidal‐thalamic19 circuit. The most common functional connection in MDD patients is the cortical‐subcortical circuit.20 According to previous findings, the frontal lobe, parietal lobe, thalamus, putamen, and hippocampus are considered hubs in these circuits.14, 21, 22

In the present review, significant structural changes in brain regions and circuits involved in MDD are reviewed, and future research directions in this field are outlined. This article focuses on the imaging findings of MDD to explore the findings of neuroimaging, which is helpful for differential diagnosis and accurate medicine.

2. SIGNIFICANT STRUCTURAL BRAIN ALTERATIONS IN MDD

2.4. Parietal lobe

3. IMPAIRED CIRCUITS IN MDD

3.1. Prefrontal‐subcortical circuit

The striatum, thalamus, and prefrontal cortex constitute the prefrontal‐subcortical circuit,47 which is involved in emotional and cognitive processing and is considered to be a potential pathophysiological target in MDD.83 The structural connectivity of the prefrontal‐subcortical circuit begins at the prefrontal cortex. The striatum receives information from the PFC and outputs the information to the globus pallidus and the substantial nigra. All information is then projected through the thalamus to the prefrontal cortex. The thalamus is the final neuronal link back to the cortex, making the circuit a closed loop. This review mainly introduces three prefrontal circuits (Figure 2 ), which were originally described by Alexander.84 In each circuit, two pathways have mainly been reported (Figure 3 ): one direct pathway goes from the striatum to the pallidum, and the other pathway projects from the striatum to the pallidum, then to the subthalamic nucleus, and back to the pallidum.85 Basic research has found that gamma‐aminobutyric acid (GABA) and glutamate participate in these two pathways.83 Directly, the prefrontal cortex, hippocampus, and thalamus elicit excitement and project to the striatum. The striatum transmits information through GABAergic neurons that project to the globus pallidus. Indirectly, the subthalamic nucleus receives information from the cortex and the globus pallidus via GABAergic neurons and then outputs through glutamatergic neurons to the globus pallidus. Both the direct and indirect pathways enter the thalamus through gamma fibers, but impairments in these two pathways could lead to differential pathology. Damage to the direct pathway results in abnormal suppression of the thalamus. In contrast, dysfunction in the indirect pathway leads to disinhibition and thalamic hyperactivity.47

3.1.1. The dorsolateral prefrontal circuit

The dorsolateral prefrontal circuit originates from the dorsolateral prefrontal cortex (BA seed based 9 and BA 10) and connects to the dorsolateral caudate. The caudate outputs to the lateral dorsomedial globus pallidus and the substantia nigra through the direct or indirect pathway. The pallidum and substantia nigra have connections with the ventral anterior and medial dorsal thalamus.86 Finally, all messages are returned through the thalamus to the dorsolateral prefrontal cortex. A functional connectivity analysis reported coactivity in the bilateral DLPFC and the dorsal caudate.54 The dorsolateral prefrontal cortex and the caudate nucleus are unable to preserve recognition. According to a previous fMRI study, decreased activity in the caudate and increased activity in Brodmann area 10 were reported during reward anticipation57 in patients with MDD. These findings suggested that patients with depression have the intention of inducing pleasurable emotions. Thus, MDD patients with impaired dorsolateral prefrontal circuits may exhibit executive dysfunction.47

3.1.2. The orbitofrontal prefrontal circuit

The orbitofrontal prefrontal circuit starts at the inferolateral prefrontal cortex (BA 10 and BA 11).87 The OFC sends fibers to the ventromedial caudate. Then, the caudate outputs through the direct and indirect pathways to the medial dorsomedial globus pallidus and the substantia nigra. The medial dorsal thalamic nucleus receives input from the pallidum and the substantia nigra and outputs to the OFC. All the information will ultimately be sent to the orbitofrontal cortex. Functional seed‐based studies of the OFC found coactivity with these limbic regions.88 Heavy connections of the orbitofrontal gyrus with other cortical and subcortical regions, such as the parahippocampal gyrus, the ACC, and the posterior cingulate cortex,89 have been reported. A functional MRI study showed that a decrease in the OFC circuit connections was associated with unexpected reward receipt tasks90 and pleasant stimuli91 in MDD patients. The causal relationship between the OFC and the ACC is positively correlated with the severity of depression.20 In conclusion, the orbitofrontal circuit may be negatively related to the severity of depression and the source of negative thinking.92

3.1.3. The anterior cingulate‐prefrontal circuit

The anterior cingulate‐prefrontal circuit begins in the anterior cingulate cortex (BA 24). The ACC outputs messages to the ventral striatum and the substantia nigra. The striatum and the substantia nigra project to the medial dorsal thalamus.86 Finally, all the information is sent back to the anterior cingulate gray via the thalamus. It is not clear whether there is a direct or indirect connection between the ACC and the striatum. However, there is evidence that the connections between the ventral striatum and thalamic neurons are present.93 The nucleus accumbens is a part of the ventral striatum, which receives excitatory inputs from the ACC and outputs to the thalamus, and has been linked with anhedonia. The relationship between the nucleus accumbens and the thalamus is negatively correlated with the severity of depression94 and is related to emotional regulation and motivational function.95 Functional connectivity studies revealed the coordination between the ventral striatum, the bilateral middle temporal lobe (amygdala and hippocampus), and the ventral midbrain (substantia nigra).54 According to previous findings, the ACC plays an important role in anhedonic symptoms in patients with MDD.90 Therefore, damage to the anterior cingulate circuitry may be negatively correlated with the severity of depressive symptoms.

Different circuits also have correlations. As mentioned earlier, the functional connectivity of the ACC and the DLPFC is increased. This indicates an increase in the sensitivity to effective conflict.35 A correlation between the OFC and the ACC has also been mentioned. The causal interaction between the OFC and the ACC is positively related to the severity of depression.20 The ACC receives input from the PFC and outputs to other brain regions.96 A powerless DLPFC and OFC in MDD result in a failure to activate the ACC, ultimately leading to circuit impairment.

3.2. Prefrontal‐hippocampal circuit

In the early stage of MDD, a DTI study reported that the prefrontal‐hippocampal circuits,13 which originate from the fornix and output fibers to the hippocampus, project to the mammillary bodies, the anterior nuclei of the thalamus, and finally back to the prefrontal cortex. A lower FA value was observed in the fornix and the hippocampal cingulum17 of depressive patients. The fornix comprises the major fibers that track through the hippocampus, and it is related to the reduction in the hippocampal volume.97 Disruptions in the fornix would result in barriers to the transmission of information between the PFC and the hippocampus. Resting‐state functional research found decreased functional connectivity among the bilateral hippocampus, the DLPFC, and the ventral PFC17 in MDD patients, which might indicate emotional and cognitive dysfunction in MDD. There was a significant correlation between the white matter integrity of the fornix and the functional connectivity of the PFC‐hippocampal circuit in healthy controls, but this was found to be impaired in the MDD patients.17 In conclusion, prefrontal hippocampal structural damage can explain the deficits in attention, information processing, and autobiographical memory in depressive patients.17

3.3. Frontothalamic circuit

To our knowledge, Professor Jia and his team are the first ones to find and put forward the "suicide loop"6 (Figure 4 ). That particular DTI study found that the FA value of the left internal capsule was lower in patients who attempted suicide.1 Abnormalities in the fiber connections passing through the left anterior limb of the internal capsule that projects to the left middle frontal cortex and the OFC and finally posteriorly to the left thalamus in MDD patients who committed suicide were found to be more severe than those who did not commit suicide and controls. The middle frontal cortex and the OFC are related to decision making and problem solving and can affect modulation,49, 98 and the thalamus is involved in the mood‐related neural network.49 These three regions are considered hub nodes of brain connections.21 Changes in the frontal and thalamic circulation may lead to cognitive and emotional changes, thereby increasing the vulnerability to suicidal behavior in patients with depression. The results demonstrating these white matter changes are consistent with those of other studies.99, 100 Abnormal gray matter in the temporal and parietal lobes was also found in the patients who committed suicide. Decreased gray matter volume in the limbic cingulate gyrus and the right middle temporal gyrus and increased gray matter volume in the right parietal lobe101 were reported, and a negative correlation was observed between the limbic cingulate gyrus and dysfunctional attitude scores. The attitude score reflects the perception of oneself and the world,102 and cognitive distortions often lead to negative beliefs and behaviors, such as suicide. The reduction in the magnetization transfer ratio in the left inferior parietal lobule and the right superior parietal lobule in patients who attempted suicide was consistent with previous findings.103 Decision‐making barriers are associated with suicidal behavior.68 Thus, the alterations in the parietal lobule may lead to suicidal behaviors. In addition, the hippocampus and the angular gyrus are the biological markers for MDD, but little is known about the relationship between the volume of these regions and suicide attempters. An interesting finding reported that suicide attempters have reduced gray matter volume in the hippocampus104 and in the left angular gyrus,98 especially in cases of acute suicide. It was also found that the total volume of the hippocampal threshold of 5 cm ³ had a negative predictive value of 98.2% for acute suicide attempts.104 The angular gyrus is known to be part of the default‐mode network, and impairments in this region in patients are associated with negative thoughts about the future or themselves.98 Disruptions in the angular gyrus may lead to suicidal behaviors or may increase the risk of suicide.

4. CONCLUSION AND FUTURE DIRECTION

In vivo MRI scans have made great achievements in the study of psychiatric disorders, which have resulted in the dawn of the understanding of the pathophysiology of psychosis, especially of MDD. Many brain region alterations have been reported, and some crucial circuits have also been revealed via imaging studies. The discovery of brain network put forward new ideas in the understanding of the disease of depression, providing effective stimulation sites and efficacy evaluations for the commonly used transcranial magnetic stimulation or deep brain stimulation techniques. In addition, these findings also suggest that MDD is not only due to local lesions but is also a multiloop disorder. However, previous studies still had limitations, and more research is needed in the future. First, most of the studies mentioned small sample sizes, which could have increased the false‐positive and (or) false‐negative rates of the results. Therefore, multicenter cooperation not only would solve this problem of sample content but also could result in more in‐depth research. Second, the identification of significant lesions relies on long‐term follow‐ups and the comparison of treated and nontreated patients. Future studies need to conduct longitudinal studies with larger samples. Moreover, using animal experiments to verify the neuroimaging findings and applying the results to humans is very important and will be a big step in the application of neuroimaging to the clinical field.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGMENTS

This study was supported by the National Natural Science Foundation (Grant Nos. 81771812, 81621003, 81571637, and 81271532), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, Grant No. IRT16R52) of China. Q.G. received the support of Changjiang Scholar Professorship Award (Award No. T2014190) of China and the CMB Distinguished Professorship Award (Award No. F510000/G16916411) administered by the Institute of International Education, USA.

Notes

Zhang F‐F, Peng W, Sweeney JA, Jia Z‐Y, Gong Q‐Y. Brain structure alterations in depression: Psychoradiological evidence. CNS Neurosci Ther. 2018;24:994-1003. 10.1111/cns.12835 [[ PubMed] [ CrossRef] PMC free article] [ Google Scholar]

Contributor Information

Zhi‐Yun Jia, Email: moc.liamtoh@aijnuyihz.

Qi‐Yong Gong, Email: nc.gro.crrmh@gnoggnoyiq.

Articles from CNS Neuroscience & Therapeutics are provided here courtesy of Wiley-Blackwell

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Brain structure alterations in depression: Psychoradiological evidence

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Depression is the leading cause of disability around the world, but little is known about its pathology. Currently, the diagnosis of depression is made based on clinical manifestations, with little objective evidence. Magnetic resonance imaging (MRI) ...

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A negative change in the brain's concentration of a monoamine ie. serotonin, has been proved to show prolonged emotional and behavioral changes.

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Abstract

The present review addresses major depressive disorder (MDD) and the implications of antidepressant treatment in the field of brain neuroplasticity, an effect initially considered adjacent but currently passed as central in the process of remission of MDD. Both in experimental animal studies and in human studies in subjects with mood disorders, neuroplasticity is considered the fundamental mechanism of neural defense against stress. Stress is the mediator between neurofunctional, neuroendocrine, neurobiological and neuroimmune disorders and depressive pathology of various intensities. Neurons have a high potential to adapt to the influences of internal and external factors. We are talking about neuroplasticity at different levels: structural neuroplasticity involving adult neurogenesis (such as plastic changes, dendritic reconstruction, when the morphology of the spine is affected); synaptic functional neuroplasticity and molecular and cellular mechanisms involved. These two major dimensions explain the pathophysiology of depression, as well as the convergence of the mechanisms involved in stress, major depressive decompensations, and the concept of neuroplasticity as the present target for new effective and potent antidepressant treatments.

Keywords: antidepressants, neuroplasticity, prefrontal cortex, hippocampus, cognition

⧉ Introduction

Hypostases and intensities of the depressive phenomenon:

▪ Major depressive disorder (MDD) is known to be defined by at least two weeks in which the underlying thymic mood is fallen and represents a significant change, noticed by the person in question or his entourage, compared to the patient's natural mood. In parallel, MDD involves decreased self-esteem, loss of interest and pleasure in previously pleasurable activities, reduced vitality, motivational-volitional unevenness, and pain without a clear cause (the concept of hidden depression) [ 1]. Patients with MDD may occasionally develop false beliefs, such as irrational beliefs, or they may overlap perceptual phenomena, such as accusatory and hallucinatory auditory hallucinations. There are patients with major depressive episodes spaced by significantly long intervals, in which the person in question works eutymically (recurrent depressive disorder), as well as clinical situations in which those in question may have symptoms for 2-3 years (more common chronic depression in men and over the age of 60). MDD negatively affects quality of life, outstanding job potential, educational, professional, or academic success, sleep and eating behaviors and health [ 2]. A percentage of 2-8% of adults that are diagnosticated with MDD go to suicide and die, and a percentage of 50% of adults who commit suicide have had MDD or have been diagnosticated with a mood disorder. Adjacent symptoms include delusions, concentration disorders, stability and selectivity of attention, fixation hypomnesia, withdrawal from social situations, decreased libido, irritability, recurrent and intrusive thoughts of death [ 3, 4]. Awakening insomnia is a typical symptom of a major depressive episode and is accompanied by marked anxiety, especially when the pattern of the episode is with melancholy features or psychotic phenomena.

▪ Psychotic depression, classically called depressive psychosis, involves a major depressive episode that associates delusional ideation, mostly guilt and guilt and/or visual illusions or auditory hallucinations (voices of deceased loved ones shouting at the person in question). Psychotic depression may occur in a recurrent depressive disorder or in a bipolar affective disorder [ 5, 6].

▪ Melancholic depression has noradrenergic coloration being characterized by athymhormia, loss of pleasure for most activities, failure to react to previously pleasant stimuli, a mood altered in the sense of sadness significantly more pronounced than moral pain or loss. The characteristics are severe intensity of symptoms in the first part of the day, awakening insomnia, bradykinesia, significant weight loss with absence of hunger (differential diagnosis with anorexia nervosa in which hunger is present) and feelings of guilt developed and felt in excess [ 7].

▪ Atypical depression has as fundamental axis paradoxical anhedonia and a pseudo-positivity. This refers to a significant weight gain in parallel with the increase in appetite and the feeling of mental comfort and peace with each meal. We also encounter hypersomnia as a defense mechanism, subjective sensation of heaviness in the limbs known as lead paralysis, feelings of social depreciation inconsistent with reality and hypersensitivity to the alleged interpersonal rejection that they perceive [ 8].

▪ Catatonic depression is a form of MDD, that is severe and involves significant alteration of motor behavior with mutism, akinesia, stupors change of consciousness, immobility, or the presence of aimless movements, sometimes bizarre. The differential diagnosis is made with catatonic schizophrenia, manic episodes that can be suddenly complicated by stupor or malignant neuroleptic syndrome.

▪ Dysthymia, also called persistent depressive disorder (PDD), in which the same symptoms appear in the physical area, as well as problems in the cognitive sphere as in depression, but these are of a lower intensity and longer duration [ 9]. During the period of two years of mood swings, we find a maximum of two months, the difference between dysthymia and major depressive episode being that in the first case two out of six symptoms are sufficient for diagnosis, while in MDD are necessary four of nine criteria, of which mandatory are anhedonia, concerns for uselessness, guilt or suicide, the presence of motor pathology that can vary between slowness and agitation [ 10].

▪ Recurrent brief depression (RBD) is defined by intermittent depressive episodes unrelated to menstrual cycles (in women). During a year, there may be between 6-12 such episodes, each meeting the criteria for MDD except for duration (in MDD the change in mood in the depressive sense is for at least 14 days, while for RBD, it is between 5-7 days).

▪ Minor depressive disorder has more than two symptoms characteristic of depression at the same time, being also a mood disorder.

▪ Adaptation disorder occurs when the person in question has significant difficulty adapting to cope with a significant psychosocial stressor. The subject reacts through inadequate responses that involve seemingly natural emotional and behavioral reactions, but which are more intense than the broad boundaries of normalcy, causing marked psychological distress, recurring concerns about the stress that caused the adjustment disorder, quasi-continuous recollections and negative inferences about the consequences, facts that ultimately affect the functionality.

▪ Premenstrual dysphoric disorder (PMDD) affects between 1.8-5.8% of women with active sexual life and is linked to the premenstrual syndrome, being a more severe and disabling form [ 11]. PMDD if formed of a sum of affective, somatic, and behavioral symptoms that reappear in each the moon, corresponding to the luteal phase of the menstrual cycle. Women characterized by PMDD will have the symptoms described above from adolescence to menopause, except in situations where they enter into hypothalamic amenorrhea or during pregnancy or lactation.

▪ Depression with peripartum onset is an intense depression that leads to disability, sometimes felt only after birth, but often, at a close look, symptoms are identified during pregnancy. In Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), it was classified as postpartum depression, the terminology being changed to DSM-V in order not to exclude the cases of women who were depressed even during pregnancy [ 12]. We are talking about unspecified depressive disorder with peripartum onset, because it turned out that in over 50% of cases, the clinically evident postpartum onset had actually taken place before birth. The increase in the number of women who want to carry a pregnancy with the risk of depressive decompensation determines etiological and pathophysiological searches that allow extensive understandings for the complex approach to the depressive phenomenon, being known the association of depression with various neurobiological changes [ 13].

⧉ Cerebral neuroplasticity

The brain has a high level of plasticity if approached in a certain moment of time. The care environment and the prominent attachment figures from childhood, substantially influence the development of the brain. Preclinical studies were performed in rats that involved a pattern of maternal deprivation. These studies found that there is an association between impaired hypothalamic-pituitary-adrenal (HPA) function and changes of the density of glucocorticoid receptors (GRs). In parallel, there was a decrease in dendritic branches and a decrease in density in the spine, as well as a deterioration of synaptic transmission with potentiation and signal delay in the hippocampus. Childhood opposition disorder is a well-known risk factor for the person in question to develop depression in adulthood because, generally, is based on loss, neglect, or abuse [ 14].

Over the past decade, research has focused on the interaction between genetic and environmental factors in the clinical expression of depression. The interaction between heredity and the environment determines a long-term programming of gene expression, a possibility to change the expression of gene function even if the sequence itself remains unchanged. The phenomenon is known as epigenetic change, the process in question mediating the effects of environmental and social environment in childhood on gene expression. An example would be deoxyribonucleic acid (DNA) methylation that can persist into adulthood and can dictate personal vulnerability to the psychopathological area by influencing the activity of the HPA axis. The activity of above-described axis consists in regulating the stress response [ 15]. Regarding the neurobiology of depression, there are clearly different areas of the brain in which we find hyperactivity: amygdala, striated nucleus, limbic and subcortical regions. The recent conceptualization of depression is done in terms of a network dysfunction in terms of corticolimbic loops. The above-described hyperactivity normalizes after antidepressant treatment and corresponds to the clinical improvement of symptoms. Like medication, psychotherapy alters brain function, although the neural correlations developed in depressive psychotherapy are less studied. In psychotherapy, initially, hyperactivity was found in the limbic and subcortical regions, later, with the increase of the number of sessions, in the same regions reporting hypoactivity [ 16].

Neural neuroplasticity involves the ability of the nervous system to modify its activity based on an intrinsic and extrinsic stimulus, to reorganize itself from structural, functional point of view and its connections. A fundamental property of neurons is their ability to alter their power in terms of the efficiency of synaptic transmission through a diverse number of mechanisms. This process depends on the actions and activities performed by the subject and is called synaptic plasticity. In the last century, it was considered to be a characteristic of different species of insects, currently being noted as a fundamental property of the human nervous system. The psychological modalities of cognitive training specific to different superior gnostic functions address synaptic plasticity as an intrinsic function of brain development and target the learning and memory processes. Redoubtable specialists are those who correctly appreciate the time windows in which plasticity can be maximally optimized by reshaping neural interconnectivity. Synaptic changes during learning and memorization lead to cognitive leaps in development and can be the premise of effective protocols for quality academic learning. Studies in human tissue indicate that synaptic plasticity could be a mechanism involved in the process of learning and memory, even though the real mechanism is still insufficiently studied.

⧉ Neurobiology of depression

Severe depression is a serious illness with a significant risk of suicide. The World Health Organization (WHO) estimates that by 2020 depression will be number two on the Global Burden of Disease list [ 17]. MDD is debilitating through biological, cognitive, and psychological symptoms (we are talking about a double depression-psychological reaction of depressive coloration superimposed on a major endogenous depressive episode) with personal and social consequences, with high levels of morbidity and mortality [ 18]. Depression affects between 10-15% of the general population throughout life, the biological bases being complex, with interaction disturbances that affect both neurons and glial cells in certain areas of the brain. Depressive symptoms include anhedonia, lack of self-worth, anergy, poor concentration, changes in appetite, along with motor changes, recurrent thoughts of death, all based on dysfunction of the neural network. At the molecular level, several biological processes are involved in depression, without limitation to changes in monoaminergic neurotransmitters to changes in the hormonal homeostasis of stress. Other mechanisms involved are reduced neurotrophic support, metabolic dysfunction, impaired immune response with increasing inflammation, oxidative stress, and mitochondrial dysfunction. Depression affects the plasticity of the brain and synaptic functions. Similar changes were found during a major depressive episode with those during aging, which led to the hypothesis that major depression could be associated with accelerated aging [ 19]. A meta-analysis performed for patients with clinical depression took into account as criteria for diagnosing the present episode minimum five symptoms, which should be present most of the time for at least two weeks: altered mood in a depressive or expansive sense, low interest and pleasure for everyday activities, changes in weight, changes in sleep, changes in routine activity with fatigue or anergy, feelings of loss of self-worth or even guilt, decreased attention span, suicidal thoughts [ 20].

⧉ Prefrontal cortex (PFC)

PFC is located anterior to the premotor area and the primary motor area. PFC has a multimodal function, integrating sensory-motor information with motivational-affective function in the major depressive episode, being affected exactly this connectivity. PFC has three major sections: the dorsolateral prefrontal cortex (DLPFC), the orbital and medial paralimbic cortex, and the anterior cingulate cortex (ACC).

The ventromedial prefrontal cortex (VMPFC) is connected by the cingulate gyrus and hippocampus to the DLPFC. VMPFC has the functions of generating normal emotions, especially those with social connotations and for the regulation of autonomous and neuroendocrine responses, for the modulation of pain, for the expression of aggression, as well as for sexual and eating behaviors. Orbital PFC corrects the emotional or behavioral responses generated partially by the amygdala. DLPFC is involved in cognitive control, in solving complex tasks, in maintaining information in the buffer and manipulating it in working memory [ 21]. PFCs, the amygdala and especially the hippocampus are the brain structures considered to be most directly related to depressive pathology. Magnetic resonance imaging (MRI) studies support reduced brain volume in patients with depression compared to groups of healthy subjects, large decreases of the ACC, orbitofrontal cortex (OFC), and temperate decreases in the hippocampus, putamen, and caudate nucleus [ 21]. PFC has high levels of GRs and regulates HPA activity under stressful conditions and behaviors. All of the above support the association between dysfunctional pathology of PFC and MDD. Another significant argument in favor of PFC dysfunction in patients with MDD is the presence of ruminations along with impaired prosexual function and irrationally negative cognition in the perception of the future within MDD [ 18].

There are primary neurological diseases that cause secondary depression. In such clinical situations, the anatomical substrate is represented by the basal ganglia and the frontal cortex, especially the lesions that affect the striatal area or the left PFC lead to major depressions of organic cause. In clinical situations where major depression is primary, computed tomography (CT) examinations showed nonspecific differences, such as ventricular enlargement, global cortical atrophy, without explicitly highlighting any abnormalities in those regions. MRI studies of focal hyperactivity showed a more prevalent white matter lesions in territories linked to the frontal cortex and basal ganglia. Also, specific volumetric abnormalities involving the frontal cortex are noted in primary depression [ 22]. MDD implies a decrease in the ability to react to the reward and the left prefrontal hypoactivity observed in depression supports the behavioral deficit in approaching the reward-punishment system. In a study on the effects of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) treatment in treatment-resistant melancholic depression, it demonstrates the success of the repetitive transcranial magnetic stimulation approach as related to metabolic changes of the anterior cingulate gyrus (ACG) - Brodmann areas 24 and 32 [ 23].

⧉ Glial cells

Post-mortem studies performed on patients with MDD have shown both a low number of glial cells and an alteration of their morphology, which is mainly found in PFC compared to other regions of the brain. Exposure to stress according to recent studies, induces pathologies in glial cells, a fact demonstrated by decreasing their density in the hippocampus and decreasing the density of astrocytes in PFC in studies performed on animals exposed to chronic stress. The results suggest that glial function is deficient or even compromised in PFC and represents the anatomical substrate of depressive symptoms. We are talking here about a junctional intercellular communication that involves a gap between sections, a noticeable gap in astrocytes and which in turn leads to changes in neural function in PFC [ 18].

⧉ The limbic system

In depression, we find hyperactivity in limbic areas, known to be associated with emotion processing. They are inhibited by the prefrontal areas in case they become inadequate. The above, support the limbic-cortical model encountered in depression, a well-established circuit that includes lateral PFC, medial PFC, OFC, ACC, hippocampus, thalamus, and amygdala. The cortico-striatal model highlights that the subcortical structures are important in information processing. There are overlapping cortical-striatal-pallado-thalamic loops located in parallel, and any striatal dysfunction causes symptoms of psychomotor retardation. Reaction time is dependent on the level of oxygenation of the blood, which in turn regulates the concentration, stability, and selectivity of attention (blood oxygenation level-dependent - BOLD). An increased activity is found in the areas exposed above when the subject performs actions directed towards a goal, which involves both emotionality and cognition at the decision-making level. We find an impairment of BOLD, as well as a hypoactivity in the cortical areas described in clinically depressed people, compared to the control groups [ 20].

PFC has a significant inhibitory regulatory effect on limbic structures. When PFC is compromised in depression, the balance between the structures of the neurocircuit is disturbed due to decreased activity in the PFC. This dysfunction produces clinical symptoms in terms of behavior and intellect, neurophysiopathology being based on neuroendocrine disorders, neurotransmitter disorders, disorders of the autonomic system and immune dysfunctions, all of which are characteristic of MDD. Antidepressants increase the concentrations of monoaminergic neurotransmitters and can reverse structural changes leading to beneficial modulations on the disrupted PFC limbic neurocircuit [ 8].

⧉ The amygdala

The amygdala is involved in signaling recruitment and coordinating the cortical excitation response, which in turn produces a neuroendocrine response to nonspecific stimuli, such as surprising or ambiguous ones. The amygdala is involved in memory processes and learning through emotions. There has been found correlations between the hyperactivity in the amygdala and the intensity of depression, with the inclination towards ruminations and intrusive thoughts, with satellite anxiety. The above described are valid both in MDD from recurrent depressive disorder and in MDD from bipolar affective disorder [ 21]. Another study on 352 healthy participants based on structural neuroimaging found that early exposure to psychotraumatic events is associated with a lower volume of the amygdala in adolescence, a volume that decreases even more over time, as that group of subjects reaches adulthood [ 24]. Another meta-analysis performed on four studies that investigated amygdala volume in patients with post-traumatic stress disorder (PTSD) in adult life, but who were exposed to different types of abuse since childhood, reveals similar findings, namely that the group subjects with PTSD showed a significant bilateral reduction in amygdala volume compared to the control group of healthy subjects [ 14].

The amygdala plays a major role in expressing emotional expression, mood in situations of suffering or threat, the psychological part being involved in the previous organization of the endocrine response. There is a hyperactivity of the amygdala when the depressed patient is exposed to negative stimuli but also a hypoactivity at this level when the person in question benefits from positive stimuli. Stress hormones are secreted in excess in patients with MDD.

⧉ Hippocampus

One of the main studied structure is the hippocampus because of its correlation with depression, both in animal studies and in human studies. The reasons behind this are: the fundamental role of the hippocampus in learning and memory processes, hippocampal dysfunction is responsible for environmental and situation-dependent emotional responses, the hippocampus has many corticosteroid receptors, being related with the hypothalamus from anatomical and physiological point of view by a bunch of axons that penetrates through the fornix and reaches the HPA axis, providing inhibitory regulatory feedback. The hippocampus is one of the two areas of the brain where it is known that neurogenesis still continues in the mature brain in both animals and humans, dictating the high capacity of neuroplasticity of the hippocampus and the need for brain anti-depressant medication with action at this level [ 21].

The opposition reaction from childhood, constantly present and at a formidable intensity, damages in time the microstructure of the hippocampus, affecting neurogenesis, as well as the survival of neurons and glial cells. Consequently, large-scale synaptic loss will occur, leading to damage to the cortisol-inhibited reaction loop in the HPA axis. At the same time, control over the secretion of corticosteroids in stress is disrupted. Thus, hypercortisol is due to the child's prolonged opposition disorder and results in negative feedback in the hippocampus. In turn, the hippocampus will exert a neurotoxic effect, which will lead to altered neuronal plasticity or directly to cellular apoptosis. MRI studies support significant changes in hippocampal volume in adults who were abused and abused in childhood, their hippocampal volume being significantly reduced compared to groups of subjects who were not exposed to stressors [ 14].

Impaired hippocampal function is reflected in impaired verbal memory test results in patients no matter the number of depressive episodes. The difference is, however, that hippocampal volume is reduced only in the group of patients with multiple depressive episodes, suggesting that hippocampal dysfunction precedes their detectable structural changes. In the case of patients treated with effective and potent antidepressants, in which we notice the clinical improvement of the symptomatology, we can later see the reversibility of the structural changes. In other words, patients with remitted depressive episodes have higher hippocampal volumes compared to patients with chronic depression. However, subjects who recovered without medication and emerged from a major depressive episode, known with a history of recurrent depressive history, are those with persistent small hippocampal volumes. It is thus suggested that the structural abnormalities of the hippocampus are a characteristic feature of depression. Another argument in the same direction is that in adolescents at high risk of depression, which is associated with psychotrauma in early childhood, hippocampal volumes are small, even if at the time of MRI measurements, the subjects do not show clinically manifest mood changes [ 25].

Neuroplasticity of antidepressants in the hippocampus works by linking: the hippocampus as a brain region extremely sensitive to stress-personality structure vulnerable to psychotrauma-MDD. The small volumes of gray matter in the hippocampus are primarily correlated with poor memory performance. There is a clinical debate about what changes occurred per primam: mood disorders versus disorders of congruent memory or explicit memory (decreasing reliability in solving the task). A significant role belongs to the medial temporal lobe, lesions that affect the expression of emotional behavior affecting the membranous-cortical-striatal-pallidal-thalamic circuits, circuits that include: PFC, amygdala, hippocampus, striated nucleus, ventromedial, mid-dorsal thalamic nucleus, midline, and the ventral pallidum nucleus.

Between 4-6% of subjects with MDD had smaller hippocampal volumes, the analysis included 1167 depressed patients and 1088 control subjects with a wide age range from pediatrics to the geriatric population [ 23].

⧉ Cortical gray matter

Childhood opposition disorder has long-term detrimental effects on many higher gnostic functions, such as working memory and learning, but also on other processes: inhibitory control, prosexual function, emotion processing, reward motivation system. Dysfunctions at this level not only lead to impaired intelligence quotient (IQ) or academic achievement, but also determine issues related to emotion regulation or impulse control. In other words, structural neuroimaging studies have shown that the opposition disorder present in childhood correlates in adult life with gray matter abnormalities in various cortical regions, with changes in volume and impairment of neural circuits of emotional processing, motivation-reward or knowledge (higher cognitive functions of planning, sequencing, operationalization, control, and feedback). The neuroanatomical structures involved are ACC, DLPFC, OFC, VMPFC [ 14].

When we refer to the other range of age (geriatric patients) with late-onset depression, it has been shown gray matter loss up to 20% in the right parietal cortex and going up to 10% decrease in posterior portions of the superior and inferior temporal gyrus. The researchers used a three-dimensional (3D) vector deformation field technique based on MRI scans [ 26].

⧉ Subcortical abnormalities of the white matter

Until recently, studies focused mainly on gray matter in the depression neurocircuit, neglecting connections to the subcortical white matter. Abnormalities at this subcortical level have been described in depressed elderly people (late-onset depression), which initially led to the idea that it is a neurological problem associated with ischemic vascular pathology. MRI signal show that in the prefrontal area there are many hyperdensities of white matter, being associated with low metabolism in the frontal lobe and cortical atrophy [ 21]. Opposition disorder present in childhood is considered to be associated with low structural connectivity of several white matter neural tracts located at the following levels: corpus callosum, hooked bundle, cingulum, fornix, upper longitudinal bundle, lower longitudinal bundle, inferior fronto-occipital bundle. We find the anomalies described above in both children and adolescents and adults. Of all, the decrease in the integrity of the corpus callosum is the most consistent finding. The corpus callosum is a broad commissure fiber, which connects the cortical cortex of the two hemispheres, having a crucial role in ensuring the integrity of interhemispheric communication in terms of processing higher cognitive functions but also processing perception and arousal, as well as everything that means emotional-motivational-volitional regulation. The corpus callosum integrity decreases in people who experienced opposition disorder or early depression [ 14].

The progression of white matter changes has been associated with cardiovascular risk factors especially with high blood pressure and smoking, and with age. The severity of the changes is associated with a poor response to treatment and the development of new depressive symptoms despite the timely introduction of appropriate, long-term treatment, the mood deteriorating. Despite these findings, the direct causality between white matter changes and depression remains unclear, as most studies are conducted in cross section. However, changes in white matter have a negative influence on the progression of depression. There remains the possibility that both white matter changes and depressive symptoms may be based on a common pathological origin, and depressive symptoms may precede the development of white matter changes in a manner similar to how cardiovascular disease precedes stroke [ 27].

⧉ Immunological mechanisms

The complex pathophysiology of depression is linked with immunological mechanisms from the idea that pro-inflammatory cytokines (signaling molecules of the immune system) cause fatigue and fatigue followed by anxiety and depression, which can lead to clinically obvious depression. It is known that patients receiving interferon (IFN) treatments for other systemic conditions are at risk of decompensating with depression. The immune activation and especially increased cytokines concentrations is associated with severe depression [ 21].

Rodent studies have shown that cytokines can induce depressive behavior, suggesting causal links between inflammation and depressive mood swings. Cytokines, including interleukin (IL) 1, IL6, IFN, and tumor necrosis factor alpha (TNF α), have been shown in preclinical and clinical studies to be involved in the development of a depressive pattern dominated by anhedonia, fatigue, bradykinesia, decreased appetite, and sleep disturbances. If anti-inflammatory cytokines, cytokine receptor antagonists or IL1 receptor antagonists (IL1-RA) are administered in those clinical situations, the behavior of depressive disorder may be ameliorated. A recent meta-analysis performed on dispositional normal subjects revealed that a significant increase in TNF α, IL6 and C-reactive protein (CRP) may indicate depression [ 28]. Another review suggests a significant association between interferon-gamma (IFN- γ) and IL2 [ 13].

The HPA axis releases corticotropin-releasing hormone (CRH) from the hypothalamus in response to stress. CRH stimulates the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, which in turn releases glucocorticoids from the adrenal glands. Glucocorticoids act through two receptors: mineralocorticoid receptor (MR), with high affinity for glucocorticoids and GR, with low affinity for glucocorticoids. An increase in glucocorticoid levels saturates MRs and activates GRs, which causes negative feedback on the HPA axis. Both GR and MR are present in high concentrations in PCF and hippocampus. That is why it has been suggested that they are strongly involved in the pathology of depression. On the other hand, for over 50 years, it has been known that a prolonged increase in cortisol causes neuronal dysfunction by decreasing glucose absorption, reducing dendritic arborization, apoptosis or cell loss in PFC and hippocampus [ 18].

The autonomic nervous system and the HPA axis are directly related to the concept of stress. On the other hand, in a secular view, depression is considered to be caused by a psychotraumatic factor, in other words "everything starts with an upset". Healing a depressive episode involves not only alleviating the clinical symptoms of depression but also eradicating the alleged pathogen from the subject's mind (development of psychotrauma). It remains a discussion in itself the breakdown of the concept of stress between the distress that produces the mentioned functional and neuroanatomical changes and the stress that is necessary for the optimal state of preparation of the organism for the success in the current activities.

⧉ Neurochemistry and neurotransmitters

Classic tricyclic antidepressants act on a multitude of receptors, with significant correlations not only with serotonergic and noradrenergic receptors, but also with histamine and muscarinic ones. The importance of the enteric system and the disposition of the receptors at that level should not be neglected, the correspondent being the multitude of gastrointestinal symptoms in major depression. We should also discuss the current trend of young adults in the US to abuse antidepressants (in a manner similar to antibiotic abuse), in an empirical desire to "tune" their body not only for adaptive social-professional functionality, high but also for strengthening immune mechanisms.

Understanding the mechanism of action of antidepressants must start from understanding the pathogenesis of depression. The early hypothesis that survives to this day is that of "monoamine depression", in other words depression as a disorder is caused by a deficiency of a monoamine, be it serotonin (5-hydroxytriptamine - 5-HT) (mild to moderate intensity anxiety) or noradrenergic type (apatabolic staining, endogenous expression).

Subsequent animal studies show changes in density at other adrenergic and serotonergic receptors, as well as changes in receptor sensitivity in areas located in the terminal between the neuronal and the soma, and post-synaptic. Adaptive mechanism that responds when the neurotransmitter availability increases is associated with receptor changes [ 29].

Research on people who are healthy in terms of mood (euthymic) have shown that the administration of anti-depressants has acted on the adrenergic system by increasing its activity. Thus, the beta receptor regulation hypothesis was not supported.

Studies made on animals have shown that, despite a reduction in post-synaptic beta-adrenoreceptor density, increases in associated intracellular activity (protein synthesis) and hypoactivation of the post-receptor signal transduction cascade have been found. These findings refine the monoamine hypothesis by demonstrating that antidepressants work by increasing the synaptic transmission of the chemical neurotransmitter. There are studies highlighting the changes in serotonin concentrations and norepinephrine (noradrenaline - NA) metabolites, decreases of their values, showing that neuroendocrine responses to serotonergic and noradrenergic receptor stimulation have been unsuccessful, with depressive symptoms recurring. This is the case of treatment-resistant depression or depression in which relapses occur during the same episodes when in the first weeks of treatment the results are effective for the antidepressants used and yet, relapse cannot be prevented. There are also clinical situations in which depressed patients are treated with Tryptophan (5-Hydroxytryptophan - 5-HTP) or alpha-methyl-para-tyrosine (AMPT), which reduce the concentration of serotonin and NA and support the hypothesis that the transmission of these neurotransmitters is affected in depression [ 21].

Because the neurobiochemical serotonin deficit in the pathogenesis of the major depression is overemphasized and the selective serotonin reuptake inhibitors and related antidepressants are extensively administered in clinical practice, the negative consequence is a decreasing of the dopamine (DA) transmission. This phenomenon is based on the decreased firing in the dopaminergic neurons from the hippocampal system and from the basolateral amygdala.

This reduced dopaminergic neurotransmission efficacy may be augmented by the association of antipsychotics. Lower dopaminergic system efficacy may be an important factor for the onset of pharmacological resistance in MDD, due to dysconnectivity between hippocampal and amygdala with the thalamus and frontal cortex. As clinical consequences of this phenomenon, persistent anhedonia syndrome and treatment non-responsivity have been reported [ 30]. This disconnective pattern can be frequently associated in the elderly with the onset of cognitive decline and rapid progression of invasion of neurodegenerative elements into the cortico-hippocampal cognitive circuits in Alzheimer's disease [ 31].

In humans, the solute carrier family 6 member 4 ( SLC6A4) gene is the transporter of serotonin and is located on chromosome 17q11.1-17q12. It encodes 5-hydroxy-tryptamine (serotonin) transporter (5-HTT), which is involved in absorbing serotonin in serotonergic neurons. Deleting or inserting a single other element in tandem with 44 bases and this happens in the region of the 5'-flanked promoter of this gene, 5-hydroxytryptophan-transporter-linked polymorphic region ( 5-HTTLPR), produces a short ( S) or long ( L) allele. The 5-HTTLPR S allele is linked with reduced tryptophan expression and consequently decreased serotonin uptake activity. It has been demonstrated that one or two copies of the S allele are associated with a higher risk of developing depression if the genetic component interacts with inappropriate psychosocial environments, such as stressful, early, or late life events, or opposition disorder from an early age [ 14].

Brain-derived neurotrophic factor (BDNF) appears to be a crucial link in the neurobiology of depression, referring to effects of antidepressant drugs, neurotransmitter function, HPA abnormalities [ 21].

The hippocampus, that plays a major role in neuronal growth, is rich in BDNF. It also plays an important role in neuronal survival and maturation, dendrite arborization, and synaptic neuroplasticity in the brain of adults. Stress suppresses BDNF synthesis in the hippocampus, while antidepressants increase synthesis by sending signals to PFC and hippocampus. In patients with depression, serum BDNF levels are low in proportion to the severity of the depression. These concentrations increase as antidepressants are administered or electroconvulsive therapy (ECT) sessions are performed. Post-mortem studies in depressed patients at death revealed significant differences in hippocampal BDNF concentrations between treated patients and those who did not accept antidepressant medication.

⧉ Genetic aspects

Two of major risk factors in MDD are represented by genetic factors and a positive family history of depression. There are also intermediate concepts, such as that of heritability or that of family agglomeration or that of cross-inheritance between various psychiatric disorders ( e.g., between MDD and alcoholism). Having parents diagnosed with depression increases three times the risk of offspring in terms of developing a depressive episode. Research claims that family history is not exclusively related to symptoms but even associated with neuroanatomical structural changes [ 15].

In depression, the influence of environmental factors is strong related to it and the current model according to which specialists judge each clinical case is the diathesis-stress, which examines the interaction of genes with the environment. Therefore, for depressed patients, exposed to early psychotrauma, serotonin receptor 3A genotype ( HTR3A-42C.T) has been linked to a loss of gray matter in the hippocampus and PFC [ 21]. The interaction of environmental factors is also supported by the fact that in approximately 7-8% of cases, the first episode of MDD is preceded by a severe stressful life event [ 18], after which the following depressive episodes can be determined by intensity stressors from smaller and smaller (endoreactivity hypothesis). The regulatory model of the system on the HPA axis in depression includes atypical responses to Dexamethasone, increased basal cortisol levels and hyperreactivity to stressors at psychological level. This leads to abnormalities in the negative feedback system of the HPA axis, as well as abnormalities in the production of hormones in the range of corticotrophins (CRH). We also notice a sensitivity of the pituitary gland in the conditions of an intact adrenal gland. In MDD patients (both periods of depression and remission), studying the peripheral blood cells, a reduced messenger ribonucleic acid (mRNA) expression of the GR- α - the isomorphic GR that binds glucocorticoids. In addition, grade 1 relatives of patients with bipolar affective disorder also show a reduction in mRNA and GR- α, findings that, taken together, suggest abnormalities of the HPA axis at least at the GR level and can be considered an important marker in disorders of disposition.

Depressed patients with childhood abuse history, if subjected to a new psychosocial stressor in adulthood, when a low-dose Dexamethasone is administrated, improved their HPA axis responses as well as the ACTH and cortisol response. The same results are not found in patients with MDD who do not have a history of childhood abuse. High cortisol responses to Dexamethasone or CRH have been found to healthy subjects that have a high genetic risk for affective disorders have. There are significant differences between the extent of such responses in healthy subjects and without a family history of depression compared to patients who manifest overt clinical symptoms. The increased reactivity of patients with depression to Dexamethasone or CRH compared to the control group remained at the same high levels for a period of four years of follow-up. According to these studies, genetic vulnerability has a key role in depression rather than early life experience [ 21].

⧉ Psychopharmacological intervention in depression

Plasticity helps the brain recover from damage caused by events such as strokes or head trauma. Plasticity implies the ability to manipulate specific neural pathways and synapses, to receive new functions and implications through psychotherapeutic or psychopharmacological interventions.

Studies on brain adaptation demonstrate the existence of four major forms of functional neuroplasticity studied in humans: ( i) taking over the functions by the homologous area; ( ii) cross-reassignment; ( iii) extension of cortical mapping corresponding to a specific sensory or motor homunculus-compensatory masquerade.

The adaptation of the homologous zone supposes the assumption of the respective cognitive process will be taking over by the opposite hemisphere through a homologous region. Cross-reassignment appears when structures previously devoted to the processing of a particular type of sensory input now accept the receipt of that input through a new sensory mode. The extension of the brain map involves the enlargement of a functional region of the brain from close to close, by accumulating new performances of areas that previously did not deal with that function or mental process. Compensatory masquerade involves the allocation of a certain cognitive process to a new area of the brain that previously did not perform those tasks.

When in adult life the neurons are generated from neuronal stem cells, we assist to a process called neurogenesis. This genesis differs from neurogenesis in intrauterine life. Many authors consider that stress is the most important factor for the onset of depression after genetic predisposition [ 32]. Hippocampal cells are sensitive to stress and the risk is decreased neurogenesis at exactly this level where the process itself is vital. Studies in rats whose adrenal glands have been removed have shown, in the dentate gyrus, an increased neurogenesis process. The response to a stressor that is highlighted by the cortisol production is linked to the adrenal gland. When cortisol is produced in large quantities and in a chronic manner, it causes down-regulation of serotonergic receptors and suppresses neurogenesis. In studies in normal animals, corticosterone has been shown to suppress neurogenesis.

The first step in the administration of antidepressants is selective serotonin reuptake inhibitors (SSRIs). The neurogenesis can explain the efficiency of SSRIs. In a normal brain, increased serotonin suppresses the hormone that releases CRH through action in the hippocampus. The action is done directly on the paraventricular nucleus, to reduce the release of CRH and downregulate the discharge of NA from the locus coeruleus. Neurogenesis involves the production of several brain cells, especially by acting on the 5-HT1A receptor in the dentate gyrus of the hippocampus, which improves the symptoms of depression. Normally, neurogenesis requires between 3-6 weeks for the maturation of newly formed neurons, this being exactly the time required for SSRIs to act. The correlation reinforces the hypothesis that SSRIs reduce the symptoms of depression through the mechanism of neurogenesis.

⧉ Modulation of the brain network by treatment

New dentate granule cells (DGCs) capable of processing information are generated by the dentate gyrus of the adult hippocampus. In adult neurogenesis, neuronal progenitor cells take a new path, migrate, and mature over several weeks. At the same time, the young DGCs expand their axon and dendrites by establishing an adequate input-output connectivity within the pre-existing network. Thus, there are improvements in cognitive deficits in depression, even if the regions of the brain have suffered structural damage. ECT is perhaps the most effective antidepressant therapy, with the most profound effects on the mechanisms of brain neuroplasticity. Unfortunately, the short-term retrograde amnesia that occurs after each ECT session makes it difficult to examine cognitive improvement in depressed patients treated with ECT. There are also studies that support the improvement of memory and other cognitive functions in depressed patients after drug treatment. Although currently withdrawn from the Romanian pharmacological market, Moclobemide, as a standard drug for monoamine oxidase inhibitors (MAOIs), in studies conducted abroad, has been shown to be superior to Viloxazine (adrenergic agonist) or Maprotiline (tetracyclic antidepressant) [ 31]. In the present studies, superiority refers to improved memory. Studies have shown that for MDD patients, treated with Fluoxetine, the verbal memory improved. The patients with late-onset depression after treatment with Fluoxetine or Reboxetine have shown an improvement in memory and attention. The limitations of this study come from the absence of a control group that was treated with placebo [ 33].

Stress can cause atrophy of both the hippocampus and PFC, with morphological changes in both regions being observed in patients with depression. Under these conditions, an ideal antidepressant should prevent cortical atrophy and stimulate the mechanisms of neurogenesis. Some studies that examine the volume of the hippocampus in patients with a long history of depression, find correlations with the time spent by the patient in symptomatic conditions. This suggests that a successful treatment quickly reduces symptoms and stops the deteriorating processes. Even in patients with PTSD, where we also find a reduction in hippocampal volume, antidepressants improve declarative memory.

⧉ Conclusions

Cerebral neuroplasticity is the central axis of the remission of MDD and the fundamental mechanism by which neurons defend themselves against stress. HPA function requires changes in GR density. Dysfunction delays synaptic transmission in the hippocampus. Childhood abuse, neglect, or opposition disorder are risk factors for depression in a busy life. Some epigenetic changes, such as DNA methylation, can persist into adulthood and dictate personal vulnerability to stress. This is correlated with the activity of the HPA axis. In depression there are hyperactivity in the amygdala, striated nucleus, limbic and subcortical regions. Not only antidepressants but also psychotherapy can alter the functionality of the brain. Neurons have their own ability to change their power in terms of the efficiency of synaptic transmission. At the neurobiological level, we are talking about the remodeling of interconnectivity and at the psychological level, we are talking about active will. PFC has a multimodal function being focused on the connectivity between the sensory-motor information with the motivational-affective ones. In major depression, there is a dysfunction of PFC proven by ruminations, negative cognition, and negative perception of the future, as well as disorders of concentration, stability, and selectivity of attention.

In major depression, there is a hyperactivity of the white matter in the territories related to the frontal cortex and basal ganglia. Major depression involves altering the reward-punishment system. HF-rTMS produces metabolic changes in the ACG. Post-mortem in major depression, a reduced number of glial cells was found in the PFC; here there is also a dysfunctional junctional intercellular communication, which consists in a visible decrease in the transmission of the signal between astrocytes. Depression involves hyperactivity in the limbic areas where emotions are processed, with inhibition of the prefrontal areas. Hyperactivity is found especially in the amygdala, correlating directly with ruminant tendencies, intrusiveness, and adjacent anxiety. The amygdala is a key point in modulating affectivity. The hippocampus, which has numerous receptors for corticosteroids, is responsible for reactive-mediated emotional responses to life situations. The hippocampus is also the area where neurogenesis continues in the mature brain, being the area with high neuroplasticity. Opposition disorder in childhood causes decreased hippocampus, impaired neurogenesis, impaired glial cells, synaptic impairment, all of which ultimately lead to HPA axis dysfunction. MRI studies support low hippocampal volume in adults known as former abused children. The reduction of the hippocampal volume occurs only in the case of multiple depressive episodes or in patients left untreated. When effective antidepressants are used, structural changes are reversible. Impaired hippocampal function correlates with poor results on verbal memory tests. Dysfunction of cortical gray matter correlates with IQ damage, emotion regulation, or impulse control. White matter abnormalities are found in the elderly, as well as in subjects at cardiovascular risk. These subjects have a poor response to medication and are at risk of developing new depressive symptoms. Subjects with childhood opposition disorder or depression that occurred at an early age affected the integrity of the corpus callosum. Proinflammatory cytokines (IL1, IL6, IFN and TNF α) are involved in the development of a depressed pattern dominated by the apatho-abulic component and anti-inflammatory cytokines, cytokine receptor antagonists or IL1 receptor antagonists are administered for amelioration.

Serotonergic depression has the following stages of increase: SSRIs; serotonin antagonist and reuptake inhibitors (SARIs); 5HT1 receptor agonist (Buspirone has full agonist on 5HT1A somatodendritic receptors and partial agonist on 5HT1A receptors; the mechanism is unknown, maybe linked to release of DA and NA in PFC [24]; although Buspirone also has D2 receptor antagonism, it is not considered or used as a neuroleptic because it has no clinical antipsychotic effects); association of thyroid hormones; 5HT1A receptor antagonist (Pindolol - 5HT1A receptor and β-adrenergic antagonist mainly on serotonin presynaptic autoreceptors thus blocking the self-inhibition of serotonergic transmission; it has no action on postsynaptic serotonin receptors; 5-HT2A serotonin receptor (Fluphenazine is a 5-HT receptor agonist/antagonist, used in the therapy of obesity, in the therapy of childhood autism and in bipolar disorders, as a predictor of Lithium prophylaxis for the manic phase; it acts through its active metabolism, with a half-life of 11-20 hours).

The noradrenergic depression, in which the steps of increase would be: inhibitors of noradrenaline (NA) reuptake (Reboxetine, Desipramine, Maprotiline); inhibitors of NA and DA reuptake (Bupropion); associations with previous medication by: dopaminergic agonists (Bromocriptine), association of thyroid hormones, presynaptic DA release [Pemoline is a noradrenergic-type psychostimulant agent used in post-ECT mental disorders and adjuvant in the therapeutic management of depressive states, hyperkinetic syndromes, attention deficit hyperactivity disorder (ADHD) and narcolepsy]; Amphetamine or Methylphenidate supplementation.

The adaptive deficit may be correlated with the triggering of apoptotic mechanisms and the installation of irreversible cerebral structural alterations. Thus, the use of antidepressants without anticholinergic effect, as well as the new classes of medication, ensures the prophylaxis of structural changes at the cortical level.

BDNF is a major link in the neurobiology of depression. Structural neuroplasticity is involved in the neurogenesis of adult subjects through mechanisms such as dendritic reconstruction, and functional neuroplasticity involves molecular and cellular mechanisms at the synaptic level.

Conflict of interest

The authors declare that they have no conflict of interests.

References

9. Patel RK, Rose GM. StatPearls [Internet] Treasure Island, FL, USA: StatPearls Publishing; 2020. Persistent depressive disorder (dysthymia). 2020 Jun 29. [ Google Scholar]

12. American Psychiatric Association (APA) Diagnostic and statistical manual of mental disorders (DSM-5) 5. Arlington, VA, USA: APA; 2013. [ Google Scholar]

23. Baeken C, De Raedt R, Van Hove C, Clerinx P, De Mey J, Bossuyt A. HF-rTMS treatment in medication-resistant melancholic depression: results from [ ¹⁸FDG-PET brain imaging. CNS Spectr. 2009;14(8):439-448. [ PubMed] Google Scholar]

Articles from Romanian Journal of Morphology and Embryology are provided here courtesy of Romanian Academy Publishing House

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The present review addresses major depressive disorder (MDD) and the implications of antidepressant treatment in the field of brain neuroplasticity, an effect initially considered adjacent but currently passed as central in the process of remission of ...

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Victims of depression suffer prolonged feelings of sadness, hopelessness, and impending doom. About 17.1 million Americans will get Major Depressive Disorder each year.

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What are some of the identified causes of depression?

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What are some of the identified causes of depression?

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Depression has a variety of different causes and triggers, this disorder is different for everyone. Common causes of this disorder include stressful events, family history, pregnancy, life-threatening illness, and more.

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There's no single cause of depression. It can occur for a variety of reasons and it has many different triggers.
For some people, an upsetting or stressful life event, such as bereavement, divorce, illness, redundancy and job or money worries, can be the cause.

Different causes can often combine to trigger depression. For example, you may feel low after being ill and then experience a traumatic event, such as a bereavement, which brings on depression.

People often talk about a "downward spiral" of events that leads to depression. For example, if your relationship with your partner breaks down, you're likely to feel low, you may stop seeing friends and family and you may start drinking more. All of this can make you feel worse and trigger depression.

Some studies have also suggested that you're more likely to get depression as you get older, and that it's more common in people who live in difficult social and economic circumstances.

It's thought that your chance of getting severe depression may be partly affected by the genes you inherit from your parents.

Stressful events

Most people take time to come to terms with stressful events, such as bereavement or a relationship breakdown. When these stressful events occur, your risk of becoming depressed is increased if you stop seeing your friends and family and try to deal with your problems on your own.

Personality

You may be more vulnerable to depression if you have certain personality traits, such as low self-esteem or being overly self-critical. This may be because of the genes you've inherited from your parents, your early life experiences, or both.

Family history

If someone in your family has had depression in the past, such as a parent, sister or brother, it's more likely that you'll also develop it.

It's thought that severe depression in particular may be partly caused by the genes you inherit from your parents.

But depression is usually caused by a combination of triggers such as life events, so having a family history of depression does not always mean that you'll develop it.

Pregnancy and giving birth

Some women are particularly vulnerable to depression after pregnancy. The hormonal and physical changes, as well as the added responsibility of a new life, can lead to postnatal depression.

Sometimes depression starts before you give birth. Depression in pregnancy is known as antenatal depression.

Menopause

Menopause is when your periods stop due to lower hormone levels. Sometimes menopause can trigger depression, particularly in the first few years.

Menopause can also cause symptoms such as sadness and mood swings. Mental health symptoms caused by menopause are different from depression.

Loneliness

Feeling lonely, caused by things such as becoming cut off from your family and friends, can increase your risk of depression.

Alcohol and drugs

When life is getting them down, some people try to cope by drinking too much alcohol or taking drugs. This can result in a spiral of depression.

Cannabis can help you relax, but there's evidence that it can also bring on depression, particularly in teenagers.

"Drowning your sorrows" with a drink is also not recommended. Alcohol affects the chemistry of the brain, which increases the risk of depression.

Illness

You may have a higher risk of depression if you have a longstanding or life-threatening illness, such as coronary heart disease, cancer or a condition that causes long-term pain.

Head injuries are also an often under-recognised cause of depression. A severe head injury can trigger mood swings and emotional problems.

In some people an underactive thyroid (hypothyroidism) can cause depression.

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Read about what causes depression in adults. There's no single cause and there are many possible risk factors.

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Who is most likely to suffer depression by genetics? 

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Who is most likely to suffer depression by genetics? 

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If someone has a parent or sibling with major depression, that person most likely has a 2 or 3 times greater risk of developing depression compared with the average person. Depression can still be genetic if they show up in your older family members as well. Each person inherits an individual combination of genes from their mother and father, and certain combinations can predispose to a certain illness.

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How common is major depression? At least 10% of people in the U.S. will experience major depressive disorder at some point in their lives. Two times as many women as men experience major depression.

How do we know that genes play a role in causing depression? Scientists look at patterns of illness in families to estimate their "heritability," or roughly what percentage of their cause is due to genes. To do this we find people with the disease who have a twin, and then find out whether the twin is also ill. Identical (monozygotic) twins share 100% of their genes, while non-identical ("fraternal" or dizygotic) twins share 50% of their genes. If genes are part of the cause, we expect a patient's identical twin to have a much higher risk of disease than a patient's non-identical twin. That is the case for major depression. Heritability is probably 40-50%, and might be higher for severe depression.

This could mean that in most cases of depression, around 50% of the cause is genetic, and around 50% is unrelated to genes (psychological or physical factors). Or it could mean that in some cases, the tendency to become depressed is almost completely genetic, and in other cases it is not really genetic at all. We don't know the answer yet.

We can also look at adoption studies, to see whether an adopted person's risk of depression is greater if a biological parent had depression. This also seems to be the case.

What about non-genetic factors? There are probably many non-genetic factors that increase risk of depression, many of which are probably not yet known. Severe childhood physical or sexual abuse, childhood emotional and physical neglect, and severe life stress are probably all risk factors. Losing a parent early in life probably also increases risk to some extent.

If someone has a family history of depression, are they at very high risk? If someone has a parent or sibling with major depression, that person probably has a 2 or 3 times greater risk of developing depression compared with the average person (or around 20-30% instead of 10%).

The situation is a little different if the parent or sibling has had depression more than once ("recurrent depression"), and if the depression started relatively early in life (childhood, teens or twenties). This form of depression is less common - the exact percentage of the population is not known, but is probably around 3-5%. But the siblings and children of people with this form of depression probably develop it at a rate that is 4 or 5 times greater than the average person.

Is there a "depression gene"? Some diseases are caused by a single defective gene. Cystic fibrosis, several kinds of muscular dystrophy, and Huntington's disease are examples. These are usually rare diseases. But many common disorders like depression, diabetes and high blood pressure are also influenced by genes. In these disorders, there seem to be combinations of genetic changes that predispose some people to become ill. We don't yet know how many genes are involved in depression, but it is very doubtful that any one gene causes depression in any large number of people.

So no one simply "inherits" depression from their mother or father. Each person inherits a unique combination of genes from their mother and father, and certain combinations can predispose to a particular illness.

How are major depression and bipolar disorder related? Most people who suffer from depression do not have episodes of mania. We use the term major depression for depression without mania. Most people who experience mania also have major depression. We use the term bipolar disorder (or manic-depression) for this pattern. Major depressive disorder and bipolar disorder are the two "major mood disorders." For more information on the symptoms of mania abd bipolar disorder, see the links at the bottom of this page. Most people with major depression do not have close relatives with bipolar disorder, but the relatives of people with bipolar disorder are at increased risk of both major depression and bipolar disorder.

What about major depression and anxiety disorders? There are probably genetic changes that can increase the predisposition to both major depression and to certain anxiety disorders including generalized anxiety disorder, panic disorder and social phobia. Also, some people have a more general lifelong tendency to experience unpleasant emotions and anxiety in response to stress. Psychologists use terms like "neuroticism" and "negative affectivity" to refer to this tendency, and people who have it are also more likely to experience major depression.

However, many people who develop major depression did not have this type of personality before their depression started.

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A research project at Stanford University's School of Medicine to find genes that contribute to depression.

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A reason for this can contribute to including family problems, academic pressure, and social media use. Primarily the reason is academic tress and social media kids are comparing themselves to what they see and not accepting themselves as is.

Teen Depression: Why Today's Teens are More Depressed Than Ever | Psychreg

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Depression is one of the most common mental health disorders in the US. It affects people of all ages, but it can be particularly difficult for teenagers.

In fact, teen depression rates are on the rise, and experts believe that this is because today's teens are more stressed than ever before.

There are many different reasons why teens might experience depression, including family problems, academic pressure, and social media use. If you think your teen might be depressed, it is important to get help right away.

Stonewater Adolescent Recovery Center is a unique, adolescent, substance use disorder and dual diagnosis treatment program providing every resident with a comprehensive and customised level of care.

Keep reading as we discuss teen depression symptoms and why experiential therapy can be a helpful treatment option.

According to the National Institute of Mental Health, almost 3.2 million teens between the ages of 12 to 17 experienced at least one sizable depressive breakdown in 2017. This means that teen depression is actually pretty common, and it's nothing to be ashamed of.

However, teen depression rates have been increasing in recent years. In fact, the number of teens who reported experiencing a depressive episode in 2017 was up from just under two million in 2005. So what's causing this increase?

There are many possible explanations, but one of the most likely causes is stress. Today's teens are facing more academic pressure than ever before, and they are also dealing with social media comparisons and other challenges that didn't exist a few years ago.

It can be difficult to tell if a teen is depressed because many of the symptoms, such as fatigue and irritability, are also common during adolescence.

However, there are some teen depression symptoms that are more likely to occur than others. These include:

Withdrawing from friends and activities that were once enjoyed

Changes in eating or sleeping habits

Difficulty concentrating

Feelings of hopelessness or worthlessness

Thoughts of death or suicide

If you notice any of these teen depression symptoms in your child, it is important to get help as soon as possible.

Do you think that teen depression is only caused by stress? While stress may be a trigger for some teens, there are actually many different causes of teen depression.

These can include genetic predisposition, brain chemistry, and trauma. For some teens, depression may be caused by a combination of several different factors.

It is important to remember that each teen is unique, and there is no one-size-fits-all cause for teen depression.

Teen depression is different from the normal ups and downs of adolescence. Depression is a real medical condition that affects your mood, thoughts, body, and behavior.

While some teen girls may be more likely to experience depression due to hormone changes during puberty, boys are just as likely to be affected. Depression doesn't discriminate.

Getting the proper treatment for depression is very important, as it can lead to long-term recovery.

According to the Mental Health Administration, about 60% of teens with major depression did not receive treatment from 2017-2018. This leaves them at risk for long-term consequences.

Signs of depression are often symptoms of another physical or psychological medical condition. It's important to work with a medical professional to identify the type of depression you are experiencing and, ultimately, develop a treatment plan.

Depression is a mental disorder characterized by persistent sadness and low mood, which may be accompanied by feelings of anxiety or guilt.

Depression can be categorized into various types, such as short-term symptoms that last for a few days or chronic symptoms that last for months.

There are different types of depression, which can be classified according to their cause, severity, and duration. Some types of depression include:

Regardless of the type of depression that you're experiencing, it's important that you seek professional help. A treatment plan should be developed that's specifically designed for you.

While medication and traditional talk therapy can be helpful for some teens, experiential therapy is often the best option for treating teen depression.

This is because experiential therapy focuses on helping teens to identify and express their emotions in a healthy way. This can be done through activities such as art, music, and movement.

Experiential therapy can also help teens to build self-esteem and learn coping skills that will be helpful in the future. If you are looking for a teen depression treatment that is holistic and effective, experiential therapy is a great option.

Cognitive-behavioral therapy (CBT) is a type of talk therapy that can be helpful for teen depression. CBT helps teens to identify and change the negative thoughts and behaviors that may be contributing to their depression.

This type of therapy can be very effective in helping teens to feel better and to get back to their normal activities. If you are looking for a teen depression treatment that is specifically designed to help teen girls, CBT may be a good option for you.

CBT has been shown to be an effective treatment for teen depression, but it is important to find a therapist who is experienced in working with teenagers.

The therapist should also be someone who you feel comfortable talking to. If you are not sure if CBT is right for you, you can always talk to your doctor or mental health professional about other teen depression treatment options.

Depression is a serious issue, but it is important to remember that help is available. If you think your teen might be depressed, don't hesitate to reach out to a mental health professional for help.

Robert Haynes did his degree in psychology at the University of Hertfordshire. He is interested in mental health, wellness, and lifestyle.

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Teen Depression: Why Today's Teens are More Depressed Than Ever

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Depression is one of the most common mental health disorders in the US.

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Depression can cause the victim to either have insomnia or struggles to stay awake. Another symptom that is common and can be detected early, insomnia/sleepiness may depend on outside factors such as medication.

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Guy Sleeping In A Flooded Room With Watermelon

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depression is a disorder that causes an everyday change in emotion, behavior and anxiety intensity which could also be a genetic problem.

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Overview

What is depression? A Mayo Clinic expert explains.

Learn more about depression from Craig Sawchuk, Ph.D., L.P., clinical psychologist at Mayo Clinic.

Hi, I'm Dr. Craig Sawchuk, a clinical psychologist at Mayo Clinic. And I'm here to talk with you about depression. Whether you're looking for answers for yourself, a friend, or loved one, understanding the basics of depression can help you take the next step.

What is depression?

Depression is a mood disorder that causes feelings of sadness that won't go away. Unfortunately, there's a lot of stigma around depression. Depression isn't a weakness or a character flaw. It's not about being in a bad mood, and people who experience depression can't just snap out of it. Depression is a common, serious, and treatable condition. If you're experiencing depression, you're not alone. It honestly affects people of all ages and races and biological sexes, income levels and educational backgrounds. Approximately one in six people will experience a major depressive episode at some point in their lifetime, while up to 16 million adults each year suffer from clinical depression. There are many types of symptoms that make up depression. Emotionally, you may feel sad or down or irritable or even apathetic. Physically, the body really slows down. You feel tired. Your sleep is often disrupted. It's really hard to get yourself motivated. Your thinking also changes. It can just be hard to concentrate. Your thoughts tend to be much more negative. You can be really hard on yourself, feel hopeless and helpless about things. And even in some cases, have thoughts of not wanting to live. Behaviorally, you just want to pull back and withdraw from others, activities, and day-to-day responsibilities. These symptoms all work together to keep you trapped in a cycle of depression. Symptoms of depression are different for everyone. Some symptoms may be a sign of another disorder or medical condition. That's why it's important to get an accurate diagnosis.

What causes depression?

While there's no single cause of depression, most experts believe there's a combination of biological, social, and psychological factors that contribute to depression risk. Biologically, we think about genetics or a family history of depression, health conditions such as diabetes, heart disease or thyroid disorders, and even hormonal changes that happen over the lifespan, such as pregnancy and menopause. Changes in brain chemistry, especially disruptions in neurotransmitters like serotonin, that play an important role in regulating many bodily functions, including mood, sleep, and appetite, are thought to play a particularly important role in depression. Socially stressful and traumatic life events, limited access to resources such as food, housing, and health care, and a lack of social support all contribute to depression risk. Psychologically, we think of how negative thoughts and problematic coping behaviors, such as avoidance and substance use, increase our vulnerability to depression.

The good news is that treatment helps. Effective treatments for depression exist and you do have options to see what works best for you. Lifestyle changes that improve sleep habits, exercise, and address underlying health conditions can be an important first step. Medications such as antidepressants can be helpful in alleviating depressive symptoms. Therapy, especially cognitive behavioral therapy, teaches skills to better manage negative thoughts and improve coping behaviors to help break you out of cycles of depression. Whatever the cause, remember that depression is not your fault and it can be treated.

To help diagnose depression, your health care provider may use a physical exam, lab tests, or a mental health evaluation. These results will help identify various treatment options that best fit your situation.

Help is available. You don't have to deal with depression by yourself. Take the next step and reach out. If you're hesitant to talk to a health care provider, talk to a friend or loved one about how to get help. Living with depression isn't easy and you're not alone in your struggles. Always remember that effective treatments and supports are available to help you start feeling better. Want to learn more about depression? Visit mayoclinic.org. Do take care.

Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. Also called major depressive disorder or clinical depression, it affects how you feel, think and behave and can lead to a variety of emotional and physical problems. You may have trouble doing normal day-to-day activities, and sometimes you may feel as if life isn't worth living.

More than just a bout of the blues, depression isn't a weakness and you can't simply "snap out" of it. Depression may require long-term treatment. But don't get discouraged. Most people with depression feel better with medication, psychotherapy or both.
Depression care at Mayo Clinic
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Symptoms

Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

Feelings of sadness, tearfulness, emptiness or hopelessness

Angry outbursts, irritability or frustration, even over small matters

Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports

Sleep disturbances, including insomnia or sleeping too much

Tiredness and lack of energy, so even small tasks take extra effort

Reduced appetite and weight loss or increased cravings for food and weight gain

Anxiety, agitation or restlessness

Slowed thinking, speaking or body movements

Feelings of worthlessness or guilt, fixating on past failures or self-blame

Trouble thinking, concentrating, making decisions and remembering things

Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide

Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Depression symptoms in children and teens

Common signs and symptoms of depression in children and teenagers are similar to those of adults, but there can be some differences.

In younger children, symptoms of depression may include sadness, irritability, clinginess, worry, aches and pains, refusing to go to school, or being underweight.

In teens, symptoms may include sadness, irritability, feeling negative and worthless, anger, poor performance or poor attendance at school, feeling misunderstood and extremely sensitive, using recreational drugs or alcohol, eating or sleeping too much, self-harm, loss of interest in normal activities, and avoidance of social interaction.

Depression symptoms in older adults

Depression is not a normal part of growing older, and it should never be taken lightly. Unfortunately, depression often goes undiagnosed and untreated in older adults, and they may feel reluctant to seek help. Symptoms of depression may be different or less obvious in older adults, such as:

Memory difficulties or personality changes

Physical aches or pain

Fatigue, loss of appetite, sleep problems or loss of interest in sex - not caused by a medical condition or medication

Often wanting to stay at home, rather than going out to socialize or doing new things

Suicidal thinking or feelings, especially in older men

When to see a doctor

If you feel depressed, make an appointment to see your doctor or mental health professional as soon as you can. If you're reluctant to seek treatment, talk to a friend or loved one, any health care professional, a faith leader, or someone else you trust.

When to get emergency help

If you think you may hurt yourself or attempt suicide, call 911 in the U.S. or your local emergency number immediately.

Also consider these options if you're having suicidal thoughts:

Call your doctor or mental health professional.

Contact a suicide hotline.

In the U.S., call or text 988 to reach the 988 Suicide & Crisis Lifeline, available 24 hours a day, seven days a week. Or use the Lifeline Chat. Services are free and confidential.

U.S. veterans or service members who are in crisis can call 988 and then press "1" for the Veterans Crisis Line. Or text 838255. Or chat online.

The Suicide & Crisis Lifeline in the U.S. has a Spanish language phone line at 1-888-628-9454 (toll-free).

Reach out to a close friend or loved one.

Contact a minister, spiritual leader or someone else in your faith community.

If you have a loved one who is in danger of suicide or has made a suicide attempt, make sure someone stays with that person. Call 911 or your local emergency number immediately. Or, if you think you can do so safely, take the person to the nearest hospital emergency room.

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Causes

It's not known exactly what causes depression. As with many mental disorders, a variety of factors may be involved, such as:

Biological differences. People with depression appear to have physical changes in their brains. The significance of these changes is still uncertain, but may eventually help pinpoint causes.

Brain chemistry. Neurotransmitters are naturally occurring brain chemicals that likely play a role in depression. Recent research indicates that changes in the function and effect of these neurotransmitters and how they interact with neurocircuits involved in maintaining mood stability may play a significant role in depression and its treatment.

Hormones. Changes in the body's balance of hormones may be involved in causing or triggering depression. Hormone changes can result with pregnancy and during the weeks or months after delivery (postpartum) and from thyroid problems, menopause or a number of other conditions.

Inherited traits. Depression is more common in people whose blood relatives also have this condition. Researchers are trying to find genes that may be involved in causing depression.

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment.

Factors that seem to increase the risk of developing or triggering depression include:

Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic

Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems

Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide

Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren't clearly male or female (intersex) in an unsupportive situation

History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder

Abuse of alcohol or recreational drugs

Serious or chronic illness, including cancer, stroke, chronic pain or heart disease

Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Complications

Depression is a serious disorder that can take a terrible toll on you and your family. Depression often gets worse if it isn't treated, resulting in emotional, behavioral and health problems that affect every area of your life.

Examples of complications associated with depression include:

Excess weight or obesity, which can lead to heart disease and diabetes

Pain or physical illness

Alcohol or drug misuse

Anxiety, panic disorder or social phobia

Family conflicts, relationship difficulties, and work or school problems

Social isolation

Suicidal feelings, suicide attempts or suicide

Self-mutilation, such as cutting

Premature death from medical conditions

Prevention

There's no sure way to prevent depression. However, these strategies may help.

Take steps to control stress, to increase your resilience and boost your self-esteem.

Reach out to family and friends, especially in times of crisis, to help you weather rough spells.

Get treatment at the earliest sign of a problem to help prevent depression from worsening.

Consider getting long-term maintenance treatment to help prevent a relapse of symptoms.

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Depression (major depressive disorder) - Symptoms and causes

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Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest and can interfere with your daily functioning.

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Alcohol and drug abuse are common among people with clinical depression. They’re especially common among teens and among young and middle-age males. It is very important to encourage these people to get help, because they are more likely to attempt suicide.
Signs of drug and alcohol abuse include:

Inability to maintain personal relationships

Secretive alcohol use

Self-pity

Tremors

Unexplained memory loss

Unwillingness to talk about drugs or alcohol

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Long term depression can cause long lasting effects on the mind and body such as blood pressure. Prolonged seasons of depression can cause high blood pressure over time which can cause problems such as; heart attack/stroke, heart failure, kidney damage, and vision problems.

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Relationship Difficulties and Family Conflicts

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Relationship Difficulties and Family Conflicts

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When dealing with depression it can be difficult to feel close with friends and family. Oftentimes people begin to feel like a burden to their loved ones and they either deny help or do not ask for help. It is possible that this mindset is due to the person feeling like their close relationships will not understand their depression, therefore they will judge them. These actions of pushing loved ones away can unfortunately lead to long term complications within the relationship.

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Long term effects of depression can be malnutrition which means the body does not have the sufficient amount of vitamins, proteins and fats it needs to function.

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Nutrients. 2022 Mar; 14(5): 1107.

Cielo García-Montero, 1, 2,*† Miguel A. Ortega, 1, 2,*† Miguel Angel Alvarez-Mon, 1, 2, ³ Oscar Fraile-Martinez, 1, ² Adoración Romero-Bazán, ¹ Guillermo Lahera, 1, 2, ⁴ José Manuel Montes-Rodríguez, 1, ⁵ Rosa M. Molina-Ruiz, ⁶ Fernando Mora, 3, ⁷ Roberto Rodriguez-Jimenez, 7, ⁸ Javier Quintero, 3, ⁷ and Melchor Álvarez-Mon 1, 2, ⁹

Paolo Brambilla, Academic Editor and Alessandra Mazzocchi, Academic Editor

Abstract

Major depressive disorder (MDD) is an incapacitating condition characterized by loss of interest, anhedonia and low mood, which affects almost 4% of people worldwide. With rising prevalence, it is considered a public health issue that affects economic productivity and heavily increases health costs alone or as a comorbidity for other pandemic non-communicable diseases (such as obesity, cardiovascular disease, diabetes, inflammatory bowel diseases, etc.). What is even more noteworthy is the double number of women suffering from MDD compared to men. In fact, this sex-related ratio has been contemplated since men and women have different sexual hormone oscillations, where women meet significant changes depending on the age range and moment of life (menstruation, premenstruation, pregnancy, postpartum, menopause...), which seem to be associated with susceptibility to depressive symptoms. For instance, a decreased estrogen level promotes decreased activation of serotonin transporters. Nevertheless, sexual hormones are not the only triggers that alter neurotransmission of monoamines and other neuropeptides. Actually, different dietary habits and/or nutritional requirements for specific moments of life severely affect MDD pathophysiology in women. In this context, the present review aims to descriptively collect information regarding the role of malnutrition in MDD onset and course, focusing on female patient and especially macro- and micronutrient deficiencies (amino acids, ω3 polyunsaturated fatty acids (ω3 PUFAs), folate, vitamin B12, vitamin D, minerals...), besides providing evidence for future nutritional intervention programs with a sex-gender perspective that hopefully improves mental health and quality of life in women.

Keywords: depression, stress, malnutrition, deficiencies, sex differences, menstrual cycle, premenstrual syndrome, premenstrual dysphoric disorder, pregnancy, postpartum, menopause

1. Introduction

Major depressive disorder (MDD), commonly known as depression, is an incapacitating global health problem characterized by altered mood, including loss of interest and pleasure, as well as impaired cognitive and vegetative functions [ 1]. This disorder affects at least 3.8% of the population and it is estimated that there are approximately 290 million new cases per year [ 2], becoming one of the six drivers that increased the global burden of disease in the period from 1990 to 2019 [ 3]. Likewise, according to the projections foreseen for 2030 by the World Health Organization (WHO), MDD will lead the group of disabling diseases [ 4].

In addition, depression leads to a prolonged disturbance in daily activities [ 5] that, consequently, will be associated with both direct and indirect costs. Presenteeism and absenteeism accounted for around 50% of the USD 210 billion of total spending in the US in 2010. Although the indirect costs imply a greater economic impact, we must consider the direct costs, which involved an outlay of USD 98.9 billion in the same year [ 6]. Likewise, according to the report carried out by the WHO in 2007 the socioeconomic costs in Europe follow the same trend, accumulating an amount of EUR 136.3 billion invested, with around 70% of this attributable to the lack of productivity [ 7].

A greater number of women with depression have been detected compared to men; the ratio remains at 2:1 [ 8]. The main source of this difference has been found in the biological factor; it is estimated that the heritability of this disorder ranges between 30 and 40%, assuming a greater probability of inheritance in women compared to men [ 9, 10]. Moreover, the patient's vulnerability to external factors during the course of depressive episodes will be increased by the action of sexual hormones and the repercussion of the oscillations will be significant and will change depending on the age range [ 11]. Thus, for example, in adolescence, the initial moment of activation of these hormones and the start of menstruation are a focus in the case of girls, who suffer higher levels of chronic stress than boys [ 12]. Fluctuations in ovarian hormones could be one of the potential causes of the disparity in prevalence between the sexes, since the group in question develops forms of depression such as premenstrual syndrome (PMS), postpartum depression and postmenopausal depression [ 13]. Certain cycle imbalances such as heavy bleeding have been significantly associated with the diagnosis of MDD [ 14]. In addition, MDDs trigger the appearance of suicidal thoughts in at least 60% of adolescents [ 15], making it the second leading cause of death in this group [ 16]. These events have also been related to the first menses of puberty in girls [ 17].

On the other hand, the impact of socioeconomic aspects, age, race and the presence of other comorbidities cannot be ignored [ 18]. In this sense, it has also been shown that the risk of suffering from MDD worsens when the framework of difference in political participation or economic independence is less egalitarian, leading to a clear increase in symptoms, as well as persistent depression [ 19, 20]; if we find ourselves again in the range between 14 and 25 years, the dissimilarity will be more accentuated between both sexes, while it is not so evident in older age groups [ 21].

Going deeper into the investigation of MDD in women would help to decipher the causes of the events, thus providing new management and treatment tools. It is true that the patient's nutritional status is closely related to depression and may be a key tool for its prevention and treatment [ 22]. In this line, repeated eating patterns and specific physiological situations have been observed in the case of women (menstrual cycle, childbirth, postpartum, menopause), which lead to marked nutritional deficiencies, especially micronutrients such as vitamin D, omega-3 fatty acids (FA ω-3), methyl-folate and S-adenosyl methionine (SAMe). These components have also been the object of study in preclinical and clinical trials, standing out for their benefit as potential adjuvant nutraceuticals in patients with MDD [ 23, 24].

The main objective of this paper is to critically and descriptively review the impact of malnutrition on the pathophysiology of MDD in women, also evaluating possible strategies based on nutritional intervention that may be helpful in limiting the progression or promoting recovery from depression, as well as preventing the appearance of future depressive episodes.

2. Major Depressive Disorder in Women

2.1. General Pathophysiology

2.1.1. Can MDD Be Located in the Brain?

One of the big questions that many researchers have historically asked is: Can MDD be located in the brain? Unlike other neuropsychiatric diseases that affect specific regions or mechanisms of the nervous system, in MDD, the alteration is not located in any specific region. In contrast to other diseases where the main organ affected is the brain, in MDD the alteration is not localized, thus affecting different parts of this organ.

In addition, it should be noted that the volume of the hippocampus is reduced by up to 1.2% in people with recurrent depressive episodes or when the onset of the pathology manifests itself at an early age, not showing this difference in the first episodes or in people with late onset [ 34]. Atrophy occurs as a consequence of an increase in glucocorticoid levels due to the alteration of the hypothalamic-pituitary-adrenal (HPA) axis [ 35]. Moreover, it has been proven that functional and structural changes in this brain region lead to abnormal emotional processing and defective cognition [ 36].

2.1.2. Cellular and Molecular Changes Associated with MDD

In the same context, cortisol (steroidal hormone or glucocorticoid) plays a substantial role in the development of the pathophysiology of depressive disorder. Under the effect of a stressful stimulus, the HPA axis will be activated by the secretion of corticotropin-releasing factor (CRF), arginine-vasopressin (AVP) and other neuropeptides. As a consequence, the adrenocorticotropic hormone (ACTH) is produced, which, in turn, stimulates the adrenal glands, synthesizing them as cortisol. In patients with MDD, hypercortisolemia leads to overstimulation of the HPA axis, followed by a clear disruption of neurotransmitter metabolism [ 42].

In this sense, it is of great importance to know the monoaminergic hypothesis, which maintains that there is a decrease in monoamines in the synaptic space due to disturbances in physiological mechanisms; that is, low sensitivity of the receptors, alteration of the secretion to the synaptic space or storage failure [ 43]. Until now, the monoamine hypothesis has been a pioneer as the basis for the target of the development of antidepressants. One of the keys to the pathophysiology of this condition lies in the serotonin transporter membrane protein (SERT), as well as neuronal serotonin receptors [ 44]. It has also been shown that norepinephrine and its alpha-adrenergic receptors are highly relevant in the regulation of cognitive development or response systems to adverse situations, such as fear or anxiety [ 45]. Similarly, understanding the disruption of the dopaminergic system mechanisms is the key to mediating characteristic symptoms of this disease, such as anhedonia [ 46]. On the other hand, low concentrations of other types of neurotransmitters, such as glutamate, GABA or acetylcholine, have been shown in patients with MDD compared to controls, which opens up an interesting research opportunity for more effective therapies [ 47]. Oxytocin (OXT) and AVP, whose release is promoted by anxiogenic, stressful and notably social stimuli, both positive and negative, have also become attractive research targets [ 48, 49]. The predominance of one of these neuropeptides has a direct impact on the other and vice versa; this could be explained by the benefits obtained by inhibiting AVP so that the balance shifts towards OXT secretion in order to improve depressive behavior [ 50].

2.1.3. Systemic Alterations Associated with MDD

As can be seen, major depressive disorder has a large network of interconnected mechanisms that give rise to its pathophysiology, which is why other fields such as the immune system have been investigated more thoroughly. A wide variety of proinflammatory cytokines, such as IL-1β, IL-2, IL-6, IL-12 and tumor necrosis factor (TNF-α), in addition to some antibodies (ribosomal antibody-P and anti-N-receptor methyl-D-aspartate) interfere in the mediation of the inflammatory processes of depression [ 51]. The lesions produced in the central nervous system, mainly due to stressors, will trigger the activation of microglia and this will lead to the start of the immune cascade. During this process, there will be an increase in the secretion of cytokines, which could pass the blood-brain barrier and, as a consequence, increase blood levels, thus becoming highly relevant markers. In addition, this dysregulation will contribute to an exacerbated activation of the HPA axis, giving rise to the cycle of pathological mechanisms characteristic of depressive disorder [ 52].

In this sense, there is evidence that suggests the close relationship between the immune system and the intestinal microbiota, an example of which is the production of immunocytokines in response to the metabolism of intestinal bacteria [ 53]. The overstimulation of the HPA axis will lead to an increase in the permeability of the intestinal barrier; subsequently, a phenomenon known as endotoxemia occurs, in which the bacterial endotoxins pass into the blood circulation, triggering the onset of peripheral inflammation; the signals will arrive at the CNS via the vagus nerve, again promoting the neuroinflammatory response of glial cells [ 54]. This fact will lead to a greater systemic deterioration of the subjects with depression [ 55].

Other factors also intervene in the pathophysiology of MDD; since time immemorial, it has been suspected that sleep is essential to good health. This idea led, decades ago, to the search for keys to understanding depression, and a plethora of studies argue for the disruption of circadian rhythms in patients with MDD [ 56, 57]. Additionally, the brain is especially vulnerable when we talk about the action of reactive oxygen species (ROS), as this is a structure with high content of oxidizable lipids and an oxygen requirement. It has been observed that there is an increase in ROS as a consequence of the alteration of the antioxidant power of cells in depressive subjects. Due to this, it has become another of the factors in the investigation of this pathology [ 58, 59]. A summary related to the three main points herein exposed can be found in Figure 1 .

2.2. Pathophysiology Specific to MDD in Women

2.2.1. Biological Mechanisms

It has been observed that there is divergence in molecular processes in both sexes. In the case of women, there is an increase in genes linked to neuronal synapses, as well as a reduction in markers of immune function and microglia, in contrast to the findings observed in men [ 60]. In accordance with the above, different investigations agree that the pro- and anti-inflammatory response is attenuated in women with depression and there is greater reduction in those with more severe symptoms [ 61, 62]. A possible explanation for this finding is an increase in tolerance due to pre-exposure to endotoxins due to the imbalance of the intestinal barrier [ 61]. Moreover, the recent study by Chen et al. has observed significant differences in the microbiota according to the sex of the patient; among other things, it is possible to relate the severity of the pathology to the state of the microbiota, finding a negative relationship in women when there is a predominance of Streptococcus or Clostridium [ 63]. The latter plays an important role in the regulation of non-ovarian estrogen levels, affecting the risk of suffering from conditions of a different nature in postmenopausal women and elderly men [ 64].

In this sense, and based on new findings, it is worth highlighting the role of the estrobolome, which is the set of genes belonging to intestinal microorganisms responsible for modulating estrogen levels in the blood through various mechanisms [ 65]. The appearance of contemporary depressive episodes with hormonal fluctuations is evident, which are manifested above all in puberty, postpartum or menopausal transition periods [ 66, 67, 68]. In the follicular phase and in perimenopause, where normal levels of estradiol (E2) are low, a greater vulnerability when receiving stressful events or negative emotions has been observed, all due to hormonal disturbance of the activity of the structures involved in affective regulation; the opposite occurs in phases of the cycle with high levels [ 69]. Several pieces of evidence confirm the relationship between hormones and the estrobolome; for example, genera that produce short-chain fatty acids, such as Prevotella, Ruminoccocus and Roseburia, decrease in postmenopausal women compared to premenopausal women [ 70]. Moreover, animal models reflect the existence of a change in the intestinal microbial composition due to the hormonal changes typical of menopause [ 71]. In the same way, the induction of progesterone in ovariectomized mice led to an improvement in depressive behavior, all of which was related to the increase in Lactobacillus and the decrease in IL-6 [ 72].

Biological particularities related to women in different moments of life are briefly shown in Figure 2 .

2.2.2. Psychological and Sociocultural Factors

It must not be forgotten that there are plenty of non-biological factors that help to explain the different rates of MDD in women in comparison to men. As mentioned above, psychological stress is a major driver of depression, associated with multiple structural and functional changes in the brain. Chronic stress and early life stress (ELS) are frequently involved in the onset and development of depression independently from sex-gender [ 78, 79]. However, different studies have observed that there is a differential response in the brain between men and women, and also the perceived origin stress can be different in both populations. ELS comprises various forms of child abuse and neglect affecting a large number of children worldwide, being closely related with the development of several psychiatric disorders [ 80]. Prior mice models have suggested that women appear to be more sensitive to the detrimental effects of ELS, showing an early emerging female-specific depressive phenotype and a rapid response to antidepressants [ 81]. For instance, it is known that despite the hippocampus not being affected due to ELS in females, the reward system may be altered, explaining the differential long-term consequences of ELS observed in women, including the higher risk of MDD [ 82, 83]. On the other hand, women with higher levels of chronic stress are more prone to suffer from depressive episodes, especially after an occurrence of acute stress [ 84]. Interpersonal relationships can be considered a major source of stress and depression risk in women, as depressed women often inhabit a complicated interpersonal environment, including divorce, marital problems or difficulties with their children [ 85, 86]. Other psychosocial factors implicated in the onset and development of MDD in women include negative and ruminative thinking, low self-esteem, depression stigma and the diagnosis of a chronic disease, with an inverse relationship with spiritual well-being [ 87].

Last but not least, there is no denying the fact that cultural dictation of female roles is one of the key determinants of depression in women, along with the lack of emotional and social support [ 88]. The influence of some traditions or religions and immigration in the higher prevalence of depression in certain groups of women is of note [ 89, 90, 91]. A low socioeconomic status, especially at old age, is directly correlated with a greater risk of depression in women [ 92]. Educational level, occupational situation, sexual satisfaction and even the neighborhood or living in rural versus urban areas can also influence the development of depression in women [ 93, 94, 95, 96]. Despite depression affecting virtually all ethnic groups, there are some disparities in the prevalence and treatment-seeking behavior across race [ 97].

Overall, there are numerous psychological, social and cultural factors associated with the development of depression in women. Besides, these factors appear to be frequently accompanied and exert a cumulative effect on depression (i.e., ELS causes functional and structural changes in the brain that may be related with interpersonal difficulties, low self-esteem, professional difficulties and other factors with detrimental effects on the life of women). All these multiple factors involved in the onset and pathophysiology should be considered collectively in the clinical management of women with MDD in order to properly address the different causes and consequences of depression.

2.3. MDD Clinic

2.3.1. General MDD Manifestations and Approaches

The diagnostic criteria proposed by the " Diagnostic and Statistical Manual of Mental Disorder (DSM-V)" state that there must be a deficit in the functional capacity of the individual that lasts for more than two weeks, a period during which there is a continuous manifestation of five or more symptoms, among which we must include the loss of reactivity to pleasant stimuli, which is usually caused by the daily activities carried out, and the presence of a sad or irritable mood, which we find in some cases of children and adolescents. These main criteria are accompanied by secondary disturbances, both somatic, including insomnia and hypersomnia, loss of energy, changes in appetite or weight, and non-somatic, for example, poor concentration or the appearance of suicidal thoughts [ 98]. The clinical guidelines for the diagnosis should focus on aspects related to the repetitiveness of the episode (one-off or periodic), improvement of symptoms, attention to the appearance of psychotic symptoms, as well as their severity ⁶. To make a quantitative evaluation of this last parameter, the Hamilton Depression Rating Scale (HAM-D) is used, which stipulates a question for each clinical criterion that will be given a certain score, the sum of which will be between the values of 0 and 56 [ 99]. According to Zimmerman et al. various reference ranges have been established; a score of 0-7 is considered a non-depressive state; 8-16 is diagnosed as mild or moderate depression; at 17-23, the patient suffers from severe MDD, while values > 24 are categorized as very severe depression [ 100].

2.3.2. Women's MDD Clinic

MDD has twice the incidence in the female population compared to the male [ 2]. This fact is also reflected in the fact that the prescription of antidepressants is around 17.2% in women, while 8.2% of male patients receive this treatment [ 105]. As previously mentioned, ovarian hormone fluctuations could be one of the potential causes of the disparity in prevalence, giving rise to unique clinical presentations such as PMS, postpartum depression (PPD) and postmenopausal depression (PMD) [ 13].

Studies from the end of the last century have already revealed the differences that major depression presents in relation to the sex of the patients [ 106, 107]. There is clear evidence of the symptomatologic disparity; in women a greater presence of some classic symptoms of this disorder has been observed, such as loss of interest or alteration of the sleep cycle, added stress and irritability, both associated with a bad mood. Increased appetite, linked to weight gain, or the appearance of obsessive thoughts is very representative in this group [ 108]. In addition, in women, the appearance of anxiety disorders is frequent in MDD, while in men it has comorbidity with substance use. The severity of the symptoms is greater in the female population; however, the appearance of more episodes in the other group stands out [ 109]. In the same way, it was deduced that the prescription of drugs that stimulate immune function would be convenient for female patients, while antidepressants that reduce immune activation are indicated for males [ 60]. It cannot be neglected that the factors that confirm the differences between the responses to treatment are not decisive at all, although it is stated that the efficacy of serotonergic antidepressants is increased in women compared to men, and another important observation is that women in the postmenopausal period experience a decrease in response compared to those of a younger age [ 110].

3. The Importance of Malnutrition in MDD from a Sex-Gender Perspective

Malnutrition in general encompasses various manifestations that reflect a poor diet, both in terms of lack and excess, leading to an imbalance between energy intake and expenditure [ 111]. In this sense, the relationship between depression and poor nutritional intake has been investigated, confirming the existence of this; however, in all the studies, they highlight the need to continue investigating this aspect further, due to the limitations of the studies carried out [ 112, 113, 114].

Eating behavior in women seems to play an important role. A recent study suggested that 13% of participants with MDD had lifelong eating disorders and 39% showed clinically significant disordered eating behavior, versus 3% and 11%, respectively, of participants without diagnosed depressive disorders. Therefore, the authors concluded that the rate of altered eating behaviors is higher in women with depression [ 115]. Along these lines, it is well known that emotional hunger is one of the basic characteristics of eating disorders [ 116]. The oscillations of ovarian hormones could have a close link with "emotional hunger" and the desire for more palatable foods rich in sugars. It has been observed in girls that high levels of leptin in the blood are related to high stress [ 117]. Several investigations in women have investigated the existence of differential responses to appetizing food throughout the cycle, concluding that in phases with a high concentration of estrogen, motivation for reward is lower, so emotional hunger is reduced; on the contrary, in the luteal phase where the predominant levels are those of progesterone, the desire for appetizing food increases exponentially [ 118]. Women more susceptible to binge eating have compromised interoceptive awareness of physiological states [ 119], resulting in dietary limitation that, as a consequence, could negatively affect the dopaminergic system [ 118].

However, binge eating is not the norm in MDD in general. On the other hand, we know that, especially in depressed older people, there is a great tendency to loss of appetite, skipping meals and involuntary weight loss [ 120, 121], due to hypoactivation of the middle insular cortex. It would be interesting to carry out studies in which, when monitoring pregnant women, it can be detected if their frequent lack of appetite or other irregularities [ 122] are related to prevalence of postpartum depression; or to determine if, in women with postpartum depression, there is a tendency towards loss of appetite or binge eating in pregnancy.

From this association between eating disorders and MDD, the terms "depression-related increased appetite" and "depression-related loss of appetite" can be found in the scientific literature [ 123]. In any case, different eating patterns will lead to excesses in certain macronutrients and deficiencies in others, as well as deficiencies in certain micronutrients that seem to play important roles in the patient's homeostasis.

3.1. Macronutrients

Macronutrients encompass carbohydrates, proteins and fats, and they play a central role in cognition and brain functioning [ 124]. In the case of women, macronutrients consumption appears to vary across the menstrual cycle. For instance, an increased intake of protein, particularly animal protein, can be reported during the luteal phase of the menstrual cycle [ 125], with more carbohydrate intake per day after ovulation [ 126]. These variations are due to sexual hormonal fluctuations and, in turn, adequate food intake is crucial for ensuring the functioning and actions of these hormones in tShe body [ 127]. In this part we will summarize the role of macronutrients and their deficiency in the onset and progression of MDD, PMS, PPD and PMD.

In recent decades, carbohydrate consumption has been stigmatized and closely linked to mood. The mechanisms that allow this interaction appears to be linked to the synthesis of different neurotransmitters, although special emphasis is placed on the serotonergic system due to the ability of insulin to increase tryptophan bioavailability in the brain [ 128]. There seems to be a clear derangement of glucose metabolism in patients with MDD [ 129], and high glycemic blood levels have been linked to suicidal behavior [ 130] and disruption in brain networks [ 131]. Despite the widespread belief that sugar consumption is necessary for the brain and improves mood, compelling evidence refutes this hypothesis, also suggesting projected harm in greater fatigue, a symptom associated with MDD [ 132]. Conversely, diets with poor carbohydrate intake could also be counterproductive, causing compromised metabolism [ 133]. There have been some studies conducted in women correlating carbohydrate consumption, mood and the risk of suffering PMS. Houghton et al. [ 134] found a direct association between maltose intake and the development of PMS, although high dietary glycemic index was found to be correlated with decreased premenstrual symptoms in a group of young Japanese women [ 135]. In the same line, high dietary glycemic index but not glycemic load was found to be associated with fewer depressive symptoms in young and middle-aged women [ 136]. It should be remarked here that the origin of the dietary carbohydrates should be deeply studied, although it seems that high dietary glycemic index may benefit women's mood and brain function in reproductive ages. However, further studies are required, as there are other works suggesting the opposite conclusions without considering a sex-gender perspective [ 137, 138]. On the other hand, the evidence has failed to find any relationship between carbohydrate intake and PPD [ 139, 140]. Besides, a study carried out in a cohort of postmenopausal women revealed the negative influence of diets rich in refined carbohydrates, which consequently increase the risk of depression [ 141]. Conversely, high consumption of fiber appears to be directly correlated with sex-hormone-binding globulin (SHBG), a protein involved in sex hormone transportation. Interestingly, in postmenopausal women, SHBG and sex hormone levels have been associated with depressive symptoms, although more efforts are needed in this field [ 142].

Proteins also play a vital role in multiple biological processes. They are molecules formed by amino acids linked together forming chains; the products derived from the hydrolysis of these will be used by the bacteria of the digestive system, by the cells for the synthesis of metabolites involved in relevant physiological processes and are destined to play a role in the formation of other tissues such as the muscle [ 143]. Animal studies have helped us gain further insights into the negative effects of deficient protein intake. For instance, greater susceptibility has been observed in female mice in developing depressive symptoms at an early age when they have been deprived of protein intake in the perinatal stage [ 144]. Likewise, there was loss of neurons and alteration of the precursor genes of hippocampal neuroplasticity in young adult female mice with protein malnutrition [ 145]. In addition, not only the amount of protein but also its quality is essential for a healthy diet [ 143]. Despite some studies reporting a negative association between excessive protein intake and depressed mood in women [ 146], no relationship has been found between protein consumption and PMS [ 147]. More studies are needed to evaluate the effects of protein intake and depression in women.

Another of the macronutrients that are linked to depression is lipids. It seems that women are in general more prone to having intakes that exceed recommendations for total and saturated fat [ 148]. First of all, it should be highlighted that trans fatty acids, as poor-quality lipids in the induction of dysbiosis, promote the proliferation of harmful bacteria such as Proteobacteria and reduce those that provide benefits to metabolic processes [ 149]. Thus, in premenopausal women, a positive link between high trans fatty acids intake and depressive symptoms has been reported [ 150]. Likewise, their consumption seems to increase proinflammatory responses [ 151] and enhance the permeability of neuronal membranes, implying the compromise of the dopaminergic system and the appearance of anxious symptoms [ 152]. On the other hand, there is evidence of the benefits provided by some, such as omega 3 polyunsaturated fatty acids (ω-3 PUFAs), specifically eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA). Mainly, two physiological mechanisms associate them with depression; EPA and DHA, being part of the cell membranes of neurons, are crucial for the correct neurotransmission and cell signaling and, in turn, have the power to inhibit the proinflammatory cytokines characteristic of patients with MDD and inflammatory eicosanoids that are elevated in these cases [ 153]. Women with MDD usually present low intake of ω-3 PUFAs, which is inversely correlated with depressive symptoms and is directly associated with brain functional connectivity [ 154]. Besides, the benefits from increasing ω-3 PUFAs have also been reported in PMS, PPD and PMD, although further studies are required to confirm these results [ 155, 156, 157]. Linked to the low intake of ω-3 PUFAs, the consumption of omega 6 fatty acids (ω-6 FAs) is increased in Westernized diets. Over the decades, the ratio has changed from a balance of both fatty acids to ω-6/ω-3 ratios between 10:1 and 20:1. These long-chain polyunsaturated lipids are derived from linoleic acid and share the enzymes (elongases and desaturases) that are involved in their biosynthesis. Consequently, abundant consumption of ω-6 PUFAs interferes with the desaturation of ω-3 PUFAs, thus leading to loss of homeostasis, promoting the genesis of cardiovascular, inflammatory or cancer disorders, among others [ 158]. High ω-6 PUFAs intake appears to be linked with a higher risk of depressive symptoms among pregnant women, with total fatty acids intake and omega-6/omega-3 ratio above recommendation [ 159] also being predictive as a potential risk factor of later PPD [ 160]. In this sense, the fatty acids in question stand out for their role in the regulation of inflammatory pathways. The association of the ω-6/ω-3 imbalance has been found with the increase in IL-6, exacerbating inflammatory reactivity; therefore, it will mean greater vulnerability to the appearance of depressive symptoms [ 161]. The reversal of the balance towards the fatty acids balance could be beneficial for the improvement of subjects with MDD.

3.2. Micronutrient Deficiencies Related to Reproductive Age, Postpartum and Later Life

Firstly, vitamins are a group of essential micronutrients that appears to be affected in women with MDD. Vitamin D (Vit D) is a fat-soluble hormone, known for its role in calcium homeostasis and bone growth. It also plays a decisive role in neurological development. The synthesis and elimination of this micronutrient, as well as vitamin D receptors (VDR), are found in the brain [ 162]. Consequences of vitamin deficiency that have been related to the pathogenesis of MDD are alterations in the hippocampus in animal models [ 163] and imbalance in neuronal excitation and inhibition pathways [ 164]. Evidence has been found of the improvement that this nutrient produces in depressive symptoms; however, it is not so conclusive that adequate concentrations can prevent the development of depression [ 165].

Among the processes in which vitamin B12 is involved, DNA synthesis, blood cell synthesis and neurological functions stand out for their relevant action [ 166]. Interdependence with folate increases the processes in which B12 interferes [ 167]. Research, both in childhood and adolescence as well as in adulthood [ 168], shows that these two micronutrients, as well as homocysteine, are involved in one-carbon metabolism and methylation processes of neurotransmitters, proteins and phospholipids of the cell membrane. Low concentrations of B12 and folate are linked to the alteration of the above [ 169]. Moreover, in this situation, the production of a neurotoxic metabolite of homocysteine is stimulated; as a consequence, there is overstimulation of NMDA receptors that increases the flow of intracellular calcium, increasing oxidative stress and apoptotic responses [ 170]. All this leads to the contribution of the pathogenesis of MDD [ 168].

On the other hand, women with MDD seldom meet mineral requirements. Several studies point to a usual low serum zinc level in patients with MDD [ 171]. The influence of the micronutrient on the glutamatergic system has been demonstrated, producing the inhibition of the N-methyl D-aspartate (NMDA) receptor via the zinc receptor GPR39, a process necessary to preserve glutamate and GABA homeostasis [ 172]. Likewise, it is stipulated that part of its benefit lies in its ability to activate neuronal plasticity processes and its interaction with monoamines [ 173]. Selenium (Se), among other things, is part of the selenoproteins highly involved in the signaling of redox processes [ 174]. In this line, other organic compounds containing selenium have been investigated, such as, for example, 3-((4-chlorophenyl) selanyl)-1-methyl-1H-indole (CMI), which has shown results regarding its inhibitory power on the inflammation associated with oxidative stress in in vitro studies [ 175] and in mice models [ 176]. The cross-sectional study by Li et al., in a population of American adults with MDD shows, once again, the indirect association between the concentrations of this element and other essential elements and depressive behavior [ 177]. The meta-analysis led by the same researcher suggests that there could be an inverse relationship between iron intake (Fe ²⁺) and the risk of MDD [ 178]. Fe ²⁺ levels are known to be closely associated with brain function [ 179]; for example, they are cofactors of tyrosine and tryptophan hydrolase, involved in the genesis of monoamines [ 180]. The functions of the striatum and the hippocampus are compromised by Fe ²⁺ deficiency, affecting even the embryonic stage of the individual [ 181]. Magnesium (Mg ²⁺) is involved in many physiological processes in the human body; of these, its calcium antagonist power has been related to mood by blocking NMDA receptors; in the same way, it is involved in the monoaminergic and glutamatergic systems and increases BDNF expression and reduces systemic inflammation, among other things [ 182].

Importantly, plenty of studies have been found to be related to specific micronutrient deficiencies at reproductive age, postpartum and later life; all of them are to be regarded as potential risk factors for different manifestations of depression. For this reason, it is of note to consider the different moments of life in women to manage specific requirements they may need with the aim to improve their prognosis in the case of diagnosed MDD, or to prevent the onset.

3.3. Specific Micronutrient Deficiencies Related to Menstruation, PMS and PMDD

Approximately 20-25% of women have moderate to severe PMS; and it is estimated that 5% of women have been diagnosed with its most severe form, PMDD [ 183]. It should be noted that prevalence increases in adolescence [ 184]. Lower levels of calcium and Mg ²⁺, but not vitamin D, have been observed in women with PMS compared to controls [ 185]. Based on these facts, there seems to be an association between cyclical changes in women and calcium levels, thus affecting patients with PMS. Generally, serum calcium concentration is lower in this group, being inversely correlated with the incidence and symptoms of PMS [ 186]. However, despite the fact that there is the possibility of a relationship between vitamin D concentrations in women and premenstrual disorders, the benefits of its prescription are still not clear [ 187].

On the other hand, zinc seems to play a prominent role not only in mental but also in physical health, as has been shown in several placebo-controlled trials [ 188, 189]. The review carried out by McCabe et al. shows the possible effectiveness of essential fatty acids in reducing premenstrual anxiety, having detected positive effects with the combination of vitamin B6 and Mg ²⁺ [ 190]. To date, only one study has determined the relationship between iron and premenstrual syndrome; it is intuited that the mechanism that links them could be related to hormonal fluctuations, as happens in PPD. Having said that, the authors were able to affirm that high intake of non-heme iron is positively related to the reduction of premenstrual symptoms. In addition, the opposite occurred with high amounts of potassium, which produced an increased risk of PMS, possibly due to its aldosterone agonist power, which consequently increases fluid retention [ 191]. We cannot ignore the changes in appetite during the different phases of the menstrual cycle; estrogens and progestogens participate in this [ 192]. Due to the fact that patients with PMDD are more sensitive to hormonal variations, it has been concluded that there is an increased desire for sweet foods in the late luteal phase; this does not happen with foods with high salt content. It is proposed to focus on this fact to achieve new strategies that help in the clinical intervention of women with PMDD [ 193].

3.4. Specific Micronutrient Deficiencies Related to Perinatal and Postpartum Depression

There is a clear link between disruptions in both neurotransmitter and hormonal levels and fluctuations in micronutrients in women with PPD; therefore, it is important to know their influence and the antidepressant power of each one, with the aim to find alternative therapies with optimal effects. It is desired to obtain null adverse effects for lactation or ability to create addiction [ 194], which, a priori, will have a positive reception by patients in this group due to the harmless effect on their babies [ 195].

Several cohort studies suggest low levels of the circulating form of vitamin D, that is, 25-hydroxyvitamin D (25-[OH]-D), in patients with PPD [ 196, 197]. The interdependence of vitamin D with calcium is widely known, and it is intuited that it plays an important role in the matter in question, since calcium stimulates signaling for the activation of gonadotropin, which in turn will lead to an increase in luteinizing and follicle-stimulating hormone which, as a consequence, increases the production of estradiol (E2). After childbirth, the demand for calcium increases and, with it, the demand for vitamin D. However, a study in which supplementation with vitamin D and calcium was combined in women with PPD versus placebo concluded that it cannot be stated that vitamin D decreases the severity of symptoms through increased E2 [ 198]. It should be noted that vitamin D could play an important role in improving depression in this group, but the lack of studies casts uncertainty on whether its effect is due to the relationship in the HPA axis, serotonin, hormonal and inflammatory levels or other mechanisms involved in the pathophysiology of PPD [ 199, 200, 201]. The same facts accompany perinatal depression [ 200, 201].

Pregnancy is accompanied by increased blood cell volume and fetal and placental development, suggesting a sharp increase in Fe ²⁺ demand [ 202]. A cross-sectional study with 142 pregnant women of more than 20 weeks, all of them with a history of mental disorders, such as anxiety or depressive episodes, concluded that there is a relationship between iron deficiency and perinatal depression [ 203]. The same thing happened in a study related to PPD, again evidencing this inverse relationship [ 204]. In contrast, the research carried out by Armony-Sivan et al. found no relationship between these two variables [ 205]. There is divergence in the results; however, there seems to be a significant relationship between low concentrations of hemoglobin or iron and the risk of suffering from depression after childbirth [ 206, 207]. As in previous cases, it has been suggested that the decrease in ω-3 PUFAs levels is a factor that encourages the development of PPD. Women with an index greater than 5% of ω-3 during pregnancy have a lower risk of suffering from depression during the following year after birth [ 208]. However, a study of a cohort of Japanese women found no benefit of EPA and DHA supplementation in reducing risk [ 209]. Generally, prescription is not recommended as the main therapy, but it is considered a good complement [ 210]. NMDA receptor antagonist micronutrients such as Zn and Mg ²⁺ have also been studied in this area, although it is true that the results have not been significant in improving symptoms in patients treated versus placebo [ 211], or a very slight positive effect has been seen [ 212]. However, in animal models, it seems that the combination of these microelements reduces the percentage of depressive symptoms after birth [ 213], which turns out to be encouraging data in order to continue focusing on the research on these micronutrients.

3.5. Specific Micronutrient Deficiencies Related to Peri- and Postmenopausal Depression

Perimenopause is considered a stage of high vulnerability for the development of depressive symptoms or behaviors, even in women without precedent [ 214]. The same thing happens in the post-menopausal phase [ 215].

Serum levels of some micronutrients such as vitamin D, iron, calcium and Mg ²⁺ are lower in women with postmenopausal depression. Vitamin D deficiency is correlated with an increased incidence of changes in bone mass, commonly related to menopause [ 216]. In perimenopause, a negative association between vitamin D levels and depressive symptoms has also been found [ 217]. The deficiency is mainly due to low intake in the diet, little exposure to the sun due to the limitation of outdoor activities and reduced capacity for calcitriol synthesis [ 218]. Another trace element whose values are above the norm in postmenopausal women is copper, which, combined with the low concentration of Mg ²⁺, seems to increase vulnerability to depression [ 219]. In contrast, the levels of vitamin B12 and folate are not altered in these depressive patients. ω-3 PUFAs have also been investigated in this field; it was determined that when the intake of these fats is higher, the prevalence is reduced, although the causes are unknown [ 220].

All these common nutritional deficiencies observed in women with MDD at different ages are summarized in Figure 3 .

4. Nutritional Intervention in Women with MDD

Addressing the nutritional status of patients with depression can be a profitable tool to aid in the possible pharmacological and psychological treatment of MDD, as well as prevention. Next, some of the most relevant findings will be detailed in relation to nutrients and bioactive components that have been gathered as evidence in clinical trials, in an attempt to translate the results by specifically focusing on women with depression. In this line, the concept of nutraceuticals stands out, which encompasses those food components that are essential and/or beneficial for the pathophysiology of the patient [ 221].

4.1. Fatty Acids

The human body does not synthesize fatty acids by itself, so it is necessary to incorporate them into the diet; the adequate amount of omega 3 should be 250 mg daily. The foods that most contribute this molecule are of both plant and animal origin; among them are chia seeds, soybeans, flax, nuts, vegetable oils, oily fish and shellfish [ 222]. There is strong evidence for the benefit of ω-3 PUFAs in depression [ 223, 224]. The increase in EPA and DHA in cell walls correlates with the improvement of depressive symptoms and greater treatment effect [ 225]. Similarly, their antidepressant effect could be their anti-inflammatory and serotonin-modulating power, among others. Proinflammatory cytokines and BDNF mediate serotonin neurotransmission; cyclic AMP-responsive element-binding protein (CREB) has been found to be key to BDNF activation [ 226] which, as a consequence, translates into increased serotonin synthesis and reduced TNF-α, IL-6 and other proinflammatory cytokines. DHA and EPA modulate the levels of the neurotransmitter by this pathway [ 227]. Likewise, a study with ovariectomized rats investigated the synergy of estradiol and ω-3 PUFA, determining its antidepressant effects by the same route described previously. In addition, estradiol produced the regulation of glutamate, myo-inositol and cerebral glucose, which is related to less neuroinflammation and reduced neuronal death promoted by Glu [ 227, 228]. The supplementation of ω-3 FA has been suggested in pregnant and lactating women; animal studies have shown a transfer of 25% of brain DHA to the fetus, which translates into a progressive depletion of the resource if the intake is not adequate; as a consequence, there would be a disruption of the release, reuptake and transmission of serotonin, as it is a main component of the terminal synaptic membranes. EPA correction, mainly in postmenopausal women, is recommended, among other things, for providing an improvement in psychotic symptoms [ 222].

4.2. Vitamins

4.2.1. Vitamin D

The way in which we can obtain more of this fat-soluble molecule is by exposing the skin to ultraviolet radiation from the sun. To a lesser extent, it is found in foods such as milk, fatty fish or some vegetables [ 23].

This nutraceutical not only seems to have an impact on the aforementioned; in research carried out in a population with a sample size of 897 adolescent girls, both without problems and with some condition associated with the menstrual cycle, they were given 50,000 IU/week of cholecalciferol during the nine weeks that the intervention lasted. Supplementation led to a drop in the prevalence of PMS and dysmenorrhea, from 14.9% to 4.8%, and 35.9% decreasing to 32.4%, respectively, as well as associated psychological and physical symptoms [ 237]. A clinical trial also observed the positive effect of vitamin D supplementation, this time combined with probiotics, on women with polycystic ovary syndrome [ 238]; this endocrine disorder appears to be linked to depression and anxiety [ 239].

4.2.2. Vitamin B

Vitamin B deficiency seems to be a risk factor for the development of brain disorders such as cognitive disorders or dementia, due to its essential role in the folate and methionine cycles involved in nucleic acid methylation and homocysteine regulation. In addition, they are important cofactors in the biosynthesis of phospholipids and neurotransmitters [ 240]. Vitamin B9, also known as folic acid or folate (anionic form) is involved in the one-carbon cycle through the methionine cycle. Its active form, 5-methyltetrahydrofolate (5-MTHF), is crucial for the conversion of homocysteine to methionine through a reaction catalyzed by vitamin B12 and methionine synthase [ 241]. Likewise, methionine is the precursor for the production of SAMe, an important methyl donor for histones and DNA. Low levels of vitamin B stimulate the production of homocysteine [ 242]. These facts are closely linked with the menstrual cycle, assuming constant regeneration of endothelial tissue and follicular development; in this sense, a clinical study observed, by means of senescence markers p16, p21 and p53, the importance of folate as an antagonist of homocysteine in cell proliferation [ 243]. In accordance with the above, Michels et al. suggest that high homocysteine concentrations are related to altered hormonal changes and sporadic anovulation [ 244], abnormalities associated with polycystic ovary syndrome (PCOS) [ 245], assuming a risk factor for depressive symptoms and other psychiatric disorders [ 246]. Supplementation of B vitamins is suggested as a treatment to improve ovulation and fertility [ 244]. The prescription of folic acid during pregnancy is well known, among other things, because of its importance in the development of the fetus and the formation of the neural tube. Recent research correlates this with a lower risk of suffering from psychotic symptoms during pregnancy; in fact, in the animal model that was given doses of 1 and 5 mg/kg of folic acid, this nutrient was postulated as a potential contributor of cognitive alterations in the prenatal stage postpartum [ 247]; clinical trials agree with this evidence; thus its supplementation is recommended to reduce the risk of PPD [ 248]. This improvement appears to be linked to increased expression of pathways related to neuronal genesis, BDNF and synaptic transmission in the hippocampus [ 247].

4.2.3. Minerals

For its part, iron is an important trace element that seems to be related to MDD. Although there is no solid evidence of the benefit of its supplementation in patients with MDD, the indications in animal tests justify future investigations. A randomized trial developed an experiment in which half of their patients were treated during the last 6 weeks of pregnancy with 50 mg of ferrous sulfate and the other half was the placebo group; the result was the improvement of PPD [ 254]. Additionally, the systematic review carried out by Lomagno et al. maintains that research in women would be of special importance due to the changes in levels such as those that can occur during menstruation, pregnancy or menopause. In this same study, the potential of zinc as a nutraceutical was also evaluated; in this case, the studies seem to point to the positive influence it has on mood regulation [ 255]. In the double-blind, placebo-controlled trial in young women, a multivitamin capsule and zinc 7 mg/day were combined for 10 weeks. The intake led to a reduction in scores related to anger, depression and discouragement along with an increase in serum zinc; these changes were not seen in the placebo group [ 256]. Accordingly, the general population with MDD could also obtain advantages, since the research review of patients treated with antidepressants plus supplementation versus placebo concluded that there was better response and recovery for those treated with this trace element [ 257]. Selenium is also a vital molecule for our body; the proper dose of it, along with other nutrients, can have a moderate impact on rectifying the development of TDM [ 258]. Furthermore, the possible protective effect on DPP has been suggested [ 259].

The inconsistency and scarcity of studies carried out on treatment with minerals justify the increase in research of this nature.

4.2.4. S-Adenosyl Methionine

In summary, the prescription of SAMe as a supplement in patients with MDD seems to be beneficial, mainly when it acts together with antidepressants; however, the particularities of each patient should be studied before doing so. The need to delve into the mechanisms of which SAMe is a part can be glimpsed for future research.

4.2.5. Creatine and Amino Acids

Creatine (N-aminoiminomethyl-N-methyl glycine) is an endogenous nitrogenous molecule composed of amino acids. Its synthesis occurs in the liver, pancreas and kidney, but this supplies only half of the necessary amount, so its intake in the diet is essential, through foods such as red meat and fish, or by supplementation. It is known for its ergogenic benefits in athletes; however, recent research shows its interest in other areas [ 268]. Arginine, methionine and glycine are the amino acids necessary for its synthesis. The amidino group of arginine is transferred to the glycine molecule whose products will be ornithine and guanidinoacetate; then, SAMe donates a methyl group to guanidinoacetate to form creatine [ 269]. Creatine is mainly found in tissues with high energy demand due to its transformation into derivatives with great potential as rapid energy intermediates, such as phosphocreatine [ 268]. Compromise in the ability to metabolize creatine and alteration of serum levels in patients with MDD have been demonstrated [ 270], as well as the relationship of these with low intake from the diet [ 271]. Both preclinical and clinical studies demonstrate the antidepressant power of creatine due to its involvement in different pathways [ 270].

Along these lines, other amino acids such as tyrosine could also have antidepressant therapeutic properties, although the current literature is not conclusive [ 279].

4.2.6. Bioactive Compounds

Various authors have debated the most approximate definition of a bioactive compound. Assessing the different points of view, Guaadaoui et al. [ 280] described it as "a compound that has the capacity and ability to interact with one or more components of living tissue, presenting a wide range of probable effects" We can extract them from plant, animal, microorganism or synthetic sources.

Phytoestrogens

They are polyphenols with functions similar to estrogens due to the similarity of their structures. Soy is the main source of this nutrient, although we can also find it in other legumes and vegetables. There are several benefits that phytoestrogens seem to have. Benefits have been observed in cancer, vascular diseases, osteoporosis and even in menopause. In the same way, it seems to have neuroprotective potential, related to its antioxidant power and its link with estrogen receptors [ 281].

Flavonoids, a type of phytoestrogens, positively intervene in neuroinflammatory processes, neurogenesis or GABAergic and monoaminergic transmission [ 282]. In humans, the consumption of orange juice rich in flavonoids (5.4 mg of flavonoids daily) for 8 weeks led to the modification of the intestinal microbiota, increasing species of the Lachnospiraceae family, correlated with the activation of BDNF signaling. Likewise, the evaluation of the Depression Scale of the Center for Epidemiological Studies noted an improvement in depressive symptoms [ 283]. Another clinical study, this time with women in the postnatal period, supports the facts stated above. Daily intervention with flavonoids over the course of two weeks showed significant differences between groups in the parameters of anxiety and perceived quality of life [ 284]. On the other hand, phytoestrogens have gained popularity among menopausal women, especially those who have certain doubts about hormone replacement therapy, due to the different advantages that their consumption entails. A meta-analysis determined that low doses of phytoestrogens (25 mg/d-100 mg/d) could relieve depressive symptoms [ 285]. However, the limitations of the studies make its use as monotherapy unfeasible; therefore, further research is necessary.

Caffeine

Caffeine is one of the most important bioactive components since it has neuroprotective effects. Although there are other compounds such as chlorogenic acid or caffeic acid, caffeine is the most widely used coffee nutraceutical [ 286]. Caffeine consumption has been linked to a lower risk of depression [ 287], in addition to the fact that some studies show that its consumption improves the effectiveness of antidepressant therapy [ 288], producing improvements in the treatment of motivational dysfunction and increasing dopamine levels as a result of the non-selective antagonist for adenosine A1/A2 receptors [ 289].

Similarly, in another study, positive results were obtained in those women with higher-than-average caffeine consumption (>261 mg), showing lower probability of developing dementia or other cognitive impairment disorders, unlike those who had lower than average consumption (<64 mg), indicating an inverse association between caffeine consumption and age-related cognitive decline [ 290]. These facts were supported in the longitudinal study by Lucas et al. [ 291]; in the study that was carried out with women divided by age, it caused an increase in blood pressure and a decrease in subjective feelings of mood, especially in those who were older. In addition, it was found that caffeine side effects were more likely in less physically active young women compared to physically active women [ 292]. Accordingly, its consumption is contraindicated in people suffering from PMS because it reduces the irritability and insomnia typical of this phase [ 293]. Finally, it should be noted that the dose of caffeine ingested affects some health factors of people with depression; high doses can generate mixed affective states, changes in the circadian rhythm, increased anxiety and/or dysregulation [ 294].

Anthocyanins

Anthocyanins are pigments from the group of flavonoids that we can find in red fruits, with blueberries being the largest natural source of this resource. In recent decades, their contribution to guarding against the risk of suffering from cardiovascular, neurological or diabetes diseases, among others, has been known [ 295]. The microorganisms of the intestine are involved in the complex degradation of this molecule at different levels. Likewise, its consumption will directly influence the colonizing species, since, according to the ample evidence provided in both in vitro, animal and human studies, an increase in beneficial flora such as Lactobacillus spp. and Bifidobacterium spp. inhibits the uncontrolled growth of harmful microorganisms. The ability to mold the microbial community and the precursor of short-chain fatty acids contributes to the possibility that anthocyanins also act as prebiotic agents [ 296]. In a study, the inflammatory improvement of the offspring of rats fed with different types of diets, one of them rich in anthocyanins, was verified. The results reflected the intervention of these flavonoids by decreasing the activation of the NFκB pathway, and expression of mRNA of TNF-α, IL-6 and proteins of the zona occludens (ZO-1), thus improving the general health of the digestive system [ 297].

On the other hand, their antioxidant power is widely known; in vitro studies and animal models highlight delphidin, cyanidin-3-glucoside and malvidin for their ability to bind oxygen radicals, be scavengers of superoxide anions and protect against oxidative stress [ 298].

Although it is true that the effect of this nutraceutical on depression has not been investigated, the clinical trial carried out on elderly adults with cognitive disorders, who ingested juice with a high content of anthocyanins (201 mg) for 8 weeks, obtained a reduction in serum TNF-α compared to the other groups, which may be indicative of cognitive improvement [ 299]. Another study supports this statement, since the magnetic resonance imaging tests reflected the increase in brain activity related to increased perfusion in regions responsible for this task [ 300]. Likewise, anthocyanin supplementation decreased the concentration of C-reactive protein in women with metabolic syndrome, along with improvements in cardiometabolic risk in the rest of the participants [ 301].

Resveratrol

Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenol that can be found in red grapes, red wine and some nuts. Its appeal lies in its cytoprotective, antioxidant and anti-inflammatory power [ 302]. Recent studies have highlighted its beneficial effects on fatigue, sleep quality and anxious or depressive behaviors, such as anhedonia [ 303].

The effect of this flavone has been extensively studied in animal models. Resveratrol treatment of rats inoculated with high concentrations of corticosterone reversed the pathophysiological changes produced after 21 days of the trial, evidencing its interaction with the HPA axis [ 304]. Its anti-inflammatory power lies mainly in its ability to downregulate the expression of NF-kB, reduce the activation of microglia and reduce the proinflammatory response [ 303]. Likewise, the possibility of modulating processes of neuronal genesis was revealed, since it possibly regulates the activity of CREB, increasing the synthesis of BDNF [ 305]. The literature indicates that supplementation with this nutraceutical produces a decrease in monoamine oxidase (involved in the degradation of serotonin and norepinephrine) and, consequently, an increase in serotonin. In addition, the effect of the nutraceutical decreased in the absence of serotonin, proving its involvement in the monoamine system [ 306]. Tianyao et al. wanted to test the effect of resveratrol on behaviors similar to depression and anxiety due to lack of estrogen. Ovariectomized female mice were treated for 2 weeks with 20 mg/kg resveratrol. They concluded that estrogen deficiency inhibits the expression of Sirt (a key hippocampal protein for depression in rodents), an effect that was reversed by the action of resveratrol by inhibiting the NF-κB signaling pathway and the NLRP3 inflammasome in the hippocampus, which subsequently prevented inflammatory progress [ 307]. The estrogen deficiency in this trial simulates what could be the menopausal stage of women, so these encouraging findings put resveratrol in the spotlight as a possible antidepressant. Certainly, clinical trials of treatment with this polyphenol in women in this vital period have confirmed its benefit for health, reducing the pain related to the loss of bone mass, improving somatic symptoms, vaginal dryness, sleep and circulation disorders, in short, bringing about an improvement in overall quality of life [ 308, 309].

Despite all the possible benefits found in animal models, clinical trials have not shown significant differences in the use of this nutraceutical [ 310]; however, the scarcity of human studies regarding this molecule cannot be ignored. Because of this, we suggest future research to optimize its effectiveness on health.

Cannabidiol

One of the bioactive compounds whose application is booming in recent times is cannabidiol (CBD), which is subtracted from the Cannabis sativa plant. This plant contains a large number of molecules known as phytocannabinoids; some of these, for example, tetrahydrocannabinol (THC), have psychotropic activity, producing physiological alterations after consumption. However, CBD does not have psychoactive properties and its toxicity is very low, so its use has been investigated for the treatment of different diseases such as epilepsy, chronic pain or Parkinson's disease [ 311]. Among the mechanisms that link CBD and depression are the stimulation of neurogenesis and neuroplasticity in brain regions related to MDD [ 312]. Likewise, its participation in neurotransmission systems such as serotonergic, GABAergic and glutamatergic has the power to mitigate anxiety and decrease nausea [ 311]. Despite the facts, the lack of clinical evidence in patients with MDD or patients who have other particularities that could increase the risk of developing MDD in women (endometriosis or loss of quality of life in pregnancy) means that its use cannot be recommended [ 313, 314, 315]. It can be concluded that future research is necessary to discover the advantages that this nutraceutical provides in the particularities of the MDD pathology.

4.2.7. Probiotics and Prebiotics

Probiotics are considered to be the set of live bacteria capable of providing health benefits; we find them in the form of supplements or in some fermented foods such as yogurt or kefir. By contrast, prebiotics are substrates that will act as nutrients for these microorganisms, causing a specific metabolism that results in a healthy ecosystem within the host. Currently, they are beginning to be focused on in order to use them as a key tool for the prevention and treatment of neuroimmune and neuroinflammatory disorders [ 316]. Due to this, the concept of "psychobiotics" arose, which corresponds to bacterial metabolites with regulatory activity of neurotrophic factors against the disruption of the gut-brain axis. Treatment with strains modified by genetic engineering, such as Bifidobacterium breve CCFM1025, recomposed the lost microbiota, increasing the production of short-chain FA, BDFN and serotonin [ 317]. In addition, the OXT/AVP complex can be regulated by intestinal microorganisms, with Lactobacillus reuteri being one of the main regulators known to date, favoring social behaviors [ 318]. Similarly, the efficacy of commercial formulas, composed of a combination of bacterial strains ( B. bifidum W23, B. lactis W51, L. brevis W63, L. casei W56, Lc. lactis W19, among others), has been proven through striking data confirming the improvement of memory processes and sad mood in patients with mild or moderate MDD [ 319]. Women with PCOS were randomly divided into two groups; one of them was treated with a mixture of Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus fermentum and Bifidobacterium bifidum plus 200 μg/day of selenium and the other was the placebo group. The results reflected the increase in glutathione and with it a greater antioxidant response, decreasing inflammatory markers such as C-reactive protein. In addition, the scores of the questionnaires were lower, a fact that shows improvement of mental health after treatment [ 320].

On the other hand, prebiotics do not seem to directly modify symptoms of anxiety or MDD according to the meta-analysis by Kazemi et al. [ 321]. However, the pro/prebiotic symbiosis can be considered key to the optimization of some strains. The use of these combinations has been transferred to the development of foods, from solids to beverages, with fermented foods being of great relevance. In this sense, it should be noted that food by itself does not provide benefits, since, for its determination, we must take into account the interaction between its components, together with its processing [ 319]. Due to the many limitations and lack of consistent facts in human studies, the benefits of consuming fermented foods cannot be assumed; however, preclinical trials point in the opposite direction [ 322], justifying the proposal that the investigation continues in this direction.

All these components are listed in Table 1 , and their key aspects are also highlighted.

Table 1

Nutraceutical

Main Dietary Sources

Probable Antidepressant Effects

Clinical Evidence in MDD Patients

Specific Evidence in Women with MDD

References

ω-3 PUFAs

Nuts, seeds, oily fish and shellfish

EPA and DHA components of cell walls;
neurotransmission and cell signaling; serotonin modulation via CREB; BDFN activation;
anti-inflammatory; synergy with estradiol

Increased EPA and DHA in cell walls improve depressive symptoms and response to treatment; homeostasis ratio FA ω-6/ω-3 could be beneficial in patients with MDD

>5% FA ω-3 intake during pregnancy decreases the risk of PPD.
Diets high in FA ω-3, mainly EPA, reduce prevalence of postmenopausal depression and improve depressive symptoms

Vitamin D

Oily fish, milk, some vegetables

Involved in neurological development; serotonin synthesis via tryptophan hydrolase 2; hippocampal integrity; balance in neuronal excitation and inhibition pathways; interaction with the intestinal microbiota, leading to joint action in the proinflammatory regulation and signaling of NFĸB; maintenance of antimicrobial peptides

-

Balance of the microbial ecosystem; reduction of inflammation produced by estrogenic fluctuations.
<50 nmol/L of 25-[OH]-D in DPP alters sleep-wake patterns and timing of eating.
50,000 IU/week of cholecalciferol led to a drop in the incidence of PMS, dysmenorrhea and associated psychological and physical symptoms.
Improves symptoms associated with PCOS

[ 23, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239]

Vitamin B
(B6, B9, B12)

Spices, nuts, liver, fish, meat, soybeans, vegetables, endogenous synthesis, supplementation

Involved in methylation processes; neurotransmitters and phospholipids synthesis; anti-inflammatory effect; homocysteine antagonist; SAMe precursor

-

Treatment for the improvement of alterations typical of PCOS.
Folate supplementation during pregnancy decreases the risk of PPD

[ 240, 241, 242, 243, 244, 245, 246, 247]

SAMe

Endogenous synthesis or supplementation

Power methylation processes; regulation of monoamine synthesis; anti-inflammatory effects; relation to the gut-brain axis

Effective adjuvant of antidepressants, also in patients with treatment resistance. Another trial determined the use of SAMe as a viable monotherapy

No improvements in severity measured with the Hamilton scale are observed in women. Scarce research makes it difficult to determine its possible benefits in this group

[ 260, 261, 262, 263, 264, 265, 266, 267]

Magnesium

Whole grains, green leafy vegetables, nuts

NMDA antagonist; antioxidant; anti-inflammatory; involved in neurogenesis (BDNF)

248 mg/day of Mg improves mild-moderate MDD with rapid power of action and low toxicity

100 mg magnesium, 4 mg zinc, 400 mg calcium plus 200 IU vitamin D for 12 weeks had beneficial effects on hormonal profiles, biomarkers of inflammation, and oxidative stress in women with PCOS.

[ 251, 252, 253]

Iron

Legumes, seeds, seafood

Tyrosine and tryptophan cofactor; monoamine synthesis

-

50 mg of ferrous sulfate can improve PPD

[ 254, 255]

Zinc

Meat, seafood, egg, some vegetables

NMDA antagonist; interaction with monoamines; neuroplasticity

Antidepressants together with
zinc provides
greater efficacy

7 mg/day of Zn + 1 multi-vitamin capsule for 7 weeks reduces anger, depression and discouragement.

[ 255, 256, 257]

Selenium

Nuts, red meat, grains, garlic

Antioxidant: anti-inflammatory

Diets with adequate amounts of Se and other micronutrients have a moderate impact on the inhibition of development of MDD

Possible protective effect of DPP

[ 258, 259]

Tryptophan

Legumes, nuts, seeds

Serotonin synthesis

Reversal of anxious and depressive symptoms after treatment.
Balanced diet plus tryptophan improves mood in healthy people

Sex-dependent differences, genotype S/S′ in women presents greater neuroprotection, decreased cortisol and consequent mood repair.

[ 276, 277, 278]

Creatine

Red meat, fish

Synthesis of energy intermediaries

Several clinical studies show the improvement of the pathology after supplementation

Sex-dependent differences: coadjuvant of antidepressant drugs, improvement of neuronal integrity and increased connection of neural networks. In another study, the increase in creatine was directly linked to a higher level of monoamines.
Muscle and bone fortification, protection from brain damage in pregnancy and preservation of cognition and sleep hygiene

Phytoestrogens

Soy, legumes, vegetables

Antioxidant; anti-inflammatory; GABAergic and monoaminergic genesis and transmission; regulation of the gut microbiota

5.4 mg/day of flavonoids improves depressive symptoms and increases the Lachnospiraceae species, implicated in the activation of BDNF

Flavone supplementation in the postnatal period showed benefits in parameters of anxiety and quality of life.
Doses of 25 mg/day-100 mg/day of phytoestrogens could alleviate depressive symptoms

[ 281, 282, 283, 284, 285]

Caffeine

Coffee, tea

Neuroprotection; dopaminergic regulation

Its consumption reduces the risk of depression and increases the effectiveness of pharmacological treatment.
High doses could alter some factors related to health (circadian rhythms, anxiety, mixed affective states)

Differences in efficacy according to age:
Doses > 261 mg of caffeine reduce the risk of developing dementia and cognitive disorders in later life.
In young women, its benefit is not so decisive. Reduces irritability and insomnia in PMS.

[ 286, 287, 288, 289, 290, 291, 292, 293, 294]

Anthocyanins

Red fruits, red apple, cherry, black soybeans

Bidirectional relationship with the intestinal microbiota; possible prebiotic agent; anti-inflammatory; antioxidant

Increased beneficial flora ( Lactobacillus spp. and Bifidobacterium spp.)
201 mg/day of anthocyanins produced the reduction of TNF-α, related to cognitive improvement

Decreased C-reactive protein in women with metabolic syndrome

Resveratrol

Red grape, red wine, nuts

Antioxidant; anti-inflammatory; cryoprotective; interaction with the HPA axis; neurogenesis; involved in the regulation of monoamines

Clinical trials demonstrate its power to improve fatigue, anhedonia or sleep quality.
There is no specific evidence of improvement of MDD in humans

Increased quality of life, benefit in somatic and physical symptoms in menopausal women

[ 302, 303, 304, 305, 306, 307, 308, 309]

CBD

Supplements

Implicated in neurogenesis and neuroplasticity; neurotransmission

-

-

[ 311, 312, 313, 314, 315]

Prebiotics and probiotics

Yogurt, kefir, tempeh, miso, legumes, fruits, vegetables

Benefits for the development of a healthy bacterial ecosystem; modulation of neurotrophic factors (BDNF); gut-brain axis regulation;

Supplementation with commercial formulas of probiotics improves mood and memory.
Prebiotics by themselves do not intervene in the state of health, but they are key for the optimization of probiotics

In women with PCOS, the combination of bacteria of the genus Lactobacillus and Bifidobacterium +200 μg/day of selenium had antioxidant and anti-inflammatory power and resulted in higher scores on the mental health questionnaires.

5. Conclusions

MDD is a rising condition affecting a large percentage of people worldwide, especially women, who present approximately 2-fold greater incidence than men. Despite the similarities, some critical differences in the pathophysiology and clinical presentation of MDD in women have been reported. Besides, there are specific subtypes of MDD in this group, including PPD or PMD. Besides, hormonal variations during the menstrual cycle can also be associated with the development of depressive symptoms, PMS and PMDD. Diet is a central element involved in the onset and progression of MDD, as many women affected by this condition appear to be malnourished, presenting inadequate macronutrient intake and deficits in several micronutrients. These alterations can be related to abnormal neurotransmission, negatively influencing sexual hormone levels and their actions. Furthermore, they may promote an inflammatory environment, with noteworthy gut dysbiosis, altering brain functioning and other pathophysiological mechanisms implicated in MDD. We encourage the promotion of integrative therapies for MDD patients from a sex-gender perspective with the aim to improve mental health in women since significant biological differences (menstrual cycle, pregnancy, menopause...) herein discussed are heavily associated with depressive symptoms. Nutritional programs constitute a profitable adjuvant to address MDD patients. Specific nutritional requirements have been observed at pregnancy, postpartum, menopause and even during hormonal fluctuations in the menstrual cycle. These deficiencies increase the risk of depression, with specific denominations according to the following life phases: depressive-like symptoms associated with PMS and PPDD; perinatal and PPD; peri and postmenopausal depression. Pharmacological treatment is sometimes inconceivable, especially during pregnancy and lactation. In this sense, addressing female MDD patients from a nutrition perspective would imply one step forward for precision medicine with a sex-gender perspective.

Author Contributions

Conceptualization, C.G.-M., M.A.O., M.A.A.-M., O.F.-M. and A.R.-B.; methodology, C.G.-M., M.A.O., M.A.A.-M., O.F.-M. and A.R.-B.; investigation, C.G.-M., M.A.O., M.A.A.-M., O.F.-M., A.R.-B., G.L., J.M.M.-R., R.M.M.-R., F.M., R.R.-J., J.Q. and M.Á.-M.; resources, M.Á.-M. writing-original draft preparation, C.G.-M., M.A.O., M.A.A.-M., O.F.-M., A.R.-B., G.L., J.M.M.-R., R.M.M.-R., F.M., R.R.-J., J.Q. and M.Á.-M.; writing-review and editing, C.G.-M., M.A.O., M.A.A.-M., O.F.-M., A.R.-B., G.L., J.M.M.-R., R.M.M.-R., F.M., R.R.-J., J.Q. and M.Á.-M.; supervision, M.Á.-M.; project administration, M.A.O.; funding acquisition, M.Á.-M. All authors have read and agreed to the published version of the manuscript.

Funding

This study (FIS-PI18/01726, PI19/00766) was supported by the Instituto de Salud Carlos III (Plan Estatal de I + D + I 2013-2016) and cofinanced by the European Development Regional Fund "A way to achieve Europe" (ERDF) and B2017/BMD-3804 MITIC-CM, B2020/MITICAD-CM funded as part of the Union response to the pandemic of COVID-19 and Halekulani S.L.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

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Articles from Nutrients are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

# data[].attributes.attachment_link.title
The Problem of Malnutrition Associated with Major Depressive Disorder from a Sex-Gender Perspective

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Major depressive disorder (MDD) is an incapacitating condition characterized by loss of interest, anhedonia and low mood, which affects almost 4% of people worldwide. With rising prevalence, it is considered a public health issue that affects economic ...

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Behavior therapy is a form of therapy that uses techniques derived from behaviorism and cognitive psychology. On average, sessions cost $60-$200 and they are usually once a week for 50 minutes. By law, this form of therapy is required to be covered by insurance. If someone does not seek this care their mental health will most likely worsen and the negative issues may become more apparent.

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The average cost for a gym membership in America each year is around $624. However, other cheaper gyms are available for as low as $130 yearly. Insurance rarely covers gym memberships because most are considered "recreational". In most instances of coverage, one of the cheaper or more specialized gym memberships will be awarded to the insured. It is most likely not because of cost one might not pursue a gym membership. Perhaps it is more of the question of motivation. The long term affects of that may include; obesity, worse depression, restlessness, motivationless behavior, and isolation.

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$15-$50 per session with someone that is insured by blue cross blue shield, and $100 to $250 without insurance, 25 sessions per person after that they on they own. Long term consequence could be an increase in social anxiety and maybe isolation from people.

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For many people struggling with depression, their experiences are remarkably similar. They find it difficult to get out of bed. They are exhausted, not interested in making an effort, or unable to even think about getting help.

Taking that first step to getting better feels impossible.

In fact, a new Kaiser Permanente study found that many people with depression are not getting the help they need; only about a third of patients start taking antidepressants or receiving talk therapy after a depression diagnosis.

If dealing with depression is bad, NOT dealing with it can be even worse - both physically and emotionally.

Depression can negatively influence your health and life. Understanding the consequences can provide an incentive to schedule an appointment with a doctor and start treatment.
1. Serious (Additional) Health Issues
Depression and pain share a similar pathway in the brain, which is why people with depression also may experience everyday aches and pains - headaches, backaches, stomachaches, and joint and muscle aches. In fact, people with these symptoms may go to the doctor and learn that they have depression (read more about that here). If you are experiencing any of these symptoms, you should discuss them with your physician.

Additionally, depression can raise your risk for other chronic diseases such as cardiovascular disease, diabetes, Alzheimer's, stroke, and more. The link isn't entirely understood. However, people with depression are often less likely to engage in physical activity or stick to a healthy diet and sleep schedule which contribute to overall wellness and feeling healthy, said Kevin Chapman, Ph.D., a licensed psychologist in Louisville, Kentucky.
2. Relationship Trouble
Depression can put a heavy strain on relationships - leading to lost friendships, severed connections, and break ups or divorces.

"Depression has a profound impact on not just you, but also on those who you care about and interact with. It affects the quality of life for you and those around you," said Dr. Chapman.

A study by University of Waterloo psychologist Uzma Rehman and colleagues (2015) showed that "people who have major depressive disorder (the clinical form of depression) have higher levels of distress in relationships, feel that their marriages are less satisfactory, and become unusually upset when problems develop in their relationships."

However, Psychology Today writes that depression is a treatable condition "as long as you are sensitive to [its] role in your relationship quality. Things may seem to be going downhill due to your bleak assessment of your life; as such a negative mood continues, what seems to be problems may evolve into actual problems. If you can intervene before that happens, you'll be better able to redraw the map on your relationship so that it heads in a favorable direction."
3. Lack of Productivity
Depression robs you of your motivation. In fact, you may find that you're unable to perform your usual tasks, whether assignments at work or chores at home. This is because, as depressive symptoms increase, productivity typically decreases. This can have a significant impact on your job and your ability to complete your usual amount (or quality) of work.

All of this adds up. According to Mental Health America, depression can cost more than $51 billion in absenteeism from work and lost productivity.
4. Alcoholism or Drug Dependency
The connection between depression and alcohol or drug dependencies goes both ways, said Leonard Doerfler, Ph.D., an adjunct professor of psychology at the University of Massachusetts Medical School.

"People who abuse alcohol or drugs are more likely to become depressed, and those who are depressed are more likely to turn to these substances in order to cope with their feelings," said Dr. Doerfler.

According to a 2014 National Survey on Drug Use and Health, 7.9 million people in the U.S. experienced both a mental disorder and substance use disorder simultaneously. This dual diagnosis results in a treatment program that often first starts with detoxification and withdraw, then moving to a mental health treatment plan.
5. Suicide
Tragically, suicide claimed the lives of about 45,000 people in 2016 in the United States, according to the National Institute of Mental Health.

"There is a link between depression and suicide," said Dr. Doerfler. "Fortunately, most people who are depressed are not thinking of killing themselves, and when they do, only a small portion of those people follow through."

If you're having suicidal thoughts, call the 24/7 National Suicide Prevention Lifeline at 1-800-273-8255 or visit www.suicidepreventionlifeline.org.

Depression Treatment Can Help

Finding the right treatment for depression could help in numerous ways. "Not only do people feel better, but they go back to doing things that are important in their lives, like spending time with family and friends," said Dr. Doerfler.

Reaching out to your doctor is the first step toward a happier, more fulfilling life. He or she may direct you toward talk therapy with a psychiatrist, psychologist, or other mental health professional. Your doctor can help you find the right medication to treat the condition.

In addition to following through with treatment for depression, it's also important to focus on self-care. Make room in your routine for exercising, eating a healthy diet, and participating in activities that you enjoy.

If you ever feel like your symptoms are worsening, let your doctor know. Together, you can rethink your strategy for fighting depression.

You can read about other people who have overcome their depression struggles at https://genesight.com/stories/. To read more about this topic, please read our blog post at https://genesight.com/blog/patient/five-things-you-can-do-to-manage-depression-symptoms/.

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What Long-Term Emotional Risks and Consequences are Caused by Untreated Depression? - GeneSight

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There could be serious consequences to not getting help for depression, including other health issues, drug/alcohol dependency and lack of productivity.

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Psychotherapy spend between $60 to $120 on average for an hour-long session. Given this range, most therapists charge an average rate of $90 per hour. The amount of coverage you can expect will vary from plan to plan. In many instances, you'll have a deductible to pay before your services are covered. Copays and coinsurance may also apply. untreated depression and not going to Psychotherapy can lead to several physical and mental illnesses, including anxiety, heart disease, and diabetes. It can also lead to issues with employment and relationships, as well as an overall decrease in quality of life.

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CBT teaches the victim coping skills for the struggles of their depression. It focuses on how your thoughts and beliefs affect your feelings and actions. This treatment could possibly treat conditions stemming off of depression such as psychosis or social anxiety. Only a Cognitive Behavioral Therapist may give out treatment.

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Problem-Solving Therapy is a psychosocial treatment for patients experiencing depression and distress related to inefficient problem-solving skills. The PST model instructs patients on problem identification, efficient problem-solving, and managing associated depressive symptoms. This treatment can help those with including adaptations for those in primary care and those who are homebound, medically ill, and elderly. It can be delivered by, mental health professionals, social workers, and health professionals, including primary care physicians and nurses.

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Problem-Solving Therapy (PST) is a brief psychosocial treatment for patients experiencing depression and distress related to inefficient problem-solving skills. The PST model instructs patients on problem identification, efficient problem-solving, and managing associated depressive symptoms.

While there are different types of PST, they are all based on the same principle of resolving depression by re-engaging the client in active problem-solving and activities. In general, PST involves the following seven stages: (1) selecting and defining the problem, (2) establishing realistic and achievable goals for problem resolution, (3) generating alternative solutions, (4) implementing decision-making guidelines, (5) evaluation and choosing solutions, (6) implementing the preferred solutions, and (7) evaluating the outcome. A primary focus is learning and practicing PST skills, which are centered around empowering patients to learn to solve problems on their own.

Overall, the number of PST sessions may range from between 4 and 12. Individual sessions are, on average, 40 minutes long; however, group sessions can last up to 90 minutes. Each PST session follows a typical structure of agenda-setting, reviewing progress, engaging in the PST model problem-solving activities, reviewing action plans, and wrap-up.

PST can be used in wide range of settings and patient populations, including adaptations for those in primary care and those who are homebound, medically ill, and elderly. It can be delivered by a variety of providers, including mental health professionals, social workers, and health professionals, including primary care physicians and nurses.
Designation as a "Program with Evidence of Effectiveness"
SPRC designated this intervention as a "program with evidence of effectiveness" based on its inclusion in SAMHSA's National Registry of Evidence-Based Programs and Practices (NREPP).

Outcome(s) Reviewed (Evidence Rating)*

Suicidal Thoughts and Behaviors (Effective)

Depression and Depressive Symptoms (Effective)

Self-Concept (Effective)

Social Competence (Promising)

Self-Regulation (Promising)

Non-Specific Mental Health Disorders and Symptoms (Promising)

Physical Health Conditions and Symptoms (Ineffective)

General Functioning and Well-being (Ineffective)

Anxiety Disorders and Symptoms (Ineffective)

Read more about the program's ratings.

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* NREPP changed its review criteria in 2015. This program was reviewed under the post-2015 criteria. To help practitioners find programs that fit their needs, NREPP reviews the evidence for specific outcomes, not overall programs. Each outcome was assigned an evidence rating of Effective, Promising, or Ineffective. A single program may have multiple outcomes with different ratings. When considering programs, we recommend (a) assessing whether the specific outcomes achieved by the program are a fit for your needs; and (b) examining the strength of evidence for each outcome.

2012 NSSP Objectives Addressed:

Objective 8.3: Promote timely access to assessment, intervention, and effective care for individuals with a heightened risk for suicide.

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Problem-Solving Therapy (PST) is a brief psychosocial treatment for patients experiencing depression and distress related to inefficient problem-solving skills. The PST model instructs patients on problem identification, efficient problem-solving, and managing associated depressive symptoms. While there are different types of PST, they are all based on the same principle of resolving depression by re-engaging the client in active problem-solving and activities.

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Psychotherapy, otherwise known as talk therapy, is when a individual, family, couple, or group sits down to discuss with a therapist or a mental health professional. Topics of discussion include mood, thoughts, and behaviors. Psychotherapy is beneficial long-term as it helps people learn life long coping skills which makes depression manageable. Many types of professionals can deliver psychotherapy, some are clinical psychologists, social workers, psychiatrists, and more.

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Read about psychosocial treatments, different types of psychotherapy and social and vocational training.

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This type of therapy the patient has electrical currents sent through the brain; patient is also given muscle relaxants as the currents can sometimes cause muscle spasms. This treatment can help cure depression, but a long-term effect can possibly be memory loss and is usually last resort. treatment can only be done by a EC therapist.

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Electroconvulsive therapy (ECT) is a treatment for certain mental illnesses. During this therapy, electrical currents are sent through the brain to induce a seizure.

The procedure has been shown to help people with clinical depression. It's most often used to treat people who don't respond to medication or talk therapy.

ECT has a varied past. When ECT was first introduced in the 1930s, it was known as "electroshock therapy." In its early use, patients regularly suffered broken bones and related injuries during therapy.

Muscle relaxants weren't available to control the violent convulsions ECT caused. Because of this, it's considered one of the most controversial treatments in modern psychiatry.

In modern ECT, electrical currents are administered more carefully, in a more controlled manner. Also, the patient is given muscle relaxants and sedated to reduce the risk of injury.

Today, both the American Medical Association and the National Institutes of Mental Health support the use of ECT.

ECT is most often used as a treatment of last resort for the following disorders:

Bipolar disorder

Bipolar disorder is characterized by periods of intense energy and elation (mania) that may or may not be followed by severe depression.

Major depressive disorder

This is a common mental disorder. People with major depressive disorder experience frequent low moods. They may also no longer enjoy activities they once found pleasurable.

Schizophrenia

This psychiatric disease typically causes:

There are two major types of ECT:

In bilateral ECT, electrodes are placed on either side of your head. The treatment affects your entire brain.

In unilateral ECT, one electrode is placed on the top of your head. The other is placed on your right temple. This treatment affects only the right side of your brain.

Some hospitals use "ultra-brief" pulses during ECT. These last less than half a millisecond, compared to the standard one-millisecond pulse. The shorter pulses are believed to help prevent memory loss.

To prepare for ECT, you'll need to stop eating and drinking for a specified period of time. You may also need to change certain medications. Your doctor will let you know how to plan.

On the day of the procedure, your doctor will give you general anesthesia and muscle relaxants. These medications will help prevent convulsions associated with the seizure activity. You'll fall asleep before the procedure and not remember it afterward.

Your doctor will place two electrodes on your scalp. A controlled electrical current will be passed between the electrodes. The current causes a brain seizure, which is a temporary change in the brain's electrical activity. It will last between 30 and 60 seconds.

During the procedure, your heart rhythm and blood pressure will be monitored. As an outpatient procedure, you'll typically go home the same day.

Most people benefit from ECT in as few as 8 to 12 sessions over 3 to 6 weeks. Some patients require a once-a-month maintenance treatment, although some may require a different maintenance schedule.

According to Dr. Howard Weeks of the Treatment Resistant Mood Disorder Clinic at UNI, ECT therapy has a 70 to 90 percent success rate when it comes to patients getting better. This compares to a 50 to 60 percent success rate for those taking medications.

The reason ECT is so effective remains unclear. Some researchers believe it helps to correct an imbalance in the brain's chemical messenger system. Another theory is that the seizure somehow resets the brain.

ECT works for many people when drugs or psychotherapy are ineffective. There are typically fewer side effects than with medications.

ECT works quickly to relieve psychiatric symptoms. Depression or mania may resolve after only one or two treatments. Many medications require weeks to take effect. Therefore, ECT can be especially beneficial for those who are:

However, some people may require maintenance ECT, or medications, to maintain the benefits of ECT. Your doctor will need to monitor your progress closely to determine the best follow-up care for you.

ECT may be safely used on both pregnant women and those with heart conditions.

Side effects associated with ECT are uncommon and generally mild. They can include:

headache or muscle ache in the hours following treatment

confusion shortly after treatment

nausea, usually shortly after a treatment

short-term or long-term memory loss

irregular heart rate, which is a rare side effect

ECT can be fatal, but deaths are extremely rare. About 1 in 10,000 people die from ECT. This is lower than the United States suicide rate, which is estimated to be 12 in 100,000 people.

If you or a loved one is dealing with suicidal thoughts, call 911 or the National Suicide Prevention Lifeline at 1-800-273-8255 right away.

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ECT been shown to help 78 percent of people with clinical depression. Find out what to expect during treatment and read about side effects and risks.

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One physical/occupational treatment for depression are relaxation techniques. Practicing slowly breathing can lower your heart rate and in turn can lower the effects of depression. Depression can cause short term anxiety and these relaxation techniques can also be used to treat this anxiety. A physical therapist or a CBT can give out these treatments or demonstrate them to the person dealing with depression.

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Occupational Therapy for depression focuses on the aspect of daily activities with groups or individuals. Their goal is to help clients become more motivated when it comes to their physical fitness, stress management, and utilizing resources. This form of therapy is meant to leave long lasting affects for the patient. An occupational or physical therapist can help guide the patient for this treatment but they are not necessary to prescribe it.

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Friends can play a pivotal role in helping individuals cope with depression. In the midst of a depressive episode, the isolation and loneliness that often accompany the condition can be overwhelming. Friends provide a crucial source of social support and a sense of belonging, offering a listening ear, empathy, and understanding. Their presence and companionship can act as a buffer against the emotional turbulence of depression, making individuals feel valued and less alone in their struggles.

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Regular exercise may help ease depression and anxiety by Releasing feel-good endorphins, natural cannabis-like brain chemicals (endogenous cannabinoids), and other natural brain chemicals that can enhance your sense of well-being. In people who are depressed, neuroscientists have noticed that the hippocampus in the brain—the region that helps regulate mood—is smaller. Exercise supports nerve cell growth in the hippocampus, improving nerve cell connections, which helps relieve depression," explains Dr. Miller.

https://www.skylandtrail.org/6-habits-to-improve-mental-health/

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Older adults are a special population that is affected by depression. They are more susceptible to depression due to the fact that they are more likely to be isolated and lonely. It is difficult for this population to avoid mental illness because with age comes loss, it is inevitable. Treatment can include living in senior living homes as it surrounds the individual with others in similar situations and provides them with a sense of community and care.

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The highest rate of depression (16.2 percent) was found among bus drivers. Some of the stress sources of bus drivers are different from other drivers, especially time pressure, shift work, lack of social support, and passenger harassment and violence. All these stresses can exacerbate unhealthy psychological conditions of bus drivers, such as anxiety, depression, anger, depression, and fatigue.

They may face trouble getting the care they need because they don't have the best health care. Or simply because they don't want to seek help.

https://www.theatlantic.com/business/archive/2014/12/which-jobs-have-the-highest-rate-of-depression/383947/

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It's known that in some cases pregnant women can develop postpartum depression. ways to help or treat this issue would can be psychotherapy or antidepressant meds non therapy treatments would be communicating with other moms and taking needed rest.

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Diagnosis

Your health care provider will usually talk with you about your feelings, thoughts and mental health to help determine if you have a short-term case of postpartum baby blues or a more severe form of depression. Don't be embarrassed - postpartum depression is common. Share your symptoms with your provider so that you and your provider can create a useful treatment plan.

As part of your evaluation, your health care provider may do a depression screening, including having you fill out a questionnaire. Your provider may order other tests, if needed, to rule out other causes for your symptoms.

Treatment

Treatment and recovery time vary, depending on how severe your depression is and what your individual needs are. If you have an underactive thyroid or an underlying illness, your health care provider may treat those conditions or refer you to the appropriate specialist. Your health care provider may also refer you to a mental health professional.

Baby blues

The baby blues usually fade on their own within a few days to 1 to 2 weeks. In the meantime:

Get as much rest as you can.

Accept help from family and friends.

Connect with other new moms.

Create time to take care of yourself.

Avoid alcohol and recreational drugs, which can make mood swings worse.

Ask your health care provider about getting help from a health professional called a lactation consultant if you're having problems with producing milk or breastfeeding.

Postpartum depression

Postpartum depression is often treated with psychotherapy - also called talk therapy or mental health counseling - medicine or both.

Psychotherapy. It may help to talk through your concerns with a psychiatrist, psychologist or other mental health professional. Through therapy, you can find better ways to cope with your feelings, solve problems, set realistic goals and respond to situations in a positive way. Sometimes family or relationship therapy also helps. Examples of therapies used for postpartum depression include cognitive-behavioral therapy (CBT) and interpersonal psychotherapy.

Antidepressants. Your health care provider may recommend an antidepressant. If you're breastfeeding, any medicine you take will enter your breast milk. However, most antidepressants can be used during breastfeeding with little risk of side effects for your baby. Work with your provider to weigh the potential risks and benefits of specific antidepressants.

Other medicines. When needed, other medicines may be added to your treatment. For example, if you have postpartum depression that includes severe anxiety or insomnia, an antianxiety medicine may be recommended for a short time.

Brexanolone (Zulresso) is the first drug approved by the U.S. Food and Drug Administration specifically for postpartum depression in adult women. Brexanolone slows the rapid drop of certain hormones after childbirth that may lead to postpartum depression. Potential serious side effects require a stay in a health care facility and monitoring by a health care provider while receiving the medicine through a vein over 60 hours. Because of this, the treatment is not yet widely available.

Research continues on an oral medicine for postpartum depression with promising results. The medicine being studied works in a way similar to brexanolone. But it could be taken daily as a pill and may not have the same serious side effects.

With appropriate treatment, postpartum depression symptoms usually improve. In some cases, postpartum depression can continue and become long term, which is called chronic depression. It's important to continue treatment after you begin to feel better. Stopping treatment too early may lead to a relapse.

Postpartum psychosis

Postpartum psychosis requires immediate treatment, usually in the hospital. Treatment may include:

Medicines. Treatment may require a combination of medicines - such as antidepressants, antipsychotic medicines, mood stabilizers and benzodiazepines - to control your signs and symptoms.

Electroconvulsive therapy (ECT). If your postpartum depression is severe and you experience postpartum psychosis, ECT may be recommended if symptoms do not respond to medicine. ECT is a procedure in which small electrical currents are passed through the brain, intentionally starting a brief seizure. ECT seems to cause changes in brain chemistry that can reduce the symptoms of psychosis and depression, especially when other treatments have been unsuccessful.

A hospital stay during treatment for postpartum psychosis can challenge a mother's ability to breastfeed. This separation from the baby makes breastfeeding difficult. Your health care provider can recommend support for lactation - the process of producing breast milk - while you're in the hospital.

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

In addition to professional treatment, you can do some things for yourself that build on your treatment plan and help speed recovery.

Make healthy lifestyle choices. Include physical activity, such as a walk with your baby, and other forms of exercise in your daily routine. Try to get enough rest. Eat healthy foods and avoid alcohol.

Set realistic expectations. Don't pressure yourself to do everything. Scale back your expectations for the perfect household. Do what you can and leave the rest.

Make time for yourself. Take some time for yourself and get out of the house. That may mean asking a partner to take care of the baby or arranging for a sitter. Do something you enjoy, such as a hobby or some form of entertainment. You might also schedule some time alone with your partner or friends.

Avoid isolation. Talk with your partner, family and friends about how you're feeling. Ask other mothers about their experiences. Breaking the isolation may help you feel human again.

Ask for help. Try to open up to the people close to you and let them know you need help. If someone offers to babysit, take them up on it. If you can sleep, take a nap, or maybe you can see a movie or meet for coffee with friends. You may also benefit from asking for help with parenting skills that can include caregiving techniques to improve your baby's sleep and soothe fussing and crying.

Remember, taking care of your baby includes taking care of yourself.

Coping and support

The already stressful, exhausting period following a baby's birth is more difficult when depression occurs. But remember, postpartum depression is never anyone's fault. It's a common medical condition that needs treatment.

So, if you're having trouble coping with postpartum depression, talk with your health care provider. Ask your provider or a therapist about local support groups for new moms or women who have postpartum depression.

The sooner you get help, the sooner you'll be fully equipped to cope with depression and enjoy your new baby.

Preparing for your appointment

After your first appointment, your health care provider may refer you to a mental health provider who can create the right treatment plan with you. You may want to find a trusted family member or friend to join you for your appointment to help you remember all the information discussed.

What you can do

Before your appointment, make a list of:

Any symptoms you've been experiencing and for how long.

All of your medical issues, including physical health conditions or mental health conditions, such as depression.

All the medicines you take, including prescription and over-the counter medicines, as well as vitamins, herbs and other supplements, and the doses.

Questions to ask your provider.

Questions to ask may include:

What is my diagnosis?

What treatments are likely to help me?

What are the possible side effects of the treatments you're suggesting?

How much and how soon do you expect my symptoms to improve with treatment?

Is the medicine you're prescribing safe to take while breastfeeding?

How long will I need to be treated?

What lifestyle changes can help me manage my symptoms?

How often should I be seen for follow-up visits?

Am I at increased risk of other mental health problems?

Am I at risk of this condition recurring if I have another baby?

Is there any way to prevent a recurrence if I have another baby?

Are there any printed materials that I can have? What websites do you recommend?

Don't hesitate to ask any other questions during your appointment.

What to expect from your doctor

Your health care provider or mental health provider may ask you some questions, such as:

What are your symptoms, and when did they start?

Have your symptoms been getting better or worse over time?

Are your symptoms affecting your ability to care for your baby?

Do you feel as bonded to your baby as you expected?

Are you able to sleep when you have the chance and get out of bed when it's time to wake up?

How would you describe your energy level?

Has your appetite changed?

How often would you say you feel anxious, irritable or angry?

Have you had any thoughts of harming yourself or your baby?

How much support do you have in caring for your baby?

Are there other major stressors in your life, such as financial or relationship problems?

Have you been diagnosed with any other medical conditions?

Have you ever been diagnosed with any mental health conditions, such as depression or bipolar disorder? If so, what type of treatment helped the most?

Your provider may ask additional questions based on your responses, symptoms and needs. Preparing for questions will help you make the most of your appointment.

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Learn the risk factors and symptoms of depression in new mothers, as well as effective treatment that can help you manage symptoms and bond with your baby.

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Peer Support Intervention - Perinatal Depression

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Peer Support Intervention - Perinatal Depression

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Peer support intervention has shown effectiveness in treating or preventing perinatal depression. Perinatal depression is a major issue that effects women world wide, it is defined as "the occurrence of major and minor depressive episodes that occur during pregnancy or in the first 12 months after delivery". Peer support intervention is a method that provides care for the mother from a social network member who has the necessary knowledge of specific behaviors that occur during post partum. This method is promising as it allows the mother to have a reliable network of people who are there for her, which prevents the common depressive feeling of isolation. From this study it was apparent that peer support intervention was well receptive by pregnancy and postpartum women. It may introduce another cost-effective type of human resource when it comes to addressing mental health care. However, it should be noted that this method is not guaranteed to work for every individual considering that there are many different levels of depression and no person is the same.

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Benefits of Web Based Self Help Resources for Depression

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Benefits of Web Based Self Help Resources for Depression

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In the study by JAMA Psychiatry, the focus was on victims of back pain. Back pain is shown to cause depression so researchers decided to give the participants of the study a double blind test. 149 of the adults with back pain received the treatment and the other 146 did not. The participants receiving the treatment showed a reduction of the risk of depression by 52%. The web based self help resources have been shown to be able to prevent depression by giving the subjects affirmative words and reasoning with the subjects. These web sites provided users with at home activities to do to prevent depression such as yoga, social interaction, exercise, and self care. Thus giving them an extra sense of security in themselves and keeping away the causes of depression. The preventative measure being online gives the advantage of easy accessibility. However, people who may need more motivation may tend to skip this beneficial resource if they are alone. In the event that the subject follows and goes through the web self help resources thoroughly, improvements in well being and mental health are sure to come while also preventing depression.

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Electroconvulsive therapy is a form of treatment for depression. The treatment works by stimulating the brain with small amounts of electricity that ultimately produces a small monitored seizure, due to this the patient must be under anesthesia. The shocks causes changes in the brain chemistry and regional connectivity that reduce symptoms of mania, depression, and catatonia. Electroconvulsive therapy usually takes 4-6 treatments for the patient to see improvement.

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Studies show that monitored virtual reality experiences can be an aid in helping treat depression. The virtual reality gives the individual a break from the outside world occupying them with games and activities in virtual reality. This can also treat other psychological disorders like anxiety and post traumatic stress disorder. It may only take as a little as one treatment to notice a difference in mood.

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For the diagnosis of mental disorders such as depression, an electroencephalogram (EEG) is a powerful tool due to its high temporal resolution, low cost, noninvasive technique, and easy setup. EEG is also widely used in clinical applications. Counselors may find that digital platforms allow the development of deeper working relationships with clients. An EEG can help identify specific brain patterns or biomarkers associated with depression.

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Introduction

Depression, a common mental disorder, is a leading cause of disability worldwide, with a global prevalence ranging from 20% to 25% in women and 7% to 12% in men,1 and it has exhibited an increasing trend in recent decades.

Based on analysis of evidence from several studies that exhibit an existence of inherent and intrinsic reciprocal comorbidity between depression and epilepsy, the author believes that the categorisation of TRD based on the mere failure of two antidepressants could appear premature and erroneous. Therefore, in view of this analysis, this brief paper proposes a justified deliberation for revising the diagnostic criteria for TRD.

Clinical importance of electroencephalography in psychiatry and neurology

Several other researchers have highlighted the utility of an EEG in treatment selection,6 7 and classification of mood disorders8 9; an EEG can even aid in the identification of subgroups within a psychiatric population.10 One study suggests that EEG can also assist in differentiating patients with depression from other clinical disorders and from normal individuals.11

The application of EEG in clinical settings is constantly evolving with emerging developments. Advances in machine learning and artificial intelligence have the potential to automatically analyse EEG data and identify patterns that are associated with specific disorders. The importance of quantitative EEG (QEEG) is increasingly recognised and is expected to be used for diagnosing and managing psychiatric illnesses such as depression and schizophrenia. Therefore, QEEG offers an economical alternative to other functional brain imaging modalities in psychiatric disorders.6 QEEG analysis has revealed several consistent abnormalities in patients with depression. Decreased delta power, increased high-frequency power, reduced interhemispheric coherence and altered frontal EEG alpha asymmetry scores have been shown in patients with depression.11 12 For example, abnormal EEG with epileptiform activities has been proposed as a possible predictor of lithium resistance in bipolar disorder.7

EEG has not been given the significance it deserves in diagnosing and managing patients with TRD for several reasons, despite that the inventor of the EEG, Hans Berger, was a psychiatrist. First, there has been a lack of consensus among mental health professionals about the potential role of EEG in the diagnostic process. Second, EEG has been viewed as an infrastructure-intensive, manpower-intensive and time-consuming procedure and, thus, not feasible for widespread use in routine clinical practice. Third, large-scale clinical studies that could demonstrate the potential value of EEG in diagnosing and managing TRD have been lacking. An EEG should be considered an important tool in managing TRD because it can aid in identifying underlying and concomitant TLE and assist in strategizing a more effective treatment modality for TRD.

The importance of EEG in psychiatric diseases is increasingly being recognised as it has the potential for diagnosis and to guide treatment. The Psychiatric EEG Evaluation Registry (PEER) is a clinical phenotypic database comprising data correlating EEGs and medication treatment outcomes for various mental health diagnoses.13 The purpose of PEER is to collect and analyse data to better understand the relationship between EEG findings and medication treatment outcomes and to improve diagnosis and treatment in psychiatry and neurology. An EEG can help identify specific brain patterns or biomarkers associated with depression. The further availability of a publicly accessible database for EEG recordings annotated with clinical features and clinical outcomes in psychiatric diseases will enhance research in this direction.

Reciprocal comorbidity between depression and epilepsy

The comorbidity and reciprocal relationship between depression and epilepsy, especially TLE, appears inherent and intrinsic. This relationship has been known since ancient times as it was mentioned in Hippocrates' writing around 400 BC: 'melancholics ordinarily become epileptics, and epileptics, melancholics'. The comorbidity of epilepsy and depression has been increasingly recognised in recent times.

The relationship between depression and epilepsy has intrigued neurologists and psychiatrists for many years. TLE is considered a suitable biological model for understanding the common structural link between depression and epilepsy. The temporal lobe is the most epileptogenic region of the human brain, and TLE is the most frequent form of partial epilepsy in adults. Furthermore, TLE is frequently drug-resistant, necessitating non-pharmacological adjunctive therapies, and is often associated with mental disorders, especially depression and anxiety.16-18

The longitudinal studies evaluating the prevalence of epilepsy in patients with depression are lacking. One population-based study of 83 cases with incident unprovoked seizures and 130 control subjects found that a history of depression increased the risk for the development of unprovoked seizures by sevenfold.19 In a controlled study, the incidence of major depression in patients having unprovoked seizures was 6%, which was six times higher than in controls.20 Another recent population-based cross-sectional study from Iran reported a prevalence of 4.8% (95% CI: 2.9% to 7.4%) of epilepsy in children and adolescents with depression.21 Cohort studies evaluating the causal effect of depression on epilepsy are lacking; however, evidence suggests that the relationship is bidirectional, and depression has been reported to predate the onset of epilepsy in some studies.22-24

In patients with TLE caused by mesial temporal sclerosis, the frequency of depression reported is as high as 50%-60%.25 26 Comorbidity of epilepsy with depression has been reported in other studies also16 18 27-29; as mentioned earlier, patients with TLE are more likely to exhibit this comorbidity in comparison with other epilepsy forms. In addition, several other studies have demonstrated an association between hippocampal volume loss and mood disorders,30-33 indicating a possible involvement of the limbic system in depression, a finding also observed in patients with TLE.

Epilepsy and depression also share a similar neurocircuitry involving temporal lobes and neocortex, the frontal lobes with cingulate gyrus, subcortical structures (such as basal ganglia and thalamus) and their connecting pathways.34 Thus, both clinical and structural evidence indicates that depression and epilepsy probably represent an epiphenomenon, and therefore not surprisingly, neural networks are also shared commonly. Voxel-based morphometry studies have also provided strong evidence in favour of the notion that depression and mesial TLE represent an epiphenomenon sharing similar neural networks that involve several brain regions.34 Neuroimaging studies have revealed a common neuroanatomic localisation in TLE and depression, with hippocampal volume loss in both disorders.35

There are several treatment challenges in patients with comorbid depression and epilepsy. Although some patients with depression and epilepsy may respond well to standard treatments with antidepressants and antiepileptic drugs, there is an increased risk of TRD in the presence of comorbid epilepsy.15 When depression and epilepsy co-occur, treatment resistance can develop in either or both conditions. In these cases, the comorbidity of TRD and epilepsy can be complex and challenging to manage as it can increase the risk of adverse effects and drug interactions and impair adherence to a management strategy.

Author's postulation

In the author's opinion, and given their intrinsic comorbidity, depression and epilepsy appear inseparable disease entities. Therefore, diagnosing TRD without an EEG and the oversight of highly probable comorbid epilepsy could sound premature and erroneous. Along similar lines, managing TRD without considering the probability of concomitant epilepsy could also be incomprehensive and compromised, leading to apparently premature and possibly unjustified referral for aggressive NIBS techniques like ECT that retain an association with a social stigma.

Anecdotal experiences (including the author's personal experience) also report that patients with TRD, even those with suicidal tendencies, have exhibited temporal lobe IEDs (unilateral or bilateral, but predominantly left-sided). Successful treatment of IEDs has resulted in a marked decline in the severity of depression and even total elimination of suicidal tendencies and ideation. The author thus proposes that the possibility of the role of IEDs in aggravating the severity of depression and suicidal ideation cannot be ruled out totally and warrants an in-depth exploration.

From the above-cited studies, it is evident that concomitant EEG changes are common in depression. Therefore, diagnosing TRD may be premature in the absence of an EEG, which is an invaluable, simple, non-invasive and cost-effective investigation, especially for the detection of IEDs required for the clinical diagnosis of epilepsy. Therefore, an EEG of all patients with TRD before being referred for NIBS techniques appears justified and is strongly recommended.

In line with several other researchers who have advocated augmentation and adjunctive strategies,42 the author strongly recommends EEG as a novel adjunctive strategy and its inclusion as a guideline/criterion in the diagnosis of TRD in an attempt to favourably impact the management and quality of life of patients with TRD. In most cases of TRD, the possibility of comorbid epilepsy is generally ignored, potentially leading to an inadvertent significant treatment gap; treatment of TLE might actually make the management of depression more effective and successful. Therefore, there is a need to reframe guidelines and include EEG as an adjunctive strategic tool in the diagnosis of TRD. This would involve updating clinical practice guidelines, promoting research and providing training and resources to mental health professionals to help them use EEG in the diagnosis and management of TRD.

Conclusion

The current diagnostic criterion (ie, failure of two antidepressants) therefore, can lead to the erroneous inclusion of a larger-than-justified number of patients in the category of TRD as a significant number of patients could actually be treatable by drugs alone upon considering the possibility of concomitant epilepsy and its treatment if found to co-occur. The inclusion of EEG in clinical practice can thus aid in diagnosing concomitant TLE in patients with TRD, potentially leading to better therapeutic outcomes.

Therefore, serious deliberation on revising the current diagnostic criteria that could aid in improved treatment of TRD and possibly spare many patients from being subjected to unwarranted NIBS techniques, like ECT, appears justified and is strongly recommended. However, despite significant evidence in favour of the utility of EEG in TRD, well-designed retrospective and prospective studies are recommended to validate the author's postulation on including an EEG as a guideline/criterion in TRD.

Biography

Dr Harinder Jaseja graduated from GR Medical College in India in 1980 and did his post-graduation (MD) in 1985. He has worked as a faculty member at GR Medical College for more than 33 years. He has also worked as a professor in physiology at the National Institute of Medical Sciences (NIMS) in India. Since 1992, he has been working as a consultant at the Vellore EEG Center in India. In 2005, Dr Jaseja initiated a debate on the epileptogenic potential of meditation. Dr Jaseja has advocated the inclusion of EEG in the management of patients with cerebral palsy (CP) and has shown the efficacy of vagal nerve stimulation (VNS) in CP, post which CP has been included in the list of indications of VNS. In 2013, he was ranked second in Epilepsy Research in India. His current work has been on deep brain stimulation (DBS) in intractable epilepsy (IE). He has postulated a new target for DBS in IE, namely the Pedunculopontine nucleus. He has also propounded a theory based on EEG-guided selection of DBS parameters. His main research interest has been in epilepsy and epileptogenesis.

Footnotes

Contributors: HJ is sole author and contributor to the submitted manuscript and has contributed totally.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Not applicable.

References

10. Kanner AM, Bermeo-Ovalle A. EEG in psychiatric disorders: does it have a role in their evaluation? In: Niedermeyer's electroencephalography: basic principles, clinical applications, and related fields. 7th ed. Oxford University Press, 2017: 686-94. 10.1093/med/9780190228484.003.0025 [[ CrossRef] Google Scholar]

37. Schaffer CE, Davidson RJ, Saron C. Frontal and parietal electroencephalogram asymmetry in depressed and nondepressed subjects. Biol Psychiatry 1983;18:753-62. [[ PubMed] Google Scholar]

Articles from General Psychiatry are provided here courtesy of Shanghai Mental Health Center

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Electroencephalography in the diagnosis and management of treatment-resistant depression with comorbid epilepsy: a novel strategy

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Depression, a common mental disorder, is a leading cause of disability worldwide, with a global prevalence ranging from 20% to 25% in women and 7% to 12% in men,1 and it has exhibited an increasing trend in recent decades.

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Public health has brought many therapies to help depression such as cognitive behavioral therapy (CBT). This therapy has helped them because they pinpoint life events that contribute to their depression and help them find ways to change, accept, or adapt to those situations. Set realistic goals for the future for the patient. CBT aims to teach people that it is possible to have control over your thoughts, feelings, and behaviors. CBT helps you to challenge and overcome automatic beliefs, and use practical strategies to change or modify your behavior.

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IPT (interpersonal therapy) is a form of public health regulation in that it helps all age groups adolescence, adults and teenagers handle and deal with personal issues that may be aiding in their development of depression.

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Interpersonal therapy, or IPT, is a short-term, focused treatment for depression. Studies have shown that IPT, which addresses interpersonal issues, may be at least as effective as short-term treatment with antidepressants for mild to moderate forms of clinical depression. Originally developed to treat depression in adults, it has been shown to be effective in treating adolescent depression and is commonly recommended as a treatment for depression in children.

Events surrounding interpersonal relationships do not cause depression. But depression occurs within an interpersonal context and affects relationships and the roles of people within those relationships. By addressing interpersonal issues, interpersonal therapy for depression puts emphasis on the way symptoms are related to a person's relationships, including family and peers.

The immediate goals of treatment are rapid symptom reduction and improved social adjustment. The long-term goal is to enable people with depression to make their own needed adjustments. When they can do that, they are better able to cope with and reduce depressive symptoms.

Interpersonal therapy is a manual-based treatment. That means the therapist strictly adheres to a treatment process whose effectiveness is supported by evidence.

According to the International Society for Interpersonal Therapy, there are three components to depression.

Symptom formation

Social functioning

Personality issues

IPT is a short-term treatment option that typically consists of 12 to 16 one-hour weekly sessions. The therapist focuses on identifiable problems in how an individual interacts with or doesn't interact with others. When those problems are addressed, the patient realizes a benefit in their experience of symptoms.

Except to check on their severity and the effect of the various treatments, symptoms are not addressed in therapy sessions. Instead the therapist works collaboratively with the patient, either individually or in a group, to identify and then address one or two significant problems in their interactions. The number of problems addressed is deliberately limited to one or two for the whole course of treatment. The result is an intense focus on how to make the necessary adjustments in interpersonal situations that will help reduce symptoms of depression.

The types of problems addressed fall into four categories:

Interpersonal disputes or conflicts. These disputes occur in marital, family, social, school, or work settings. The disputes emerge from differing expectations of a situation. They become a problem that needs to be addressed when the conflicts that come from the expectations lead to significant distress.

Role transitions. Changing circumstances, whether they're developmental, stem from shifts in work or social settings, or result from a life event or end of a relationship, require adaptations from the individual. With depression, those changes are felt as losses and contribute to the depression.

Grief. In IPT, grief is the experience of loss through death. Grief becomes a problem when it is delayed or becomes excessive so that it lasts beyond the normal time for bereavement.

Interpersonal deficits. This refers to the patient reporting "impoverished" personal relationships either in number or in quality.

By focusing on issues from these categories, the therapist can help the person with depression learn how to make the adjustments that are needed to address the interpersonal issue and improve relationships.

With issues involving interpersonal disputes, the therapist works with the patient to define how serious the issue has become in terms of how difficult it is to move beyond it. For instance, there might be a dispute between husband and wife that stems from the wife's attempts to be more independent. The therapist would lead the patient, in this case the husband, in an effort to discover the sources of misunderstanding. Then the therapist might use problem-solving approaches, communication training, or some other technique to enable the patient to resolve the conflict in a way that doesn't worsen the symptoms of depression.

In role transition issues, the therapist helps the patient determine the differences between the old and the new roles. Then together they would focus on identifying exactly what is causing the difficulties and work to find a solution for the problem.

For issues involving grief, the therapist facilitates the grieving process to help the patient move beyond it. Two important techniques used to do this are:

Empathetic listening, which provides support and a safe outlet for the patient's feelings

Clarification, which is a technique for helping the patient examine their own misconceptions about the situation

With interpersonal deficits, the therapist will work with the patient to explore past relationships or the current relationship the patient has with the therapist. The goal is to identify patterns, such as excess dependency or hostility, that interfere with forming and maintaining good relationships. Once those patterns are distinguished, the focus turns to modifying them. Then, with the therapist's guidance and assistance, the patient is urged to make new relationships and to apply the therapeutic adjustments that have been made.

As the sessions progress, the therapist gradually lessens their level of intervention. The goal is for the patient to self-intervene more and make more of their own adjustments. This becomes easier as time goes on, and the patient's ability to self-intervene continues to improve after the sessions end, often not peaking until three to six months after therapy is over.

Interpersonal therapy typically takes place in one-hour sessions, usually weekly, that continue for 12 to 16 weeks. Depending on the severity of the depression, sessions might be continued for an additional four or more weeks.

If you were being treated for depression with interpersonal therapy, the first few sessions, usually from one to three weeks, would be used for assessing your depression, orienting you to the IPT focus and process, and identifying specific interpersonal issues or problems you have. Together, you and the therapist would create a record of your interpersonal issues, rank them, and decide which one or two issues seemed most important to address in terms of your depression.

At least the next eight sessions would be focused on addressing those issues -- understanding them more, looking for adjustments that you can make, and then applying those adjustments. Throughout this portion of the therapy, the therapist would use a number of different techniques, including among others:

Clarification, which has the purpose of helping you recognize and get beyond your own biases in understanding and describing your interpersonal issues.

Supportive listening.

Role playing.

Communication analysis.

Encouragement of affect, which is a process that will let you experience unpleasant or unwanted feelings and emotions surrounding your interpersonal issues in a safe therapeutic environment. When you do, it becomes easier to accept those feelings and emotions as part of your experience.

The entire focus of the sessions will be on addressing the identified issues. This is hard for some individuals to get used to -- especially those who are familiar with more traditional, open-ended and introspective approaches to therapy. It may take you several weeks before your own primary focus shifts to the IPT approach.

Another important aspect of the IPT process is an emphasis on terminating therapy. From the beginning the patient is aware that therapy is defined by a limited amount of time. In the final four or so weeks of therapy, the sessions will turn to termination issues.

With IPT, termination of therapy is seen as a loss to be experienced by the patient. So you would be asked to consider what the loss means to you. What issues does it bring up, and how can you apply the interpersonal adjustments that you've learned to make over the course of therapy to evaluating and getting through the loss? The idea is for the patient to become more aware of their ability to deal with interpersonal problems that have kept them from being able to actively manage the symptoms of depression.

There are several advantages to interpersonal therapy being applied to group therapy. First, the members of the group have an opportunity to learn through observing what other members in the group are learning. Learning also takes place through a process of modeling the adjustments and behavior of others in the group. There is also more opportunity to see various types of interpersonal interactions and associations. These can help the individual better understand various approaches to making interpersonal adjustments.

Before you would join a group, you would have one or two individual sessions in order to learn about the group process. You would also use those sessions to identify the one or two interpersonal issues that you will want to focus on during therapy.

Initially, the group would go through a process of engagement. This would involve identifying the common goals and common focus of the group. The therapist would then facilitate the group's establishment of a collaborative approach. That would be followed by members of the group differentiating themselves and figuring out how to work on their individual issues. During this second phase, conflicts are likely to arise and partnerships or alliances formed.

As the sessions progress, each individual's focus would be addressed and both the therapist and the other group members would help that person learn how to adjust their approach to the issues. The therapist might suggest role playing or brainstorming to help find the right intervention. Or the therapist might suggest communication training among members of the group. When conflict arises between group members, the therapist will often allow the group members to resolve it themselves while serving as a mediator to help avoid excessive negativity or criticism.

As with the individual therapy, termination is an important part of the process. There is still the same sense of loss, and members of the group are asked to confront that loss and to make themselves aware of the evolution of their own adjustments and how to use them to manage symptoms that may emerge when the sessions end.

Because depression is sometimes a recurrent condition, and because some people may experience multiple recurrences, patients are encouraged to supplement IPT with ongoing maintenance. Maintenance takes the form of once-monthly sessions in which the adjustments made during the short-term IPT are reinforced. The goal is to prevent the stress of increased social interaction from leading to new episodes of depression, and to help the individual continue to function at least at the level they were at when regular sessions ended.

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WebMD discusses interpersonal therapy for depression. Find out how it works.

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Our focus condition was very interesting in many ways. For example, I found it very sad with the amount of side effects it has because it can really ruin one's health and well-being. It's not just feeling sad it is something deeper than that. It's very unfortunate that many people suffer from this but it shouldn't be taken as something different.

The symptoms include

Persistent sad, anxious, or “empty” mood.

Feelings of hopelessness or pessimism.

Feelings of irritability, frustration, or restlessness.

Feelings of guilt, worthlessness, or helplessness.

Loss of interest or pleasure in hobbies and activities.

For the physiology of it, there are many possible causes of depression, including faulty mood regulation by the brain, genetic vulnerability, and stressful life events.

Women are more likely to have depression than men. An estimated 3.8% of the population experience depression including 5% of adults (4% among men and 6% among women), and 5.7% of adults older than 60 years. Approximately 280 million people in the world have depression. This is because of female hormone fluctuation. Medications and psychotherapy are effective for most people with depression. A primary care doctor or psychiatrist can prescribe medications to relieve symptoms and this really has helped many people with depression from all over the world.

I believe that the challenges people face with depression are not only depression itself but also the healthcare system. The reason why is that many insurance don't cover the cost of going to therapies. Not only that but many people don't have insurance and just going for one visit can be extremely expensive. People also don't have enough time in the day to go to therapy due to work, school, and other daily activities. Many people also refuse to go to therapy because they think it's a waste of time and money but those who gave it a shot say they almost always feel relieved after each session.