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IAPMD run Support Groups

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Support — International Association for Premenstrual Disorders

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The power of Peer Support is incredible, and we know just how important it is to be able to reach out and speak with others who understand Premenstrual Disorders. International Association of Premenstrual Disorders (IAPMD) Peer Support is available in several ways, all free and accessible.

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A small comic a made to communicate how PMDD affects my life. (Click first image then use arrow keys to navigate panels)

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Through our work we have found that sometimes young people can struggle to understand where to go when they are upset and seeking support with how they are feeling. It can be helpful to work with a young person to identify key people or services in their life who they can talk to when they are upset or distressed, so that they can receive appropriate support.

We have created this resource and activity, called 'Who Can I Talk To?', for parents and professionals to work through in collaboration with young people, in order to support them to understand what options they have when they need help.

As well as helping young people to understand their support options, it also covers things such as the idea of seeking emotional consent before 'venting' to someone, how to deal with others wanting to vent to you, and links to mental health services and helplines.

Through our work we have found that sometimes young people can struggle to understand where to go when they are upset and seeking support with how they are feeling. It can be helpful to work with a young person to identify key people or services in their life who they can talk to when they are upset or distressed, so that they can receive appropriate support.

We have created this resource and activity, called 'Who Can I Talk To?', for parents and professionals to work through in collaboration with young people, in order to support them to understand what options they have when they need help.

As well as helping young people to understand their support options, it also covers things such as the idea of seeking emotional consent before 'venting' to someone, how to deal with others wanting to vent to you, and links to mental health services and helplines.

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'Who Can I Talk To?': Supporting Young People to Access Help and Support

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Through our work we have found that sometimes young people can struggle to understand where to go when they are upset and seeking support with how they are feeling.

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What are PMS and PMDD? Chronic pre-menstrual conditions explained | RCN Magazine

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Finding support for LGBTQIA+ mental health

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Those of us who are LGBTQIA+ may have challenges with getting good mental health support. Find tips to get the right support for you.

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StayAlive | Essential suicide prevention for every day life

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The StayAlive app is a suicide prevention resource for the UK, packed full of useful information and tools to help you stay safe in crisis.

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General medical council guidelines on Trans Healthcare

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General medical council guidelines on Trans Healthcare

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NICE Diagnostic criteria for premenstrual dysphoric disorder

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The NICE Clinical Knowledge Summary (CKS) site is only available to users in the UK, Crown Dependencies and British Overseas Territories

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The NICE Clinical Knowledge Summary (CKS) site is only available to users in the UK, Crown Dependencies and British Overseas Territories

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What is PMDD? | Types of mental health problems | Mind

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Premenstrual dysphoric disorder (PMDD) is a very severe form of PMS. Learn more about it, what might cause it and how it might affect your mental health.

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Histamine and PMDD: The Hidden Link Worsening Your Symptoms

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Understanding the connection between histamine and PMDD could be the missing piece in managing your monthly symptoms more effectively.

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The prevalence of early life trauma in premenstrual dysphoric disorder (PMDD).

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Frontiers | The role of the neuroinflammation and stressors in premenstrual syndrome/premenstrual dysphoric disorder:A review

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Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are prevalent emotional disorders in females, characterized by cyclic variations in ph…

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Prevalence of Premenstrual Syndrome in Autism: A Prospective Observer-rated Study - H Obaydi, BK Puri, 2008

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A systematic, prospective observer-rated study was carried out to determine the prevalence of late luteal phase dysphoric disorder (premenstrual syndrome) in wo…

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Recent Research Points to a Clear Conclusion: Autistic People are Thinking About, and Dying by, Suicide at High Rates

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. Author manuscript; available in PMC: 2024 Apr 24.

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Suicidality in women with Premenstrual Dysphoric Disorder: a systematic literature review - Archives of Women’s Mental Health

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Previous research has identified how menstruation is an important factor in both attempted and completed suicides for women. The purpose of this review was to outline (a) the risk profile for suicidality in women who were identified to experience Premenstrual Dysphoric Disorder (PMDD), a condition characterized by severe physical and psychological changes that occur during the luteal menstrual phase, and (b) the implications of these findings for clinical practice. A systematic literature review was conducted using five databases to identify any peer-reviewed articles published between 1989 and 2019. Ten papers eligible for inclusion were identified: three pertaining to suicide cognitions, five to suicide attempts and two to both cognitions and attempts. Findings showed that suicidal thoughts, ideation, plans and attempts were strongly associated with experiences of PMDD and that these findings were independent of psychiatric co-morbidities. However, women with PMDD did not present with more severe risk profiles for suicide attempts (in terms of frequency, impulsivity and lethality) or make more frequent attempts during the luteal menstrual phase compared with suicide attempters without PMDD. Women with PMDD should be considered a high risk group for suicidality; thus, identifying and treating symptoms are vital in reducing suicide attempts. Implications for clinical practice are outlined in the discussion.

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PMDD & ADHD Connection People with periods and ADHD are more vulnerable to hormone-related mood disorders such as PMDD. It’s speculated that both

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‘Suicide or deliberate self-inflicted harm’ identified as the most common category of death in autistic children without a learning disability - Autism Centre of Excellence

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Thursday 18 July 2024 Charity calls for urgent action to address the increased risk of suicide for autistic people The Autism Centre of Excellence at Cambridge (ACE) is calling for urgent action from the Government following a report which revealed the most common category of death in autistic children without a learning disability1 is ’suicide or […]

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Risk Factors for Premenstrual Dysphoric Disorder in a Community Sample of Young Women: The Role of Traumatic Events and Posttraumatic Stress Disorder.

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Skip to content Background: There is some evidence that the onset and course of premenstrual syndrome is related to stress; however, few studies have explored the role of traumatic events and posttraumatic stress disorder (PTSD) as risk factors for the development of premenstrual dysphoric disorder (PMDD).

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Prevalence of hormone-related mood disorder symptoms in women with ADHD - PubMed

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This is the first study to assess the prevalence of symptoms of premenstrual dysphoric disorder (PMDD), episodes of postpartum depression symptoms (PPD) after first childbirth, and climacteric mood symptoms in Attention-Deficit/Hyperactivity Disorder (ADHD). 209 consecutive women (18-71 years) with …

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GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan

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The female lifespan is marked by periods of dramatic hormonal fluctuation. Changes in the ovarian hormones estradiol and progesterone, in addition to the progesterone metabolite allopregnanolone, are among the most significant and have been shown to…

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Cortical γ-Aminobutyric Acid Levels Across the Menstrual Cycle in Healthy Women and Those With Premenstrual Dysphoric Disorder

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Background There is increasing support for the hypothesis that gonadal steroids involved in the regulation of the human menstrual cycle modulate γ-aminobutyric acid (GABA) neuronal function. This study tests the hypothesis that cortical GABA neuronal function, reflected in brain GABA…

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When you're feeling low or overwhelmed, it can be hard to know how to cope. But distracting yourself or doing one of our activities or games can help you feel better.

Even doing just one positive thing every day can help your mood. Not sure what you want to do today? Use our tool to help.

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When you're feeling low or overwhelmed, it can be hard to know how to cope. But distracting yourself or doing something positive can really help. We've got lots of activities for you to try!

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When I first read about Rejection Sensitive Dysphoria I was like "Wow. That's exactly what I experienced."

There's still a lot of research being done about RSD* and while it is not something that you can be diagnosed with, it is a way to describe symptoms and it resonates with a lot of people - specifically those with ADHD, Autism, social anxiety, and a history of trauma.

No one likes criticism or rejection but for people who experience RSD the emotional impact of rejection or criticism goes to the extreme to the point that it negatively affects your relationships, your job, or your life. It's much like anxiety - everyone has moments of anxiety but it becomes a disorder when it interrupts your life and the symptoms are uncontrollable.

As far as treatment goes - that's a little bit more complicated. It's best to talk to your doctor or therapist to come up with a plan that works for you.

I think RSD played a huge part in my life in my 20s.

My 20 year-old-self had huge mood swings whenever there was criticism or perceived rejection in my job or in my relationships. One time my boss gave me a small amount of criticism and I quit my job on the spot. Thankfully she was able to coax me back but I remember thinking that small comment meant that I sucked as an employee and it wouldn't matter if I left anyway.

I have struggled to take criticism for as long as I can remember. A huge part revolves around social anxiety because it makes me hyper-aware of how other people perceive me and my brain always tells me that the perception is bad. As I've grown older with a ton of coping skills (especially positive self-talk!) and therapy under my belt, I believe what used to be rejection sensitive dysphoria has mellowed into sensitivity to rejection for me. I'm still awful at taking criticism or rejection and it can sometimes cause me to spiral but I'm pretty good at regulating myself now.

I wanted to share this to let you know that if it's something that you struggle with you are not alone!

Here are some things that might help but therapy is always the best place to start!

CBT or Cognitive-behavioral therapy: It helps you understand why you feel the way you do and then works on changing your thought patterns.

Mindfulness and Relaxation Techniques: Sometimes you need something to pull you back from your racing thoughts of "I am the worst, suckiest, person in the world and should disappear." Mindfulness helps you do that by focusing on staying in the moment. Sometimes just that minute of breathing exercises can bring us down a bit and re-center ourselves.

Positive Self-Talk: This is the big one. It might feel like everyone else is rejecting you and being overly critical of you but you have the power to talk back to those thoughts and even if it's just a small quiet voice saying, "Hey, you're doing okay. It's okay to make mistakes." It can make the biggest difference. Maybe your brain a kind place to be even when the world feels the opposite.

Grounding Techniques: Grounding techniques, much like mindfulness, gives you the time and space to let your brain settle a little. It can help you manage what you're feeling in a way that is less intense or destructive. can help you redirect your focus from your internal world to what's around you in the present moment. This can be helpful in managing intense emotional reactions.

Emotion Regulation Skills: For me, DBT was hands down one of the biggest things that helped me overcome a lot of RSD traits I can't recommend it enough. While I always, always, encourage working with a professional, a lot of DBT skills can be easily learned and integrated into your life.

Understand RSD: Call out those thoughts. Learn how to spot when it's RSD and learn how to recognize when your brain is spiraling. You might not be able to do anything about it but as you build up coping skills and self-talk it slowly starts to get easier to manage.

Do you experience RSD? How does it affect your life?

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6 Ways to Manage Rejection Sensitive Dysphoria | Self-Love Rainbow

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When I first read about Rejection Sensitive Dysphoria I was like "Wow. That's exactly what I experienced."

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(This is part of a series of posts about Autism and Trauma) This is a guide is focused on understanding the theory of autism and trauma....

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Bloody Good Period fights to eradicate shame and stigma around periods and menstruation through conversation, education and action.

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Understanding Meltdowns - Autism Understood

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An introduction to the limbic system. Meet the Panic Monkey and the Dino Brain. The process of a meltdown and how panic monkey and dino brain can help

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Understanding Anxiety Part 1: Introduction to Autism and Anxiety

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Calm Harm is an award-winning app funded by teenage mental health charity stem4, to help manage the urge to self-harm. It was developed by Clinical Psychologist Dr. Nihara Krause MBE, in collaboration with young people and uses principles from an evidence-based psychological treatment called Dialectical Behaviour Therapy (DBT).

The urge to self-harm is like a wave. It feels the most powerful when you start wanting to do it.

Learn to ride the wave with the Calm Harm app by choosing activities from these categories:
, , Express Yourself , , and .

There is also a breathing exercise to help you be mindful and stay in the moment, regulate difficult emotions, and reduce tension.

When you ride the wave, the urge to self-harm will fade.

The Calm Harm app provides some immediate activities and techniques to help you break the cycle of self-harm behaviour and explore underlying trigger factors; the app supports you in building a 'safety net' of helpful thoughts, behaviours, and access to supportive people, as well as providing the opportunity to journal and self-reflect. The Calm Harm app also signposts to help.

The app is private, anonymous, and safe.

Please note that the Calm Harm app is not a substitute for the assessment and individualised treatment by a health or mental health professional.

Our app is for young people over the age of 13.

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Calm Harm is a free app to help teenagers manage the urge to self-harm. Available on Google Play & App Store.

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A shutdown has all the same overwhelming & distressing feelings as a meltdown, but instead of being expressed outwardly, feelings are trapped inside

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Premenstrual Dysphoric Disorder (PMDD) is a severe negative reaction in the brain to natural changes in hormone levels in people who menstruate (have periods)

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Buy The Autism-Friendly Guide to Periods Illustrated by Robyn Steward (ISBN: 9781785923241) from Amazon's Book Store. Everyday low prices and free delivery on eligible orders.

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Gynecologic Management of Pediatric and Adolescent Patients with Ehlers-Danlos Syndrome

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Neurodivergent people more likely to experience pain, due to hypermobility

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Neurodivergent people are more than twice as likely to have hypermobile joints and are far more likely to experience pain, new research finds.

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. Author manuscript; available in PMC: 2020 May 1.

Abstract

The menstrual cycle is known to impact mood and cognitive function and has been shown to lead to variability in symptoms of obsessive-compulsive disorders and anxiety. Using a within-subject design, the present study examined ovarian hormones, the error-related negativity (ERN), and self-reported checking symptoms in both the mid-follicular and mid-luteal phases of the menstrual cycle. ERN amplitude and checking symptom severity did not vary between the follicular and luteal phases. However, a more negative ERN was associated with greater checking symptoms in the luteal phase of the menstrual cycle, even when controlling for ERN amplitude in the follicular phase. Moreover, changes in checking symptoms between phases were associated with phase-related changes in the ERN. Finally, a significant mediation model was found such that the ERN measured in the luteal phase mediated the association between progesterone in the luteal phase and checking symptoms in the luteal phase. Collectively, the present findings suggest that levels of progesterone in the luteal phase could impact checking symptoms by modulating response monitoring and sensitivity to errors, and that fluctuation in the ERN between menstrual cycle phases may play an important role in the expression of anxious and obsessive-compulsive symptoms.

Keywords: error-related negativity, EEG/ERP, anxiety, checking, OCD, progesterone, menstrual cycle

Introduction

The pubertal period is a pivotal time of risk for internalizing disorders, including both depression and anxiety. While both sexes have equal incidence of mood and anxiety disorders throughout childhood, an imbalance in the incidence of these disorders emerges in the pubertal period, such that women experience depression and anxiety at twice the rate of men by midadolescence ( Cohen et al., 1993). For girls, the onset of menstruation is a major facet of pubertal development, and thus, hormonal changes associated with the onset of menses may play a role in increasing internalizing psychopathology and related symptoms.

The menstrual cycle has increasingly been investigated in relation to psychological changes. While studies examining whether transition between menstrual cycle phases is associated with changes in mood and cognition have produced mixed findings, hormones of the menstrual cycle-estradiol and progesterone in particular-have been associated with changes in emotional reactivity ( Farage et al., 2008). The menstrual cycle can be divided into three phases that are characterized by distinct fluctuations in endogenous hormones ( Farage et al., 2008). The follicular phase begins with menstrual bleeding and typically lasts 13-14 days. During the early part of the follicular phase, women experience low levels of estrogen and progesterone, while the latter part of the follicular phase is characterized by a sharp increase in both estrogen and luteinizing hormone levels. The increase in luteinizing hormone leads into the 16- to 32-hour ovulatory phase, when estrogen levels decrease rapidly and an egg is released. The luteal phase begins after ovulation, lasts for approximately 14 days, and is characterized by a peak of progesterone and estrogen in the mid-luteal phase that is flanked by relatively decreased levels of both hormones in the early- and late-luteal phases. The late-luteal phase is also commonly referred to as the pre-menstrual phase. Natural variability in levels of estradiol and progesterone across the menstrual cycle are depicted in Figure 1.

Figure 1.

Schematic depicting the natural variability in the menstrual hormones estradiol and progesterone across the menstrual cycle. Reprinted with permission from Mulligan et al., 2018, Psychophysiology, e13268.

In women, greater estradiol has been linked to decreased reactions to negative emotional stimuli, and estrogen therapy has been shown to decrease depressive symptoms in some perimenopausal women ( Sakaki & Mather, 2012; Cohen et al., 2003). Similarly, in animal models, estradiol has been shown to reduce anxious behavior ( Walf & Frye, 2007; Walf & Frye, 2010). On the other hand, progesterone has been shown to increase reactions to negative stimuli ( Sakaki & Mather, 2012). Naturally high levels of progesterone in the mid-luteal compared to the early follicular phase have been related to heightened amygdala activity to negative stimuli ( Andreano & Cahill, 2010), and exogenous progesterone administration increased negative mood in women that were in the early follicular phase ( Klatzkin et al., 2006). Furthermore, progesterone administration has been shown to increase amygdala reactivity to angry and fearful faces ( Van Wingen et al., 2008), and greater levels of progesterone have been associated with increased self-reported proneness to anxiety in the form of excessive doubts, compulsions, obsessions, and unreasonable fears ( Avgoustinaki et al., 2012).

In line with these findings, reproductive cycle phases have been linked to risk for onset and exacerbation of obsessive-compulsive disorder (OCD) in women ( Gugliemi et al., 2014). Previous studies suggest that pre-existing OCD is often exacerbated in pregnancy and the postpartum period, which are periods characterized by high fluctuation in ovarian hormones ( Ross & McLean, 2006; Forray et al., 2010). Further, the premenstrual phase, which occurs during the luteal phase of the menstrual cycle, has also been linked to the exacerbation of OCD symptoms. In a study by Vulink and colleagues (2006), 49 percent of outpatients with OCD reported exacerbated symptoms during the pre-menstrual (or late-luteal) phase. Several other studies find similar results indicating worsening of OCD symptoms in the late-luteal phase of the menstrual cycle ( Labad et al., 2005; Williams & Koran, 1997). Thus, hormonal changes that occur over the course of the menstrual cycle may play a role in the severity of OCD symptoms in women.

Given evidence from previous studies that the menstrual cycle may impact severity of OCD symptoms, it is of interest to examine whether biomarkers of OCD and anxiety also vary across the menstrual cycle. For instance, one previous study by Lithgow and Moussavi (2017) examined whether electrovestibulography (EVestG) features, which have been previously proposed to be biomarkers of depression (Lithgow et al., 2015) and have been linked to anxiety (Balaban et al., 2011), vary across the menstrual cycle. They found that EVestG features linked to anxiety differed across early follicular, late follicular and luteal menstrual phases ( Lithgow & Moussavi, 2017).

One of the most replicated findings in the neurobiology of OCD is an enhanced error-related negativity (ERN) event-related potential (ERP). However, no studies have examined whether ovarian hormones impact the ERN. The ERN is a negative deflection in the ERP that peaks approximately 50 milliseconds (ms) after a participant makes an incorrect response, or error ( Hajcak & Foti, 2008). Previously source-localized to the anterior cingulate cortex (ACC; Holroyd et al., 1998; Herrmann et al., 2004), the ERN is thought to reflect early error processing activity of the ACC ( Olvet & Hajcak, 2008), and to reflect the integration of information regarding pain, threat, and punishment for optimizing goal-directed behavior ( Meyer, 2016; Shackman et al., 2011). Importantly, the ERN has been found to be accentuated (i.e., is more negative) in individuals with OCD ( Ruchsow et al., 2005; Gehring et al., 2000; Johannes et al., 2001; Hajcak et al., 2008; Endrass et al., 2010; Endrass et al., 2008; Xiao et al., 2011; Klawohn et al., 2016), as well as those with heightened symptoms of OCD ( Hajcak & Simons, 2002; Santesso et al., 2006), suggesting that these populations are more vigilant to making errors. In line with these findings, the ACC, the cortical region to which the ERN has been localized, has been shown to be hyperactive in OCD patients as compared to healthy controls during a cognitive task designed to elicit errors ( Fitzgerald et al., 2005). Moreover, the ERN has even been shown to be enhanced in unaffected first-degree relatives of OCD patients ( Riesel et al., 2011; Carrasco et al., 2013). For these reasons, an overactive ERN has been suggested to be a candidate endophenotype or biomarker of OCD ( Riesel et al., 2011).

The ERN has also been found to be increased in individuals with generalized anxiety disorder (GAD; Weinberg et al., 2015; Weinberg et al., 2012; Weinberg et al., 2010; Ladouceur et al., 2006) and social anxiety disorder (SAD; Endrass et al., 2014), as well as non-clinical individuals reporting symptoms of worry and general anxiety ( Hajcak et al., 2003; Meyer, 2016). Given these reported associations between an enhanced ERN and multiple clinical disorders, recent studies have investigated the association between the ERN and cross-diagnostic symptoms. In a study by Weinberg and colleagues (2015), the ERN was measured in a sample of healthy controls as well as individuals with generalized anxiety disorder, OCD, major depressive disorder, or a combination of the three disorders. Across all groups, checking symptoms (i.e., inspection of one's own behaviors to reduce anxiety about potential adverse outcomes) were associated with a larger ERN ( Weinberg et al., 2015). Furthermore, in a sample of 515 never-depressed adolescents, Weinberg and colleagues (2016) similarly found that a larger ERN was related to self-reported checking symptoms. In both of these studies, when scores from all anxiety symptom subscales (i.e., panic, social anxiety, claustrophobia, traumatic intrusions, traumatic avoidance, checking, ordering, and cleaning) were entered into a multiple regression predicting ERN amplitude, checking symptoms displayed the most robust relationship with the ERN, over and above other symptom dimensions ( Weinberg et al., 2015; Weinberg et al., 2016) As a result of these studies, it has been posited that checking may be the best cross-diagnostic phenotype to characterize individual differences in the ERN ( Weinberg et al., 2016).

Checking behaviors, which consist of repetitive checking (e.g., repetitively checking on the safety of loved ones or checking that you locked the door) despite knowing that checking is unnecessary, are the most common compulsion in individuals with OCD ( Rasmussen et al., 1992) and have been found to be significant predictors of OCD ( Watson et al., 2012). Additionally, previous research has indicated that non-clinical compulsive checkers demonstrate higher levels of perfectionism, worry, and cognitive impairment than anxious controls ( Gershuny & Sher 1995), that individuals with high checking symptoms are more likely to have depression and anxiety in the postpartum period ( Abramowitz et al., 2010), and that dysfunctional beliefs underlying checking behavior are a risk factor for OCD ( Abramowitz et al., 2006). Therefore, checking behaviors are both related to OCD, risk for OCD, and are problematic in their own right. However, no study has yet examined variability in the ERN and checking symptoms across the menstrual cycle. If ovarian hormones impact the ERN, checking symptoms, or their association, then menstrual phases with high balances of those hormones may represent periods of vulnerability or risk for developing OCD or anxiety ( Andreano et al., 2018). Moreover, these data could shed important light on the timing of when it is most useful to assess neural mechanisms of risk, as well as when such neural mechanisms of risk might best be targeted via intervention or prevention efforts.

In the current study, we sought to examine for the first time the relationship between ERN and checking symptoms across phases of the menstrual cycle-our primary goal was to determine whether the ERN and checking symptoms might vary across menstrual phases, and if changes in checking symptoms across menstrual phase relate to changes in the ERN. To this end, the present study used a within-subject design to examine whether checking symptoms and the ERN varied in the mid-follicular and mid-luteal phases of the menstrual cycle. Forty undergraduate females completed a hormone assay for estradiol and progesterone, a checking symptom inventory, and a task to elicit the ERN twice-once during the mid-follicular phase and once during the mid-luteal phase. Given previous findings, we hypothesized that the ERN and checking symptoms would both be elevated in the mid-luteal phase. We also hypothesized that greater checking symptoms would be associated with a heightened ERN, greater levels of progesterone, and reduced levels of estradiol. Finally, as an exploratory aim, we aimed to examine whether the ERN and checking symptoms were associated in the mid-follicular and mid-luteal phases and whether the ERN mediates associations between hormones and checking symptoms.

Methods

Participants

Fifty-three female undergraduates from Stony Brook University participated for course credit. Of these, 13 participants were excluded from analyses for not returning for their second assessment. Thus, the final sample consisted of 40 participants. The sample was college-aged ( M = 20.78 years, SD = 3.37), and ethnically diverse, including 55% Asian, 25% Caucasian, 12.5% Latino, and 7.5% Black. Demographic information can be found in Table 1. Participants were recruited from the introduction to psychology subject pool. Demographic information was obtained through an initial screening e-mail, and eligibility for participation was determined through an online pre-screen survey that assessed the use of hormonal/oral contraceptives, average menstrual cycle duration, date of onset of previous menses, and regularity of the menstrual cycle. The menstrual cycle length was defined as the number of days from the start of menses in one cycle to the start of menses in the next cycle. Inclusion criteria were age 18-35 years and regular menstrual cycle (average cycle length 28.65 days [ SD = 2.97]; average length of menstruation 5.29 days [ SD = 0.95]). Exclusion criteria were: taking hormonal/oral birth control within the past 4 months, irregular menstruation, pregnancy or lactation within the past 12 months.

Table 1.

M

SD

Follicular Phase

Lutea Phase

M SD M SD

Information on the average menstrual cycle length and the date of onset of previous menses was used to schedule eligible participants for the initial assessment. Order of menstrual phase tested was counterbalanced across participants. Of the 40 participants, 23 (57.5%) were initially tested during the mid-follicular phase (6 to 8 days following the start of menstruation) of their menstrual cycle, and 17 (42.5%) were initially tested during the mid-luteal phase (6 to 8 days before the projected start of menstruation) of their menstrual cycle. For the second assessment, each participant was scheduled during the alternate phase of her cycle. Informed consent was obtained prior to participation and the research protocol was approved by the Institutional Review Board at Stony Brook University.

Measures

Inventory of Depression and Anxiety Symptoms (IDAS-II):

The IDAS-II is a 99-item selfreport questionnaire that measures factor-analytically derived symptom dimensions of depression and anxiety ( Watson et al. 2007; Watson et al., 2012). Each item measures symptoms over the past two weeks on a 5-point Likert scale ranging from 1 (Not at all) to 5 (Extremely). The IDAS-II has good internal consistency, test-retest reliability, and convergent and discriminant validity with diagnoses and self-report measures ( Watson et al., 2012). National norms have recently been reported for the IDAS-II (Nelson et al., 2017). It has also been found to have good clinical utility, as the IDAS-II scales are reported to be good to excellent predictors of their associated DSM-5 diagnoses ( Stasik-O'Brien et al., 2018). For the purposes of this study, checking symptom scores were derived from the checking subscale within the IDAS-II.

Procedure

Participants attended two laboratory visits: one during the mid-follicular phase and the other during the mid-luteal phase. There was an average of two weeks between visits ( M = 15.24 days, SD = 3.85). All participants first provided written informed consent, and then completed self-report questionnaires. Participants then provided a salivary sample for hormone assay. All samples were assayed for salivary estradiol and progesterone using an enzyme immunoassay kit (Salimetrics, State College, PA). For estradiol assay, the test uses 100 ul of saliva, has a minimum detection limit of 0.1 pg/mL (range from 1 - 32 pg/mL), and average intra- and inter-assay variation coefficients were 7% and 6% respectively. There is minimal cross-reactivity to estriol and estrone, and no detected cross-reactivity with progesterone. For progesterone assay, 50 ul of saliva were collected. There is a minimum detection limit of 5 pg/mL (range from 10 - 2430) and average intra- and inter-assay coefficients of variation were 4% and 5.5% respectively. There is minimal cross-reactivity to corticosterone and no detected cross-reactivity to estradiol. After collection of the salivary sample and EEG setup, participants completed the flanker task (described below) while EEG was recorded. Participants completed additional EEG tasks in a random order and results from other tasks are presented elsewhere ( Mulligan et al., 2018).

The arrowhead version of the flankers task was administered using Presentation software (Neurobehavioral Systems, Inc., Albany, CA, USA) and was similar to the version used in previous studies ( Hajcak & Foti, 2008; Jackson et al., 2015). The task consisted of 330 trials presented over 11 blocks of 30 trials. On each trial, five horizontally aligned white arrowheads were presented for 200 ms. Participants were instructed to quickly indicate the direction of the central arrowhead using the left or right mouse button. Half the trials were compatible (e.g., < < < < < or > > > > >) and half were incompatible (e.g., < < > < < or > > < > >); trial type was randomly determined. Incompatible trials are often perceived as more difficult than compatible trials due to their incompatible flanking arrows. Thus, participants are more likely to make errors on incompatible trials. A variable inter-trial interval of 600 to 1000 ms followed the response. At the end of every block, participants received feedback based on their performance on the screen; if accuracy was at 75% or lower, the message "Please try to be more accurate" was displayed to increase attention to the task; when more than 90% of responses were correct, the message "please try to respond faster" was shown to increase the likelihood of the participant committing more errors; otherwise the message "You are doing a great job" was presented. On error trials, it is typically immediately apparent to the participant that they have just made a mistake. Thus, this task is designed to elicit error-related neural activity on trials where the participant chooses the direction of the central arrow erroneously.

EEG Recording and Processing

Continuous EEG was recorded using an elastic cap with 34 electrode sites placed according to the 10/20 system. Electrooculogram (EOG) was recorded using four additional facial electrodes: two placed approximately 1 cm outside of the right and left eyes, and two placed approximately 1 cm above and below the right eye. All electrodes were sintered Ag/AgCl electrodes. Data were recorded using the Active Two BioSemi system (BioSemi, Amsterdam, Netherlands). The EEG was digitized with a sampling rate of 1024 Hz using a low-pass fifth order sinc filter with a half-power cutoff of 204.8 Hz. A common mode sense active electrode producing a monopolar (i.e., nondifferential) channel was used as recording reference. EEG data were analyzed using Brain Vision Analyzer (Brain Products, Gilching, Germany). Data were referenced offline to the average of left and right mastoids and band-pass filtered (0.1 to 30 Hz, with a 24 dB/oct roll-off).

Response-locked epochs were extracted with a duration of 1,500 ms, including a 500 ms pre-response and 1000 ms post-response interval; these segments were then corrected for eye movement artifacts using a regression-based approach ( Gratton, Coles, & Donchin, 1983). Epochs containing a voltage greater than 50 μV between sample points, a voltage difference of 300 μV within a segment, or a maximum voltage difference of less than 0.50 μV within 100 ms intervals were automatically rejected. Additional artifacts were identified and removed based on visual inspection. The −500 to −300 ms pre-response interval was used as the baseline. Response-locked ERPs were averaged separately for error and correct trials in the mid-follicular and midluteal phases. The number of trials per condition that remained after artifact rejection at the FCz electrode site were as follows: error follicular ( M = 34.20, SD = 21.23), error luteal ( M = 31.62, SD = 16.82), correct follicular ( M = 286.42, SD = 34.86), and correct luteal ( M = 282.80, SD = 34.56). No subjects were excluded from the sample for committing too few errors (i.e., all subjects committed six or more errors throughout the course of the task).

The ERN and correct-related negativity (CRN) were scored as the average voltage in the window from 0 to 100 ms after the response at electrode FCz. The ΔERN was calculated by subtracting the CRN from the ERN. The ΔERN represents the difference in neural activity between error and correct trials. We compute this subtraction-based difference score to isolate the error-related activity. Behavioral measures included the number of errors, as well as average reaction times (RTs) on error and correct trials.

Results

Phase-related differences in hormones, checking, and error-related brain activity.

Consistent with previous findings, levels of progesterone were higher during the midluteal phase, M = 356.19, SD = 194.41, compared to the mid-follicular phase, M = 150.96, SD = 83.33, t(37) = −7.58, p < .001. Additionally, levels of estradiol were also higher during the mid-luteal phase, M = 2.81, SD = .72, compared to the mid-follicular phase, M = 2.48, SD = .70, t(35) = −2.57, p < .05. Self-reported checking did not vary by phase, mid-luteal: M = 6.20, SD = 2.49, mid-follicular: M = 6.12, SD = 2.90, t(40) = −.19, p = .85.

To examine ERP activity, a repeated-measures ANOVA was conducted with response (error vs. correct) and phase (mid-luteal vs. mid-follicular) entered as within-subject variables. While the main effect of response (error vs. correct) was significant, F(1, 39) = 130.12, p < .001, neither phase ( F(1, 39) = 2.24, p = .14) nor the interaction between phase and response ( F(1, 39) = .006, p = .94) was significant. These results suggest that ERN was more negative than the CRN, and this effect did not vary by phase.

Associations between checking, error-related brain activity, and hormone levels

Checking symptoms did not correlate with progesterone during the follicular ( r(38) = .06, p = .72) or the luteal phase ( r(38) = .14, p = .39). Additionally, checking symptoms did not correlate with estradiol during the follicular ( r(38) = .03, p = .87) or the luteal phase ( r(38) = − .10, p = .53). We then examined whether error-related brain activity related to hormone levels during both the mid-luteal and mid-follicular phase. Results suggested that while the ΔERN measured during the mid-follicular phase was not related to estradiol ( r(38) = −.12, p = .49) or progesterone ( r(38) = −.07, p = .68) in the mid-follicular phase and the ΔERN measured during the mid-luteal phase was not related to estradiol in mid-luteal phase ( r(38) = −.17, p = .32), the ΔERN measured during the mid-luteal phase was significantly related to levels of progesterone measured during the mid-luteal phase, r(38) = −35, p < .05. However, when we controlled for accuracy and reaction time (i.e., RT) during the flankers task, this relationship was no longer significant, r(34) = −.20, p = .26.

Phase-related differences in the association between checking and error-related brain activity.

We also examined the relationship between checking symptoms and the ΔERN during the mid-luteal and the mid-follicular phase. Results suggested that while the ΔERN measured during the mid-follicular phase was not related to checking symptoms measured in the mid-follicular ( r(40) = −.23, p = .15) or the mid-luteal phase ( r(40) = −.21, p = .20), the ΔERN measured during the mid-luteal phase was related to checking symptoms reported during the mid-luteal phase, r(40) = −.47, p < .01 and during the mid-follicular phase, r(40) = −.34, p < .05. These results suggest that the ERN and checking symptoms may be associated specifically during the midluteal phase, and not in the mid-follicular phase of the menstrual cycle.1

When we controlled for accuracy and RT during the flankers task, the relationship between the ΔERN measured during the mid-luteal phase and checking symptoms during the mid-luteal phase remained significant, r(36) = −.43, p < .01. However, the relationship between the ΔERN measured during the mid-luteal phase and checking symptoms during the mid-follicular phase was no longer significant, r(36) = −.25, p = .13. We depict the relationship between the ΔERN measured during the mid-luteal phase and checking during the mid-luteal phase in Figure 2: we conducted a median-split based on levels of checking during the mid-luteal phase (left; top = low checking; bottom = high checking). Waveforms for error, correct and the difference (error minus correct), as well as topographical head maps are also depicted (error minus correct, 0 - 100 ms). As can be seen in Figure 2, the ΔERN is larger (i.e., more negative) in individuals characterized by increased levels of checking during the mid-luteal phase. A scatter plot ( Figure 2, right) depicts the relationship between the ΔERN during the mid-luteal phase and checking symptoms.

Figure 2.

Response-locked ERPs (left) for error and correct trials measured during the mid-luteal phase, and corresponding topographic maps for the correct-error difference (middle) in individuals low (top) and high (bottom) in checking symptoms. In the mid-luteal phase, individuals with high checking symptoms showed a more negative ΔERN (i.e., the difference in amplitude between correct and error conditions) as compared to individuals with low checking symptoms. The scatter plot (right) depicts the association between ΔERN and checking symptoms in the mid-luteal phase and the line represents the line of best fit.

To further examine the specificity of the relationship between the ΔERN measured during the mid-luteal phase and checking, we z-scored and combined checking symptoms reported across both phases. We then conducted a simultaneous multiple regression wherein the both the ΔERN measured during the mid-luteal phase and the ΔERN measured during the mid-follicular phase were entered as predictors, and checking symptom scores were entered as the dependent variable. The regression model was significant ( F(2, 39) = 4.90, p < .05) with an R ² of .21. Results suggested that while the ΔERN measured during the mid-follicular phase did not significantly predict checking symptoms, B = .08, t = .45, p = .66, the AERN measured during the mid-luteal phase significantly predicted checking symptoms, B = −.51, t = −2.63,p < .05. This suggests that the relationship between the ΔERN measured during the mid-luteal phase and checking symptoms was significant even when controlling for the ΔERN measured during the mid-follicular phase-that is, checking symptoms were predicted by variance in the ΔERN that is specific to the mid-luteal phase.

Changes in checking, hormones, and error-related brain activity across phases.

Although neither ΔERN nor checking scores varied overall between mid-follicular and mid-luteal phases, it is possible that intra-individual between-phase increases in ΔERN were related to phase-related changes in checking scores (e.g., if some participants increased in their checking, whereas others decreased in checking - and these were associated with a corresponding increase and decrease in ΔERN, respectively). Thus, as an exploratory analysis, we also examined the relationship between changes in checking symptoms and the ΔERN across phases by creating regression-based change scores. This method has been shown to be useful in calculating difference scores between conditions ( Meyer, Lerner, De Los Reyes, Laird, & Hajcak, 2017). Specifically, checking symptoms during the mid-follicular phase were entered predicting checking symptoms during the mid-luteal phase, and the unstandardized residual scores were saved as a measure of change in checking symptoms across the two phases. A similar change score was computed for the ΔERN. As can be seen in Figure 3, which depicts a scatter plot of the relationship between changes in the ΔERN and changes in checking symptoms, individuals who experienced an increase in checking symptoms from the mid-follicular to the mid-luteal phase also were characterized by an increase in the ΔERN from the mid-follicular to the mid-luteal phase, r(40) = −.38, p < .05.

Figure 3.

Scatter plot depicting the association between change in ΔERN from the mid-follicular to the mid-luteal phase, and change in checking symptoms from the mid-follicular to the mid-luteal phase. The line represents the line of best fit.

Mediation Models

Next, we examined an exploratory mediation model wherein the pathway between progesterone and checking symptoms was mediated by the ΔERN. We examined this model in both phases. For the mediation analyses, variables were entered into model 4 of the PROCESS Macro for SPSS ( Preacher & Hayes, 2004). In the first mediation model ( Figure 4), the direct path between progesterone during the mid-luteal phase and checking during the mid-luteal phase was not significant, effect = .00, SE = .01, t = .27, p = .79, 95% CI [−.0100 to .0130]. However, the path from progesterone to the ΔERN, as well as the path from the ΔERN to checking symptoms were both significant, effect = −.01, SE = .00, t = −2.33,p < .05, and effect = −.22, SE = .08, t = −2.88, p < .01, respectively. Additionally, results suggested significant mediation: the indirect path from progesterone to checking via the ΔERN measured during the mid-luteal phase reached significance, effect = .002, SE = .001, 95% CI [.0002 to .0046]. We examined this same model in the mid-follicular phase. In this model, none of the direct paths, nor the indirect path reached significance, all p s > .10.

Figure 4.

Schematic depicting the a significant mediation model in which the ΔERN measured in the mid-luteal phase mediates an indirect association between progesterone in the mid-luteal phase and checking symptoms in the mid-luteal phase.

Finally, we examined an exploratory mediation model wherein the pathway from estradiol and checking symptoms was mediated by the ERN, and we examined this model in both menstrual phases. In the first mediation model, the path between ΔERN in the mid-luteal phase and checking symptoms during the mid-luteal phase was significant, effect = −.23, SE = .07, t = −3.26, p < .01. However, no other direct paths, nor the indirect path reached significance, all ps > .10. Furthermore, in the mid-follicular phase, none of the direct paths, nor the indirect path reached significance, all p s > .10.

Discussion

The present study examined the impact of cyclic changes in ovarian hormones assessed during the mid-follicular and mid-luteal menstrual phases on associations between the ERN and checking symptoms. Results indicated that participants had higher levels of both estradiol and progesterone in the mid-luteal phase as compared to the mid-follicular phase, consistent with previous work demonstrating that levels of progesterone are low in the mid-follicular phase and high in the mid-luteal phase ( Farage et al., 2008). This is also consistent with previous findings that levels of estradiol begin rising in the mid-follicular phase and are moderate in the mid-luteal phase ( Farage et al., 2008).

The present study did not find overall differences in ERN or checking symptoms between menstrual phases. Results indicated that although the ΔERN measured during the mid-follicular phase was not related to checking symptoms measured in either phase, the ΔERN measured during the mid-luteal phase was related to checking symptoms reported during the mid-luteal phase, even when controlling for the ΔERN measured during the mid-follicular phase. In previous studies, estradiol and progesterone have been suggested to have opposing effects on emotional reactivity. Specifically, greater estradiol decreases responsiveness to negative stimuli while greater progesterone increases responsiveness to negative stimuli ( Sakaki & Mather, 2012; Andreano et al., 2018). Thus, our results suggest that ERN and checking symptoms may be associated specifically during the mid-luteal phase of the menstrual cycle, and that hormonal profiles that naturally occur during the mid-luteal phase (i.e., greater progesterone relative to estradiol) may impact the severity of experienced checking symptoms by way of impacting neural systems linked to performance monitoring and error sensitivity. Consistent with this possibility, greater changes in checking symptoms between phases were associated with greater changes in the ΔERN between phases, suggesting that variability in the ERN between menstrual phases is associated with variability in checking symptoms between menstrual phases. Furthermore, a mediation analysis revealed that the ΔERN in the mid-luteal phase mediated the association between progesterone levels and checking symptoms in the mid-luteal phase. Thus, results from our mediation models indicate that progesterone may impact the intensity of checking symptoms by modulating neural sensitivity to errors.

Taken together, the present findings present novel evidence that associations between the ERN and checking symptoms may be impacted by menstrual cycle phase. The findings presented here bolster previous research suggesting the ERN is potentiated in individuals with elevated obsessive-compulsive symptoms ( Hajcak & Simons, 2002; Santesso et al., 2006), and checking symptoms, specifically ( Weinberg et al., 2015; Weinberg et al., 2016). The current findings build on previous research by suggesting that, in women, the ERN may only be associated with checking symptoms in the luteal phase of the menstrual cycle. Future studies in women of reproductive age may be able to account for more variance in associations between the ERN and checking symptoms by examining menstrual phase, or by assessing the ERN in the luteal phase of the menstrual cycle.

The present findings bear similarity to recent research from our group that revealed that greater variability in the neural response to monetary gains between the mid-follicular and midluteal phases was associated with greater depressive symptoms ( Mulligan et al., 2018). Taken together, these studies suggest that hormonal influences inherent in the menstrual cycle may impact neurobiological processes underlying reward and error processing, which, in turn, may impact the expression of internalizing symptoms. Additionally, our present finding that change in ERN across phases predicted change in checking symptoms across phases also aligns with findings from the study by Mulligan and colleagues (2018) in that both studies observed a role for variability in neural signals across menstrual phases in impacting symptoms. This may imply that the change or fluctuation of hormone levels across phases, rather than absolute hormone levels, impact depressive and obsessive-compulsive symptoms. This may also explain why the late luteal or premenstrual phase, a phase characterized by falling levels of estradiol and progesterone, is a particularly vulnerable for increases in OCD and related behaviors. The premenstrual phase, which is characterized by steady decline of both hormones, may be a time of exacerbation of symptoms due to the marked withdrawal from hormones occurring in that time period. Future studies seeking to replicate and extend on these findings in clinical samples have potential to illuminate when it is most useful to assess neural mechanisms of risk. Additionally, the present study sets the stage for future work examining the impact of ovarian hormones and menstrual cycle phases on potential interventions and experimental manipulations

Contrary to previous studies which find exacerbation of OCD in the late-luteal phase ( Vulink et al., 2006; Labad et al., 2005; Williams & Koran, 1997), the present study did not find significant differences in checking symptoms between mid-follicular and mid-luteal menstrual phases. This could be because the present study examined differences in checking symptoms between the mid-follicular and mid-luteal phases, as opposed to the late-luteal phase. It could also be because the present study utilized a non-clinical sample. Thus, future studies could extend the current work by examining the ERN in OCD patients and examining whether checking symptoms and amplitude of the AERN differ between the follicular and late-luteal phases. Moreover, the IDAS-II checking subscale assesses mean levels of checking symptoms over the past two weeks, which was the approximate duration between the two assessments. Thus, the IDAS may not have been sensitive to changes in checking symptoms that fluctuate more rapidly over the course of a menstrual cycle. Future studies could utilize self-report measures of checking symptoms with greater temporal precision via ecological momentary assessment to detect shorter-term variation in symptoms.

Additionally, the present study did not find significant differences in ERN amplitude between menstrual phases. This could also be due to the timing of our data collection within the menstrual cycle. Estradiol is low in the early-follicular phase and high in the late-follicular phase. Given that our follicular assessment took place in the mid-follicular phase, we may not have been able to observe the full impact of peaking estradiol in the late-follicular phase, which may have had greater effects on ERN amplitude. Finally, hormone levels did not directly relate to checking symptoms in the present study, nor did they relate to ΔERN amplitude after controlling for accuracy and reaction time. This could be due to our limited sample size, limited variability in change in estradiol levels between phase ( M = −0.30, SD = .77), or that the present study utilized a non-clinical sample.

The present study had several limitations that warrant consideration. First, due to the undergraduate sample and exclusion criterion of hormonal contraceptive use, results may not generalize to older or younger female populations, or women who are on hormonal contraceptives. Future studies should examine whether the present pattern of findings are also evident in women on hormonal contraceptives and whether these effects appear in adolescence and persist through adulthood. Second, although hormone measures were used to verify that assessments of mid-follicular and mid-luteal phases were correctly timed, the current study did not include other biological indicators of menstrual cycle phase and relied on day count to time menstrual phases. Therefore, it's possible that women were in other distinct hormonal periods of their follicular and luteal phases, which may have diluted the findings and limited our ability to see menstrual cycle effects on the ERN and checking symptoms. Accurate tracking of menstrual cycle phases can be done utilizing ovulation kits, which often involve urine sampling ( Poromaa et al., 2014). Future studies may wish to employ multiple biological measures of menstrual phase to confirm accurate timing of assessments. Third, a limitation of the IDAS-II checking subscale is that the scale consists of only three items. Therefore, in addition to utilizing this or other scales of checking symptoms, future studies might consider incorporating a behavioral measure of checking propensity to allow for a multi-method assessment approach. Finally, the present study examined continuous checking symptoms in a non-clinical sample, and thus it will be important for future studies to examine the relevance of these findings in clinical samples.

In conclusion, the present study examined the impact of menstrual cycle phase and ovarian hormones on the ERN and checking symptoms and found that a more negative ERN was associated with greater checking symptoms in the mid-luteal phase of the menstrual cycle, even when controlling for ERN amplitude in the mid-follicular phase. Also, greater changes in checking symptoms between phases were associated with greater changes in the ΔERN between phases. Finally, the ΔERN in the mid-luteal phase mediated the association between progesterone levels and checking symptoms in the mid-luteal phase. Collectively, our findings suggest that the ERN and checking symptoms may be impacted by naturally-occurring hormonal variation related to the menstrual cycle, and that these hormonal changes may impact the severity of checking symptoms by modulating neural mechanisms associated with response monitoring and sensitivity to errors.

Highlights.

Larger error response (ERN) related to greater checking symptoms in the luteal phase.

Change in ERN and checking symptoms between menstrual phases were correlated.

Luteal ERN mediated links between luteal progesterone level and checking symptoms.

Hormonal fluctuations may impact checking symptoms via neural sensitivity to errors.

Acknowledgments

This work was supported by the following grant: NIMH T32 MH 093311.

Footnotes

Declarations of interest: none.

¹

To correct for our number of t-tests and correlations, which consisted of 16 tests, we have employed the Benjamini-Hochberg step-up procedure ( Benjamini & Hochberg, 1995) with a false discovery rate of .15. All comparisons and associations reported as significant survived this correction.

As with the original submission, there are no conflicts of interest to report.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

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Abstract

Transgender and gender-diverse (TGD) menstruators are individuals assigned female at birth (AFAB)*, who retain the capacity to menstruate and have a gender identity that differs from their natal sex. Reports indicate up to 1.6 million individuals in the US identify as TGD. Until recently, the mainstream menstrual discourse has failed to capture the experience of transmenstruators. However, a better understanding of the menstrual experiences of TGD-AFAB will allow for more individualized patient-centered care. In this review, we provide the relevant data necessary to inform the psychiatric management of menstruation in TGD-AFAB individuals, including experiences of menstruation, preferences for menstrual management, and the impact on mental health. Our review indicates that menstrual care in TGD patients must be tailored to the individual; clinicians should remain open-minded to the unique experience of transmenstruators; gender-affirming menstrual care is necessary to reduce psychological burden. It should not be assumed that TGD-AFAB menstruators are utilizing appropriate contraceptive methods and should receive contraceptive and fertility preservation counseling. We highlight the importance of having these conversations early in the reproductive arch, even before puberty onset. Keeping in mind the gender minority stress model, in the upcoming sections, we discuss the limited body of literature on mood disorders in TGD-AFAB individuals who menstruate, undergo menstrual suppression, or continue to ovulate. The psychological impact of hormonal therapies is also reviewed.

Keywords: menstruation, transgender, transmen, mood disorder, gender diverse, menstruator, gender dysphoria

1. Introduction

Earlier estimates based on population-based surveys approximated that 0.3-0.6% of the United States population, or 1 million people, identify as transgender; however recent reports indicate that figure may be closer to 1.6 million ( 1, 2). Similarly, the DSM-V documents the prevalence of gender dysphoria as 0.005-0.014% for those assigned male at birth, and 0.002-0.003% for adults assigned female at birth, with recent reports indicating increasing numbers ( 3). Still, there is a lack of familiarity and competency around the medical and mental health needs of TGD individuals. According to the 2022 US Transgender Survey (USTS), amongst 92,329 respondents, 38% identified as nonbinary, 35% as transgender women (transwomen), and 25% as transgender men (transmen) ( 4). Of those respondents, 24% did not seek medical care, and 48% reported at least one negative experience due to their gender identity, including being misgendered; being refused care; being addressed with harsh or abusive language; or being subjected to physically rough treatment ( 4). Seelman et al., 2020 found that in the 2015 USTS, 54% of transmen found their routine healthcare providers knew very little ("nothing" or "some things") about trans-related care ( 5).

Although some TGD individuals undergo medical transition, many do not ( 6). A social transition is when an individual changes their appearance and pronouns. A legal transition involves legally changing one's name and documents to reflect this and their identified gender. Medical transition may involve gender-affirming hormone therapy (GAHT) and/or gender-affirming surgery. In TGD-AFAB individuals, common gender-affirming surgeries include masculinizing chest surgery (i.e., mastectomy), body contouring, and metoidioplasty, as well as non-surgical chest binding. Masculinizing GAHT in TGD-AFAB individuals is usually continued lifelong to maintain virilization independent of genital surgery. Testosterone is the mainstay of masculinization, which aims to induce secondary sex characteristics and suppress feminine physical features, and in most cases causes amenorrhea. At least 80% of TGD individuals have either taken, tried, or wanted to take GAHT at some point ( 7). Gender nonbinary or gender non-conforming individuals who do not identify as transgender may take hormones to develop more masculine sexual secondary characteristics. Although some gender-affirming treatments include a hysterectomy or oophorectomy, many TGD-AFAB menstruators wish to maintain their reproductive organs and childbearing potential ( 8- 11).

Compared to other medical specialties, psychiatry has had a more fraught relationship with the TGD community. The Diagnostic and Statistical Manual of Mental Disorders (DSM) 3rd and 4th editions, for example, conceptualized gender identity disorder (GID) as pathologic. Although GID was subsequently reclassified as gender dysphoria ( Supplementary Table 2) in DSM-V ( 3), literature continues to indicate a higher prevalence of mental health disorders among transgender individuals compared to the general population or cisgender individuals. TGD people experience a two-fold higher risk of receiving a psychiatric diagnosis compared to cisgender people and are diagnosed with a mood, anxiety, or psychotic disorder, with odd ratios of 1.5:1, 3.9:1, and 3.8:1 respectively ( 12). These disparities can be understood through the minority-stress framework, which describes the complex interaction between majority (cis-gender) and minoritized groups (transgender and nonbinary) communities.

Building on this, we aim to provide a comprehensive review of the experiential and clinical data necessary to inform the care of TGD-AFAB individuals. We review the gendered history of menstruation; the value of gender-inclusive menstrual dialogue; guidelines for transgender health around menstrual suppression, fertility preservation, and contraceptive counseling; and elucidate the interplay between gender dysphoria, menstruation, and hormone-related mood disorders in TGD-AFAB individuals.

2. Methods

We searched PubMed from March to July 2024 without date limitations for studies of TGD menstruators. We did not utilize any language restrictions and included historical and contemporary terms related to gender identity such as "transgender", "transgender diverse", "transmen", "menstruators", "assigned female at birth", "nonbinary", and "gender diverse". We utilized similar terms through Google to locate magazine articles, books, government announcements, and websites.

3. Historical and social considerations

Menstruation is a biological process that is steeped in historical significance. In Greek mythology, menstrual blood is referred to as "the supernatural red wine," conferring "miraculous power" to the gods ( 13). In Ancient Rome, menstruators were also thought to have "great powers," and menstrual blood was recommended as a treatment for illnesses of all kinds, including rabies, malaria, and epilepsy ( 13). Many indigenous tribes emphasize the strength of menstruators and menstruation itself. The Cherokee Nation of Oklahoma believes that menstruation is powerful, a source of feminine strength, and a destructive force against evil and enemies ( 14). In Cherokee mythology, Stoneclad, a cannibalistic monster was undefeated by warriors until he was in the presence of seven menstruating virgins who took his strength away ( 13). To channel the power of menstruators, Cherokee men would also practice bloodletting before games and battles ( 14).

Menstruation has also been invoked as evidence of women's inferiority, a notion that dates as far back as Aristotle ( 15). In biblical Jewish culture, menstruating women were required to remain separate from men for the duration of their menses. Orthodox Jewish women continue to use the ritual bath (mikvah) following menstruation and before engaging in intercourse after menses. The Roman Catholic Church of Thirteenth Century Europe perpetuated the "stigma of menstrual uncleanliness ... [and] perceptions of menstrual blood as vile and polluting," encouraging women to refrain from taking Holy Communion while menstruating ( 16). In Islamic culture, menstruating women are unable to pray, enter mosques, or touch the Quran; they are required to clean themselves through a spiritual bath (ghusl) each time menses concludes ( 17). Additionally, if menstruating, they are barred from completing the final ritual of Hajj, Tawaf-ul-Ziyarah, which involves circumnavigating the Kaaba to commemorate the end of the annual pilgrimage to Mecca ( 17).

By suggesting that menstruation was not a signifier of shame or weakness, but rather something that could be "managed," the feminist movement of the 20 th challenged the historical menstrual and reproductive rhetoric and through the lens of women's empowerment, moved conversations around menstruation into the mainstream ( 18). More recently, conversations around menstruation have come to encompass an even wider range of perspectives, including those of transgender and non-binary menstruators. Kosher et al. (2023) refer to this as "the plurality of menstrual experiences," encapsulating the increasingly common viewpoint that "not all women menstruate, and not all menstruators are women'' ( 19, 20). Said differently, menstruation is a deeply nuanced and subjective experience for TGD-AFAB individuals ( 21, 22).

While the experience of menstruation among TGD individuals is conventionally understood as "the individual who was AFAB; identifies with masculinity; experiences intense dysphoria around menstruation because it is gendered feminine; and is actively undergoing intervention to suppress or eliminate menstruation," the reality is much more complex ( 19). Fortunately, data examining TGD-AFAB individuals' attitudes toward menstruation, considerations around menstrual management, and decisions about menstrual suppression are emerging. Chrisler et al. (2016) surveyed 150 TGD-AFAB individuals to examine attitudes toward menstruation and menstrual suppression ( 21). While some respondents expressed a positive view of menstruation, the majority reported "mixed or ambivalent attitudes." Half of the participants reported that they would elect to suppress menstruation if suppression were possible without the use of testosterone. Fifty percent also agreed that "not menstruating would enhance their sense of their masculine identity" ( 21). More recently, Kosher et al. (2023) identified three major themes pertaining to menstruation in the TGD population: 1) dysphoria; 2) tensions between femininity and masculinity; and 3) transnormative pressures ( 19). A 2023 study by Schwartz et al. examined TGD adolescents' (N=129) experiences of menstruation and found that a majority (93%) experienced menstrual-related dysphoria ( 23). A substantial number (88%) were interested in menstrual suppression, with the primary reason being a desire for a complete cessation of menses (97%) and the second to improve menstrual-related dysphoria (63%) ( 23).

Beyond menstrual bleeding itself, the management of menstruation can be a source of distress for TGD menstruators ( 24). Although femininity is neither a predicate for menstruation nor an outcome of menstruation, terms like "feminine hygiene product" or "feminine care" abound in the marketing and sale of menstrual products. Furthermore, TDG-AFAB individuals may experience aversion to vaginal penetration ( 21), and many menstrual products are designed for insertion into the vaginal opening. In 2016, the Thinx period product brand released its Boyshort style underwear with a series of video and print advertisements featuring trans male model, Sawyer DeVuyst. According to Miki Agrawal, Thinx's Chief Executive Officer at the time, the Boyshort was "specifically designed with the trans male menstruating community in mind" and a deliberate step by Thinx to be part of "shifting [public] perspective" on the needs of the trans community ( 25). The introduction of the Boyshort to the period product market also came on the heels of a major shift in Thinx's marketing strategy. Moving away from its original For Women with Periods advertising campaign, Thinx opted for a revised For People with Periods tagline. The goal, Thinx says, was an acknowledgment that menstruation "is not a trait of, nor a defining factor of, a specific gender. It is something that can occur amongst all people'' ( 26).

However, the lack of inclusive period products is just one way in which TGD-AFAB individuals have been impacted by a menstrual landscape designed almost exclusively for cis-gender women. The issue of period poverty for menstruators is an underrecognized public health issue. Broadly, period poverty refers to a lack of access to menstrual education, menstrual products, and facilities that allow for proper menstrual hygiene and disposal of menstrual products ( 27). It also refers to "the increased economic vulnerability menstruating people face due to the financial burden posed by menstrual supplies....[and] costs accrued from pain medication and underwear used during the menstrual cycle ( 28). " Period poverty also contributes to the cycle of generational poverty by adding to the marginalization of menstruators in the form of missed days of work, missed days of school, and diversion of monthly income to meet menstrual needs. TGD-AFAB communities are particularly vulnerable to the impact of period poverty. According to the University of Wisconsin-Madison Institute for Research on Poverty, nearly 34% of transmen and 24% of gender nonbinary individuals live in poverty, compared to 16% of cis-gendered individuals ( 29). In the 2022 USTS, TGD individuals reported facing substantially higher rates of housing instability compared to the general population ( 4).

To address issues of period poverty and menstrual inequity, at least 30 states and Washington D.C. have passed a combined total of 60 bills designed to improve access to menstrual health resources. While laws differ by state, they are generally aimed at improving access and affordability by eliminating sales tax for menstrual products and ensuring free menstrual products are available to individuals in public schools, correctional facilities, and homeless shelters ( 30). However, menstrual product availability in male-designated restrooms has become a topic of controversy in political and public discourse. Events that took place in a Connecticut (CT) High School made national headlines in 2024 after a tampon dispenser, affixed to the wall of a boys' restroom, was torn down. The tampon dispenser was placed in the boys' restroom in response to a relatively new CT state law that mandates public schools to provide free access to menstrual products for students. According to The Connecticut Department of Health "[t]he law was designed to affirm all genders in making empowered decisions about their health, including menstrual health. As a result, the law requires products to be provided in all-gender bathrooms, one men's restroom per school, and all women's restrooms in the building" ( 27).

However, such policies have not been applied uniformly across the United States. Nearly 47% of respondents in the 2022 USTS had thought of "moving to another state because their state government considered or passed laws that target transgender people for unequal treatment (such as banning access to bathrooms, health care, or sports), and 5% of respondents had moved out of state because of such state action" ( 4). In 2023, Florida signed House Bill 1521, barring TGD individuals from using locker rooms or public bathrooms consistent with their gender, highlighting continued barriers to menstrual management ( 31).

Unsurprisingly, research suggests that a majority of TGD-AFAB individuals feel "unsafe" or "very unsafe" managing menstruation in men's restrooms ( 21). The risk of being 'outed' by the use of individually wrapped menstrual products (tampons, pads) appears to contribute, in part, to the preferential use of extended-use period products like menstrual cups, adult diapers, or period underwear ( 21). A study by Lane et al. (2022) also identified public restroom design as a "significant barrier to menstrual management" ( 32). Participants described large gaps between stalls, the "reflective gaze" of the mirrored sinks, high urinal-to-stall ratios, and lack of disposal sites for menstrual products as being some of the most fraught aspects of queer menstruation.

4. Applying consensus guidelines in gender-affirming medical care

A professional body spanning disciplines and geographic regions, the World Professional Association for Transgender Health (WPATH) tasks itself with promoting evidence-based care, education, research, public policy, and respect for transgender health. WPATH is associated with 7 regional organizations: United States, European, Canadian, Asia, Australia, Aotearoa (New Zealand, and Southern Africa. Since the organization's formal inception in 1979, it has iteratively published standards of care (SOC). These documents have served as consensus guidelines and best practice recommendations for professionals caring for transgender and gender-diverse populations throughout the world ( 33). Within the last few years, there has been a shift in European countries with guideline implementation. The National Health Services England released the CASS Report in 2024, closed its Gender Identity Development Service, and recently banned puberty blockers for adolescents ( 34). Sweden, Finland, and Denmark continue to follow similar patterns.

While experiences of and feelings about menstruation among TGD-AFAB individuals are diverse, some may experience an exacerbation of incongruence between gender identity and perception of their bodies during menses. To address this, the most recent WPATH SOC-8 contains recommendations regarding the suppression of menstruation in adolescent and adult TGD-AFAB individuals ( 33). In most, GAHT with exogenous testosterone at adult physiologic doses will precipitate amenorrhea due to the sex steroid's effect on the endometrium, and resultant endometrial atrophy ( 35). However, menstrual suppression with GnRH agonists, combined estrogen-progestin, or progestin-only methods can be indicated, especially in adolescent populations.

WPATH recommends considering menstrual suppression agents in adolescents only once they have reached the early stages of puberty. The Endocrine Society Guidelines from 2017 also recommend against puberty-blocking and GAHT in pre-pubertal children ( 36). Adolescents may wish to halt puberty to further explore gender expression and identity, take time to consider GAHT initiation with testosterone, or use adjunctive agents for breakthrough bleeding during the early stages of initiation of GAHT. Furthermore, if there is a delay in consensus about GAHT among the individual, provider, and/or guardian, menstrual suppression should be considered as an initial step ( 33). Engaging TGD-AFB individuals in conversations about menstrual suppression can also provide a forum to explore readiness for gender-affirming treatment and any associated mental health needs ( 37).

The choice of menstrual suppression agent (between GnRH agonist and progestin-only or combined estrogen-progestin methods more commonly used as contraceptive agents) is dictated largely by the developmental status of the individual, consideration of individual medical risk factors (specifically venous thromboembolism in estrogen-containing methods), potential dysphoria caused by estrogen-containing agents, cost, and availability. While GnRH agonists can delay further progression of puberty and cause the regression of some early secondary sex characteristics, these agents are costly, and not always covered by insurance ( 33). In cases where GnRH agonists are not reasonably available, progestin agents (available as depot injection, oral pill, intrauterine device, subdermal implant) or combined estrogen-progestin agents (available as oral pill, transdermal patch, vaginal ring) can be used. Between 55-97% of transmasculine adults achieve amenorrhea within the first 6 months of testosterone therapy ( 38, 39). Lower rates of amenorrhea have been described in TGD-AFAB adolescents using testosterone (59% at 6 months) and higher success rates with NETA or DMPA monotherapy ( 40). Breakthrough bleeding requires clinical investigation to determine etiology and most commonly requires adjustment of testosterone dosage or additional hormonal intervention. Compared to individuals who initiated treatment with GnRHa at a later age, those who initiated at an earlier age (average age 11) had lower rates of depression, anxiety, suicidal ideation, and suicide attempts ( 41).

Ultimately, a third of TGD-AFAB individuals surveyed desired a hysterectomy, which would obviate the need for pelvic examinations and stop menses ( 5). TGD-AFAB individuals may seek a hysterectomy in response to pelvic pain ( 42). While pelvic pain has a prevalence of 25% among cis-gender women, higher rates have been reported in adult trans cohorts ( 43). In a 2020 cross-sectional survey of 486 AFAB trans participants, 72.2% reported pelvic pain after initiation of GAHT with testosterone, with most pain localizing to the suprapubic region and being characterized as "crampy" in nature ( 44). Additionally, this study found an association of pelvic pain after initiation of testosterone therapy with a personal history of PTSD, continued menstruation, and experiences of pain with orgasm ( 44). In another survey conducted between 2015-2017, 69.4% of respondents reported abdominopelvic pain specifically onset since initiation of GAHT ( 45). All respondents who reported curative treatment of this pelvic pain identified hysterectomy as the treatment method ( 43, 45).

5. Contraception and fertility preservation

WPATH and the Ethics Committee of the American Society for Reproductive Medicine (ASRM) recommend discussing fertility preservation and family planning before initiation of GAHT ( 46). The impact of testosterone on fertility depends on duration and timing of use; if started before puberty and concurrently with puberty blockers, the individual may never develop reproductive function. If GAHT is initiated after puberty, reproductive function can be restored. The use of exogenous testosterone can have lasting effects on fertility ( 43). While testosterone does not affect ovarian reserve, testosterone can induce gonadal suppression through its action on the hypothalamic-pituitary axis, preventing ovulation and follicle development ( 44). Ovarian exposure to exogenous testosterone can cause ovarian capsule thickening, which can also impair fertility ( 45). While most TGD-AFAB individuals on testosterone will achieve amenorrhea and ovarian suppression, it is still possible to ovulate and become pregnant while amenorrheic ( 47). A study of TGD-AFAB individuals on testosterone found evidence of breakthrough ovulatory events by monitoring hormonal levels.

Studies have found that a majority of TGD-AFAB individuals express parental desire and that a quarter fear infertility ( 8, 10, 11). Fertility preservation options include embryo, oocyte cryopreservation, and experimental ovarian tissue banking, which can be used before gender-affirming surgery or the initiation of GAHT regardless of puberty status ( 43). Many TGD-AFAB individuals choose to forgo fertility preservation to avoid delaying GAHT. A majority also report fears that hormone injections and the pelvic procedures required for egg retrievals will worsen gender dysphoria ( 9, 23, 48). Overall, utilization of fertility preservation remains low in TGD communities. In a survey of TGD menstruators referred to a community health clinic in Tel Aviv, Alpern et al. found that while 61.9% wanted a child, only 5.8% accessed fertility preservation ( 9). There are many barriers to access to fertility preservation, including the high out-of-pocket expense of cryopreservation and assisted reproductive technologies and lack of adequate insurance coverage; provider discomfort in discussing fertility preservation with TGD-AFAB patients; fears of discrimination for the transgender parent as well as the child; and legislation barring gender-affirming care ( 9, 11, 35, 43).

Among TGD-AFAB individuals, 30% of pregnancies are unintended ( 47). Therefore, discussing contraception options is imperative, especially given the potential teratogenicity of testosterone. The teratogenic risks of testosterone in animal studies are well documented; however, the literature on human outcomes is sparse. In utero exposure to testosterone can result in abnormal development of genitalia including labial fusion and clitoromegaly, and several hypotheses that these exposures contribute to anorexia nervosa and autism in offspring ( 49). However, a longitudinal pregnancy cohort study failed to confirm this association ( 50). In a sample of 25 TGD-AFAB individuals who were on testosterone prior to pregnancy, 20% were on testosterone for at least some portion of their pregnancies. Among this sample size, rates of fetal anomalies, developmental disorders, or disorders of sexual development were equivalent to rates in TGD-AFAB individuals not on testosterone ( 47). More research is needed to identify long-term neurodevelopmental impacts of perinatal testosterone exposure.

Contraception in this specific population is inconsistently reported; however, estimates are between 20-60% ( 51). Contraceptive methods may be underutilized due to several factors, including the lack of education provided by medical providers, lack of access, as well as the frequent misconception by both transmen and providers that testosterone provides reliable contraception ( 51, 52). Furthermore, the irregular nature of ovulation while on GAHT may make pregnancy harder to anticipate; this places TGD-AFAB menstruators at high risk for unplanned pregnancy, especially coupled with limited access and inconsistent contraceptive use. And just as menstruation can worsen gender dysphoria by the repetitive reminder of natal sex, contraceptive methods, and fertility preservation may too ( 48). Oral Contraceptive Pills (OCPs) are marketed to women and can serve as daily reminders of anatomy; longer-term options, such as IUDs are invasive, painful, and require a pelvic exam and manipulation, exposing transmen to dysphoria-based discomfort. Other barriers to contraceptive use include concerns that hormones from OCPs can counteract the effects of testosterone by increasing sex hormone-binding globulin which binds to testosterone ( 51).

6. Psychiatric and psychosocial considerations

In understanding mood disorders among TGD-AFB individuals, we consider biological and psychosocial contributors. Biologically, GAHT with exogenous testosterone in TGD-AFAB individuals is known to increase total brain volume, total gray matter volume, thalamus volume, and cortical thickness, specifically in frontal and parietal brain areas ( 46, 47, 52). Kiyar et al. (2022) found that the neural profile of TGD individuals assigned male at birth (AMAB) shifted from natal sex to their gender identity after 6-10 months of GAHT on fMRI. This confirmed that total testosterone is involved with the neural processing of emotions ( 51). However, it remains unclear how testosterone-driven neural profiles change with menstrual-related mood disorders.

The gender minority stress model outlines psychological processes that ultimately lead to mental health conditions and mood disorders ( 49). Chronic exposure to gender-based rejection; gender victimization; lack of gender affirmation; violence targeting TGD individuals; and legislation barring gender expression leads to the internalization of negative self-concept, fosters negative anticipation of upcoming experiences, and delays engagement in gender-affirming care. Internalization of negative self-concept may also contribute to gender dysphoria and a variety of mental health conditions ( 49).

6.1. Premenstrual disorder and premenstrual dysphoric disorder

There is limited data on premenstrual disorders amongst TGD-AFAB individuals as this population is often excluded from studies about menstruation ( 50). PMD symptoms are categorized as predominantly physical, emotional, or mixed ( 48). The prevalence rate of PMD among cisgender women is estimated at around 20-40 %, with around 5% of cisgender women experiencing PMDD, a severe form of PMD that was added to the DSM-V in 2013 ( 48, 53). An exclusion criterion of PMDD is an exacerbation of an underlying psychiatric disorder, which can include gender dysphoria. Undoubtedly, comorbid gender dysphoria and the inherent worsening of dysphoria for many TGD-AFAB individuals with the onset of menses complicates the diagnosis of underlying PMDD ( 50). Despite diagnostic challenges, anyone with a menstrual cycle, including a TGD-AFAB person, is susceptible to PMD and PMDD.

6.3. Post-traumatic stress disorder, post-traumatic stress symptoms and discrimination

TGD individuals report higher rates of exposure to traumatic events, including abuse in childhood, physical assault, intimate partner violence, and sexual assault ( 63- 65). They also experience pervasive discrimination, discrete traumatic events linked to discrimination, and anti-TGD bias ( 66). In a national sample, up to 63% of TGD individuals reported discriminatory events leading to eviction, job loss, losing stable housing, denial of medical care, or losing an intimate relationship ( 67). Despite this, the wide range of PTSD prevalence within the TGD community suggests that there may either be varying detection strategies for PTSD or an over-pathologizing of responses to trauma and discrimination. Studies linking symptoms to specific traumatic events found lower rates of PTSD diagnosis when compared to studies that assessed PTSD symptoms generally ( 64, 65, 68, 69). Given this, it is important to delineate trauma from discrimination in TGD individuals, as conflation of the two may result in over-pathologizing responses from discrimination-based psychological distress ( 66).

6.4. Bipolar disorder, mania

There is limited to no data to guide the management of bipolar affective disorder in patients undergoing GAHT. Studies that associate manic symptoms with exogenous testosterone are often reported in cisgender men with supraphysiologic levels of anabolic androgenic steroids ( 70, 71). This contrasts with GAHT in TGD-AFAB individuals, where the dosing of testosterone targets physiologic levels. There is limited data on the association of mania in transmen with exogenous testosterone administration ( 36). Thus far, there is no data to indicate that appropriate GAHT dosing of testosterone would lead to an induction of mania, but close monitoring during testosterone initiation in at-risk individuals is warranted.

6.5. Psychosis

Current literature indicates an increased prevalence of schizophrenia spectrum disorders and psychosis amongst TGD individuals ( 72). In a review of 254 million discharges in the United States National Inpatient Sample database in 2019, Hanna et al. (2019) found that 14.5% of TGD patients were diagnosed with psychosis, compared to 4.3% of cis-gendered patients, and 14.2% of TGD patients were diagnosed with schizophrenia, compared to 2.8% of cis-gendered patients ( 57). In their literature review, Barr et al. (2021) found variability in the reported rates of psychotic illness among TGD individuals, which they attributed to varying recruitment strategies, racial bias in diagnosis, and demographic differences, as TGD study participants were on average 17 years or younger ( 72). Through a cohort study examining birth certificates and national insurance data in the Netherlands from 2006-2020, Termorshuizen et al. (2023) found that of 5,564 TGD individuals, the TGD-AFAB cohort was substantially more likely to be diagnosed with a non-affective psychotic disorder when compared to TGD-AMAB ( 73). They also found that up to 50% of TGD individuals were diagnosed with psychosis after the first registration of data indicative of TGD status, and up to 83.7% were documented at the same time ( 73). These results, coupled with the historical classification of gender dysphoria as symptomatology within the realm of psychotic spectrum illness, suggest a continued risk of diagnostic bias of psychosis amongst TGD individuals.

6.6. Aggression

Although WPATH SOC Version 7 listed destabilization of psychiatric disorders as a potential side effect of testosterone, this was removed in WPATH SOC Version 8 ( 33). There is no documented consistent association or correlation between anger and serum testosterone levels; however, if irritability, mood changes, or anger do occur, these symptoms are more likely during the first year of initiation of GAHT ( 74, 75). Of the literature linking anger expression with testosterone in TGD-AFAB individuals, there was no increased risk for psychiatric hospitalization or self-harm ( 76, 77). Self-report measures of irritability and aggression decreased after gender-affirming surgical intervention, perhaps reflecting a decrease in depressive symptom burden ( 78). If mood changes occur with testosterone treatment, then it may be helpful to consider dose adjustments; changing from short-acting to long-acting intramuscular injections, or changing to gel formulations ( 79).

7. Age-related considerations

Despite the expectation that the number of Americans aged 65 and older will surpass children in 2023 and an estimation of at least 700,000 senior TGD individuals, there is limited literature on older TGD individuals in the United States ( 88). Most data and knowledge about TGD individuals come from European cohorts, with a larger proportion documented as transgender women. Under-representation of TGD-AFAB seniors in the literature makes it difficult to determine the long-term impact of hormonal and GAHT interventions on TGD-AFAB menstruators ( 89, 90).

Studies on cis-gendered individuals with a prostate, and post-menopausal women on hormone replacement therapy (HRT) suggest that sex hormones can be neuroprotective and improve cognition ( 91, 92). Cognitive changes in menopause are believed to be related to decreased estrogen availability, and androgen receptors in the hippocampus and prefrontal cortex ( 93). However, it remains unclear if these studies can be extrapolated to TGD-AFAB menstruators.

Data drawn from health insurance companies and ICD codes indicates TGD individuals had a statistically significant elevated probability of being diagnosed with dementia when compared to cis-gendered individuals ( 94). Furthermore, TGD-AFAB individuals aged 45+ who identified as ethnically minoritized reported more memory loss and confusion in the past year when compared to their cis-gender counterparts ( 95). It is important to note that these studies combine transgender men and women, and often do not ask further questions about non-binary and fluid identities.

When gender identity is parsed out, the findings change. Heesewijk et al. (2023) found that transgender men had an increased risk of dementia compared only to cis-gender women; later research in 2021 found that transgender men had a similar cognitive functioning profile when compared to cisgender men and cisgender women ( 96). It has been theorized that the reported increased rate of dementia may be associated with delayed gender affirmation, repeated dysphoric episodes when menstruating, as well as limited social support ( 97).

Currently, a link between GAHT and impaired cognition has not been consistently described in the literature ( 97). Although there is little to no published literature on lifestyle factors impacting cognitive decline in TGD-AFAB individuals, when compared to cis-gender people, there is an overall increased prevalence of known risk factors, including higher rates of cigarette and alcohol consumption and lower physical activity ( 97). A higher burden of depressive symptoms may also impact cognition; rates of clinically significant depressive symptoms in older transgender individuals have been reported as high as 48%, which is pointedly higher than the general population of 6-8% ( 98, 99).

8. Conclusions

The language of TGD healthcare continues to evolve towards improving inclusivity. Medical providers should engage patients in discussions about their gender identity, how they relate to it, and what it means to them, as it can vary greatly. An example is the variability of preferred pronouns- she/her/he/him/they/them. WPATH guidelines recommend providers use active listening to encourage exploration in those uncertain about their gender identity. Rather than impose their narratives or preconceptions, providers should assist people in determining their paths. These conversations should also include the changing legislation for TGD-affirming care. Supplementary Table 4 provides examples of how to address topics discussed in this review.

Limitations to our review include an emphasis on North American data and Euro-centric experiences. To extrapolate this to other cultures and ethnicities requires sensitivity to their specific identities and contexts. There are also significant limitations in the current global literature on TGD-AFAB individuals. Survey language often omits TGD-AFAB as a gender category or groups all TGD individuals into one category, which excludes the diversity and spectrum range of gender. This has led to limited literature on the impact of menstruation, menstrual-related disorders, pregnancies, fertility, and exogenous testosterone exposure among TGD-AFAB individuals.

Our review indicates that the WPATH SOC-8 has moved beyond a focus on surgery and hormones, now including sexual, reproductive, mental, and primary health care services. There remains a need for additional research on the reduction of barriers to OBGYN care, contraception, and fertility preservation in TGD-AFAB individuals. These barriers can be addressed through their inclusion in medical, psychiatric, and menstruation-related research, as well as in medical, graduate, and residency-level curricula. Doing so may allow more comfort in treating this increasingly prevalent patient population.

Funding Statement

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Author contributions

AA: Conceptualization, Writing - original draft, Writing - review & editing. SM: Writing - original draft, Writing - review & editing. SP: Writing - original draft, Writing - review & editing. MA: Conceptualization, Supervision, Writing - original draft, Writing - review & editing. AD: Conceptualization, Supervision, Writing - original draft, Writing - review & editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2024.1422333/full#supplementary-material

References

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Supplementary Materials

Articles from Frontiers in Psychiatry are provided here courtesy of Frontiers Media SA

# data[].attributes.attachment_link.title
Menstrual management in transgender and gender diverse individuals: psychiatric and psychosocial considerations

# data[].attributes.attachment_link.description
Transgender and gender-diverse (TGD) menstruators are individuals assigned female at birth (AFAB)*, who retain the capacity to menstruate and have a gender identity that differs from their natal sex. Reports indicate up to 1.6 million individuals in ...

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Premenstrual Dysphoric Disorder (PMDD) is a severe negative reaction in the brain to natural changes in hormone levels in people who menstruate (have periods)

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It is quite normal for people to compare themselves to others, especially when they are growing up. Humans are social animals, so we seek connection with other people.

Autistic brains work differently to non-autistic brains and we have different ways of communicating and expressing ourselves. Non-autistic people can find it a bit surprising if someone acts in ways that they're not used to. Sometimes, they might laugh at us, or point out these differences. Autistic young people are unfortunately more likely to be bullied because of this.

We may be taught that, in order to 'fit in' we must hide who we are and pretend to be like the people around us. To do that, a lot of autistic people can become very good at observing and imitating those around us. This is called 'masking'. The more unsafe we feel, the more we are likely to mask. If our attempts keep failing, we may withdraw from social situations altogether.

Sometimes autistic people aren't aware and mimic others subconsciously. We may also hide our feelings and pretend we're fine when we aren't. Most autistic people who mask aren't aware that not everyone does this - they think everyone is pretending as part of the social rules. Many of us will have been doing it from a very young age, so it can become almost automatic - but it is not natural for us.

Masking involves us closely observing others; translating their words, tone, mannerisms and body language into something we understand; considering how we want to respond and then finally translating that into something we think they are most likely to respond well to. We might not realise it, but this takes a huge amount of energy and concentration. If we're having a more stressful day, or something has gone wrong, we can find it much harder to mask and might find ourselves reacting to situations in ways that feel more natural to us. If we've been working really hard to 'fit in' and then the mask slips, we are often very hard on ourselves. "Why can't I just be normal?" We can start to feel quite down on ourselves and this can be hard to recover from.

Masking can keep us safe, certainly in the short term. But many people who mask will eventually reach a point where the effort causes burnout and masking is no longer possible.

Masking also stops genuine connection with others because others only get to know the mask and not the real person underneath.

Some people may choose to mask in certain situations, where connection isn't important but safety is. And some may not realise that masking is what's preventing them from creating genuine connections, and not understand that masking is preventing them from forming deeper friendships.

Many autistic people go through a process of " unmasking" once they have received their diagnosis. They recognise that masking a lot is actually quite harmful, and being around people who accept them as they are, without the need to mask, is the best way forward.

Writing led by Matthew Harrison, autistic adult and staff neurodiversity representative at The University of Manchester

What masking feels like for me

I definitely feel a lot better and I can be myself at home. I really can't be myself when I am not at home, I just can't it's hard.

Teachers don't know how I feel, no, no I don't think so.

Masking is when you hide how you feel, when you try to hide yourself.

I don't think masking is a good thing, but when I have tried to tell teachers how I feel one has just laughed and said you need to line up over there. When I looked sad a lot of people said hi to me to try to make me happy, I pretend to be happy and say hi back, but all the attention makes it bad.

If people speak to me when I am out I can't say what I want to say, I wish I could.

People would be surprised if they knew what I wanted to say, but also I would get scared if they knew.

If my friends knew how I felt, I worry they wouldn't be my friend because I'm trying to hide my feelings, this happened once.

If I could say what I wanted I would say to people who don't believe me and think I am OK, it would be, I am not well, I may not be physically ill but I am mentally ill.

The worst I have ever felt was going into school and being forced onto the stage in front of strangers for Harvest Festival, I was really scared, they gave me lines and I was forced to read it in front of them, I was really scared but I tried my best, I felt really embarrassed I don't know how badly I stuttered. Afterwards I had to serve food to other classes and then to strangers and give them soup, it was so loud, I had to eat soup but I hate soup. I tried to act happy so I wouldn't get attention, because teachers and friends would ask me a lot of questions which would make everything a lot worse, I don't like being asked questions.

Things are now getting better, but not completely, I can you know, I can share my feelings with some people and my parents.

What's changed, definitely not going back to school anymore, it was just really loud there. I would tell parents, if your child is really bad and can't manage at school move to home education because I find it a lot easier to talk to my parents than teachers. Being at home is giving me a chance to have some practice and I am managing to be myself and talk to people outside of the house.

I hope this helps other children in school who are struggling.

Written by C, age 9

Facade

This drawing is called Façade and it represents masking. Me and many other autistic people feel like we need to camouflage to fit in with our surroundings, just like the leaf insect, but it's important for us to know that we're incredible just the way we are. We are the colour and difference that the world needs.

By Hannah, autistic young person

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WHile masking can help autistic people feel safe, it will eventually lead to the point where the effort can cause burnout and masking isno longer possible.

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Belle’s App is your health ally in managing PMDD. Understand PMDD, monitor your symptoms, and receive tailored guidance.

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We're here for all of it.

Yesterday

Give a warm welcome to your period. (*slow clap.*) Levels of estrogen and progesterone are low. Your skin and stomach might misbehave. This too shall pass.

Today

Rising estrogen levels mean increased cerebral firepower. Start planning your next vacation. Or your next snack. Honestly, anything.

Last week

You are ovulating today. Thy egg hath been released. Idea: Give yourself an Ovulation Vacation. Prepare a tropical drink with a mini umbrella! Take the day off work. Your body worked hard to get here and you deserve a little treat.

Next week

The elevated progesterone continues, leading to food carvings. Go HAM on some ham. Or a vegetarian substitute. Or whatever feels necessary for your wellbeing.

Stardust is a free cycle tracking app that integrates science, ancient wisdom, astronomy and artificial intelligence to help you find contentment, manifest goals, and befriend your body

Learn how to work with your hormones, not against them

Understand seismic shifts in your mind, body and spirit with personalized trends and insights about your cycle

Track all the fun symptoms

Sync cycles with friends

Dive deeper into the folklore and magic of your own menstrual-lunar synchronicity

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We're here for all of it. Give a warm welcome to your period. (*slow clap.*) Levels of estrogen and progesterone are low. Your skin and stomach might misbehave. This too shall pass. Rising estrogen levels mean increased cerebral firepower. Start planning your next vacation. Or your next snack. Honestly, anything.

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We all have bad experiences at times, and usually we can move on from these experiences sometimes with a bit of help from others, for example by talking about what happened or finding a way to make ourselves feel safe again.

Sometimes the feelings we have during these difficult experiences can stay in our bodies, which means that every time something reminds us of them we feel the same things again. These reminders might be going to the same place, something sensory such as a sound or a smell, or anything really. It's important to know that we might not always be aware of these reminders, all we may know is that we don't feel safe.

Things that result in these traumatic memories can be one off events that make us feel unsafe and like our life might be in danger, or it can be lots of repeated things that might feel small by themselves but over time they make us feel unsafe.

An example of this can be feeling like you have to mask who you really are, which sometimes people do at school, home or in other places. Always worrying about what people might think about you or that they might reject you, can lead to feeling unsafe and this feeling gets stored in your nervous system.

School trauma is something that people are becoming more aware of, but it might be that adults around you didn't know much about this if school is something you have found hard. Things that can be difficult at school include:

behaviour systems, especially those that don't seem fair

sensory overwhelm from all the noise, lights and people, are very difficult to explain to other people - especially because it often looks as though everyone else is happy.

The first thing to know about trauma is that it completely makes sense. Our brains and nervous system are designed to keep us safe so if something does remind us of a time when we felt threatened they react to protect us by using fight, flight, freeze or fawn responses. So someone might argue, run away, hide or be very quiet and do everything they can to make sure they don't get into trouble. If you sometimes do these things and then afterwards you don't really understand why, then please reassure yourself that your survival response is doing its job to look after you.

However sometimes these responses happen when you don't want them to. For example, you might find new adults make you feel unsafe because of previous experiences and it is making some situations difficult. Maybe it means you don't feel comfortable at a club you really want to take part in. It's up to the adults around you to understand why you might feel this way and to work with you to find ways to help you feel safer. It's important to note here that even if they know you are safe, it's how you actually feel that matters.

Trauma memories can be processed and you can learn to feel safe in different situations. Ways to help with this include stopping the traumatic thing from happening. For example not going to school might mean you can be with people you can be yourself with and therefore not have to mask as much.

Processing your traumatic experiences can mean telling someone what happened, writing it down, or talking to other people who have similar feelings to you. If you can, start by telling someone you trust about some of these experiences, but only when you feel comfortable to do this.

The Mind is a Muscle

Most of the organs in our bodies function automatically. But we choose when to use our muscles, how long we use them for and how intensely we use them.

It is the same with our minds. We choose when, how hard and for how long we put them to use.

Just like a muscle, the mind can become tired and work less effectively, which means it needs rest to get back to normal. If a muscle works too hard, it can become worn down.

In the same way, our minds can become worn down either by a single, huge thing that happens, or through lots of small things over time, without having enough recovery time.

Things you used to find easy may become harder and you may want to do things, but feel unable to. This can be a really upsetting and difficult experience.

When this happens, it is really important to have time to recover, as trying to do more usually makes things worse.

There are some things that may have led to this happening which can be avoided in the future, by doing things like:

Stopping contact with people who you aren't comfortable around.

Agreeing with your parents that they won't make you go back to school, even if you start to feel happier.

Making an agreement with the people around you that they will let you quit things without asking 'Are you sure?' and without giving you a lecture about giving up too easily.

But there may also be some things you need to not do for now, which you can come back to when you are ready:

Not having people you don't know well or feel comfortable around coming into your home.

Reducing demands in your life. Demands can range from doing activities you regularly take part in, to family visits, to doing chores.

Deciding not to do so many GCSEs in one go

Deciding things need to change at school before you go back. This could also mean looking for a different school that supports you better, or looking into other forms of education.

When you are recovering, it is really important to spend time doing things you enjoy, giving yourself enough time off to recover from activities and spending time with people who help you feel good about yourself.

Written by Simon Cramer, autistic adult

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Trauma and the body and brain's responses to it makes complete sense. Help processing memories and learn to feel safe in different situations.

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Rational anxiety and what to do to help. Irrational anxiety ad what to do to help. Common reasons for anxiety in autistic people.

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Autistic burnout is like a phone that has run out of battery. Even if you need to make a phone call, you are no longer able to. You have no energy left and can become quite stuck.​Burnout happens when: * Your tasks/ expectations in the day exceed the resources you have to deal with them (i.e.

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Autistic people often describe what is known as the ‘Double Empathy Problem’. The double empathy problem explains that being autistic is not the wrong way of being, it is simply different. Because of differences in how our brains function, autistic people may struggle to understand non autistic people, and non autistic people struggle to understand autistic people. In non autistic society, autism can be seen as a negative thing/ something to change or fix. But we learn a lot about autism in spac

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Masking can look like:

"They are fine at school"

"I masked when I was in school as I was desperate to fit in. This took so much energy that by the time I got home I had nothing left, I would barricade my room shut and play games to escape from the world and to try and recharge energy to survive the next day. Sometimes, my mum said something as small as 'how are you?' and I would shout and scream. I felt horrible about this, but I realise now it is because I was so stressed I wasn't even able to process questions anymore." - Autistic adult

"This drawing is called Façade and it represents masking. Me and many other autistic people feel like we need to camouflage to fit in with our surroundings, just like the leaf insect, but it's important for us to know that we're incredible just the way we are. We are the colour and difference that the world needs." - By Hannah, Autistic Young Person.

Information for young people on the topic of masking can be found on our Autism Understood website > here <

"I masked when I was in school as I was desperate to fit in. This took so much energy that by the time I got home I had nothing left, I would barricade my room shut and play games to escape from the world and to try and recharge energy to survive the next day. Sometimes, my mum said something as small as 'how are you?' and I would shout and scream. I felt horrible about this, but I realise now it is because I was so stressed I wasn't even able to process questions anymore." - Autistic adult

"This drawing is called Façade and it represents masking. Me and many other autistic people feel like we need to camouflage to fit in with our surroundings, just like the leaf insect, but it's important for us to know that we're incredible just the way we are. We are the colour and difference that the world needs." - By Hannah, Autistic Young Person.

Information for young people on the topic of masking can be found on our Autism Understood website > <

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Masking is when someone tries their best to fit in and go unnoticed by others. It can become an automatic, natural way of being, meaning autistic people can sometimes mask without actually knowing it. Masking can be a stressful experience.

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The PMDD Collective aims to raise awareness and provide support for those impacted by PMDD

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There may be mental health support groups in your local area

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The Bidirectional Relationship of Depression and Inflammation: Double Trouble

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Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established that dysregulation of both the innate and adaptive…

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The bidirectional relationship between anxiety disorders and circulating levels of inflammatory markers: Results from a large longitudinal population-based study - PubMed

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The prospective association between agoraphobia at baseline and hsCRP levels over the follow-up period suggests that chronic low-grade inflammation may be a consequence of this condition. The decrease in IL-6 in PTSD also requires further investigation. No evidence was found for chronic low-grade in …

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Abstract

Although anxiety disorders, like depression, are increasingly being associated with metabolic and cardiovascular burden, in contrast with depression, the role of inflammation in anxiety has sparsely been examined. This large cohort study examines the association between anxiety disorders and anxiety characteristics with several inflammatory markers. For this purpose, persons (18-65 years) with a current ( N=1273) or remitted ( N=459) anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and healthy controls ( N=556) were selected from the Netherlands Study of Depression and Anxiety. In addition, severity, duration, age of onset, anxiety subtype and co-morbid depression were assessed. Inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6 and tumor-necrosis factor (TNF)-α. Results show that after adjustment for sociodemographics, lifestyle and disease, elevated levels of CRP were found in men, but not in women, with a current anxiety disorder compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l −1, P=0.04, Cohen's d=0.18). No associations were found with IL-6 or TNF-α. Among persons with a current anxiety disorder, those with social phobia, in particular women, had lower levels of CRP and IL-6, whereas highest CRP levels were found in those with an older age of anxiety disorder onset. Especially in persons with an age of onset after 50 years, CRP levels were increased compared with controls (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l −1, P=0.01, Cohen's d=0.37). In conclusion, elevated inflammation is present in men with current anxiety disorders. Immune dysregulation is especially found in persons with a late-onset anxiety disorder, suggesting the existence of a specific late-onset anxiety subtype with a distinct etiology, which could possibly benefit from alternative treatments.

Keywords: anxiety disorder, anxiety characteristics, cohort study, inflammation

Introduction

Anxiety disorders are among the most prevalent and disabling mental disorders.1, 2 Increasing evidence links anxiety to cardiovascular risk factors and diseases such as atherosclerosis,3 metabolic syndrome,4 and coronary heart disease.5, 6 As low-grade systemic inflammation is clearly involved in the etiology of these somatic conditions,7, 8, 9 it has been hypothesized that inflammation has a role in anxiety disorders and may form the link between anxiety disorders and cardiovascular burden.10 Anxiety disorders are also highly co-morbid with depression,11 which has recurrently been associated with immune dysregulation.12, 13 However, unlike depression, very few studies have investigated the relationship between anxiety disorders and inflammation. Two recent studies have correlated anxiety symptoms with increased cytokine levels, in particular C-reactive protein (CRP).14, 15 With regard to anxiety disorders, research has mainly focused on posttraumatic stress disorder, in which high levels of inflammatory markers have been found.16, 17 Sparse evidence from relatively small clinical studies ( n≈100) suggests increased inflammatory activation in patients with panic disorder18 and generalized anxiety disorder,19 which seems to be independent of co-morbid depression.

As there is yet limited research on immune dysregulation and anxiety, one can only speculate on the mechanisms linking these two conditions. Experimentally induced stress has been shown to produce an inflammatory reaction,20 which has led researchers to suggest that it is in particular the experience of acute stress, such as present in panic disorders, causing the high levels of inflammation in anxiety.18 On the other hand, chronic stress may initiate changes in the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, which in turn can trigger depression as well as anxiety.21 These pathways are not independent as the HPA-axis and the immune system are closely linked. Although the HPA axis in normal situations should temper inflammatory reactions, prolonged hyperactivity of the HPA axis could result in blunted anti-inflammatory responses to glucocorticoids resulting in increased inflammation.22, 23 Likewise, it can be hypothesized that immune changes associated with chronic disease and aging,24 could induce similar anxiety-enhancing effects. Although several mechanisms might explain an association between inflammation and anxiety disorders, it can be expected that immune dysregulation is not a general phenomenon in anxiety disorders, but might be restricted to specific subgroups. Whether this anxiety subgroup is defined by the type of disorder, the severity or duration of the disorder, the co-morbidity with depression, or its age of onset, is yet to be examined.

The present study investigates the association between several common anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and heightened inflammation (CRP, interleukin (IL)-6, tumor necrosis factor (TNF)-α) in a large sample of persons with current and remitted anxiety disorders and healthy controls. In addition, it will be examined whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) further discriminate those anxiety patients with elevated inflammation.

Subjects and methods

Sample

The Netherlands Study of Depression and Anxiety (NESDA) includes 2981 persons with and without depressive and anxiety disorders, aged 18-65 years at the baseline assessment in 2004-2007. Participants were recruited from the community (19%), general practice (54%) and secondary mental health care (27%) in order to reflect the broad range and developmental trajectory of psychopathology. Persons with insufficient command of the Dutch language or a primary clinical diagnosis of bipolar disorder, obsessive compulsive disorder, severe substance use disorder, psychotic disorder or organic psychiatric disorder, as reported by themselves or their mental health practitioner, were excluded. A detailed description of the NESDA study design and sampling procedures can be found elsewhere.25 The research protocol was approved by the ethics committee of participating universities and after complete description of the study all respondents provided written informed consent.

During the baseline interview, the presence of anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and depressive disorder (major depressive disorder, dysthymia) was established using the Composite Interview Diagnostic Instrument (CIDI) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.26 The CIDI is a highly reliable and valid instrument for assessing depressive and anxiety disorders27 and was administered by specially trained research staff. In addition, the severity of anxiety was measured in all participants using the 21-item self-report Beck Anxiety Inventory.28 For the present analyses, we selected persons with a current (that is, past 6 months) or remitted (lifetime, but not current) anxiety disorder and healthy controls. Healthy controls had no lifetime anxiety or depressive disorder and a Beck Anxiety Inventory score below 10, as a score of 10 or above indicates mild anxiety.29 Persons with anxiety disorders were allowed to have a co-morbid depression. Of these 2342 persons, 54 were excluded due to missing information on inflammatory markers, leaving a sample of 2288 persons for the present study. Persons with missing data on inflammation were less often female (55.6 versus 66.9%, P=0.08), but did not differ from included persons in terms of age, years of education and the presence of anxiety disorder.

Anxiety characteristics

Next to subtype of CIDI anxiety disorder diagnosis (generalized anxiety disorder, social phobia, panic disorder, agoraphobia), anxiety characteristics included anxiety symptoms severity as measured by the Beck Anxiety Inventory, and anxiety symptoms duration, using the Life Chart Interview (LCI).30 The LCI uses a calendar method to determine life events during the past 4 years to refresh memory after which the presence of anxiety and avoidance symptoms during that period is assessed. From this, the per cent of time patients reported anxiety symptoms was computed. The LCI has been used by other large cohort studies31 and event history calendars such as the LCI have been suggested a natural method of choice for retrospective data collection.32 To be able to test whether inflammation was in particular associated with anxiety disorders with a later onset, as we had found for depression,33 age of anxiety onset was derived from the CIDI interview. Last, the presence of a current co-morbid depressive disorder (major depressive disorder, dysthymia) was taken from the CIDI to check whether a possible inflammation-anxiety association was independent of co-morbid depression.

Inflammatory markers

Markers of inflammation were assessed at the baseline NESDA measurement and included CRP, IL-6 and TNF-α. Fasting blood samples of NESDA participants were obtained in the morning between 0800 and 0900 hours and kept frozen at −80 °C. CRP and IL-6 were assayed at the Clinical Chemistry Department of the VU University Medical Center. High-sensitivity plasma levels of CRP were measured in duplicate by an in-house ELISA based on purified protein and polyclonal anti-CRP antibodies (Dako, Glostrup, Denmark). Intra- and inter-assay coefficients of variation were 5% and 10%, respectively. Plasma IL-6 levels were measured in duplicate by a high sensitivity ELISA (PeliKine Compact TM ELISA, Sanquin, Amsterdam, The Netherlands). Intra- and inter-assay coefficients of variation were 8% and 12%, respectively. Plasma TNF-α levels were assayed in duplicate at Good Biomarker Science, Leiden, The Netherlands, using a high-sensitivity solid phase ELISA (Quantikine® HS Human TNF-α Immunoassay, R&D systems, Minneapolis, MN, USA). Intra- and inter-assay coefficients of variation were 10% and 15%, respectively.

Covariates

Sociodemographic characteristics included sex, age and years of education. As lifestyle characteristics can be associated with both anxiety and inflammation, smoking status (never, former, current), alcohol intake (<1, 1-14 (women)/1-21 (men), >14 (women)/>21 (men) drinks per week), physical activity (measured with the International Physical Activity Questionnaire34 in MET-minutes (ratio of energy expenditure during activity compared with rest times the number of minutes performing the activity) per week) and body mass index (weight in kilograms divided by height in meters squared) were assessed. In addition, several disease-related covariates were taken into account including the presence of cardiovascular disease (assessed by self-report supported by appropriate medication use (see Vogelzangs et al. 6 for detailed description)), the presence of diabetes (fasting plasma glucose level ⩾7.0 mmol l −1 or use of anti-diabetic medication (ATC code A10)) and the number of other self-reported chronic diseases for which persons received treatment (including lung disease, osteoarthritis or rheumatic disease, cancer, ulcer, intestinal problem, liver disease, epilepsy and thyroid gland disease). Medication use was assessed based on drug container inspection of all drugs used in the past month and classified according to the World Health Organization Anatomical Therapeutic Chemical classification.35 Statin use (C10AA, C10B) and use of systemic anti-inflammatory medication (M01A, M01B, A07EB, A07EC) were assessed. Antidepressant medication included regular use (>50% of the time) of selective serotonin reuptake inhibitors (SSRI; N06AB), serotonin-norepinephrine reuptake inhibitors (SNRI; N06AX16, N06AX21), tricyclic antidepressants (TCA; N06AA) and tetracyclic antidepressants (TeCA; N06AX03, N06AX05, N06AX11).

Statistical analyses

Baseline characteristics were compared between men and women using χ ² test for dichotomous and categorical variables, independent samples t-test for continuous variables, and Mann-Whitney U-test for inflammatory markers. For subsequent analyses, CRP, IL-6 and TNF-α were ln-transformed to normalize distributions, but back-transformed values are presented to enhance interpretation. Associations between anxiety disorders and inflammatory markers were examined using analyses of (co)variance, and (adjusted) means across anxiety groups (no, remitted, current) are presented. To take the effects of potential confounding factors into account, three different models were tested: unadjusted, adjusted for sociodemographics (sex, age, education) and additionally adjusted for lifestyle and disease (smoking status, alcohol intake, physical activity, body mass index, cardiovascular disease, diabetes, number of other chronic diseases, statins, anti-inflammatory medication). As depression has been reported to differentially affect inflammation in men and women,33 a sex-interaction for anxiety disorders is plausible. Therefore, we tested sex-interactions by including a sex × anxiety disorder status interaction term. When present, analyses were repeated sex stratified.

To test whether specific anxiety characteristics were related to elevated inflammation levels, we performed linear regression analyses with inflammatory markers as the outcome for each anxiety characteristic (severity, duration, age of onset, subtype, depression co-morbidity) within the sample of persons with a current anxiety disorder.

Results

Mean age of the study sample was 41.8 (s.d.=13.1) years and 66.9% were women. Baseline characteristics of the total sample and for men and women separately are shown in Table 1. Women were younger, more often non-drinkers, had a lower body mass index, less often cardiovascular disease or diabetes and less often used statins than men. In addition, women had higher levels of CRP than men. All covariates were associated with at least one of the inflammation markers, which has been presented elsewhere.33 Pearson's correlations between inflammatory markers were modest (CRP-IL-6: r=0.31; CRP-TNF-α: r=0.13; IL-6-TNF-α: r=0.12; all P<0.001).

Table 1. Baseline characteristics.

Total sample (N=2288)

Men (N=757)

Women (N=1531)

P-values a

Sociodemographics

Lifestyle and disease

Anxiety characteristics

Within persons with a current anxiety disorder (N=1273)

Inflammatory markers

C-reactive protein (mg l −1), median (IQR)

1.20 (0.54-3.00)

1.01 (0.48-2.40)

1.33 (0.57-3.30)

<0.001

Interleukin-6 (pg ml −1), median (IQR)

0.75 (0.49-1.25)

0.77 (0.51-1.31)

0.75 (0.49-1.24)

0.25

Tumor necrosis factor-α (pg ml −1), median (IQR)

0.80 (0.60-1.10)

0.80 (0.60-1.10)

0.70 (0.60-1.10)

0.13

Table 2 shows (adjusted) mean inflammation levels across anxiety groups (controls, remitted, current) based on analyses of (co)variance. In the total sample, higher CRP levels were found in persons with a current anxiety disorder compared with controls in unadjusted analyses (1.36 (s.e.=1.04) versus 1.11 (s.e.=1.05) mg l −1, P=0.001), but after adjustment, there were no associations between anxiety disorders and any of the inflammation markers. However, a significant sex × anxiety disorder interaction was found for CRP (remitted: P=0.57; current: P=0.002). Stratified analyses for CRP showed that even after full adjustment for lifestyle and disease, men with current anxiety disorders had higher levels of CRP compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l −1, P=0.04, Cohen's d=0.18). In women, anxiety disorders were not significantly associated with CRP. No sex interactions were found for IL-6 (remitted: P=0.47; current: P=0.40) or TNF-α (remitted: P=0.92; current: P=0.87). As we have previously reported associations between inflammatory levels and antidepressant use within currently depressed persons,33 we checked the influence of antidepressant use on our current results. Higher levels of CRP were found in TCA/TeCA users within our present sample of persons with current anxiety disorders ( N=1273; P=0.001). To examine whether the finding of elevated CRP in currently anxious men was independent of TCA/TeCA use, we excluded all men using TCA/TeCA ( N=36). Results remained similar, although no longer significant (men with current anxiety disorders versus controls: 1.13 (s.e.=1.05) versus 0.97 (s.e.=1.07) mg l −1, P=0.08, Cohen's d=0.15). In addition, to reduce the possible confounding effects of acute illness on inflammatory levels at the time of blood draw, all persons who reported having had a cold or fever in the week before blood draw were excluded ( N=645), but findings remained alike (men with current anxiety disorders versus controls: 1.09 (s.e.=1.06) versus 0.91 (s.e.=1.07) mg l −1, P=0.06, Cohen's d=0.19).

Table 2. Adjusted mean inflammatory marker levels across anxiety groups.

Controls

Remitted anxiety disorder

Current anxiety disorder

Mean

(s.e.)

P

Mean

(s.e.)

P

Mean

(s.e.)

P

CRP, mg l−1 a

IL-6, pg ml−1 a

Total sample

N=556

N=459

N=1273

TNF-α, pg ml−1 a

To investigate whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) were associated with inflammation, linear regression analyses were performed within the subgroup of persons with current anxiety disorders ( N=1273; Table 3). Anxiety severity and duration did not correlate with inflammation. Later age of anxiety disorder onset was associated with elevated CRP levels ( β=0.053, P=0.05), even after additional adjustment for TCA/TeCA use ( β=0.053, P=0.05). Persons with social phobia had lower levels of CRP ( β=−0.053, P=0.04) and IL-6 ( β=−0.052, P=0.05) compared with persons with other types of anxiety disorders. The association between social phobia and IL-6 appeared to be specific for women ( β=−0.089, P=0.007), but not men ( β=0.025, P=0.61; P sex-interaction=0.05). Co-morbid depressive disorder did not further differentiate anxious persons with elevated inflammation.

Table 3. Associationa of anxiety characteristics with inflammatory marker levels in persons with current anxiety disorders (N=1273).

Anxiety characteristic

Nc

CRPb

IL-6b

TNF-αb

β

P

β

P

β

P

To further illustrate the findings with regard to age of onset, we constructed five age of anxiety disorder onset groups (<20, 20-30, 30-40, 40-50, ⩾50). Figure 1 presents adjusted means of back-transformed CRP levels across controls and age of onset groups based on analysis of covariance. CRP levels were only increased in persons with an age of onset after 50 years (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l −1 in controls, P=0.01, Cohen's d=0.37). For comparison, adjusted mean CRP levels for persons with cardiovascular disease were 1.62 (s.e=1.11), illustrating the clinical relevance of this finding. Excluding persons reporting having had a cold or fever in the week before blood draw ( N=513), yielded similar findings (age of onset after 50 years versus controls: 1.73 (s.e.=1.20) versus 1.18 (s.e.=1.05) mg l −1, P=0.04, Cohen's d=0.35). Results were also similar when the analysis of Figure 1 was restricted to the sample of persons aged 50 years or above ( N=589; age of onset after 50 years versus controls: 2.05 (s.e.=1.16) versus 1.35 (s.e.=1.08) mg l −1, P=0.01, Cohen's d=0.40), underlining that higher CRP in those with an age of onset of 50 years or above was not due to the higher age itself in these persons. Last, in a post-hoc analysis, we directly compared CRP levels between persons with a late versus early onset of anxiety disorder at a cutoff of 50 years, and found significantly higher CRP levels in the late onset group (1.91 (s.e.=1.19) versus 1.35 (s.e.=1.03) mg l −1, P=0.05, Cohen's d=0.30).

Figure 1.

Adjusted mean (s.e.) C-reactive protein (CRP) levels across controls and age of anxiety disorder onset groups. Based on analysis of covariance adjusted for sex, age, education, smoking status, alcohol intake, physical activity, body mass index, cardiovascular disease, diabetes, number of other chronic diseases, statins and anti-inflammatory medication; to normalize distributions, CRP was ln-transformed and for interpretation purposes presented means were back-transformed.

Discussion

The current study is one of the first and the largest to date to examine the association between anxiety disorders and inflammation. The results show that men with a current anxiety disorder have somewhat increased levels of CRP, even after taking a large set of lifestyle and disease factors into account. Elevated levels of CRP were in particular found in those persons with a late onset of the anxiety disorder.

Our results are in line with the few previous studies examining the relationship between anxiety symptoms or disorders with inflammation. Available evidence until now was limited to assessing anxiety symptoms in the general population,14, 15 confined to specific anxiety disorders in small clinical samples16, 17, 18 or in a heart disease population.19 Our study adds to the literature by showing that elevated CRP levels can be found among several common anxiety disorders in a relatively large cohort of anxious persons and controls, specifically in those with a later onset of the anxiety disorder. CRP levels were in particular elevated among men with anxiety disorders, which is in line with the large-scale study by Liukkonen et al.,15 which showed an association between anxiety symptoms and CRP only in men. In contrast, Pitsavos et al. 14 found associations between an anxiety symptoms score and CRP levels in both men and women. Persons included in the study by Pitsavos et al. were much older (18-89 years; mean age 45 years) than those in the study by Liukkonen et al. (all 31 years old), and slightly older than those in the present study (18-65 years; mean age 42 years). Perhaps sex differences become less clear with increasing age, as a result of hormonal changes across the lifespan of women, which affect inflammation levels.36 This could be in line with our finding that CRP levels were elevated in both men and women with a late onset of anxiety disorders.

Our findings with respect to anxiety disorders are also very comparable to our earlier findings regarding depressive disorders and inflammation.33 In that study, we found elevated inflammation, specifically CRP, in depressed men, especially among those with a later depression onset. The effect sizes for CRP in men with a current disorder are also comparable for anxiety (Cohen's d=0.18) and depressive (Cohen's d=0.21) disorders. A trend for association with IL-6, which was found for current depressive disorders in men, was not found for current anxiety disorders. Of note is that in persons with an anxiety disorder, a co-morbid depressive disorder was not associated with higher inflammation levels, suggesting that the effects found for anxiety disorders are independent of depression.

In line with our previous findings for current depressive disorders,33 CRP levels were in particular elevated among persons with a later onset of anxiety disorders. In contrast, characteristics that are more often associated with an early age of onset, such as higher severity and longer duration were not associated with increased inflammation. Also, in our sample, women had an earlier age of anxiety disorder onset than men, possibly contributing to the lack of an overall association between anxiety disorders and inflammation in women. Furthermore, we found that CRP levels were lowest among persons with social phobia when compared with other anxiety disorders, in particular in women. Social phobia has been reported to have a much earlier age of onset compared with generalized anxiety disorder or panic disorder,37 which was confirmed in our sample (16.6 versus 25.9 years, P<0.001). To our knowledge, no other study has yet examined the association between social phobia and inflammation. In our study, only nine persons with social phobia had an disorder onset at or after 50 years. Therefore, low inflammation levels in persons with social phobia cannot explain our findings for elevated CRP levels in persons with an age of anxiety disorder onset after 50 years. A recent study by Copeland et al. 38 showed that, after taking health-related behaviors into account, generalized anxiety disorder was not associated with elevated CRP levels among children and adolescents. These findings argue against the idea that the inflammation-anxiety association is merely a result of acute stress experienced in anxiety disorders. Although we cannot make inferences about etiology based on our cross-sectional analyses, our current findings are in line with the growing evidence suggesting a distinct etiology involving vascular/metabolic/inflammatory factors in depression or anxiety disorders with an onset later in life.39, 40, 41, 42 Possibly, accumulating psychological and physical stress across the life-span might induce immunological changes24 that eventually results in depression and anxiety.

In our previous report,33 we had found differences in inflammation levels among different classes of antidepressant medication use, which was confirmed for higher CRP in TCA/TeCA users within our present sample of persons with current anxiety disorders. Excluding persons using TCA or TeCA, resulted in a slightly weaker effect size for the association between current anxiety disorder and CRP in men. This might suggest that the elevated CRP levels in men with current anxiety disorders are for some part due to use of TCA/TeCA. On the other hand, persons using TCA/TeCA might represent the more severe cases of anxiety disorders, in which case exclusion of these persons leads to an underestimation of the association. Adjustment for TCA/TeCA use had no effect on our findings for age of anxiety disorder onset, suggesting that late-onset anxiety disorders are independently associated with higher levels of CRP.

What are the clinical implications of our findings? First, our finding of increased CRP levels in particularly those with a late onset of the anxiety disorder might implicate the existence of a specific late-onset anxiety subtype with a distinct etiology. As we have found similar results for depression33 and because depression and anxiety are highly co-morbid disorders,11 this might suggest that depression and anxiety with a late onset share a similar etiology and represent one particular group of disorders, which might be more distinct from other depressive or anxiety disorders, which present earlier in life. As we can only speculate on etiology based on our cross-sectional research, longitudinal research is needed to validate the existence of an etiologically distinct late-onset subtype. Second, if confirmed, a distinct etiology for late-onset disorders implicates different treatment strategies for this subgroup. Perhaps anti-inflammatory medication or lifestyle interventions, such as exercise, for which (some) evidence exists that they normalize immune and metabolic dysregulation,43 as well as improve depressive symptoms to some degree,44, 45 could be beneficial in persons with late onset anxiety disorders as well.

Our study has some important strengths such as a large sample size, assessment of multiple inflammatory markers, clinical diagnoses of several anxiety disorders, adequate adjustment for potential confounders and the ability to examine the role of anxiety characteristics. However, some limitations need to be acknowledged. As our data are cross-sectional, we cannot make any inferences about the direction of the association. Also, although we adjusted for a large set of possible confounding factors, unmeasured poor lifestyle behaviors or health factors may be the explaining link between inflammation and anxiety disorders. For instance, subclinical cardiovascular disease could possibly precede both inflammation and anxiety. On the other hand, subclinical disease may be one pathway of how inflammation leads to anxiety in later life. Longitudinal studies are needed to investigate whether immune dysregulation is a precursor or the result of anxiety, or whether this relationship is bidirectional. Further, like most other studies, we assessed circulating levels of inflammatory markers, which show a high degree of intra-individual variation that could explain the rather modest overall associations between anxiety disorders and inflammation in our study.

In conclusion, our results show that low-grade systemic inflammation is present in men with anxiety disorders. Elevated inflammation is in particular found in both men and women with the onset of anxiety disorder later in life. Longitudinal studies are needed to confirm inflammation as an etiological factor in anxiety disorders with a late-life onset, followed by intervention trials investigating new treatment strategies (for example, anti-inflammatory medication, lifestyle interventions) for this subset of persons with late-onset anxiety.

Acknowledgments

The infrastructure for the NESDA study ( http://www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Institute for Quality of Health Care (IQ Healthcare), the Netherlands Institute for Health Services Research (NIVEL) and the Netherlands Institute of Mental Health and Addiction (Trimbos)). NV was supported through a fellowship from the EMGO Institute for Health and Care Research and BP through a VICI grant (NWO grant g1811602). Assaying of inflammatory markers was supported by the Neuroscience Campus Amsterdam.

The authors declare no conflict of interest.

References

1. American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders4th edAmerican Psychiatric Association: Washington, DC; 2001 [Google Scholar]

2. Lyketsos CG, Nestadt G, Cwi J, Heithoff K, Eaton WW. The life chart interview: a standardized method to describe the course of psychopathology. Int J Methods Psychiatric Res. 1994;4:143-155. [Google Scholar]

3. WHO . Anatomical Therapeutic Chemical Classification. World Health Organization: Geneva; 2007. Collaborating Centre for Drug Statistics Methodology. [Google Scholar]

4. Mead GE, Morley W, Campbell P, Greig CA, McMurdo M, Lawlor DA.Exercise for depression Cochrane Database Syst Rev 2009(3)CD004366. [DOI] [PubMed]

Articles from Translational Psychiatry are provided here courtesy of Nature Publishing Group

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Anxiety disorders and inflammation in a large adult cohort

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Although anxiety disorders, like depression, are increasingly being associated with metabolic and cardiovascular burden, in contrast with depression, the role of inflammation in anxiety has sparsely been examined. This large cohort study examines ...

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According to research undertaken by the National Centre of Transgender Equality in the United States, cyberbullying is a significant problem for everyone in the LGBT community. Their study found that there was a particular issue among transgender people. Although just under half of those questioned reported some kind of physical abuse in the past, over two-thirds of
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Sensory - Internal Senses - Autism Understood

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Autistic people often have lower sensitivity OR higher sensitivity with their internal senses. It is common for the levels of sensitivity to change according to how relaxed, stressed or tired the person is feeling. The scientific name for our internal senses is the Interoceptive System Our internal senses let us know how our body feels [...]

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Autistic people often experience lower sensitivity OR higher sensitivity with touch. It is common for the levels of sensitivity to change according to how relaxed, stressed or tired the person is feeling.

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Alexithymia means difficulty with understanding and/or describing your feelings and emotions, making it harder to make choices. What can help?

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CAMHS/ Emotional Wellbeing Report & Recommendations

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Using eye movement desensitisation and reprocessing (EMDR) with autistic individuals: A qualitative interview study with EMDR therapists

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Eye Movement Desensitisation and Reprocessing (EMDR) is an evidence‐based psychological therapy that targets distress associated with trauma and affective disturbance. Few studies have examined EMDR for autistic individuals who have co‐occurring…

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After a prolonged blogging dry spell brought on by the torture of lockdown, I am back in business with my writing. This time around I will recount what EMDR (Eye Movement Desensitisation Reprocessing) has done for me.

What is EMDR

First of all, what is EMDR? The following description is adapted from the EMDR Association UK
EMDR is a therapy used to help people recover from distressing events and the problems they have caused, like flashbacks, upsetting thoughts or images, depression or anxiety. It is recognised by NICE as a treatment for PTSD. The World Health Organisation also recognises it as an effective treatment for children. Trauma can cause a person to be overwhelmed and unable to fully process what is going on. The traumatic memory seems to become "stuck" and remains very intense and vivid, causing them to continually re-live the experience in their mind, along with the full force of the distress. EMDR aims to help the brain "unstick" and reprocess and desensitise the memory, so they can think about the event without experiencing such strong feelings.
I t works by recalling the traumatic event while also moving their eyes from side to side, hearing a sound in each ear alternately, or feeling a tap on each hand alternately. These side-to-side sensations seem to effectively stimulate the "stuck" processing system in the brain so that it can reprocess the information more like an ordinary memory, reducing its intensity.
EMDR is a complex therapeutic process that should always be delivered by properly trained therapists. EMDR Association UK has a fuller explanation
What has EMDR done for me?

Having gone to a local EMDR practitioner every Saturday since January, I can safely say that EDMR has worked wonders for me. It's being able to do things like this blogging that makes going to a particular specialist mental health service for adults with autism worth dragging myself through. For those of you not familiar with my previous posts, I have written here about my awful experience of the LANC service, to which I was referred via adult mental health.

Needs around emotional wellbeing are specified in my Education, Health and Care Plan. When the LANC service couldn't meet these needs, my Mum was able to get a personal health budget (PHB) to meet these needs. Initially, the PHB was for RDI provision, which I have previously written about here. As a result of not being able to take part in my bespoke education package during much of lockdown as well as the ongoing uncertainty it created, my mental wellbeing took a dip. I was unable to take part in the RDI, because for the most part the meetings with my RDI consultant take place virtually and I needed to be face to face with someone who could help me. Zoom doesn't work for me ☹

I used my PHB to fund trips to the EMDR sessions, which consisted of training that stimulated both sides of the brain to work together in turning obsessive thoughts into long term memory.

Hosted by the dependable psychotherapist, Patrick Melvin, EMDR has defused and diminished traumas I've carried for years. I targeted one memory of a shallow, bitter, resentful woman I knew when I was younger who abused my trust and treated me badly. I found that spending a sizeable 40 minutes with EMDR exercises could heal that memory and I also used the technique on other negative memories.

How did it work?

The instruction was to pat my left knee with my left hand, and right knee with the right hand, whilst talking about the memory. This compelled both sides of the brain to work and by bringing the trauma onto the radar with the brain working harder, the trauma faded. I had to repeat this a few times, but it worked well for me.

My golden rule is that if you are going to use this tactic, do not stop when you feel a slight reduction in the memory you targeted - continue to strike it while it is down or else it will come back after a day or two. Like pulling out a dandelion - make sure to take out the root so it can't grow back.

At home, after some well-coordinated exercises and determined effort, I managed to knock the trauma down for four days and counting - a record high. I cannot put across enough the importance of working on the same issue heavily, do not ease up when the first sign of recovery starts to show, hit the memory without mercy.

The effects of my EMDR

Overall, I found using EMDR to be highly effective in reducing ruminative thinking and negative memories and wish I'd had access to it sooner.

Aside from the core EMDR there are many other methods and techniques offered that can help prevent rumination. I'd recommend trying at least twice with EMDR.

Thanks for reading my latest work, I intend to write more often with lockdown fading away.

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