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LGBTQ issues are some of the most pressing and difficult topics facing psychiatrists today. In this podcast,

interviews Michael F. Myers about gender and sexuality. Topics of discussion include:

Current subjects in gender and sexuality, including gender dysmorphia

How psychiatry’s understanding of sexuality and gender has changed over time

His own experience as a doctor during the AIDS crisis

Find out more about Dr Myers and his experience treating patients during the AIDS crisis in his new memoir, 

is professor of Clinical Psychiatry and immediate past Vice-Chair of Education and Director of Training in the Department of Psychiatry & Behavioral Sciences at SUNY-Downstate Medical Center in Brooklyn, NY.

Michael F. Myers, MD, discusses issues of gender and sexuality, both today and in recent psychiatric history. 

Psychiatry’s Gender Trouble

Albina Veltman, MD, FRCPC and Tara La Rose, MSW, PhD, RSW, provide Suggestions on how to create an LGBTQ-positive space in health care settings.

7 Ways to Break Barriers When Working With LGBTQ-Identified Patients

In recent years, transgender and gender incongruent adolescents have been the focus of media attention, public debate (eg, around the use of preferred pronouns and bathroom use), and, last but not least, best clinical practice. While the term transgender is mostly being used as an umbrella term for all forms of gender diversity, gender dysphoria is the diagnostic term as described in DSM-5.

Adolescents with gender dysphoria experience a marked incongruence between their experienced gender identity and their gender assigned at birth (based on their sexual anatomy) accompanied by distress. Gender identity refers to one’s sense of self as female or male. Increasingly, youth identify with a gender that differs from the traditional dichotomous classification of females and males: non-binary, gender fluid, gender queer etc (For an overview of terminology, see Sidebar). Parallel to the growing public attention, there has been a marked increase in the establishment of specialty gender services around the world and a sharp increase in the number of referred adolescents. Whether this is due to a true increase or increased awareness is not yet established.

The prevalence of a DSM-5 gender dysphoria diagnosis has never been studied in systematic population-based studies in adolescents and only estimates based on referrals to adult gender identity services are available. A meta-analysis found this prevalence to be 4.6 per 100,000.

 Estimates based on adolescent population samples (eg, high schoolers) provide much higher prevalence rates of self-identification as transgender or gender-incongruent of 3.6% for birth-assigned females and 1.7% for birth-assigned males.

 Another recent observation is the overrepresentation of assigned-females compared with assigned males at birth, which was reversed in earlier years.

Transgender adolescents and their families can present in many different ways. Some adolescents seek help for further gender identity exploration, while others have an already established desire for physical sex characteristics of the experienced gender. Additionally, while some transgender adolescents have shown gender non-conformity since early childhood, other adolescents might experience gender dysphoria during or after the onset of pubertal physical changes.

Some adolescents may have kept their gender incongruence to themselves for a long time. They did not speak out because they feared non-acceptance and rejection. They may have become depressed, socially isolated, and anxious. Other adolescents have been open about their feelings from an early age and may have socially transitioned to their experienced gender role supported by family and peers.

Various studies show that transgender adolescents are at a higher risk for mental health problems compared with cisgender peers and thus can present to clinicians with mental health difficulties. Stigma presumably plays an important role in this distress. In 2003, Meyer published his 

, which posits that minorities are often confronted with rejection and discrimination.

 Subsequently, this can lead to fear and negative feelings towards their minority group and themselves.

A study of transgender adolescents showed that poor peer relations were the most important predictor of mental health difficulties.

 Despite decreased stigmatization and growing tolerance, transgender adolescents are still relatively often victims of (cyber) bullying, harassment, and violence. A survey among transgender and gender diverse students from Minnesota showed that approximately 25% to 52% experienced different types of victimization is the past month.2 These negative experiences contribute to the fact that depression and anxiety occur about five times more often in transgender adolescents.

Another major health concern is the seemingly high number of suicidal ideation in transgender adolescents. A study among American high school students found that the prevalence of suicidal ideation in gender diverse students was nearly twice as high compared with cisgender youth and that both depressive symptoms and school-based victimization were associated with this ideation.

Although the above numbers are reason for concern, there are also opportunities to change the current situation. Gender diverse adolescents growing up in a supportive and tolerant environment who trust that medical affirming treatment is provided when necessary show less co-occurring mental health difficulties.

 Projects at schools that encourage acceptance and help transgender adolescents to be open about their gender identity are important as they improve adolescent well-being.

Apart from emotional problems, there is a line of research that shows a remarkable, yet unexplained overrepresentation of autism spectrum disorder diagnoses and autism characteristics in transgender adolescents compared with cisgender adolescents with up to 15% reaching clinically relevant autism characteristics levels.

 Although it has not be established why this might be the case, transgender adolescents with autism can also profit from gender affirming medical treatment.

Abigail is a 14-year-old assigned female at birth who at age 11 received a diagnosis of autism spectrum disorder. Abigail loved to play an online game building a virtual character with other people. In this game, Abigail created the male character “Amon.” Over time, Abigail started playing the game for longer periods, often for several hours a day and became socially isolated. When her parents asked about what was going on, Abigail responded that she felt she was a boy. Since the parents thought it was important to examine this further, they went to Abigail’s child and adolescent psychiatrist. After discussing gender with Abigail, the psychiatrist decided to refer her to a gender clinic.

At the clinic, Abigail had several sessions with a psychologist. During the sessions they discussed Abigail’s childhood fixations. The psychologist tried to differentiate whether Abigail’s desire to be a boy was a fixation. Abigail showed insight in these fixations and experienced them as likeable things to do, creating happiness. On the other hand, her gender dysphoric feelings were unlikeable and made Abigail sad instead of happy. After the sessions, treatment with puberty blockers was started to release the distress Abigail experienced around body changes. After social transition and the start of puberty blockers, Abigail took the name Amon and flourished: he had more contact with other adolescents, undertook more activities, and his schoolwork improved.

Support should be tailored to the adolescent. Some adolescents need individual explorative psychotherapy, others need treatment for depression or other co-occurring psychiatric conditions. Most adolescents and their families will profit from some sort of support on how to inform friends and relatives, how to present at school, and how to deal with possible stigma. In addition, transgender adolescents who are accepted and supported show better well-being.

 Assessment of adolescents with co-occurring autism (characteristics) might be more complex to understand and additional support might be needed when considering medical affirming treatment.

Medically intervening in a healthy body is a far-reaching option that has proven its usefulness in transgender adults, but has only been studied in a few adolescents.

 According to what has been named the “Dutch model,” which includes the intervention of puberty suppression without permanent effects, gender affirming care is offered in a step-wise model.

 Before medical interventions are provided, a comprehensive assessment exploring the nature of the adolescent’s gender identity is performed in a supportive and respectful way. The adolescent is assessed whether a diagnosis of gender dysphoria (according to the DSM-5) or gender incongruence (according to the ICD-11) can be given. Co-existing mental health difficulties like depression, anxiety, risk of self-harm, and suicide as well as autism characteristics that have an impact on diagnosis or treatment should be assessed and a referral for psychotherapy given if it is indicated.

Family and school functioning are also assessed and family or other caretaker support (in case an adolescent lives in out of home care) and advocacy in schools to ensure a safe and affirming environment may be necessary. Finally, it is essential to inform the adolescent and the family of the pros and cons of medical interventions with lifelong consequences, including consequences for fertility and sexuality, and assess the adolescent’s decision-making capacity for informed consent.

After the assessment, medical treatment options for adolescents can be divided in fully reversible puberty blockers, partially reversible affirming hormone treatment (estrogens or androgens) and fully irreversible surgeries (eg, mastectomy, vaginoplasty). Current guidelines differ with regard to age limits for these different treatment options; some use age 11 to 12 for puberty blockers, age 14 to 16 for hormones and age 16 to 18 for mastectomy and age 18 for genital surgeries. It has been argued that psychological maturity might be a better indicator than age, but how to assess this is not yet established.

Medical treatment is usually provided in subsequent steps from fully reversible to fully irreversible. The fully reversible blockers provide the adolescent with rest before any decision with more permanent effects is made. Ongoing counseling and support is offered. Gender affirming hormones may have partially irreversible effects (low voice, breast growth), but still provide time before completely irreversible gender affirming surgeries are performed. Some transboys prefer a different order and want to have chest surgery before hormonal treatment and some non-binary identifying adolescents prefer either surgery or hormones only. The multifaceted quality of these interventions call for involvement of a multidisciplinary care team, in which mental health professionals collaborate with (pediatric) endocrinologists, surgeons, and fertility specialists.

Transgender care for adolescents is surrounded by controversies, challenges, and uncertainties. At present, the aforementioned increase in prevalence, the shift in sex ratio, and the presentations of non-binary gender identities are yet to be understood. Long-term outcome studies of early medical interventions still come from a limited number of clinics and include only binary identifying transgender adolescents with prepubertal onset gender incongruence.

Whether puberty blocking at a young age is effective and safe for non-binary and post-puberty onset transgender adolescents is unknown. Long-term physical consequences of puberty blocking on bone density, fertility, duration, and surgical options are uncertain. Various ethical dilemmas exist around the capacity for informed consent of adolescents, parents’ role in treatment, and whether the right for best care for transgender children should include the right for medical transitioning.

Some clinicians may be hesitant in their work with transgender adolescents. Transgender adolescents and their families experience barriers to care and specialized providers might not always be available. However, the work with transgender adolescents can be rewarding. Transgender youth can profit enormously by the psychological, emotional, and social support that mental health professionals can give by showing their compassion and understanding.

Dr Miesen is Junior Researcher Adolescent Amsterdam Cohort of Gender Dysphoria (A-ACOG) and Psychiatry Consultant, Center of Expertise on Gender Dyspgoria (CEDG); and Dr Arnoldussen is Junior Researcher, A-ACOG and Psychiatry Consultant, CEDG. Dr de Vries is Principal Investigator, A-ACOG, and Lead, Department of Child and Adolescent Psychiatry, CEDG.The authors are all affiliated with Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Child and Adolescent Psychiatry. The authors report no conflicts of interest concerning the subject matter of this article.

1. Arcelus J, Bouman WP, Van Den Noortgate W, et al. Systematic review and meta-analysis of prevalence studies in transsexualism. 

2. Eisenberg ME, Gower AL, McMorris BJ, et al. Risk and protective factors in the lives of transgender/gender nonconforming adolescents. 

3. Aitken M, Steensma TD, Blanchard R, et al. Evidence for an altered sex ratio in clinic-referred adolescents with gender dysphoria. 

4. Meyer IH. Prejudice, social stress, and mental health in lesbian, gay, and bisexual populations: conceptual issues and research evidence. 

5. de Vries AL, Steensma TD, Cohen-Kettenis PT, et al. Poor peer relations predict parent- and self-reported behavioral and emotional problems of adolescents with gender dysphoria: a cross-national, cross-clinic comparative analysis. 

6. Becerra-Culqui TA, Liu Y, Nash R, et al. Mental health of transgender and gender

nonconforming youth compared with their peers. 

7. Perez-Brumer A, Day JK, Russell ST, Hatzenbuehler ML. Prevalence and correlates of suicidal ideation among transgender youth in California: findings from a representative, population-based sample of High School students. 

8. de Vries AL, Doreleijers TA, Steensma TD, Cohen-Kettenis PT. Psychiatric comorbidity in gender dysphoric adolescents. 

9. van der Miesen AI, Hurley H, de Vries AL. Gender dysphoria and autism spectrum disorder: a narrative review. 

10. Ryan C, Russell ST, Huebner D, et al. Family acceptance in adolescence and the health of LGBT young adults. 

11. de Vries AL, McGuire JK, Steensma TD, et al. Young adult psychological outcome after puberty suppression and gender reassignment. 

12. Shumer DE, Spack NP. Paediatrics: transgender medicine-long-term outcomes from the Dutch model. 

Transgender adolescents and their families experience barriers to care and specialized providers might not always be available. However, the work with transgender adolescents can be rewarding.

Special Issues in Treating Adolescents With Gender Dysphoria

 become more interested in sex and gender differences in mental disorders.

 The reasons for this are manifold. On the one hand, sex and gender differences belong to the most stable findings in psychiatry and it is hoped that explaining them would provide interesting clues regarding the etiology of certain disorders. On the other hand, psychiatrists and psychotherapists increasingly understand that we can only deliver optimal psychiatric therapy and care if we take these differences into account.

This Special Report offers articles on gender-specific issues relevant to mental disorders. Mary Seeman, MD, focuses on 

 of gender differences in schizophrenia. In fact, many sex and gender differences in 

 have been reported, but few have been soundly replicated. A stable finding is the later age of onset in women compared with men.

A better understanding of the different etiologies and pathogenetic pathways of schizophrenic psychoses in women and men on sex (biological) and gender (psychosocial) factors is needed to better tailor treatments and improve outcomes.

. She concludes that the study of these differences is still in its infancy compared with other areas of medicine such as cardiology. She explains that in cardiology a better understanding of sex and gender differences has led to improved treatment and care for both women and men, and the same should happen regarding dementia.

into gender vulnerabilities for anxiety disorders and the influence of sex hormones. She states that our understanding of the role of sex hormones in anxiety in women, while increasing, is still in its infancy, and if sex bias in anxiety research is not addressed, our understanding and treatment of anxiety will remain less rigorous for women. She also suggests ways that clinicians can already integrate existing knowledge into their daily practice.

In her article, Florence Thibaut, MD, PhD, 

gender differences in addiction and their clinical implications. Findings from recent epidemiological studies indicate an alarming increase in the prevalence of dependence in adult women. Women’s consumption of psychoactive substances during pregnancy can be associated with serious consequences for the child. However, female outpatients are still underrepresented in specialized treatment settings. Providing services adapted to the needs of women, especially for those of childbearing age, is of emergent importance.

All the authors stress that mental health research often ignores sex and gender differences as well as the different risk factors and protective factors for both women and men. This is unfortunate, because not to investigate potentially different causal pathways and treatment responses of both genders not only undermines scientific validity of research, but also results in a failure to deliver gender sensitive treatments.

It is therefore high time for a shift in practice and research. Sex and gender aspects must be addressed more rigorously in research, psychiatric training, and clinical practice. This includes more research on gender differences in illness behavior, coping, help-seeking, and compliance as well as psychopharmacology, hormonal therapies, or gender-sensitive psychotherapy.

Introduction: Gender-Specific Issues Relative to Mental Illness

Clinical Implications of Gender Differences in Schizophrenia

Sex Hormones and Gender Vulnerabilities to Anxiety Disorders


Bronwyn M. Graham, MPsychol (Clinical), PhD

Sex and Gender Differences in Alzheimer Disease Dementia

Gender Differences in Addiction: Clinical Implications

Dr Riecher-RÃ¶ssler is Professor of Psychiatry and Head of the Center for Gender Research and Early Detection, University of Basel, Psychiatric University Clinics, Basel, Switzerland.

Dr Riecher-RÃ¶ssler reports no conflicts of interest concerning the subject matter of this Special Report.

Comment: sex and gender differences in mental disorders

 Riecher-RÃ¶ssler A, Butler S, Kulkarni J. 

Sex and gender differences in schizophrenic psychoses: a critical review

This Special Report offers insight into gender vulnerabilities and clinical implications in areas like schizophrenia, Alzheimer dementia, and anxiety disorders.

I did most of my psychiatric residency in the early 1960s on an all-women’s ward in New York City dedicated to research in schizophrenia. There were 30 beds and each patient stayed in the hospital for a long time, so I got to know the women well. I would describe them collectively as well-groomed, chatty, friendly, moody, and smart. It was consequently a shock when in 1975 in Toronto, Canada, I was put in charge of a schizophrenia outpatient clinic and discovered that the patients were mostly young men who were, by contrast to the women I had known, emotionally distant, apathetic, disheveled, and angry. Had my perception of people changed over the years, or, I wondered, does schizophrenia affect men and women differently?

I wondered why there were so many more men than women in my new clinic. Part of the answer was because the incidence of schizophrenia is higher in men than in women, especially in young adulthood. Nevertheless, the prevalence appears to be similar, perhaps because more men than women with schizophrenia succumb to suicide and accidental death. The men in my clinic were mostly young adults, whereas the women in the clinic tended toward middle age. This forcibly brought home the point that men develop schizophrenia earlier in life than women by several years.

The relative dearth of women in the clinic was also attributable to the fact that the women were too busy to attend. They were working, socializing, having babies, and living full lives to which the men could only aspire to.

The relatively few women who were eager to attend clinic activities felt outnumbered. As a result, I started a women-only therapy group. The members of this group were very friendly with each other; gossiping about clothes and diets. They went out for coffee after group together. In other words, they showed little flattening of affect, few negative symptoms, few evident cognitive defects, although they harbored many delusions and reported a variety of hallucinations.

Because the women’s group was going well, I invited the men to form their own group. By the end of a year of weekly group meetings, none of the eight men who had agreed to join knew the name of any other group member. They didn’t interact. All remarks in the group (mainly about sports, a little about cars) were addressed to me. There was evident poverty of speech, apathy, and many relatively blank facial expressions. There was also a manifest lack of grooming and basic hygiene in this group.

In 1985, I left the clinic to work at another hospital. I had learned that women with schizophrenia respond well to treatment. I had also noticed that they rarely had to be rehospitalized. Many of the women worked outside the home. Many stayed in committed intimate relationships and forged strong therapeutic alliances with their care providers. At the same time, I had unfortunately witnessed many male suicides; many men who abused alcohol and many who required extremely high dosages of antipsychotics. Most of the men did not work and continued to be dependent on aging parents.

Eight years later, I returned to the clinic, where I was in for an unexpected shock. The forlorn, listless men I had said goodbye to welcomed me back warmly and told me jokes! In some cases, their parents had died, so they now lived in group homes and were managing surprisingly well. They seemed content, even purposeful. They spent socially productive time in the hospital cafeteria, chatting and laughing with their buddies. On the other hand, the once high-achieving women had lost their jobs, were cycling in and out of the hospital, and were no longer responsive to their medications.

I am generalizing, of course, and there was much overlap between the men and the women, but the pattern was very clear. The men were doing better while the women were doing worse.

Explanations for sex differences in schizophrenia

One explanation for these observations about sex differences in this disease rests on the many and varied neuroprotective actions of estrogens.

 The hypothesis is that female hormones delay the onset of schizophrenia, allowing women to finish their schooling and to acquire substantial interpersonal skills before illness puts a stop to further socialization. Estrogens help the antidopaminergic action of antipsychotics so that dosages can stay relatively low in women, preventing adverse effects and, thus, permitting steady employment and the development of personal relationships. At menopause, however, these advantages are lost.

Further evidence confirmatory of the estrogen hypothesis are premenstrual (low estrogen) exacerbation of psychotic symptoms in women, postpartum exacerbations, and the significant improvement brought about when estrogens or selective estrogen receptor modulators (SERMS) are added to the medication regimen.

The estrogen hypothesis is not wholly satisfactory, however. Ovaries are not functional in fetal life, so much of the estrogen found in human fetal brain comes from the testosterone derived from testes in boys. Thus, the brains of girl fetuses are exposed to relatively less estrogen. Because fetal life is when schizophrenia allegedly starts, why are male brains not more (rather than less) protected than female brains at the outset?

Perhaps the early female advantage lies not only in hormones but also in the double X chromosome, in sexually dimorphic microglia, in epigenetic effects on schizophrenia genes, on structural differences in male and female brains, and in gene – environment interactions.

 Primary prevention rests in the hands of women and their clinicians. With knowledge and guidance, affected women can minimize the risk of schizophrenia in offspring by choosing male partners without a history of psychosis, who are younger than age 40 (but not too young either), and who live in their country of origin. They can time conception to avoid birth in late winter or early spring. Most importantly, they can be very assiduous in attending prenatal appointments, taking prescribed immunizations and vitamin/mineral supplements, paying attention to diet, avoiding alcohol and drugs of abuse, keeping antipsychotic doses low, managing their stress levels, avoiding infections whenever possible, and not tolerating any form of domestic abuse.

Clinicians need to ensure that pregnant women with schizophrenia are monitored frequently and have adequate incomes, safe housing, and sufficient social support. Children of both male and female parents with schizophrenia require careful monitoring and support throughout childhood and adolescence to prevent the development of psychosis or to catch and sidetrack psychotic symptoms, should they develop.

Finally, contraceptive guidance and genetic counseling are also important aspects of prevention.

 Diagnostic strategies differ in men and women. In men, it can be difficult to distinguish the beginning of schizophrenia from substance-induced psychosis. In women, because affect is preserved, schizophrenia is not easily distinguishable from affective psychosis. Also, in women, differential diagnoses such as anorexia-induced psychosis, steroid psychosis, thyroid disease-associated psychosis, and psychosis secondary to autoimmune disorder and its treatment need to be actively considered.

 Maintenance of physical health is very important in schizophrenia because mortality rates are high.

 Psychiatrists need to ensure that their patients stay in regular contact with a general practitioner and that men and women are screened for disorders relevant to their sex (ie, cervical smears, breast examinations and mammograms, prostate and colon cancer screening), that they are adequately immunized against infectious agents, and regularly checked for the sequelae of chronic intake of antipsychotic medication (ie, obesity, diabetes, hypertension, osteoporosis, cardiovascular disease). Psychiatrists should advocate for their patients to ensure prompt and state-of-the-art care when they are ill.

 Antipsychotics have sexual adverse effects that need to be asked about and addressed. Intimate relationships and contraceptive methods require attention. Women with schizophrenia usually have questions about changes in their menstrual periods and many experience premenstrual exacerbations of symptoms.

 Because of antipsychotic adverse effects, some women may believe that they are pregnant when they are not, whereas women who want to be mothers may find it difficult to conceive. Some pregnant women may deny their pregnancy; others may seek abortions. Pregnant women should be seen often, their medication dosages adjusted carefully, and their domestic situation addressed with referrals not only to obstetrics but also to affordable housing, income support, and substance abuse programs as necessary. Family meetings usually become necessary at this time to garner as much support as possible for the mother-to-be.

The postpartum period is a time of risk for women with schizophrenia. Home visits are important, with monitoring required for both mother and baby. Parenting support is critical and help from a child welfare agency may be necessary. The question of breast-feeding needs to be addressed, with most guidelines recommending no breast feeding because of unresolved safety concerns about psychotropic medications. If a medication is taken immediately after breastfeeding and just before the infant’s longest sleep period, however, and the infant’s serum drug level is monitored, there are definite advantages to breastfeeding for both infant and mother. Consultation with a lactation expert is helpful. It is critical that mothers not stop their medications during this vulnerable time.

The menopausal transition is an important one for all women. Most women experience symptoms of menopause that need to be anticipated and effectively treated. The personal meaning of menopause needs to be explored with women who have schizophrenia. Unfortunately, psychotic symptoms may worsen during this time and antipsychotic dosages may have to be adjusted.

 Safety issues are of utmost importance in the treatment of schizophrenia. Patients with severe mental illness need to be protected from their own sometimes very unhealthy lifestyles and from suicidal urges. A suicide in a treatment setting can lead to chain events in a vulnerable population. Treatment with antipsychotics can also pose risks in situations in which being fully alert matters (ie, driving, operating heavy machinery, looking after young children).

Women, more than men, must be protected from exploitation and violence inflicted by others, whether intimate others, co-patients on hospital wards, or strangers. Both men and women need protection from stigmatizing attitudes, in particular on the part of childcare workers (women), police, and the justice system (men) as well as medical professionals (men and women).

There are also understandable safety concerns about individuals with schizophrenia acting on dangerous delusional beliefs and command hallucinations, especially when inebriated. Family members are most at risk.

 Standard antipsychotic treatment frequently requires modification in women. Women respond to lower dosages and, because they are usually on many more different medications than men and have a more active immune system, they experience more adverse effects.

 Dosages may need to be adjusted over the menstrual month, during pregnancy, the postpartum, and the menopausal transition. In older age, dosages should be kept low in both women and men.

Several other clinical interventions useful to individuals with schizophrenia, such as exercise programs, substance abuse programs, employment programs, and weight-loss programs also benefit from sex-specific modifications.

In an ideal world, each patient is treated individually because no two persons are identical, but that may be impossible for now. Differentiating between men and women is a first step.

• Escott-Price V, Smith DJ, Kendall K, et al. Polygenic risk for schizophrenia and season of birth within the UK. 

• Hung YN, Yang SY, Kuo CJ, Lin SK. Diagnostic consistency and interchangeability of schizophrenic disorders and bipolar disorders: a 7-year follow-up study. 

• Lu Y, Pouget JG, Andreassen OA, et al. Genetic risk scores and family history as predictors of schizophrenia in Nordic registers. 

• Riecher-RÃ¶ssler A, Butler S, Kulkarni J. Sex and gender differences in schizophrenic psychoses: a critical review. 

• Terres NM. Resources for psychiatric clinicians working with breastfeeding mothers. 

Dr Seeman is Professor Emerita, Department of Psychiatry, Institute of Medical Science, University of Toronto, Ontario, Canada. Dr Seeman reports no conflicts of interest concerning the subject matter of this article.

 Arevalo MA, Azcoitia I, Garcia-Segura LM. The neuroprotective actions of oestradiol and oestrogen receptors. 

 Seeman MV. Menstrual exacerbation of schizophrenia symptoms. 

 Vigod SN, Rochon TG, Fung K, et al. Factors associated with postpartum psychiatric admission in a population-based cohort of women with schizophrenia. 

 Kulkarni J, Gavrilidis E, Wang W, et al. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. 

 Zhu XM, Zheng W, Li XH, et al. Adjunctive raloxifene for postmenopausal women with schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. 

 Reininghaus U, Dutta R, Dazzan P, et al. Mortality in schizophrenia and other psychoses: a 10-year follow-up of the AESOP first-episode cohort. 

 Zhu Y, Li C, Huhn M, et al. How well do patients with a first episode of schizophrenia respond to antipsychotics: a systematic review and meta-analysis. 

 Seeman MV. Schizophrenia: women bear a disproportionate toll of antipsychotic side effects. 

A deep dive into how schizophrenia affects men versus women.

Large-scale mental health surveys have consistently shown that the prevalence of anxiety disorders and related conditions is approximately 

 Despite similar patterns that occur across all anxiety subtypes, this sex difference appears most pronounced for PTSD, generalized anxiety disorder, and specific phobias.

Although the sex imbalance in the prevalence of anxiety disorders is undisputed, debate surrounds its source. Social and environmental factors undoubtedly contribute to the imbalance, for example: men may be less inclined to report anxiety symptoms because of stigma. The socioeconomic status of men and women is often different. Thus, their daily stressors are also different as is their ability to access coping resources. Although men and women may experience trauma similarly, there are stark differences in the nature of these traumas, with sexual assault (itself a strong risk factor for PTSD) being 

Apart from environment, the neurobiology of men and women also differs substantially. Responsible for many of these differences is sexually divergent gonadal sex hormone synthesis, with the male testes primarily producing testosterone and the female ovaries primarily producing estradiol (the main estrogen) and progesterone. Apart from minor diurnal fluctuations, postpubertal males have relatively steady levels of testosterone throughout their adult lives, followed by age-related declines. In contrast, postpubertal females experience dynamic fluctuations in estradiol and progesterone on a monthly basis due to the menstrual cycle and across the lifespan due to hormonal contraceptive use, pregnancy, parturition, and menopause.

Sex differences in the prevalence of many anxiety subtypes do not emerge until puberty. Similarly, women exhibit increased vulnerability to anxiety during the postpartum and perimenopause periods, times of substantial hormonal flux. Sex differences in hormone exposure and stability may exacerbate women’s risk for anxiety by interacting with the putative factors that underlie the pathogenesis of anxiety.

Why do anxiety disorders develop and persist over time?

Cognitive-behavioral models posit that genetically vulnerable individuals react in maladaptive ways to negative or stressful precipitating events that trigger the onset of anxiety symptoms (

). Several key factors subsequently prevent anxiety from spontaneously remitting. In brief, anxious individuals grossly overestimate the likelihood and the consequences of potential threat in a given situation. These catastrophic predictions fuel the physiological and affective symptoms of anxiety, thereby promoting the use of maladaptive behavioral coping strategies, most notably avoidance. Avoidance precludes the individual from acquiring corrective information about the true level of threat in the situation. Thus, the catastrophic cognitions (and in turn, the anxious symptoms) are maintained.

Cognitive behavioral therapy (CBT), the first-line psychological treatment recommended for anxiety disorders, disrupts this self-perpetuating cycle by modifying catastrophic thoughts. CBT comprises exposure therapy, in which the patient is taught to confront anxiety-eliciting situations without engaging in avoidance tactics, and cognitive restructuring, in which the patient collects evidence from multiple sources, including conducting his or her own experiments, to test the validity of (and ultimately undermine) catastrophic beliefs.

Role of sex hormones in persistent anxiety

Aside from their key role in reproduction, sex hormones (in particular, estradiol) facilitate neural plasticity, including initiation of intracellular signaling cascades, gene transcription, and growth of dendritic spines and synapses. This occurs in both females and males-many of testosterone’s actions in the brain result from its aromatization to estradiol.

 Because of cyclic fluctuations in sex hormones, postpubertal females exhibit substantial basal changes in key markers of neural plasticity in brain areas involved in memory formation.

Neural plasticity is essential for learning as well as the formation of new memories-including the learning that occurs during exposure to stressful or traumatic events, and the safety learning that occurs during CBT for anxiety. It is possible that different sex hormone levels create a state of neural plasticity that is more or less permissive for the formation of both kinds of memories. We have proposed a two-pronged model, wherein the consequences of fluctuating neural plasticity in women may differ depending on what is happening in the external environment at the time (

In brief, high sex hormone levels (and resulting increases in brain plasticity) during stress or trauma may facilitate over-consolidation of these experiences, thereby increasing the propensity to develop anxiety disorders. Conversely, once anxious symptoms have developed, high sex hormones may be beneficial during CBT by facilitating the formation of new safety memories and more adaptive means of coping.

Laboratory and clinical studies provide initial support for the central hypotheses in this model. Results from studies have demonstrated that intrusive recollections (a key symptom of PTSD) of traumatic images and films are stronger in women during periods of high sex hormones.

 Women who experienced traumatic injury during a high hormonal menstrual phase reported more numerous negative flashbacks in the subsequent week compared with women who experienced traumatic injury during a low hormonal phase.

 Women who accepted emergency contraception (which suppresses sex hormonal synthesis) following sexual assault reported 

 relative to women who refused emergency contraception.

In relation to the hypothesis that higher sex hormones may be beneficial to CBT, a decade of research has established that sex hormones, particularly estradiol, modulate fear extinction, the laboratory analogue of exposure therapy.

 In brief, females exhibit better extinction (reduced fear responses) when exposed to anxiety-provoking stimuli during periods of high, relative to low, estradiol.

In both males and females, pharmacologically blocking estradiol impairs, and administering estradiol facilitates, extinction. In females, hormonal contraceptives (which suppress sex hormones) impair extinction. In the first translation of these laboratory findings to a clinical setting, we demonstrated that the success of exposure therapy for spider phobia was correlated with women’s endogenous estradiol levels during treatment.

Women with higher estradiol progressed through treatment more rapidly and exhibited greater posttreatment reductions in spider avoidance and self-reported phobic symptoms, relative to those with lower estradiol. Of note, women using hormonal contraception (who had the lowest estradiol) showed the poorest treatment response.

Role of sex hormones in fluctuations in anxiety symptom severity

In addition to potentially modulating the development and persistence of anxiety symptoms, fluctuating sex hormones are also associated with changes in anxiety symptom severity. Increases in symptom severity have been observed during periods of declining or low sex hormones in women with panic disorder, social anxiety disorder, PTSD, and obsessive-compulsive disorder, which share clinical features of anxiety.

Although it is unclear what mediates this effect, it is known that women report maladaptive coping strategies more so than do men. One possibility is that women may alter the types of coping strategies that they use depending on their levels of sex hormones. For example, women report increased use of avoidant coping styles during the premenstrual phase (declining sex hormones).

The impact of a given coping strategy may also differ dependent on sex hormones. Although women tend to ruminate (a maladaptive coping strategy) more during periods of high estradiol, the negative impact of rumination on mood has been found to occur only in women with low estradiol.

 Hormone-associated instability in coping strategies may further exacerbate anxiety by decreasing women’s ability to self-control symptoms.

Practical considerations for screening, diagnosis, prevention, and treatment

Our understanding of the role of sex hormones in anxiety in women, while increasing, is in its infancy. Current psychobiological models of anxiety (which drive innovations in anxiety treatments) are biased in favor of males because of a preponderance of studies solely focused on male rodents and human studies inadequately powered to assess for sex differences. Regardless of whether the sex imbalance in the prevalence of anxiety disorders is primarily driven by reporting biases, or non-organic factors, female variables such as menstrual cycle and hormonal contraception, which have been historically ignored, are likely relevant to the pathogenesis and treatment of anxiety.

New mandates requiring the consideration of sex as a biological variable in research funding applications may foster a more-nuanced understanding of the relevant sex-specific factors to consider when making diagnostic and treatment decisions for anxiety disorders.

In the meantime, clinicians can help to raise the profile of this important issue, and make use of the existing research base, by integrating the following considerations into their practice:

1 Conduct an assessment of the onset and exacerbation of anxiety symptoms in relation to hormonal events (eg, use of hormonal contraction, menstrual cycle, pregnancy, parturition, perimenopause); consider changing/removing hormonal contraception if a link is established.

2 Routinely provide psychoeducation to increase women’s awareness of a potential link between hormones and anxiety, both following symptom onset and pre-emptively (eg, in patients about to experience significant hormonal change, such as preadolescents, before starting hormonal contraception, and in pregnant women and perimenopausal women).

3 For patients with anxiety disorders, encourage incorporation of menstrual cycle phase (or other hormonal events) in routine monitoring of symptom fluctuation. This may increase the sense of control over symptoms by facilitating predictability and fostering targeted use of adaptive coping strategies during identified times of heightened vulnerability.

4 Consider timing exposure therapy during periods of optimal hormonal levels. Women on hormonal contraception may require more-extended treatment sessions to achieve benefit. Note that this consideration is based on one clinical study on specific phobia, however, and the utility of this approach for other anxiety disorders awaits more extensive empirical investigation.

5 Women’s tendency to engage in maladaptive coping styles is well established. This should be a focus of attention during clinical assessment of women. Women may especially benefit from targeted cognitive interventions for anxiety (eg, rumination-focused CBT) that directly correct these maladaptive coping styles.

Dr Graham is Associate Professor, Clinical Psychology, School of Psychol ogy, University of New South Wales, Sydney,Australia.

Dr Graham reports no conflicts of interest concerning the subject matter of this article.

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Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness

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Sex differences in anxiety and depression clinical perspectives

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The influence of emergency contraception on post-traumatic stress symptoms following sexual assault

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Clinicians can help raise awareness of the role of sex hormones in persistent anxiety by integrating 5 considerations into their practice.

Alzheimer disease (AD) dementia is the most common form of dementia, comprising 60% to 70% of all cases. AD is a progressive neurodegenerative disease that causes memory loss, cognitive deficits, and behavioral changes. The hallmark characteristics of AD include the presence of extracellular amyloid-beta plaques, intracellular neurofibrillary tangles, and neurodegeneration. With the aging of the population, the burden of AD dementia is growing to epidemic proportions. More than five million people in the US have a diagnosis of AD, and it is estimated that by 2050 14 to 16 million will have a diagnosis unless new treatments or interventions to prevent or delay the onset of AD are identified.

 A declining trend in the risk of dementia has been reported for several high-income countries in the past 20 to 30 years. The impact of these trends on the future remains uncertain, however, and it is not clear what type of dementia may be driving these trends.

Precision medicine techniques and approaches have emerged over the last decade that have advanced our understanding of the pathophysiological changes associated with the development and progression of AD dementia. However, the examination of sex and gender differences has not been well integrated into these approaches. This is surprising given the extensive literature demonstrating sex differences in brain structure and function over the lifespan.

Several misconceptions also exist about the study of sex and gender in the AD field. The initial focus of this article is on whether women are at greater risk. A few examples of risk factors for AD that differ by sex are provided, followed by an overview of potential differences in comorbid neuropsychiatric symptoms. Throughout, we utilize the definitions of sex and gender from the Institute of Medicine.

 Sex refers to the biological and physiological differences between women and men, with the sex chromosomes (X and Y) contributing to these differences. Gender refers to a combination of environmental, social, and cultural influences on women and men. Gender is rooted in biology, but it is primarily shaped by environment and experience.

Are women at greater risk for AD dementia?

Historically, the primary reason stated for examining sex or gender differences in AD dementia is that “women are at greater risk” and that there is a need to understand what factors contribute to the greater risk for women. This rationale needs to be reassessed. About two-thirds of persons with a diagnosis of AD dementia are women.

 However, life expectancy for women is longer than for men, and age is the greatest risk factor for AD dementia. As a result, and similar to other aging-related diseases, the lifetime risk of AD dementia is greater for women. Although the incidence of AD dementia is higher in women, sex differences in the incidence of AD dementia are less clear.

In the US, study data overwhelmingly show that the incidence of AD dementia does not differ by sex, even after the age of 85 years.3 In other areas of the world, however, women appear to have a higher incidence. Findings from studies in several European countries indicate that women have a higher incidence of AD dementia after the age of 80.

 Nevertheless, the Cognitive Function and Aging Study in the United Kingdom, however, initially reported a higher incidence for men.

The reasons for these discrepancies are not well understood but suggest that sex and gender differences in the incidence of AD dementia may depend on the period of time and geographic region. For example, the experiences of World Wars I and II were vastly different in European countries compared with the US and in men compared with women. Further study of these worldwide differences is needed and would provide an opportunity to identify modifiable risk factors for AD dementia. Notably, these studies also highlight the fact that AD is not a disease unique to women, but that many men are also affected.

Sex and gender differences in risk factors for AD dementia

Even if women and men have the same incidence of AD dementia (age- and sex-specific incidence rate), the mechanisms, pathways, and risk factors can still differ. Many studies examining risk factors for AD adjust for sex in the analyses but do not determine whether there are actual sex differences (ie, whether the strength of the association between a risk factor and AD dementia differs by sex). There are multiple scenarios by which sex and gender differences could affect the risk of AD dementia (

Examples of sex differences in risk factors.

 Compared with men, women have twice the risk for depression.

 Depression has implications for cognition across the lifespan because mood and memory map to some of the same brain regions. Studies report that depression is a risk factor for AD dementia in both women and men. Estimates range as high as a 70% increased risk of AD dementia for those with depression in midlife.

 Therefore, because the lifelong prevalence of depression is greater in women, a diagnosis of depression may have a greater overall impact for AD dementia risk among women.

Several misconceptions exist about the study of sex and gender in the AD field. The initial focus of this article is on whether women are at greater risk.

Gender Issues