C. Neill Epperson

Sex differences and stress across the lifespan

Sex differences in stress responses can be found at all stages of life and are related to both the organizational and activational effects of gonadal hormones and to genes on the sex chromosomes. As stress dysregulation is the most common feature across neuropsychiatric diseases, sex differences in how these pathways develop and mature may predict sex-specific periods of vulnerability to disruption and increased disease risk or resilience across the lifespan. The aging brain is also at risk to the effects of stress, where the rapid decline of gonadal hormones in women combined with cellular aging processes promote sex biases in stress dysregulation. In this Review, we discuss potential underlying mechanisms driving sex differences in stress responses and their relevance to disease. Although stress is involved in a much broader range of diseases than neuropsychiatric ones, we highlight here this area and its examples across the lifespan.

Effect of Estrogen-Serotonin Interactions on Mood and Cognition

Both the neurotransmitter serotonin and the ovarian steroid estrogen have been implicated in the modulation of mood and cognition. Although significant functional interactions between estrogen and serotonin are acknowledged, the nature of their relationship has not been fully elucidated. Research using ovariectomized animals has identified estrogen-induced changes in serotonin transmission, binding, and metabolism in brain regions implicated in the regulation of affect and cognition. Studies in humans, particularly of menopausal women undergoing estrogen treatment, have provided some support for these findings and identified instances in which change in mood or cognition is accompanied by alterations in serotonin function and hormonal status. However, it is apparent that further research is required to understand the neural processes involved in the interplay between estrogen and serotonin. By reviewing animal and human data regarding estrogen and serotonins effects on mood and cognition, the authors aim to better define their relationship and highlight areas for further research.

Sex differences in anxiety and depression clinical perspectives

Sex differences are prominent in mood and anxiety disorders and may provide a window into mechanisms of onset and maintenance of affective disturbances in both men and women. With the plethora of sex differences in brain structure, function, and stress responsivity, as well as differences in exposure to reproductive hormones, social expectations and experiences, the challenge is to understand which sex differences are relevant to affective illness. This review will focus on clinical aspects of sex differences in affective disorders including the emergence of sex differences across developmental stages and the impact of reproductive events. Biological, cultural, and experiential factors that may underlie sex differences in the phenomenology of mood and anxiety disorders are discussed.

Gonadal steroids in the treatment of mood disorders

UNLABELLED Increased interest in the complex interplay between gonadal steroids and neurotransmitter systems involved in mood has led investigators to question the role of gonadal steroids in the treatment of affective disorders, especially in women. OBJECTIVES The purpose of this article is to provide a rationale for using gonadal hormones in the treatment of depression in women. METHODS The literature is reviewed regarding 1) sex-specific phenomenologic and epidemiologic differences in the manifestation of psychiatric illness, 2) sex-specific differences in the therapeutic and adverse effects of psychotropic medications, 3) the complex interplay between gonadal steroids and neurotransmitter systems implicated in psychiatric disorders, and 4) the growing literature regarding the use of estrogen and progesterone in the treatment of mood disorders in women and androgens in the treatment of depression and sexual dysfunction in both men and women. RESULTS Findings from pharmacologic trials of estrogen and androgens are encouraging, albeit mixed, in the treatment of mood disorders and decreased libido in women, respectively. Controlled studies have failed to confirm early open-label reports of the effectiveness of progesterone in the treatment of premenstrual syndrome. CONCLUSIONS Pending replication, estrogen may become an important pharmacologic agent in the treatment of postnatal and perimenopausal depression, whereas androgens have been shown to improve libido in postmenopausal women and hypogonadal men. Progesterone cannot be recommended as a treatment for premenstrual syndrome or postnatal depression.

Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders : the ISPMD Montreal consensus

Premenstrual disorders (PMD) are characterised by a cluster of somatic and psychological symptoms of varying severity that occur during the luteal phase of the menstrual cycle and resolve during menses (Freeman and Sondheimer, Prim Care Companion J Clin Psychiatry 5:30–39, 2003; Halbreich, Gynecol Endocrinol 19:320–334, 2004). Although PMD have been widely recognised for many decades, their precise cause is still unknown and there are no definitive, universally accepted diagnostic criteria. To consider this issue, an international multidisciplinary group of experts met at a face-to-face consensus meeting to review current definitions and diagnostic criteria for PMD. This was followed by extensive correspondence. The consensus group formally became established as the International Society for Premenstrual Disorders (ISPMD). The inaugural meeting of the ISPMD was held in Montreal in September 2008. The primary aim was to provide a unified approach for the diagnostic criteria of PMD, their quantification and guidelines on clinical trial design. This report summarises their recommendations. It is hoped that the criteria proposed here will inform discussions of the next edition of the World Health Organisation’s International Classification of Diseases (ICD-11), and the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) criteria that are currently under consideration. It is also hoped that the proposed definitions and guidelines could be used by all clinicians and investigators to provide a consistent approach to the diagnosis and treatment of PMD and to aid scientific and clinical research in this field.

Effects of estrogen variation on neural correlates of emotional response inhibition.

Despite behavioral evidence that variation in ovarian hormones is associated with changes in affect, the neural basis of these processes is poorly understood. We combined functional magnetic resonance imaging (fMRI) with quantitative analysis of ovarian hormones in a within-subject design to investigate brain activation patterns during affective response inhibition, comparing activation between the early follicular (low estrogen and progesterone) and mid-luteal (high estrogen and progesterone) phases of the menstrual cycle in healthy women. There was significantly increased activation in the anterior cingulate and dorsolateral prefrontal cortex (DLPFC) while inhibiting response to positive words during the luteal, compared to the follicular phase. Furthermore, luteal phase estradiol level positively correlated with DLPFC activation while inhibiting response to positive words and negatively correlated with activation in several structures while inhibiting response to negative words, supporting estrogens modulation of affective processing.

Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy.

BACKGROUND Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical gamma-aminobutyric acid (GABA) levels in male and female smokers. METHODS Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison. RESULTS Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men. CONCLUSIONS Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation.

Preliminary evidence of reduced occipital GABA concentrations in puerperal women: a 1H-MRS study

RationaleChildbirth is associated with rapid neuroendocrine fluctuations, which are thought to contribute to the phatogenesis of postpartum major depression (PPD).ObjectivesThe aim of this proton magnetic resonance spectroscopy (1H-MRS) study was two-fold; 1) to examine whether puerperium is associated with alterations in occipital cortex gamma-aminobutyric acid (GABA) concentrations and 2) to determine whether such alterations may be more prominent in women with PPD.Materials and methodsNine women with PPD, 14 postpartum healthy controls, and ten healthy follicular phase females underwent 1H-MRS at 2.1 Tesla to measure occipital cortex GABA concentrations. Postpartum women were scanned within 6 months of delivery and prior to resumption of menstruation. Healthy non-puerperal controls, drawn from a historical sample, were scanned during the early to mid-follicular phase when ovarian hormone levels would be similar to those found in the puerperium. GABA data were analyzed using analysis of covariance, and regression models were used to explore the relationship between cortical GABA concentrations and blood levels of estradiol, progesterone, and neurosteroids.ResultsCortical GABA and plasma allopregnanolone (ALLO) concentrations were reduced in both groups of postpartum women, regardless of PPD diagnosis, compared to healthy follicular phase women. There was no correlation between cortical GABA concentrations and estradiol, progesterone, ALLO, or pregnenolone (PREG).ConclusionsThis study is the first to describe reductions in occipital cortex GABA levels in the postpartum period, a time of increased vulnerability to mood disturbances in women. The concomitant reduction in peripheral ALLO levels provides further evidence of alterations in the balance between cortical excitation and inhibition during the puerperium. Women with PPD may represent a subgroup of women who fail to adequately adapt to this alteration in the neuroendocrine milieu.

Pregnant Women With Posttraumatic Stress Disorder and Risk of Preterm Birth

IMPORTANCE Posttraumatic stress disorder (PTSD) occurs in about 8% of pregnant women. Stressful conditions, including PTSD, are inconsistently linked to preterm birth. Psychotropic treatment has been frequently associated with preterm birth. Identifying whether the psychiatric illness or its treatment is independently associated with preterm birth may help clinicians and patients when making management decisions. OBJECTIVE To determine whether a likely diagnosis of PTSD or antidepressant and benzodiazepine treatment during pregnancy is associated with risk of preterm birth. We hypothesized that pregnant women who likely had PTSD and women receiving antidepressant or anxiolytic treatment would be more likely to experience preterm birth. DESIGN, SETTING, AND PARTICIPANTS Longitudinal, prospective cohort study of 2654 women who were recruited before 17 completed weeks of pregnancy from 137 obstetrical practices in Connecticut and Western Massachusetts. EXPOSURES Posttraumatic stress disorder, major depressive episode, and use of antidepressant and benzodiazepine medications. MAIN OUTCOMES AND MEASURES Preterm birth, operationalized as delivery prior to 37 completed weeks of pregnancy. Likely psychiatric diagnoses were generated through administration of the Composite International Diagnostic Interview and the Modified PTSD Symptom Scale. Data on medication use were gathered at each participant interview. RESULTS Recursive partitioning analysis showed elevated rates of preterm birth among women with PTSD. A further split of the PTSD node showed high rates for women who met criteria for a major depressive episode, which suggests an interaction between these 2 exposures. Logistic regression analysis confirmed risk for women who likely had both conditions (odds ratio [OR], 4.08 [95% CI, 1.27-13.15]). For each point increase on the Modified PTSD Symptom Scale (range, 0-110), the risk of preterm birth increased by 1% to 2%. The odds of preterm birth are high for women who used a serotonin reuptake inhibitor (OR, 1.55 [95% CI, 1.02-2.36]) and women who used a benzodiazepine medication (OR, 1.99 [95% CI, 0.98-4.03]). CONCLUSIONS AND RELEVANCE Women with likely diagnoses of both PTSD and a major depressive episode are at a 4-fold increased risk of preterm birth; this risk is greater than, and independent of, antidepressant and benzodiazepine use and is not simply a function of mood or anxiety symptoms.

Onset and Exacerbation of Obsessive-Compulsive Disorder in Pregnancy and the Postpartum Period

BACKGROUND The primary goal of this study was to examine the impact of pregnancy, childbirth, and menstruation on the onset of obsessive-compulsive disorder (OCD) and/or exacerbation of OCD symptoms. METHOD One hundred twenty-six women aged between 18 and 69 years attending a university-based OCD clinic who met DSM-IV criteria for OCD according to the Structured Clinical Interview for DSM-IV Disorders were interviewed retrospectively to assess OCD onset and symptom exacerbation in relationship to reproductive events. Women were placed into 2 groups: those who had ever been pregnant (ever pregnant group) and those who had never been pregnant. The ever pregnant group was further subdivided into those who reported onset of OCD in the perinatal period (perinatal-related group) and those who denied onset related to pregnancy (nonperinatal-related group). Between-group comparisons were done using a Student t test for continuous measures, and categorical variables were assessed using the χ² test. RESULTS Of the 78 women in the ever pregnant group, 32.1% (n = 24) had OCD onset in the perinatal period (perinatal-related group), 15.4% in pregnancy, 14.1% at postpartum, and 1.3% after miscarriage. Of 132 total pregnancies, 34.1% involved an exacerbation of symptoms, 22.0% involved an improvement in OCD symptoms, and 43.9% did not change symptom severity in women with preexisting illness. Women in the perinatal-related group and women with perinatal worsening of preexisting OCD were more likely to have premenstrual worsening of OCD symptoms compared to women in the nonperinatal-related group (66% vs 39%, P = .047). CONCLUSIONS Findings from this study provide additional evidence that pregnancy and childbirth are frequently associated with the onset of OCD or worsening of symptoms in those with preexisting disorder. In addition, there appears to be continuity between OCD onset and/or exacerbation across the reproductive life cycle, at least with menstruation and pregnancy.