Cognitive Effects of Hormone Therapy Continuation or Discontinuation in a Sample of Women at Risk for Alzheimer Disease.

OBJECTIVE: Use of estrogen-based hormone therapy (HT) as a protection from cognitive decline and Alzheimer disease (AD) is controversial, although cumulative data support HT use when initiated close to menopause onset with estrogen formulations containing 17ß-estradiol preferable to conjugated equine estrogen formulations. Little is known regarding specific populations of women who may derive benefit from HT. METHODS: Women with heightened risk for AD (aged 49-69), all of whom were taking HT for at least 1 year and most of whom initiated HT close to menopause onset, underwent cognitive assessment followed by randomization to continue or discontinue HT. Assessments were repeated at 2 years after randomization. RESULTS: Women who continued HT performed better on cognitive domains composed of measures of verbal memory and combined attention, working memory, and processing speed measures. Women who used 17ß-estradiol versus conjugated equine estrogen, whether randomized to continue or discontinue HT, showed better verbal memory performance at the 2-year follow-up assessment. An interaction was also found with HT randomization and family history of AD in a first-degree relative. All female offspring of patients with AD declined in verbal memory; however, women who continued HT declined less than women who discontinued HT. Women without a first-degree relative with AD showed verbal memory improvement (likely because of practice effects) with continuance and declined with discontinuance of HT. CONCLUSION: Continuation of HT use appears to protect cognition in women with heightened risk for AD when initiated close to menopause onset.

Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls.

OBJECTIVES: The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls. METHODS: Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone. RESULTS: Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively. CONCLUSIONS: Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene.

Phenotypic variations are emerging from investigations of carriers of the fragile X mental retardation 1 (FMR1) premutation gene (55 to 200 CGG repeats). Initial studies suggest elevated psychiatric and reproductive system dysfunction, but have largely used self-reports for assessment of psychiatric history. The present study used diagnostic psychiatric interviews and assessed reproductive and menstrual history in women with FMR1 premutation. History of psychiatric diagnoses and data on reproductive functioning were collected in 46 women with FMR1 premutation who were mothers of at least one child with the fragile X full mutation. Results showed a significantly earlier age of menopause (mean age = 45.6 years) relative to the national average age of menopause (mean age = 51 years) and a high rate (76%) of lifetime depressive or anxiety history, with 43% of the overall sample reporting a comorbid history of both diagnoses. Compared to those free of psychiatric history, significantly longer premutation length was observed among women with psychiatric history after adjusting for age, with comorbid women having the highest number of CGG repeats (mean = 95.8) compared to women free of psychiatric history (mean = 79.9). Psychiatric history did not appear significantly related to reproductive system dysfunction, though results may have been obscured by the high rates of psychiatric dysfunction in the sample. These data add to the growing evidence base that women with the FMR1 premutation have an increased risk of psychiatric illness and risk for early menopause. Future investigations may benefit from inclusion of biochemical reproductive markers and longitudinal assessment of psychiatric and reproductive functioning.

Differences in verbal memory performance in postmenopausal women receiving hormone therapy: 17ß-estradiol versus conjugated equine estrogens.

OBJECTIVE: Much controversy exists and many questions remain unanswered about the effects of hormone therapy (HT) on cognition in postmenopausal women. There is growing evidence suggesting that HT compounds containing conjugated equine estrogen (CEE) have negative effects on cognition whereas 17ß-estradiol (17ß-E) either has positive or neutral effects. The present study sought to further examine this issue in a sample of postmenopausal women with risk factors for Alzheimer's disease (AD). DESIGN: Cross-sectional neuropsychological evaluation. SETTING: Academic research clinic. PARTICIPANTS: 68 healthy postmenopausal women (aged 49-68) receiving either 17ß-E or CEE for at least one year with increased risk for AD. MEASUREMENTS: Neuropsychological test battery of the cognitive domains of attention/working memory/processing speed, verbal memory, visual memory, and executive functioning. RESULTS: Multivariate analyses of variance (MANOVA) showed significantly better verbal memory performance in women receiving 17ß-E compared to women receiving CEE regardless of age, IQ, years of education, risk factors for AD (including APOE-ε4 carriership), duration of endogenous and exogenous estrogen exposure, concurrent progesterone use, or natural versus surgical menopause status. CONCLUSIONS: Verbal memory performance was better in postmenopausal women receiving 17ß-E compared to CEE in a sample population of women with risk factors for AD. Genetic risk for AD as well as other confounds did not affect this finding. The results suggest a differential effect of HT type on verbal memory, with 17ß-E being a preferential compound. Further evaluation of HT types, regimens and duration of use on cognitive performance in postmenopausal women in a controlled longitudinal design is warranted.

Psychiatric complications of treatment with corticosteroids: review with case report.

Corticosteroids are widely used in modern medicine but can result in troubling psychiatric side-effects. Physicians and other medical professionals should be aware of the potential for these side-effects, possible means of prevention, and efficacious treatments. Herein, we review adult case report data published during the past quarter-century on adverse corticosteroid-induced psychiatric effects, and present a case of corticosteroid-induced psychotic depression. PubMed and PsychLit databases were searched using the terms 'corticosteroids', 'steroids', and the generic names of corticosteroid medications with terms for psychiatric symptoms or syndromes, including psychosis, mania, hypomania, depression, apathy, anxiety, panic, depersonalization, delirium, confusion, hallucinations, delusions, paranoia, cognitive impairment and dementia. Fifty-five cases and a number of clinical trials investigating the incidence and treatment of these psychiatric symptoms and syndromes were identified. Data on incidence, drug dose, risk factors, course of illness and treatment (when present) were tabulated. We conclude that the cumulative data indicate that psychiatric complications of corticosteroid treatment are not rare and range from clinically significant anxiety and insomnia, to severe mood and psychotic disorders, delirium and dementia. While tapering or discontinuation of the corticosteroid treatment may remedy these adverse side-effects, psychotropic medications are often required because of the medical necessity of the corticosteroid or the severity of the psychiatric symptom. Further studies are needed to better understand the deleterious psychiatric effects associated with corticosteroids.

Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus.

OBJECTIVE: Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD. METHODS: Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women. RESULTS: As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity. CONCLUSIONS: Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

Preliminary evidence that plasma oxytocin levels are elevated in major depression.

It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.

Rosiglitazone add-on in treatment of depressed patients with insulin resistance: a pilot study.

A number of cross-sectional studies have suggested an association between insulin resistance (IR) and affective disorders. However, limited data exist on potential changes in IR in a prospective treatment of depression. The present pilot study tested the hypothesis that improvement of IR with the addition of an insulin-sensitizing agent would improve mood in nondiabetic patients with unipolar or bipolar depression, who had surrogate blood markers suggestive of IR. Surrogate IR-criteria blood markers were fasting plasma glucose >100 mg/dl or triglyceride (TG) to high density lipoprotein (HDL) ratio >3.0. Open-label rosiglitazone, titrated to a dose of 8 mg/day, was administered for 12 weeks to 12 patients with depressive disorder receiving treatment as usual (TAU). Eight patients who completed the 12-week study exhibited significant declines in both depression severity by the Hamilton Depression Rating Scale and the Clinical Global Impression scale, with moderate effect sizes noted. Modest improvement in Matsuda Index scores was also noted at 12 weeks, yet declines in depression severity scores were not associated with improvements in the endocrine markers (Matsuda Index, TG/HDL ratio, and body mass index). These results suggest the potential novel use for an insulin-sensitizing agent in the treatment of depressive disorders. Larger placebo-controlled studies are warranted.

Thalamo-Basal Ganglia connectivity in postmenopausal women receiving estrogen therapy.

Cumulative data on the effects of estrogen therapy (ET) on brain function in postmenopausal women suggests that ET influences cerebral metabolism and may protect against age-related declines in various domains of cognitive function. The beneficial cognitive effects of ET may relate to its modulation of the thalamic-striatum cholinergic and dopaminergic systems, as the activity of both neurotransmitter systems in the thalamus appears to be positively influenced by estrogen. In the current study, we attempted to evaluated regional cerebral brain metabolism utilizing [18F]-fluorodeoxyglucose positron emission tomography in 11 healthy recently-postmenopausal women on ET (ET+) in comparison to 11 recently-postmenopausal and ET-naïve women (ET-) in order to assess the effects of ET on cholinergic and dopaminergic system regulation. Results showed thalamo-basal ganglia connectivity among ET+ women but not among ET- women. The presence of connectivity in the thalamo-striatal pathway in recently postmenopausal women suggests estrogen effects in preserving integrity of the cholinergic and dopaminergic systems. The results also suggest that ET initiated at or near the menopausal transition may modulate brain aging by mediating complex sensory-motor functions.

Cerebral metabolic patterns in untreated postmenopausal women with major depressive disorder.

Cerebral metabolic rates were assessed using [(18)F]-fluorodeoxyglucose positron emission tomography in six naturally postmenopausal women with untreated unipolar depression and 11 matched controls. All subjects were hormone therapy-naive and medication-free. Findings include hypermetabolism in the middle frontal gyrus and Broca regions, and hypometabolism in the pons among depressed compared with non-depressed women.

Hypothalamic-pituitary-end organ function in women with bipolar depression.

Disturbance of each of the three hypothalamic-pituitary-end organ systems [hypothalamic-pituitary-thyroid (HPT), -adrenal (HPA), and -gonadal (HPG)] has been reported in depressive disorders. Little is known about potential reciprocal interaction among the three HP-end organ systems in patients with depressive disorders. The present pilot study examined selective HPA and HPG hormones in a detailed time series in women with bipolar disorder (depressed type) before and after treatment with levothyroxine (L-T4), and in matched control subjects. Six medically stable, euthyroid, premenopausal women with bipolar depression, and 5 age-matched controls underwent overnight blood sampling from 2100 to 0900 h for measurement of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), and estradiol every 15 min. Bipolar patients underwent a second overnight blood sampling procedure following 7-weeks of open-label add-on treatment with L-T4. Results revealed lower baseline cortisol parameters in bipolar patients in comparison to control subjects, while ACTH, LH, and estradiol parameters were similar. Thyroid hormones (TSH, free and total T4) were not correlated with any of the HPA or HPG hormones. ACTH and cortisol levels were correlated in control subjects, but not in bipolar patients. After L-T4 treatment, thyroid hormones increased significantly and depression scores significantly declined. No significant changes in HPA or HPG hormones parameters were observed, although the small sample size may have limited results. Upon visual inspection, ACTH and cortisol appeared to decrease after L-T4 treatment, while estradiol appeared to increase. These pilot data suggest lower levels of cortisol in women with bipolar depression, unlike previously published studies that reported higher cortisol in patients with depression. The data also suggest reciprocal changes in the HPA and HPG axes upon pharmacological modulation of the HPT system, although whether this change was due to the L-T4 treatment or the improvement of depression is unknown. The results are preliminary, and require replication in larger samples.

Detecting psychotic major depression using psychiatric rating scales.

OBJECTIVE: The aim of this study was to assess whether individual or clusters of psychiatric symptoms can differentiate patients with psychotic major depression (PMD) from those with nonpsychotic depression (NPMD). METHOD: Data were pooled from two studies investigating patients with moderate depression. A total of 129 subjects were studied. Patients in Sample 1 were unmedicated, while the majority of the patients in Sample 2 were taking psychotropic medications. Baseline rating scales were obtained for all subjects, including the Hamilton depression rating scale and the brief psychiatric rating scale (BPRS). We used discriminant function analyses, logistic regression, and ROC analyses to determine the patterns in symptoms that differentiated the groups. RESULTS: Psychotic patients were adequately differentiated by the unusual thought content (UTC) item of the BPRS. Even mild UTC endorsement was an indicator of PMD. Furthermore, results suggest that the positive symptom subscale of the BPRS was even better at differentiating PMD from NMPD patients. Sensitivity and specificity for this scale were 84% and 99%, respectively. CONCLUSION: Psychotic major depression is often undiagnosed and poorly treated. One reason for this trend is the failure of physicians to inquire in a more detailed manner about positive symptoms in patients with primary mood symptoms. Although physicians are not likely to have the time to conduct an entire BPRS during an evaluation, our results suggest that a few key symptoms, if assessed directly, may aid the psychiatrist to more effectively diagnose and subsequently treat their depressed patients.

Insulin resistance in depressive disorders and Alzheimer's disease: revisiting the missing link hypothesis.

Several lines of evidence suggest an association between depressive disorders and Alzheimer's disease (AD). We previously suggested central nervous system (CNS) effects of insulin resistance (IR) to be an important link between depressive disorders and AD. Although the exact mechanism of central IR is not known, it is thought that central IR results in inadequate glucose metabolism in the brain. According to our hypothesis, inadequate glucose utilization resulting from IR underlies neuronal changes in crucial brain regions (i.e. limbic system) observed among patients with depressive disorders, the same brain regions affected in AD. Further, in patients with undetected and/or untreated IR, such changes in glucose utilization, if unresolved, may lead to neurodegeneration. Our studies have demonstrated a high prevalence of IR in patients with depressive disorders, and reciprocally, a high prevalence of depression in patients with the primary IR disorder polycystic ovary syndrome (PCOS), and we believe these populations have significantly increased risk of cognitive decline. Herein, we review the IR link in depressive disorders and AD and describe the results of our studies and others in support of this hypothesis.

Association between insulin resistance and cognition in patients with depressive disorders: exploratory analyses into age-specific effects.

The current preliminary cross sectional study sought to examine the effects of insulin resistance (IR) and body mass index (BMI) on cognitive performance in adult patients with a history depression, currently not in an acute Major Depressive Episode (MDD). As an exploratory post hoc investigation, special consideration was given to adults <45 years and ≥45 years old. Subjects included men and women ages 19-71 (N = 39) with a history of a non-psychotic, non-melancholic MDD. All subjects underwent an insulin suppression test to determine Steady-State Plasma Glucose (SSPG), a battery of neuropsychological tests, and measurement of BMI. Multiple linear regressions were conducted to determine whether there were differential effects of direct (SSPG) and indirect (BMI) measures on cognition in the whole sample and within dichotomized age groups (<45 and ≥45 years). Preliminary results showed that in the sample as a whole, SSPG was not associated with worse performance on any cognitive variables, while higher BMI was associated with worse dominant hand fine motor skills. Within age groups, differential effects on cognition were found in relation to SSPG and BMI. Higher SSPG was associated with worse cognitive flexibility in the group <45 years, whereas higher BMI was associated with worse estimate of global intelligence in the group ≥45 years. The potential negative impact of IR in younger adults with depression raises concerns regarding the long-term impact on cognition and risk for Alzheimer's disease in undiagnosed younger adults with IR and depression. These negative consequences may not be seen with indirect measures of IR in younger adult populations. Overweight and obesity in older adults with a history of depression appear to have further negative impacts on cognition similar to deficits seen in patients with diabetes. CLINICALTRIALSGOV IDENTIFIER: Clinical Trial NCT01106313.

Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder.

OBJECTIVES: To examine the occurrence of menstrually-entrained mood cycling in women with treated bipolar disorder as compared to healthy controls, and to explore whether there is a specific effect of lamotrigine in dampening menstrually-entrained cyclicity of mood. METHODS: Observational comparison study of daily self-ratings of mood, sleep, and insomnia obtained over a mean of four menstrual cycles in 42 women with bipolar disorder taking lamotrigine as part of their treatment, 30 women with bipolar disorder receiving mood stabilizing regimens without lamotrigine, and 13 healthy controls, all with physiological menstrual cycles. Additional exploratory analysis of interactions between psychopharmacological regimen and hormonal contraceptive use in the group of women with bipolar disorder, with the addition of 19 women with bipolar disorder who were using hormonal contraceptives. RESULTS: Women treated for bipolar disorder manifested lower average mood, longer average nightly sleep duration, and greater fluctuations in mood and sleep across menstrual cycle phases than healthy controls. Women with bipolar disorder who were taking lamotrigine had less fluctuation in mood both within and across menstrual cycle phases, and were more similar to the control group than to women with bipolar disorder who were not taking lamotrigine in this respect. In addition, medications with GABA-A receptor modulating effects were found to result in improved mood ratings when combined with hormonal contraceptives. CONCLUSIONS: Menstrually-entrained mood fluctuation is present in women treated for bipolar disorder to a greater degree than in healthy controls. Lamotrigine may be of use in mitigating this fluctuation. GABA-A receptor modulators in general may act synergistically with hormonal contraceptives to enhance mood in women with bipolar disorder; this hypothesis merits further study.

Blood levels of brain derived neurotrophic factor in women with bipolar disorder and healthy control women.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) protein has been implicated in the pathophysiology of mood disorders, with early data suggesting that blood levels may vary by severity of mood symptoms. BDNF polymorphism, val66met, has also been implicated in mood disorders. METHODS: Euthymic women with bipolar disorder (BD) (n=47) and healthy control women (n=26), ages 18-45, were clinically rated using the Montgomery-Asberg Depression Rating Scale (MADRS) and sampled for plasma BDNF concentration, with a subset undergoing genetic analysis for the val66met. RESULTS: BD and control groups did not differ on any demographic variables, nor in plasma BDNF levels or val66met polymorphism. Plasma BDNF concentration did not differ by val66met or BD subtype, nor was it correlated with age or illness duration. Within women with BD, lower plasma BDNF concentrations were significantly associated with higher MADRS scores, even after controlling for psychotropic medication use and illness duration. LIMITATIONS: The sample was relatively small and exclusive to women, with further research needed to investigate the links between BDNF markers and mood symptom severity in both men and women. CONCLUSIONS: The study provides a gender-specific investigation of plasma BDNF levels and mood, and the results add further evidence of a significant interplay between BDNF markers and psychiatric symptomatology. Further, this association did not appear to be confounded by use of psychotropic medication. Studies with larger samples of both genders are needed to further delineate this relationship.

Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia.

UNLABELLED: The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age = 58, SD = 5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT-) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-ß estradiol (17ßE)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17ßE or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17ßE therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT00097058.

Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy.

Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol.

The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes.