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.

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.

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.

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.

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.

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.

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.

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.

Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use.

Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean  = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR  = 6.26, 95% CI  = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.

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.

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.

Gender-specific lipid profiles in patients with bipolar disorder.

OBJECTIVE: High rates of dyslipidemia and insulin resistance (IR) are reported in patients with bipolar disorder (BD). We assessed gender effects upon rates of dyslipidemia/IR in outpatients with BD. METHODS: Data from 491 outpatients (ages 18-88) seen in the Stanford Bipolar Disorders clinic between 2000 and 2007 were evaluated. Patients were followed longitudinally and received naturalistic treatment. BD patients (n = 234; 61% female; 42% Type I, 47% Type II, 11% NOS) with a mean age of 40.3 ± 14.0 years, mean BMI 26.8 ± 6.4, and 81% Caucasian, who had one of four lipid measures (total cholesterol, LDL, HDL, TG) at clinicians' discretion, a psychiatry clinic visit within 2 months of laboratory, and were not medicated for dyslipidemia were included. IR was imputed from TG/HDL ratio. RESULTS: Women, compared with men, had significantly lower mean triglycerides (105.58 ± 64.12 vs. 137.99 ± 105.14, p = 0.009), higher mean HDL cholesterol (60.17 ± 17.56 vs. 46.07 ± 11.91 mg/dl, p < 0.001), lower mean LDL cholesterol (109.84 ± 33.47 vs. 123.79 ± 35.96 mg/dl, p = 0.004), and lower TG/HDL ratio (1.98 ± 1.73 vs. 3.59 ± 3.14 p < 0.001). Compared to men, women had a significantly lower prevalence of abnormal total cholesterol, LDL, TG, HDL, and TG/HDL ratio. No significant differences were found between men and women with regard to age, BMI, ethnicity, educational attainment, smoking habits, bipolar illness type, illness severity or duration, or weight-liable medication exposure. DISCUSSION: In outpatients with BD, women had more favorable lipid profiles than men despite similar demographic variables. This sample of primarily Caucasian and educated patients, receiving vigilant clinical monitoring, may represent a relatively healthy psychiatric population demonstrating gender differences similar to those in the general population.

Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD.

Differential cerebral metabolic effects of various hormone therapy formulations, and their associations with cognitive status, remain to be established. The principal aim of the current study was to assess relationships between regional cerebral metabolism and estrogen-based hormone therapies. Postmenopausal women (n=53) at elevated risk for Alzheimer's disease (AD) were on estrogen-containing hormone therapy for at least one year prior to enrollment in a prospective, randomized clinical trial. Subjects underwent an FDG-PET scan, along with neuropsychological, medical, and demographic assessments at time of enrollment, to be repeated one year following randomization to hormone therapy continuation versus discontinuation, and results from analyses of the baseline assessments are reported here. Across all subjects, years of endogenous estrogen exposure correlated most closely with metabolism in right superior frontal gyrus (p<0.0005). Women taking 17ß-estradiol (E) performed three standard deviations higher in verbal memory than women taking conjugated equine estrogen (CEE), and their verbal memory performance positively correlated with metabolism in Wernicke's (p=0.003) and auditory association (p=0.002) areas. Women taking progesterone-plus-estrogen had lower metabolism than women taking unopposed estrogen within the mesial and inferior lateral temporal regions (p<0.0005) and the inferior frontal cortex, contralateral to Broca's area (p<0.0005). In conclusion, particular areas of relatively preserved metabolism were seen in women with more years of endogenous estrogen exposure, as well as in women taking estradiol-based formulations or estrogen therapies unopposed by progesterone, together suggesting regionally specific neuroprotective estrogenic effects.

Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline.

Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized ß=0.06, Wald χ(2)=3.7, p=0.04) and with lower telomerase activity (standardized ß=-0.09, Wald χ(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity.

Insulin resistance and hippocampal volume in women at risk for Alzheimer's disease.

Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-ε4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

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.

Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: points of pathophysiological commonality with mood disorders?

BACKGROUND: It is hypothesized that diabetes mellitus (DM) and mood disorders share points of pathophysiological commonality in the central nervous system. METHODS: A PubMed search of all English-language articles published between 1966 and March 2009 was performed with the following search terms: depression, mood disorders, hippocampus, amygdala, central nervous system, brain, neuroimaging, volumetric, morphometric, and neurocognitive deficits, cross-referenced with DM. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. The primary author was principally responsible for adjudicating the merit of articles that were included. RESULTS: Volumetric studies indicate that individuals with Type 1/2 DM exhibit regional abnormalities in both cortical and subcortical (e.g., hippocampus, amygdala) brain structures. The pattern of neurocognitive deficits documented in individuals with Type 1 DM overlap with Type 2 populations, with suggestions of discrete abnormalities unique to each phenotype. The pattern of volumetric and neurocognitive deficits in diabetic populations are highly similar to that reported in populations of individuals with major depressive disorder. CONCLUSION: The prevailing models of disease pathophysiology in DM and major depressive disorder are distinct. Notwithstanding, the common abnormalities observed in disparate effector systems (e.g., insulin resistance, immunoinflammatory activation) as well as brain volume and neurocognitive performance provide the nexus for hypothesizing that both conditions are subserved by overlapping pathophysiology. This conception provides a novel framework for disease modeling and treatment development in mood 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.