Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders.

BACKGROUND: Previous studies have shown that individuals with mood disorders have a higher prevalence of both hypercortisolemia and insulin resistance. Insulin resistance is posited to contribute to the cognitive deficits observed in individuals who have depression. However, the mechanistic relationship between cortisol and insulin within the central nervous system remains to be further elucidated. This study aimed to evaluate the effects of the antiglucocorticoid agent, mifepristone, on metabolic function and cognitive performance in individuals receiving treatment for depressive disorders who were euthymic at baseline. METHODS: Participants were administered a 600 mg/day dose of mifepristone for 28 days. Oral glucose tolerance tests (OGTTs) and cognitive assessments measuring verbal memory and executive functioning were administered at baseline and after 28 days of treatment. RESULTS: Improvements in attention and verbal learning were associated with reduction of fasting plasma glucose (FPG) in response to mifepristone treatment. LIMITATIONS: Limitations include the open-label design of this study and a small sample size. CONCLUSIONS: The findings from this study suggest that improvement in fasting plasma glucose levels, upon administration of mifepristone, is associated with the improvement in early input of verbal information. Further studies are warranted in order to better evaluate the use of mifepristone or other antiglucocorticoid agents in treatment of mood disorders characterized by metabolic dysfunction.

Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study.

BACKGROUND: To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer's disease (AD) using a built-in control for the genetic risk factor for AD (apoE-epsilon4 status). METHODS: A prospective, open-label, 6-month pilot medication trial with memantine and follow-up after discontinuance conducted at the Center for Neuroscience in Women's Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community-dwelling postmenopausal women (11 apoE-epsilon4 carriers and 11 apoE-epsilon4 non-carriers) with at least one putative risk factor for AD. RESULTS: ApoE-epsilon4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend-level improvements were seen in motor dexterity of the non-dominant hand and maintained even after drug discontinuance. CONCLUSIONS: Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE-epsilon4 carrier status did not account for observed changes in cognition.

Valproate and neuroendocrine changes in relation to women treated for epilepsy and bipolar disorder: a review.

Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

Lamotrigine therapy in treatment-resistant menstrually-related rapid cycling bipolar disorder: a case report.

AIMS/OBJECTIVES: To evaluate lamotrigine in a woman with a 30-year history of treatment-resistant menstrually-entrained rapid cycling bipolar II disorder with follicular phase depressive and luteal phase mood elevation symptoms. METHODS: Lamotrigine was started at 5 mg/day and gradually increased up to 300 mg/day, while venlafaxine was tapered gradually and discontinued, and divalproex sodium 500 mg/day and levothyroxine 175 mcgm/day were continued. Daily self-reported mood ratings were obtained from the patient, using ChronoRecord software. RESULTS: As lamotrigine was increased gradually, mood cycle amplitude attenuated. There was notable decrease in the severity and duration of depressive symptoms specifically during the follicular phase of the menstrual cycle. At the time of submission of this paper, the subject had remained euthymic for a total of 12 months. CONCLUSION: This case suggests the potential utility of lamotrigine in treatment-resistant menstrually-related rapid cycling bipolar disorder, and raises the possibility that lamotrigine might be able to treat pathological entrainment of mood with the menstrual cycle. Both of these issues merit systematic assessment.

Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review.

We present the case of a young woman with treatment-resistant major depression, who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS). The resolution of her depressive symptoms resulted from the treatment for PCOS with metformin and spironolactone. The patient remained euthymic 5 months after discontinuation of the antidepressant while continuing therapy for PCOS. We briefly overview of the pertinent literature of the pathophysiology of PCOS and affective disorders, highlighting an overlap in phenotypical presentations between these two disorders. Dysregulation of the hypothalamo-pituitary axis and various end organ systems are implicated in both PCOS and affective disorders. As such, several clinical and biochemical markers are common to both disorders, namely insulin resistance, obesity, and hyperandrogenism. In addition, these metabolic abnormalities are interrelated, causing women with PCOS or affective disorders to get caught in a "vicious cycle" of hormonal dysregulation. The case report presented here illustrates how treatment of symptoms such as insulin resistance and hyperandrogenism can lead to remission of major depressive disorder and PCOS. We suggest that through treatment of underlying metabolic defects, both the mood of the patient and the metabolic condition of PCOS can be assisted.

Estrogen use and brain metabolic change in older adults. A preliminary report.

Because estrogen may influence brain blood flow and metabolism in older adults, we used positron emission tomography to evaluate cerebral glucose metabolic change in post-menopausal women and men. Women estrogen users (n=4), women non-users (n=8) and men (n=10) were scanned at baseline and two years later. Analyses focused on glucose metabolism in lateral temporal, inferior parietal and posterior cingulate brain regions, previously reported to decline in non-demented older persons. No metabolic differences in cerebral regions of interest were found among groups at baseline. At follow-up, women estrogen users showed significantly increased glucose metabolism in the lateral temporal region, whereas women non-users and men exhibited no significant metabolic change in this region. These findings suggest that estrogen use may protect against regional cerebral metabolic decline in postmenopausal women.

Menstrual cycle-related brain metabolite changes using 1H magnetic resonance spectroscopy in premenopausal women: a pilot study.

Proton magnetic resonance spectroscopy (1H-MRS) was used to assess neurochemical brain changes across the menstrual cycle in five women with premenstrual dysphoric disorder (PMDD) and six control subjects. Women with PMDD and control subjects were scanned on days 8 and 26 within one menstrual cycle (i.e. at times of complete absence and height of PMDD symptoms, respectively). The point resolved spectroscopic sequence (PRESS) was used to localize a voxel of 8 ml in the medial frontal gray matter and in the occipito-parietal white matter. The ratio of N-acetyl-aspartate to creatine in the region of the medial prefrontal cortex and the cingulate gyrus declined significantly from the follicular to the luteal phase in both groups of subjects. The menstrual phase-dependent significant increase in the ratio of choline to creatine was observed in the parietal white matter. The myo-inositol/creatine ratio exhibited a trend toward higher levels in the PMDD patients in the luteal phase of the menstrual cycle. Differences between PMDD and control subjects were not statistically significant. Menstrual cycle phase-dependent changes in ovarian hormonal concentrations may influence the neurochemistry of brain activity in premenopausal women.

Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report.

BACKGROUND: In patients with epilepsy, polycystic ovary (PCO) syndrome has been reported to be associated with the use of the anticonvulsant divalproex sodium. Whether PCO syndrome is associated with divalproex use in patients with bipolar disorder has not previously been explored. METHOD: Twenty-two female outpatients with a DSM-IV diagnosis of bipolar disorder who were between the ages of 18 and 45 years (inclusive) and who were taking lithium and/or divalproex (10, divalproex monotherapy; 10, lithium monotherapy; 2, divalproex/lithium combination therapy) were evaluated. Patients completed questionnaires about their medical, psychiatric, and reproductive health histories, and body mass indices were calculated. In the early follicular phase of their menstrual cycle, women were examined for hirsutism, given a pelvic ultrasound, and/or assessed for changes in laboratory values such as serum levels of testosterone, free testosterone, estradiol, estrone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and 17-OH progesterone. RESULTS: All 10 patients on lithium monotherapy, 6 of 10 patients on divalproex monotherapy, and both of the patients on divalproex/lithium combination therapy reported some type of menstrual dysfunction, which, in 4 cases, had preceded the diagnosis of bipolar disorder. Hirsutism was not common in any group, but obesity was prominent in all groups. Ovarian ultrasound revealed an increased number of ovarian follicles in 1 patient taking lithium and in none of the patients taking divalproex. Hormonal screening did not indicate PCO-like changes in any patient. CONCLUSION: In this pilot study of bipolar patients, PCO-like changes were not seen in women receiving divalproex or lithium. However, independent of therapeutic agent used, the bipolar women in this study reported high rates of menstrual disturbances, suggesting that the hypothalamic-pituitary-gonadal axis may be compromised in some women with bipolar disorder.

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Efficacy and response time to sertraline versus fluoxetine in the treatment of unipolar major depressive disorder.

BACKGROUND: Few studies have compared the treatment efficacy of the 2 selective serotonin reuptake inhibitors sertraline and fluoxetine. METHOD: A randomized, single-blind, parallel-group study of 10 weeks' duration comparing the efficacy of sertraline, 50 mg/day; sertraline, 100 mg/day; and fluoxetine, 20 mg/day, was conducted in 44 psychiatric outpatients with DSM-IV unipolar major depressive disorder. Antidepressant dosages were doubled at 6 weeks for subjects who had not achieved remission. Primary outcome measurements included the 21-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions-Improvement scale (CGI-I), with scores of < or = 7 on the HAM-D and < or = 2 on the CGI-I representing a positive treatment response, i.e., remission. RESULTS: At 4 weeks, significant differences in rate of positive treatment response were noted, with 0% for sertraline, 50 mg; 46% for sertraline, 100 mg; and 31% for fluoxetine, 20 mg (p = .023). At 6 weeks, positive treatment response rates were 21%, 43%, and 31% for subjects taking 50 mg of sertraline, those taking 100 mg of sertraline, and those taking 20 mg of fluoxetine, respectively, with treatment groups no longer differing significantly from each other. In subjects for whom antidepressant dose was doubled at week 6, response rates at week 10 (4 weeks on increased dose) were 40% for sertraline, 100 mg; 43% for sertraline, 200 mg; and 55% for fluoxetine, 40 mg. CONCLUSION: Subjects taking sertraline, 100 mg, and fluoxetine, 20 mg, demonstrated an earlier treatment response compared with subjects taking sertraline, 50 mg. For patients without a positive response at 6 weeks, an increased antidepressant dose resulted in remission for a substantial proportion of patients when assessed 4 weeks later.