Showing papers by "David R. Rubinow published in 2002"

Effects of ovarian hormones on human cortical excitability.

Abstract: Ovarian steroids appear to alter neuronal function in women, but direct physiological evidence is lacking. In animals, estradiol enhances excitatory neurotransmission. Progesterone-derived neurosteroids increase GABAergic inhibition. The effect of weak transcranial magnetic stimulation of the motor cortex on the motor evoked potential (MEP) from transcranial magnetic stimulation given milliseconds later is changed by GABAergic and glutamatergic agents. Using this technique previously, we showed more inhibition in the luteal phase relative to the midfollicular menstrual phase, which is consistent with a progesterone effect. To detect the effects of estradiol, we have now divided the follicular phase. We tested 14 healthy women during the early follicular (low estradiol, low progesterone), late follicular (high estradiol, low progesterone), and luteal (high estradiol, high progesterone) phases, with interstimulus intervals from 2 to 10msec (10 trials at each interval and 40 unconditioned trials). We calculated the ratio of the conditioned MEP at each interval to the mean unconditioned MEP: the higher the ratio, the less inhibition and the more facilitation caused by the first stimulus. The combined ratios increased significantly from the early follicular phase to the late follicular phase and then decreased again in the luteal phase. These findings demonstrate an excitatory neuronal effect associated with estradiol and confirm our earlier finding of inhibition associated with progesterone.

National Depressive and Manic-Depressive Association Consensus Statement on the Use of Placebo in Clinical Trials of Mood Disorders

Abstract: A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research.

Effects of metergoline on symptoms in women with premenstrual dysphoric disorder

Abstract: OBJECTIVE: The authors investigated the role of acute serotonergic modulation in the efficacy of selective serotonin reuptake inhibitors (SSRIs) in women with premenstrual dysphoric disorder. METHOD: Patients with premenstrual dysphoric disorder (whose symptoms had remitted during treatment with fluoxetine) and a group of unmedicated healthy comparison women received the serotonin receptor antagonist metergoline as part of a double-blind, placebo-controlled crossover study. RESULTS: The patients with premenstrual dysphoric disorder experienced a return of symptoms 24 hours after treatment with metergoline but not diphenhydramine (active placebo). The comparison women experienced no changes in mood. CONCLUSIONS: These data support the role of altered serotonergic transmission in the efficacy of SSRI treatment for premenstrual dysphoric disorder.

Gonadal steroids, brain, and behavior: role of context.

Abstract: The nature and extent of the impact of gender and reproductive function on mood has been the subject of speculation and controversy for centuries. Over the past 50 years, however, it has become increasingly clear that not only is the brain a major target of reproductive steroid hormones, but additionally, the steroid hormones, as neuroregulators, create a context thai influences a broad range of brain activities; ie, neural actions and resultant behaviors are markedly different in the presence and absence of gonadal steroids. In turn, the actions of gonadal steroids are themselves context-dependent. Thus, even where it can be demonstrated thai gonadal steroids trigger mood disorders, the triggers are normal levels of gonadal steroids (to be contrasted with the mood disturbances accompanying endocrinopathies), and the mood disorders appear only in a subset of susceptible individuals. The context specificity and differential susceptibility to affective dysregulation seen in women with reproductive endocrine-related mood disorders are undoubtedly important underlying characteristics of a wide range of psychiatric disorders in which the triggers have not yet been identified. Consequently, reproductive endocrine-related mood disorders offer unparalleled promise for the identification of those contextual variables that permit biological stimuli to differentially translate into depression in individuals at risk.

Reproductive hormonal treatments for mood disorders in women

Abstract: There has been a century-long view in medicine that reproductive function in both men and women is intimately involved with mood regulation. The 19th century witnessed a proliferation of medical reports documenting beneficial effects on mood and behavior after medical or surgical manipulations of women's reproductive function. More recently, the results of several studies suggest that gonadal steroids do regulate mood in some women. Thus, there is considerable interest in the potential role of reproductive therapies in the management of depressive illness, including both classical and reproductive endocrine-related mood disorders. Future studies need to determine the predictors of response to hormonal therapies compared with traditional antidepressant agents, and to characterize the long-term safety and benefits of these therapies.

Gonadal Hormones and Behavior in Women: Concentrations versus Context

Abstract: Gonadal steroids are major neuroregulators, and their actions have been proposed to underlie many of the sex differences in brain structure and function Both basic and clinical studies suggest that these neuroregulatory effects of reproductive steroids are context dependent, with context including age, sex, environment/past experience, and genotype This chapter focuses on the effects of gonadal steroids on brain function and behavior in women First, background information is provided on the reproductive endocrine system in women, including the regulation of the hypothalamic–pituitary–ovarian axis, as well as the endocrinology of the menstrual cycle, pregnancy, the postpartum, and the menopause transition Second, data will be discussed that demonstrate the role context plays in determining a differential response to gonadal steroids within the central nervous system Third, evidence from neuroimaging and neuroendocrine studies in humans is described that demonstrate the important neuroregulatory effects of gonadal steroids on physiological systems mediating affective adaptation Fourth, existing literature is reviewed regarding clinical characteristics and neurobiology of reproductive endocrine-related mood disorders Finally, recent findings are discussed that identify sources of differential behavioral sensitivity in humans, including polymorphic genetic variants in the steroid signaling pathways and differences in steroid metabolism