Mood and substance-use disorders are both associated with cognitive deficits. Patients with mood and substance-use disorders have poorer cognition than patients with only a mood disorder. Pregnenolone may have beneficial effects on mood and cognition. In a proof-of-concept investigation, 70 participants with bipolar disorder or recurrent major depressive disorder and history of substance abuse/dependence (abstinent for > or =14days prior to enrollment) were randomly assigned to receive pregnenolone (titrated to 100mg/day) or placebo for 8weeks. Participants were assessed using the Mini International Neuropsychiatric Interview, Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT-B), and Stroop Test. Mood was assessed bi-weekly, while cognition was evaluated at baseline, and weeks 4 and 8. Groups were compared using a random regression analysis that used all of the available data. The pregnenolone group showed trends toward greater improvement, relative to placebo, on the HRSD and YMRS. A post hoc analysis of completers found a statistically significant reduction in HRSD scores with pregnenolone as compared to placebo. Pregnenolone appeared to be safe and well tolerated. Findings suggest that pregnenolone use may be associated with some improvement in manic and depressive symptoms, but not cognition in depressed patients with a history of substance use. Larger trials examining the impact of pregnenolone on mood in more narrowly defined populations may be warranted.
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