Pregnenolone for cognition and mood in dual diagnosis patients.

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.

Attenuation of the effects of corticosteroids on declarative memory with lamotrigine.

An extensive animal literature suggests that excessive corticosteroid exposure is associated with changes in memory and the hippocampus. Agents that decrease glutamate attenuate corticosteroid effects on the hippocampus. Minimal data are available on preventing or reversing corticosteroid effects on the human hippocampus. We previously reported that open-label lamotrigine was associated with significant improvement in declarative memory in corticosteroid-treated patients. We now examine the impact of 24 weeks of randomized, placebo-controlled lamotrigine therapy on declarative memory (primary aim) and hippocampal volume (secondary aim) in 28 patients (n=16 for lamotrigine, n=12 for placebo) taking prescription corticosteroids. All participants with data from at least one postbaseline assessment (n=9 for lamotrigine, n=11 for placebo) were included in the analysis. Declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and weeks 12 and 24. Hippocampal and total brain volumes were manually traced from MRI scans obtained at baseline and week 24. On the basis of an ANCOVA analysis, total words learned on the RAVLT at exit were significantly greater in the lamotrigine group (n=8, missing data or dropouts n=8) compared to the placebo group (n=11, dropout n=1). RAVLT scores in the lamotrigine group increased from mildly impaired to average range. Hippocampal volume changes were small in both lamotrigine (n=7) and placebo (n=7) groups during the 24-week assessment period and between-group differences were not significant. Results suggest that lamotrigine may improve declarative memory in patients taking prescription corticosteroids although differential dropout rate in the two groups is a concern.

Cognition in bipolar disorder.

BPD is often associated with cognitive deficits that tend to be present regardless of mood state. Greater impairments tend to be seen in BPD patients who are older, have an early onset of the disease, and suffer a more severe course of illness. The literature also suggests that cognitive deficits are present early in patients with BPD and may be cumulative, showing an association with the number of affective (particularly depressed) episodes over time. Cognitive deficits in BPD may share some common characteristics with those seen in patients with schizophrenia, although the latter tend to show much greater and generalized cognitive impairment. For example, unlike patients with schizophrenia, patients with BPD typically do not score lower than normal persons on measures of global intellectual ability. There also is not overwhelming evidence of laterality or localization of cognitive deficits in BPD, although debate in the literature continues. More visuospatial deficits tend to be found in BPD and UPD than in schizophrenia, thereby raising the possibility of greater involvement of right hemisphere systems in mood disorders. In general, despite variability across investigations, deficits in executive functioning, episodic memory,sustained concentration, and, to a lesser extent, visuospatial skills seem to be the most consistent areas of impairment in BPD. Just as neuroimaging anomalies have been well documented in schizophrenia, structural brain abnormalities have been noted in BPD,most commonly involving the basal ganglia or white matter. Specific comparisons of cerebral atrophy and ventricular size between patients with schizophrenia and BPD have not been definitive, making it difficult to draw conclusions about structural brain abnormalities that might be specific to BPD. Nonetheless, there is enough evidence to suggest that white-matter abnormalities are reported with a greater frequency in BPD patients than in patients with UPD or schizophrenia. Functional neuro-imaging studies of mood disorders have indicated that the frontal cortex,basal ganglia, and temporal lobes are involved. The relationships between neuroimaging and neurocognitive abnormalities in BPD are worthy of additional investigation. Clearly, efforts directed toward phenotyping neuropsychiatric disorders using such measures, in addition to other clinical, neuroimaging, neurophysiologic, and genotypic information, may yield important insights into the development, nature, and course of illness. It is hoped that this understanding will lead to better identification of individuals who may be prone to greater cognitive impairment or decline and those who might be more responsive to specific treatments.