The influence of lithium on hippocampal volume in elderly bipolar patients: a study using voxel-based morphometry.

Recent studies have demonstrated that lithium (Li) exerts neuronal protective and regenerative effects both in vitro and in vivo. However, the effects of long-term Li treatment in the brain areas associated with memory impairment of elderly bipolar patients are still unknown. The aim of this study was to compare the hippocampal volumes of elderly bipolar patients using Li, elderly bipolar patients not using Li and healthy controls. Sociodemographic, clinical and magnetic resonance imaging data from 30 elderly euthymic bipolar patients who had been using Li for an average of >61 months; 27 elderly euthymic bipolar patients not taking Li for an average of 45 months; and 22 elderly healthy controls were analyzed. Volumetric differences in the hippocampus between groups were investigated with voxel-based morphometry (VBM) based on the Statistical Parametric Mapping technique. No statistical differences in sociodemographic and clinical characteristics and course of bipolar disorder between the two bipolar groups were observed. Using small volume correction in the VBM analysis (analysis of variance (ANOVA)), one voxel cluster of statistical significance was detected in the left hippocampus (P<0.05 corrected for multiple comparisons, extent threshold >10 voxels). Post hoc unpaired t-tests revealed increased left hippocampal volume in the Li-treated group compared with the non-Li-treated group, and decreased left hippocampal volume in the non-Li group relative to controls. Additional exploratory two-group comparisons indicated trends toward reduced right-hippocampal volumes in the non-Li-treated group relative to both the Li-treated group and controls. The findings suggested that the use of Li may influence the volume of the hippocampus, possibly due to its neuroprotective effects.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.