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Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4(CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131Tmutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901Gmutation was nominally enriched in cases (11 cases vs. 3 controls, P= 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131Tmutation carriers exhibited abnormal post-translational processing (P= 0.029), subcellular localization of mutant NG2 (P= 0.007), as well as aberrant cellular morphology (P= 3.0 × 10−8), viability (P= 8.9 × 10−7), and myelination potential (P= 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T(P= 0.006) and CSPG4V901G(P= 3.4 × 10−4) mutations. Finally, in vivodiffusion tensor imaging of CSPG4A131Tmutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P= 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

The authors conducted an open-label study of the efficacy and tolerability of venlafaxine and of lithium augmentation in outpatients with depression who were not responding to venlafaxine. Outpatients aged 18 to 70 years were eligible if they had a minimum baseline score of 16 on the 17-item Hamilton Rating Scale for Depression (HAM-D). Patients were started on venlafaxine 37.5 mg twice daily for 1 week. For weeks 2 through 4, the dose of venlafaxine was increased to 75 mg twice daily, and for weeks 5 through 7, the dose was further increased to 75 mg three times daily. At the end of the 7-week treatment period, patients with a <50% decrease in their HAM-D scores from baseline were given lithium carbonate 600 mg once daily. The dose of lithium carbonate was adjusted to maintain plasma levels in the range of 0.6 to 1.0 mmol/mL. Efficacy was assessed with the 17-item HAM-D, Montgomery-Åsberg Depression Rating Scale, and the Clinical Global Impressions Scale. Data were analyzed on an intent-to-treat basis. At the end of the 7-week treatment period, 35% of patients showed a ≥50% decrease in their HAM-D scores from baseline. Lithium augmentation was initiated in 23 patients. The results showed that the addition of lithium was well-tolerated and led to a further decrease in the HAM-D scores, with eight patients responding and two of them presenting a remission. The addition of lithium to venlafaxine was found to be a well-tolerated strategy in treatment-resistant patients.

In The Netherlands, individuals charged with rape may be prosecuted only in instances in which the suspect could have known that the victim was unconscious or in a state of powerlessness. Hypnosis might be looked upon as a method by which an unscrupulous person could sustain such a state of powerlessness in a victim. As an expert witness, the present author participated in a court case against a lay hypnotist who was accused of abusing 9 women. The methods and strategy used by the lay hypnotist are presented as well as are the diverse reactions of the women involved in the case. Feelings of nonvolition appear to have been a relevant factor in the coercion, especially in women who demonstrated hypnotic phenomena such as arm levitation, catalepsy, etc. The basis for sexual coercion was established only after the interpersonal relationship had been redefined as a therapeutic relationship. Introduction within the pseudotherapeutic relationship of a sexual rationale for the presented complaints helped to provide a framework for actual sexual acts to occur. With certain individual patients, the introduction of hypnosis enhanced the subjective experience of nonvolition and with it the vulnerability for abuse. It may be hypothesized that patients with a tendency for external attribution and high hypnotizability are specifically at risk for this kind of abuse when hypnosis is used in the context of a therapeutic relationship.