The effectiveness of assertive community treatment for elderly patients with severe mental illness: A randomized controlled trial

Background: Due to fragmented mental, somatic, and social healthcare services, it can be hard to engage into care older patients with severe mental illness (SMI). In adult mental health care, assertive community treatment (ACT) is an organizational model of care for treating patients with SMI who are difficult to engage. So far all outcome studies of assertive community treatment have been conducted in adults.Methods: In a randomized controlled trial design we compared the effectiveness of ACT for elderly patients with that of treatment as usual (TAU). Sixty-two outpatients (60 years and older) with SMI who were difficult to engage in psychiatric treatment were randomly assigned to the intervention or control group (32 to ACT for elderly patients and 30 to TAU). Primary outcomes included number of patients who had a first treatment contact within 3 months, the number of dropouts (i.e. those discharged from care due to refusing care or those who unintentionally lost contact with the service over a period of at least 3 months); and patients' psychosocial functioning (HoNOS65+ scores) during 18 months follow-up. Secondary outcomes included the number of unmet needs and mental health care use. Analyses were based on intention-to-treat.Results: Of the 62 patients who were randomized, 26 were lost to follow-up (10 patients in ACT for elderly patients and 16 in TAU). Relative to patients with TAU, more patients allocated to ACT had a first contact within three months (96.9 versus 66.7%; X2 (df = 1) = 9.68, p = 0.002). ACT for elderly patients also had fewer dropouts from treatment (18.8% of assertive community treatment for elderly patients versus 50% of TAU patients; X2 (df = 1) = 6.75, p = 0.009). There were no differences in the other primary and secondary outcome variables.Conclusions: These findings suggest that ACT for elderly patients with SMI engaged patients in treatment more successfully.Trial registration: NTR1620

Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine: A Pragmatic Randomized Controlled Trial (CYSCE Trial)

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

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 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation 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 CSPG4A131T mutation 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 vivo diffusion tensor imaging of CSPG4A131T mutation 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