Robin Emsley

Violence in male patients with schizophrenia: risk markers in a South African population

OBJECTIVEnWe investigate the role of functional variants in the catecholamine-O-methyl transferase gene (COMT) and the monoamine oxidase-A gene (MOA-A), as well as previously identified non-genetic risk factors in the manifestation of violent behaviour in South African male schizophrenia patients.nnnMETHODnA cohort of 70 acutely relapsed male schizophrenia patients was stratified into violent and non-violent subsets, based on the presence or absence of previous or current violent behaviour. Standardized violence rating scales were also applied and the COMT/NlaIII and MAO-A promoter region variable number of tandem repeats (VNTR) polymorphisms were genotyped.nnnRESULTSnA multiple logistic regression model based on the clinical, genetic and socio-demographic variables indicated that delusions of control (OR = 3.7, 95% CI = 1.21-11.61) and the combined use of cannabis and alcohol (OR = 6.89, 95% CI = 1.28-37.05) were two significant predictors of violent behaviour in this schizophrenia population. No association was found between the tested polymorphisms and violent behaviour.nnnCONCLUSIONSnAlthough the sample size may have limited power to exclude a minor role for these specific gene variants, such a small contribution would have limited clinical relevance given the strong significance of the non-genetic markers. These findings suggest that currently proactive management of violent behaviour in this schizophrenia population should continue to be based on clinical predictors of violence.

The new and evolving pharmacotherapy of schizophrenia

Based on the evidence presented here, the following tentative conclusions can be drawn. Atypical antipsychotics (except amisulpride) have shown superiority over placebo in acute schizophrenia. Compared with conventional antipsychotics, they are at least as effective. Generally, analyses employing conservative criteria (e.g., Cochrane reviews) report few efficacy differences between atypical and conventional agents. There are now many well-controlled studies indicating modest advantages for the atypical antipsychotics, however, particularly in specific symptom domains. For the treatment of negative symptoms, olanzapine and to a lesser extent amisulpride seem most promising. Risperidone, olanzapine, and quetiapine display advantages in improving cognitive and depressive symptoms. There are indications that the atypical antipsychotics are associated with decreased likelihood of rehospitalization and improved quality of life. In head-to-head comparisons of atypical antipsychotics, none have shown consistent efficacy advantages. In severely refractory samples, no atypical antipsychotics have consistently been shown to be as effective as clozapine or superior to conventional agents. There are indications, however, that risperidone, olanzapine, and quetiapine have advantages over conventional agents in less severely refractory patients. Few maintenance RCTs have been published, and efficacy advantages for atypical antipsychotics in prospective RCTs in first-episode schizophrenia have not been reported.

Evidence-based pharmacotherapy of schizophrenia.

The introduction of the new-generation antipsychotics has changed the way we treat patients with schizophrenia. This article reviews these agents, focusing mainly on the published randomized controlled trials and meta-analyses in which the new-generation antipsychotics are compared with placebo, conventional antipsychotics or with one another. Agents included are risperidone, olanzapine, quetiapine, ziprasidone, sertindole, amisulpride and aripiprazole. Acute-phase and maintenance studies are reviewed, as well as randomized trials for pre-psychotic, first-episode schizophrenia and refractory schizophrenia. Finally, specific areas of current clinical interest are dealt with. These are: conventional vs. new-generation antipsychotics, head-to-head comparisons of new-generation antipsychotics, and side-effect profiles.

Towards a treatment model for family therapy for schizophrenia in an urban African setting: Results from a qualitative study

Background: Family interventional programmes are effective adjuncts to pharmacotherapy in patients with schizophrenia. Modification in content of such programmes in response to local challenges is considered important, but has not been fully explored in Africa. Aims: To assess the feasibility and acceptability of an interventional family study for people with schizophrenia and their families in a socially deprived urban community in South Africa and to explore the contextual factors that could influence implementation of the intervention. Method: A psychiatric nurse facilitated semi-structured interviews with four multi-family groups, each comprising adult outpatients with schizophrenia and their caregivers. Six sessions were held per group. Thematic analysis was applied. Results: Three themes emerged: stigma and abuse; substance abuse comorbidity and caregiver burden of multiple stressors. Many of these stressors relate to the challenges of an impoverished urban environment. Conclusions: Multi-family groups with a psycho-educational and behaviour modification frame are acceptable. Negative symptoms are seen as protective in areas of community violence. Modification of traditional models of family therapy to include factors related to poverty, violence, caregiver burden, stigma and limited health care access should be considered in this setting.

Is the ongoing use of placebo in relapse-prevention clinical trials in schizophrenia justified?

BACKGROUNDnPlacebo-controlled randomised controlled trials (RCTs) continue to be required or recommended by regulatory authorities for the licensing of new drugs for schizophrenia, despite ongoing concerns regarding the risks to trial participants.nnnMETHODSnIn this article we consider the scientific and ethical pros and cons associated with use of placebo in RCTs in schizophrenia, systematically review the published relapse-prevention placebo-controlled RCTs with second generation antipsychotics (SGAs) in schizophrenia, and examine the risks associated with these trials.nnnRESULTSnWe identified 12 studies involving 2842 participants of which 968 received placebo. Relapse rates were 56% for placebo and 17.4% for active treatment groups. There is a lack of well-designed longitudinal studies investigating the psychosocial and biological consequences of exposure to placebo, to treatment discontinuation and to relapse in schizophrenia.nnnCONCLUSIONnIn the absence of such studies it is risky to assume that patients are not at risk of significant distress and long-term harm, and therefore it is difficult to justify the ongoing use of placebo in relapse-prevention RCTs in schizophrenia.

The confirmatory factor structure of neurological soft signs in Nigerians with first episode schizophrenia.

We describe empirically derived categories of NSS in first episode schizophrenia among indigenous Africans. A total of 84 Nigerian patients with the disease were assessed using the neurological evaluation scale. An exploratory factor analysis with orthogonal varimax rotation was first conducted and the factors derived based on a priori criteria were subjected to confirmatory analyses using SPSS 18.0 and AMOS 18.0. We tested four different competing models to identify the structure with the best fit to the data. The relationship of the derived NSS structure with the clinical characteristics of schizophrenia was then explored using the Pearson correlation method. The overall clinical status was assessed using the positive and negative syndrome scale and clinical global impression. Additional assessments included the pre-morbid adjustment scale and calgary depression scale for schizophrenia. A three factor structure in which stereognosis is prescribed to load into a perceptual and motor sequencing category (audio-visual integration, fist-edge palm, rhythm tapping, extinction, right-left confusion) provided the best fit to the data (chi-square goodness of fit test=1.25; comparative fit index=0.95; root square means error of approximation <0.05). The other two factors were: eye movement (synkinesis, convergence, gaze impersistence) and motor co-ordination and graphaesthesia (Tandem walk, adventitious flow, graphaesthesia). The signs were associated with severe negative (r=0.456, p<0.001), and disorganization (r=0.559, p<0.001) psychopathologies. NSS in this sample are heterogeneous, but aggregates into three correlated categories with significant overlap with previously described classifications.

Childhood Trauma Associated White Matter Abnormalities in First-Episode Schizophrenia

Schizophrenia is associated with brain connection irregularities within and between brain regions. Childhood trauma increases the risk of schizophrenia suggesting that the relationships between childhood trauma and brain connectivity requires further investigation. Here, we examine the relationship between childhood trauma (as measured by the Childhood Trauma Questionnaire) and fractional anisotropy (FA) in 54 minimally treated first-episode schizophrenia (FES) patients and 51 community matched controls. Patients who experienced high levels of trauma had significantly lower FA in the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and inferior fronto-occipital fasciculus (IFOF) compared with controls who experienced high levels of childhood trauma. A history of childhood sexual abuse in patients was associated with lower FA in the IFOF, ILF, SLF, and forceps major compared with patients without a history of sexual abuse. However, patients who had experienced childhood emotional neglect had higher FA in the right SLF compared to patients with low levels of emotional neglect. Our findings highlight altered cortico-limbic circuitry in FES patients compared with controls and differential effects of childhood emotional neglect and sexual abuse on white matter in patients. Although stress-related white matter (WM) pathways appear to be involved in both schizophrenia and otherwise healthy controls previously exposed to childhood trauma, the pattern of disruption of WM integrity in FES patients appears to be distinct.

A PROSPECTIVE STUDY OF THE CLINICAL OUTCOME FOLLOWING TREATMENT DISCONTINUATION AFTER 2 YEARS IN FIRST-EPISODE SCHIZOPHRENIA

Background: An important unanswered question in the management of schizophrenia is how long antipsychotic treatment should be continued after a first psychotic episode. This study assessed the clinical consequences of antipsychotic discontinuation after 2 years of uninterrupted treatment in patients treated for a first episode of schizophrenia or related illness. This is a pre-specified interim analysis after 1 year of treatment discontinuation. Methods: This study is an extension of a previously published 24month, open-label study in which 50 patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated with flexible doses of risperidone long-acting injection (RLAI). At the completion of that study, patients were offered enrolment in this follow-up study evaluating the effects of treatment discontinuation. Patients opting to participate in the discontinuation trial had RLAI tapered over a period of up to 6 weeks, with follow-up while off antipsychotic therapy or until relapse, defined operationally. Following RLAI discontinuation, patients were assessed every 2 months. RLAI was immediately re-instituted when relapse was identified. This is a pre-specified interim analysis of all subjects who completed 1 year of follow-up. Relapse rates, time to relapse, and antecedents to relapsewere evaluatedwith Positive and Negative Syndrome Scale (PANSS) and Patient-assessed Global Impression of Change (PGI-C) scores. Results: Of the 50 patients who completed the 2-year treatment study,19men and 14women (mean age 27.5±7.9 years and baseline PANSS score of 45.0±7.4) entered the discontinuation study and were followed for 1 year or until relapse. At baseline, 28 patients (84.8%) were in remission. 26 patients (79%) relapsed within 1 year. Kaplan-Meier estimate of median time to relapse was 163 days (95% CI 96–199). 8 patients were hospitalized as a result of relapse. There were no differences between those who relapsed and those who did not in terms of baseline PANSS scores or remission status. PANSS total scores remained similar to those at baseline up until (and including) the visit prior to relapse. Discussion: Similar to previously reported studies with oral and depot antipsychotics,2,3 relapse rates were high within 1 year of treatment discontinuation in patients who had been treated with RLAI for firstepisode of schizophrenia for 2 years. First relapses occurred suddenly, without clear-cut warning signs. These findings have important clinical implications, suggesting that antipsychotic discontinuationafter 2 years of treatment may not be in the best interest of the majority of patients.