The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

http://enigma.ini.usc.edu/wp-content/uploads/2015/07/ENIGMA-Schizophrenia-Molecular-Psychiatry-van-Erp-T-2015.pdf

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(12)60239-6.pdf

Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis

Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies

Cortical gray matter deficits have been found in patients with schizophrenia, with evidence of progression over time. The aim of this study was to determine the extent of progressive cortical gray matter volume changes over time in schizophrenia, their site and time of occurrence, and the role of potential moderators of brain changes. English language articles published between 1 January 1983 and 31 March 2012 in the MEDLINE and EMBASE databases were searched. Longitudinal magnetic resonance imaging studies comparing changes in cortical gray matter volume over time between patients with schizophrenia and healthy controls were included. Hedges g was calculated for each study. Analyses were performed using fixed- and random-effects models. A subgroup analysis was run to explore the pattern of brain changes in patients with first-episode schizophrenia. A meta-regression statistic was adopted to investigate the role of potential moderators of the effect sizes (ESs). A total of 19 studies, analyzing 813 patients with schizophrenia and 718 healthy controls, were included. Over time, patients with schizophrenia showed a significantly higher volume loss of total cortical gray matter, left superior temporal gyrus (STG), left anterior STG, left Heschl gyrus, left planum temporale and posterior STG bilaterally. Meta-analysis of first-episode schizophrenic patients showed a more significant pattern of progressive loss of whole cerebral gray matter volume involving the frontal, temporal and parietal lobes, and left Heschl gyrus compared with healthy controls. Clinical, pharmacologic and neuroradiological variables were found to be significant moderators of brain volume changes in patients with schizophrenia. The meta-analysis demonstrates that progressive cortical gray matter changes in schizophrenia occur with regional and temporal specificity. The underlying pathological process appears to be especially active in the first stages of the disease, affects the left hemisphere and the superior temporal structures more and is at least partly moderated by the type of pharmacological treatment received.

/pdf/progressive-loss-of-cortical-gray-matter-in-schizophrenia-a-5228f2xjju.pdf

Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies

Background: Multiple relapses characterise the course of illness in most patients with schizophrenia, yet the nature of these episodes has not been extensively researched and clinicians may not always be aware of important implications. Methods: We critically review selected literature regarding the nature and underlying neurobiology of relapse. Results: Relapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse; many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs; once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode; while most patients respond promptly to re-introduction of antipsychotic treatment after relapse, the response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients. These observations are consistent with contemporary thinking on the dopamine hypothesis, including the aberrant salience hypothesis. Conclusions: Given the difficulties in identifying those at risk of relapse, the ineffectiveness of rescue medications in preventing full-blown psychotic recurrence and the potentially serious consequences, adherence and other factors predisposing to relapse should be a major focus of attention in managing schizophrenia. The place of antipsychotic treatment discontinuation in clinical practice and in placebo-controlled clinical trials needs to be carefully reconsidered.

/pdf/the-nature-of-relapse-in-schizophrenia-2w1cxpqloh.pdf

The nature of relapse in schizophrenia.

The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients. Sixteen remitted, stable patients with first-episode schizophrenia, schizoaffective or schizophreniform disorder and 20 healthy controls were included. Two magnetic resonance imaging brain scans were obtained from all subjects with a 1-year interval. The patients either discontinued (n = 8) their atypical antipsychotic medication (olanzapine, risperidone, or quetiapine) or did not (n = 8) discontinue during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens, and putamen were obtained. Multiple linear regression analyses were used to assess main effects for group (patient-control) and discontinuation (yes-no) for brain volume (change) while correcting for age, sex, and intracranial volume. Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls. Our data suggest decreases in the nucleus accumbens and putamen volumes during the interval in patients who discontinued antipsychotic medication, whereas increases were found in patients who continued their antipsychotics. We confirmed earlier findings of excessive gray matter volume decrements in patients with schizophrenia compared with normal controls. We found evidence suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication. This might suggest that discontinuation reverses effects of atypical medication.

/pdf/brain-volume-changes-after-withdrawal-of-atypical-5bwivxmr2v.pdf

Brain volume changes after withdrawal of atypical antipsychotics in patients with first-episode schizophrenia.

Duration of untreated illness in schizophrenia is not associated with 5-year brain volume change.

Objective. To assess the effect of withdrawal of antipsychotic treatment on relapse risk in remitted fi rst-episode schizophrenia patients. Methods. First-episode 1-year stable and remitted outpatients with a schizophrenic disorder were randomly allocated to continuation of their antipsychotic regimen for at least 6 months ( N � 9), or gradual withdrawal ( N � 11). Primary outcome was the difference in cumulative relapse-free survival at 9 months. Results. Recruitment was terminated prematurely on 26 October 2005. The cumulative relapse-free survival was 88% (SE � 0.12) in the continuation and 18% (SE � 0.12) in the discontinuation group ( P � 0.001) at 9 months follow-up. Conclusions . Discontinuation of antipsychotic medication markedly increases the risk of relapse in stable remitted fi rst-episode schizophrenia patients. In future studies the topics of safety monitoring and sampling of patients should receive extra attention.

Antipsychotic prophylaxis is needed after remission from a first psychotic episode in schizophrenia patients: results from an aborted randomised trial.

RATIONALE, AIMS AND OBJECTIVES: Antipsychotics are approved treatment for severe conditions and have serious side effects. Antipsychotics are often prescribed off-label. Although a substantial proportion of antipsychotics are prescribed in primary care, it is largely unknown what motivates the general practitioner (GP) to initiate antipsychotic treatment. Therefore, we sought to examine the relation between pre-defined, licensed as well as off-label, reasons for antipsychotic treatment and the initiation of this treatment by the GP as well as report registration and incidence of antipsychotic treatment in general practice. METHODS: In a case-control study, 723 patients selected from an electronic database and with a new antipsychotic prescription were compared with 3615 controls receiving any other new prescription. Using logistic regression, six pre-defined categories of International Classification of Primary Care (ICPC) codes ('psychosis', 'depression and anxiety', 'sleeping disorders', 'acute stress and surmenage', 'dementia' and 'somatic indications') were associated with initiating antipsychotic treatment. RESULTS: All, including off-label, categories were significantly related to initiating antipsychotic treatment. The incidence of initiating antipsychotic therapy was 1.28 per 1000 persons per year (95% confidence interval: 1.09, 1.48). GPs registered an ICPC code in 50% and prescribed typical antipsychotics in 90% of the cases. Prescription of atypical antipsychotics increased almost threefold over the study period. CONCLUSIONS: The results suggest that GPs prescribe antipsychotics off-label. Despite serious side effects and relatively infrequent occurrence in Dutch general practices, GPs seem imprecise in underpinning and registrating the initiation of antipsychotic treatment. GPs increasingly prescribe atypical antipsychotics although the prescription of typical antipsychotics still dominates.

/pdf/initiation-of-antipsychotic-treatment-by-general-3pav2a7zuf.pdf

Geartsje Boonstra

Papers

Brain volume changes after withdrawal of atypical antipsychotics in patients with first-episode schizophrenia.

Duration of untreated illness in schizophrenia is not associated with 5-year brain volume change.

Antipsychotic prophylaxis is needed after remission from a first psychotic episode in schizophrenia patients: results from an aborted randomised trial.

Initiation of antipsychotic treatment by general practitioners. A case-control study

Brain volume changes after withdrawal of atypical antipsychotics in first-episode schizophrenia patients