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Schizophrenia remains one of the leading causes of global disease burden in adults despite more than 50 years of drug development.¹ Understanding its neurobiology is critical for future rational drug discovery.^2,3 The dopamine hypothesis of schizophrenia was first proposed more than 30 years ago on the basis of indirect evidence. It received support from studies of postmortem brain tissue that found increased striatal D_2/3 receptor density and dopamine levels in patients with schizophrenia and from studies of dopamine and its metabolites in cerebrospinal fluid.^4-8 However, postmortem studies are not able to measure some aspects of the dopaminergic function, such as dopamine release, and are potentially biased by the effects of antipsychotic treatment and agonal events, whereas the cerebrospinal fluid studies were inconsistent and unable to provide insights into the regional aspects of dopamine dysfunction.^9-11 The introduction of positron emission tomographic (PET) and single-photon emission computed tomographic (SPECT) imaging enabled the investigation of in vivo cerebral dopamine neurotransmission free of these limitations.^11-13

Existing treatments for schizophrenia can improve positive symptoms, but it is unclear if they have any impact on negative symptoms. This meta-analysis was conducted to assess the efficacy of available treatments for negative symptoms in schizophrenia. All randomized-controlled trials of interventions for negative symptoms in schizophrenia until December 2013 were retrieved; 168 unique and independent placebo-controlled trials were used. Negative symptom scores at baseline and follow-up, duration of illness, doses of medication, type of interventions, and sample demographics were extracted. Heterogeneity was addressed with the I² and Q statistic. Standardized mean difference in values of the Negative Symptom Rating Scale used in each study was calculated as the main outcome measure. 6503 patients in the treatment arm and 5815 patients in the placebo arm were included. No evidence of publication biases found. Most treatments reduced negative symptoms at follow-up relative to placebo: second-generation antipsychotics: −0.579 (−0.755 to −0.404); antidepressants: −0.349 (−0.551 to −0.146); combinations of pharmacological agents: −0.518 (−0.757 to −0.279); glutamatergic medications: −0.289 (−0.478 to −0.1); psychological interventions: −0.396 (−0.563 to −0.229). No significant effect was found for first-generation antipsychotics: −0.531 (−1.104 to 0.041) and brain stimulation: −0.228 (−0.775 to 0.319). Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale. Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.

Despite the emphasis placed on childhood trauma in psychiatry, comparatively little is known about the epidemiology of trauma and trauma-related psychopathology in young people. We therefore aimed to evaluate the prevalence, clinical features, and risk factors associated with trauma exposure and post-traumatic stress disorder (PTSD) in young people. We carried out a comprehensive epidemiological study based on participants from the Environmental Risk Longitudinal Twin Study, a population-representative birth-cohort of 2232 children born in England and Wales in 1994-95. At the follow-up home visit at age 18 years, participants were assessed with structured interviews for trauma exposure, PTSD, other psychopathology, risk events, functional impairment, and service use. Risk factors for PTSD were measured prospectively over four previous assessments between age 5 and 12 years. The key outcomes were the prevalence, clinical features, and risk factors associated with trauma exposure and PTSD. We also derived and tested the internal validity of a PTSD risk calculator. We found that 642 (31·1%) of 2064 participants reported trauma exposure and 160 (7·8%) of 2063 experienced PTSD by age 18 years. Trauma-exposed participants had high rates of psychopathology (187 [29·2%] of 641 for major depressive episode, 146 [22·9%] of 638 for conduct disorder, and 102 [15·9%] of 641 for alcohol dependence), risk events (160 [25·0%] of 641 for self-harm, 53 [8·3%] of 640 for suicide attempt, and 42 [6·6%] of 640 for violent offence), and functional impairment. Participants with lifetime PTSD had even higher rates of psychopathology (87 [54·7%] of 159 for major depressive episode, 43 [27·0%] of 159 for conduct disorder, and 41 [25·6%] of 160 for alcohol dependence), risk events (78 [48·8%] of 160 for self-harm, 32 [20·1%] of 159 for suicide attempt, and 19 [11·9%] of 159 for violent offence), and functional impairment. However, only 33 (20·6%) of 160 participants with PTSD received help from mental health professionals. The PTSD risk calculator had an internally validated area under the receiver operating characteristic curve of 0·74, indicating adequate discrimination of trauma-exposed participants with and without PTSD, and internally validated calibration-in-the-large of -0·10 and calibration slope of 0·90, indicating adequate calibration. Trauma exposure and PTSD are associated with complex psychiatric presentations, high risk, and significant impairment in young people. Improved screening, reduced barriers to care provision, and comprehensive clinical assessment are needed to ensure that trauma-exposed young people and those with PTSD receive appropriate treatment. The Medical Research Council, the National Institute of Child Health and Development, the Jacobs Foundation, the Nuffield Foundation, the National Society for Prevention of Cruelty to Children, the Economic and Social Research Council, the National Institute for Health Research, MQ, and Canadian Institutes for Advanced Research.

Background: The aim was to critically appraise and synthesize the literature relating to set-shifting ability in eating disorders. PsycINFO, Medline, and Web of Science databases were searched to December 2005. Hand searching of eating-disorder journals and relevant reference sections was also undertaken.Method: The 15 selected studies contained both eating disorder and healthy control groups, and employed at least one of the following six neuropsychological measures of set-shifting ability; Trail Making Test (TMT), Wisconsin Card Sort Test (WCST), Brixton task, Haptic Illusion, CatBat task, or the set-shifting subset of the Cambridge Neuropsychological Test Automated Battery (CANTAB). The outcome variable was performance on the set-shifting aspect of the task. Pooled standardized mean differences (effect sizes) were calculated.Results: TMT, WCST, CatBat and Haptic tasks had sufficient sample sizes for meta-analysis. These four tasks yielded acceptable pooled standardized effect sizes (0·36; TMT −1·05; Haptic) with moderate variation within studies (as measured by confidence intervals). The Brixton task showed a small pooled mean difference, and displayed more variation between sample results. The effect size for CANTAB set shifting was 0·17.Conclusion: Problems in set shifting as measured by a variety of neuropsychological tasks are present in people with eating disorders.