Schizophrenia Bulletin

Objective: To carry out an up-to-date comprehensive survey of the content and quality of intervention trials relevant to the treatment of people with schizophrenia. Design: Data were extracted and analyzed from 10,000 trials on the Cochrane Schizophrenia Group's Register. Main outcome measures: Source, type and date of publication, country of origin, language, size of trial, interventions, and outcome measures. Results: In the last decade, there has been a great increase in the number of trials relevant to schizophrenia and an improvement in the accessibility to reports. The number of trials per year is rising (currently ∼600/year) with China now producing 25% of the annual total. The number of reports of trials is increasing at an even greater rate due to multiple publications. Drug trials still dominate (83%) although an increasing proportion of studies are now evaluating psychological therapies (21%). Trials remain small (median 60 people) and often employ new nonvalidated outcomes scales (2194 different scales were employed with every fifth trial introducing a new rating instrument). Conclusions: A more collaborative, pragmatic, and patient-centered approach is necessary to produce larger schizophrenia trials. Wider consultation and careful consideration of all relevant perspectives would result in trials with greater clinical utility and direct value to people with the illness and their families or carers.

Although structural brain alterations in schizophrenia have been demonstrated extensively, their quantitative distribution has not been studied over the last 14 years despite advances in neuroimaging. Moreover, a volumetric meta-analysis has not been conducted in antipsychotic-naive patients. Therefore, meta-analysis on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients was conducted. Three hundred seventeen studies published from September 1, 1998 to January 1, 2012 comprising over 9000 patients were selected for meta-analysis, including 33 studies in antipsychotic-naive patients. In addition to effect sizes, potential modifying factors such as duration of illness, sex composition, current antipsychotic dose, and intelligence quotient matching status of participants were extracted where available. In the sample of medicated schizophrenia patients (n = 8327), intracranial and total brain volume was significantly decreased by 2.0% (effect size d = -0.17) and 2.6% (d = -0.30), respectively. Largest effect sizes were observed for gray matter structures, with effect sizes ranging from -0.22 to -0.58. In the sample of antipsychotic-naive patients (n = 771), volume reductions in caudate nucleus (d = -0.38) and thalamus (d = -0.68) were more pronounced than in medicated patients. White matter volume was decreased to a similar extent in both groups, while gray matter loss was less extensive in antipsychotic-naive patients. Gray matter reduction was associated with longer duration of illness and higher dose of antipsychotic medication at time of scanning. Therefore, brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression.

This article is based on my own personal experience of having undergone “coma treatment” and being given approximately 37 coma injections between the period 1983–1993 despite the fact that I was not psychotic and was normal in every way. The experiences I had following the injections and the forcible administration of innumerable antipsychotics and drugs have shaped my perspective of what it is to be a victim of “iatrogenic” psychiatric treatment—iatrogenic because it induced symptoms of schizophrenia or at the least schizoidism in a normal person like me—an inability to think, feel, and reason, over time. I have also with my own eyes seen at least 7 or 8 women who look me (my clones) that has reinforced my belief that the injections split me. The British psychiatrist, Richard David Laing (Encyclopedia Britannica 2004 DVD [DVD]) also theorized that it is the division of the self that leads to the symptoms of schizophrenia such as splitting and fragmentation of the mind.

Torrey and Yolken wonder whether the killing of mentally ill persons in Nazi Germany reduced the risk for schizophrenia in the following generation. Epidemiological data from Germany do not permit reliable comparisons. Torrey and Yolken point out that horrible crime is still only little known. Strous and several contributors on the Schizophrenia Research Forum confirm that view. The history of ideas shows that social Darwinism in the educated classes and the doctrine of degeneration in psychiatry widely influenced thinking prior to World War II. Psychiatrists, lacking effective treatment for steadily growing numbers of the mentally ill, were susceptible to these ideologies. In a first step, several countries introduced compulsory sterilization as a genetic means of preventing diseases believed to be hereditary. Hitler's megalomaniac idea of creating a new human species by steering human evolution through the elimination of “unfit” genes in the mentally ill and inferior races led to the breach of human rights. His euthanasia program—the biggest crime ever perpetrated on the sick—turned out to usher in the gas chambers of the Holocaust.

Epidemiological studies suggest that auditory verbal hallucinations (AVH) occur in approximately 10%-15% of the general population, of whom only a small proportion has a clinically relevant psychotic disorder. It is unclear whether these hallucinations occur as an isolated phenomenon or if AVH in nonclinical individuals are part of a more general susceptibility to schizophrenia. For this study, 103 healthy individuals with frequent AVH were compared with 60 controls matched for sex, age, and education. All participants were examined by a psychiatrist using standardized diagnostic interviews and questionnaires. The individuals with AVH did not have clinically defined delusions, disorganization, or negative or catatonic symptoms, nor did they meet criteria for cluster A personality disorder. However, their global level of functioning was lower than in the controls and there was a pronounced increase on all subclusters of the Schizotypal Personality Questionnaire (SPQ) and the Peters Delusion Inventory, indicating a general increased schizotypal and delusional tendency in the hallucinating subjects. History of childhood trauma and family history of axis I disorders were also more prevalent in these individuals. We showed that higher SPQ scores, lower education, and higher family loading for psychiatric disorders, but not presence of AVH, were associated with lower global functioning. Our data suggest that AVH in otherwise healthy individuals are not an isolated phenomenon but part of a general vulnerability for schizophrenia.

The "social brain" of humans reflects widespread neural resources dedicated to understanding the conversational language, emotionality, states of mind, and intentions of other persons. A social deafferentation (SDA) hypothesis for induction of active schizophrenia is proposed. Analogous to hallucinations produced by sensory deafferentation, such as phantom limb, the SDA hypothesis assumes that high levels of social withdrawal/isolation in vulnerable individuals prompt social cognition programs to produce spurious social meaning in the form of complex, emotionally compelling hallucinations and delusions representing other persons or agents. Arguments against the SDA hypothesis are discussed, and predictions deriving from the hypothesis are offered.

This editorial reflects the work of all of the members of the WHO Working Group on the Classification of Psychotic Disorders, which include Jonathan Burns (South Africa), Peter Falkai (Germany), Saeed Farooq (Pakistan), Wolfgang Gaebel, Chair (Germany), Silvana Galderisi (Italy), Philippa Garety (UK), Michael Green (USA), Assen Jablensky (Australia), Veronica Larach Walters (Chile), Toshimasa Maruta (Japan), and Pichet Udomratn (Thailand), assisted by WHO Secretariat members Geoffrey Reed and Shekhar Saxena and consultant Michael B. First. Jürgen Zielasek (Germany) is rapporteur for the Working Group. The views expressed in this editorial reflect the opinion of its author and, except as specifically noted, do not represent the official policies and positions of the Working Group, the Advisory Group for the Revision of ICD-10 Mental and Behavioural Disorders, or of WHO.

The physical and psychological characteristics of hypotonic schizophrenic children are described. It is hypothesized that hypotonic schizophrenia constitutes a homogeneous subgroup within the schizophrenic spectrum. The criteria for diagnosing hypotonic schizophrenia are stated. By selecting a homogeneous subgroup of schizophrenic patients, investigators may improve the probability of identifying a common biochemical etiology within this subgroup.

The development of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and International Classification of Diseases, Eleventh Edition, deserves a significant conceptual step forward. There is a clear need to improve and refine the current diagnostic criteria, but also to introduce dimensions, perhaps not as an alternative but rather as a useful complement to categorical diagnosis. Laboratory, family, and treatment response data should also be systematically included in the diagnostic assessment when available. We have critically reviewed the content, concurrent, discriminant, and predictive validity of bipolar disorder, and to overcome the validity problems of the current classifications of mental disorders, we propose a modular system which may integrate categorical and dimensional issues, laboratory data, associated nonpsychiatric medical conditions, psychological assessment, and social issues in a comprehensive and nevertheless practical approach.

This study examined the course of illness and factors affecting it in schizophrenias with onset between the ages of 14 and 18. Noteworthy in comparison to findings from other followup studies is the higher proportion of chronic courses of illness, about 50 percent. In addition, the type of course of illness corresponds in general with the treatment status. A possible explanation for this observation is the early age of onset, at which point the patient has not yet developed a sufficient degree of social and emotional independence and maturity before developing a schizophrenic psychosis. The age of onset is also shown to be an important predictor for the overall course of illness, as in other studies.

The diagnoses of paranoia, catatonia, and hebephrenia preceded the use of dementia praecox and Bleuler's subsequent recognition of a heterogenous "Group of Schizophrenias." With some modification, traditional schizophrenia subtypes have been formalized for many years in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD) classification systems. While widely used in the past, it is not clear that the schizophrenia subtypes remain in wide use or are influential in 21st-century research and clinical practice, and especially in the scientific literature. A review of published articles reveals over the last 20 years (1990, 2000, 2010) the use of traditional subtypes in the literature has fallen from 27.7% to 9.8% to 6.5%. Thus, by 2010, the use of subtypes in the leading literature venues declined to <10%. These facts strongly support DSM-5 and ICD-11 proposed elimination of traditional schizophrenia subtypes from a research and evolving knowledge perspective because traditional subtypes are simply no longer being used much in the scientific literature.

Stimulant drugs such as cocaine and amphetamine are among the most commonly abused substances by schizophrenic patients. This may be due in part to aspects of the illness and treatment side effects that impel patients to use dopamine agonist drugs. Dopaminergic neural systems have been shown to mediate both stimulant drug effects and schizophrenia. Because of the hypothesized overlap in the pathophysiology of schizophrenia and the neurobiological effects of chronic stimulant use, the potential for serious complication of the primary disease by substance abuse exists. This article reviews the neurobiological mechanisms of behavioral sensitization and neurotoxicity associated with chronic stimulant administration in the context of pathophysiological theories of schizophrenia. Discussion focuses on the potential impact of stimulant use on the disease process as well as the manifest phenomenology and course of schizophrenia.

Cognitive impairment is a core feature of schizophrenia as deficits are present in the majority of patients, frequently precede the onset of other positive symptoms, persist even with successful treatment of positive symptoms, and account for a significant portion of functional impairment in schizophrenia. While the atypical antipsychotics have produced incremental improvements in the cognitive function of patients with schizophrenia, overall treatment remains inadequate. In recent years, there has been an increased interest in developing novel strategies for treating the cognitive deficits in schizophrenia, focusing on ameliorating impairments in working memory, attention, and social cognition. Here we review various molecular targets that are actively being explored for potential drug discovery efforts in schizophrenia and cognition. These molecular targets include dopamine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergic excitatory synapse, various serotonin receptors, and the gamma-aminobutyric acid (GABA) system.

Wayne Fenton was a major driving force behind the establishment of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) project mechanisms. These projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified 3 drug mechanisms of particular interest: cholinergic, dopaminergic, and glutamatergic. The TURNS project is designed to select potential cognitive-enhancing agents and evaluate their potential efficacy in the context of proof of concept or clinical efficacy trials. This article reviews the rationale for these 3 approaches and provides an update on the development of therapeutic agents, which act through one of these 3 mechanisms.

Early nonresponse to antipsychotics appears to predict subsequent nonresponse to treatment when assessed in randomized controlled trials of predominately acute inpatients treated for schizophrenia. This study assessed the predictive accuracy of early nonresponse to treatment and its clinical, functional, and economic ramifications in the naturalistic treatment of predominately chronic outpatients treated for schizophrenia. This post hoc analysis used data from a 1-year, randomized, open-label study of olanzapine, risperidone, and typical antipsychotics in the treatment of schizophrenia. If clinically warranted, patients could switch antipsychotics following 8 weeks of treatment. Patients completing 8 weeks of treatment (n = 443 of 664 enrollees) were included. Patients with early response (> or = 20% improvement from baseline on the Positive and Negative Syndrome Scale at 2 weeks) were compared with early nonresponders on symptom remission, functionality, perceptions of medication influence, and total health care costs at 8 weeks. Early response/nonresponse at 2 weeks predicted subsequent response/nonresponse at 8 weeks with a high level of accuracy (72%) and specificity (89%). After 8 weeks, early nonresponders were less likely to achieve symptom remission (P < .001), improved less on functional domains (P < .05), perceived medication as less beneficial (P = .004), and incurred total heath care costs over twice that of early responders ($4349 vs $2102, P = .010). In the usual care of schizophrenia patients, early nonresponse appears to reliably predict subsequent nonresponse to continued treatment with the same medication to be associated with poorer outcomes and higher health care costs. Identifying early nonresponders may minimize prolonging exposure to suboptimal or ineffective treatment strategies.

Models of the neuronal mediation of psychotic symptoms traditionally have focused on aberrations in the regulation of mesolimbic dopaminergic neurons, via their telencephalic afferent connections, and on the impact of abnormal mesolimbic activity for functions of the ventral striatum and its pallidal-thalamic-cortical efferent circuitry. Repeated psychostimulant exposure models major aspects of the sensitized activity of ventral striatal dopaminergic transmission that is observed in patients exhibiting psychotic symptoms. Based on neuroanatomical, neurochemical, and behavioral data, the hypothesis that an abnormally reactive cortical cholinergic input system represents a necessary correlate of a sensitized mesolimbic dopaminergic system is discussed. Moreover, the abnormal cognitive mechanisms that contribute to the development of psychotic symptoms are attributed specifically to the aberrations in cortical cholinergic transmission and to its consequences on the top-down regulation of sensory and sensory-associational input functions. Experimental evidence from studies demonstrating repeated amphetamine-induced sensitization of cortical cholinergic transmission and the ability of antipsychotic drugs to normalize the activity of cortical cholinergic inputs, and from experiments indicating the attentional consequences of manipulations that increase the excitability of cortical cholinergic inputs, supports this hypothesis. Relevant human neuropathological and psychopharmacological data are discussed, and the implications of an abnormally regulated cortical cholinergic input system for pharmacological treatment strategies are addressed. Given the role of cortical cholinergic inputs in gating cortical information processing, even subtle changes in the regulation of this cortexwide input system that represent a necessary transsynaptic consequence of sensitized mesolimbic dopaminergic transmission profoundly contribute to the neuronal mediation of psychotic symptoms.

Computer simulations of parallel distributed processing (PDP) neural networks have increased our understanding of brain functioning. This article reviews how PDP concepts can contribute to our understanding of schizophrenic symptoms. Psychotic states induced by phencyclidine and the adult form of metachromatic leukodystrophy, as well as neurometabolic studies, suggest that schizophrenia reflects a breakdown in communication between cortical areas. A computer simulation of this type of brain pathology has suggested two neurocognitive consequences: some cortical circuits will become functionally autonomous, and a subset of these circuits will yield "parasitic foci" that slavishly reproduce the same cognitive output. Delusions of control, paranoid delusions of the idee fixe type, thought broadcasting, "voices," and certain deficit symptoms are postulated outcomes of parasitic foci located at different levels of language processing. A neurodevelopmental model of impaired corticocortical communication is described, and this model's implications for further study are outlined.

Background: Alterations in striatal dopamine neurotransmission are central to the emergence of psychotic symptoms and to the mechanism of action of antipsychotics. Although the functional integrity of the presynaptic system can be assessed by measuring striatal dopamine synthesis capacity (DSC), no quantitative meta-analysis is available. Methods: Eleven striatal (caudate and putamen) [(11)C/(18)F]-DOPA positron emission tomography studies comparing 113 patients with schizophrenia and 131 healthy controls were included in a quantitative meta-analysis of DSC. Demographic, clinical, and methodological variables were extracted from each study or obtained from the authors and tested as covariates. Hedges' g was used as a measure of effect size in Comprehensive Meta-Analysis. Publication bias was assessed with funnel plots and Egger's intercept. Heterogeneity was addressed with the Q statistic and I(2) index. Results: Patients and controls were well matched in sociodemographic variables (P > .05). Quantitative evaluation of publication bias was nonsignificant (P = .276). Heterogeneity across study was modest in magnitude and statistically nonsignificant (Q = 19.19; P = .078; I (2) = 39.17). Patients with schizophrenia showed increased striatal DSC as compared with controls (Hedges' g = 0.867, CI 95% from 0.594 to 1.140, Z = 6.222, P < .001). The DSC schizophrenia/control ratio showed a relatively homogenous elevation of around 14% in schizophrenic patients as compared with controls. DSC elevation was regionally confirmed in both caudate and putamen. Controlling for potential confounders such as age, illness duration, gender, psychotic symptoms, and exposure to antipsychotics had no impact on the results. Sensitivity analysis confirmed robustness of meta-analytic findings. Conclusions: The present meta-analysis showed consistently increased striatal DSC in schizophrenia, with a 14% elevation in patients as compared with healthy controls.

The issue of neurodegeneration in schizophrenia is controversial. Although most studies indicate that neurocognitive deficits are relatively stable over the course of the illness, conclusions are limited by relatively short follow-up periods and absence of age-matched control groups. Furthermore, nearly all studies deal with adult-onset schizophrenia, and few studies have considered the possible effect of age of onset. The current study represents the first attempt to compare groups of adolescents with schizophrenia, attention deficit/hyperactivity disorder (ADHD), and normal controls on a comprehensive neurocognitive test battery in a longitudinal design over 13 years. In the baseline study, adolescents with schizophrenia were examined with a broad battery of neurocognitive tests. The comparison groups consisted of adolescents with ADHD and adolescents without a psychiatric diagnosis, between 12 and 18 years of age. In the follow-up study, the schizophrenia group consisted of 15 of the initial 19 individuals, the ADHD group of 19 of the 20 individuals, and the normal comparison group of all 30 individuals. They were reevaluated with the neurocognitive test battery and clinical measures. Subjects with schizophrenia showed a significant decline or arrest in neurocognitive functioning compared with the other 2 groups, particularly in verbal memory, attention, and processing speed. The impairments may be specific to early-onset schizophrenia due to interaction between ongoing brain maturation during adolescence and disease-related mechanisms and/or secondary to neuroleptic treatment in young age and/or social isolation.

Background The term psychosis refers to a combination of symptoms, without pointing to the origin of these symptoms. In a subset of psychotic patients, symptoms are attributable to an organic disease. It is important to identify these organic causes of psychosis early, as urgent treatment of the primary disease may be required. Some of these underlying organic disorders can be identified on magnetic resonance imaging (MRI) scans. Whether routine screening for all psychotic patients should therefore include MRI scans is still a matter of debate.Methods This study investigated the prevalence of clinically relevant abnormalities detected on MRI scans from psychotic patients and a matched control group. We could include MRI scans from 656 psychotic patients and 722 controls. The standard radiological reports of these scans were classified as normal, as a nonrelevant abnormality or as a clinically relevant brain abnormality by means of consensus, blind to diagnosis.ResultsA normal aspect of the brain was reported in 74.4% of the patients and in 73.4% of the controls. We found clinically relevant pathology in 11.1% of the patients and in 11.8% of the controls. None of the neuropathological findings observed in the patients was interpreted as a possible substrate for organic psychosis. Brain abnormalities that were classified as not clinically relevant were identified in 14.5% of the patients and in 14.8% of the controls.Conclusions This suggests that MRI brain scans are not an essential part of routine screening for psychotic patients. © The Author 2012. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

A workshop on "Antipsychotics: Past and Future" was convened by the National Institute of Mental Health (NIMH), Division of Services and Intervention Research (DSIR), on July 14, 1998, to review the results of recent antipsychotic drug research, discuss current standards of treatment, and identify areas needing further study. There has been a proliferation of new antipsychotic medications and a rapid increase in their clinical utilization. The new atypicals are beginning to supplant the older typical neuroleptic antipsychotics, and the scientific and ethical issues raised by this transition prompted the workshop. Given the apparent, albeit not fully defined, advantages of atypical drugs, particularly their safety profiles, the question is whether more comparisons with typical antipsychotics are warranted and whether clinical trial designs warrant (or would be justified in) the inclusion of typical drugs as standard active comparators. Workshop participants--including clinical researchers, patient advocates, bioethicists, and NIMH staff--discussed the conclusions drawn from current data, ethical issues for subjects in clinical trials, funding for ongoing studies using typical agents, and appropriate comparators for trials using atypical agents.

Cerebral metabolic hypofrontality in schizophrenia is a controversial research finding. In this article we discuss some of the issues that fuel this controversy, and we speculate on the neural mechanisms that may be responsible for the finding. Most regional cerebral blood flow (rCBF) studies using radioactive xenon have found hypofrontality; the results of positron emission tomography (PET) studies have been less consistent. Several technical factors are discussed that might contribute to the inconsistencies, including airway artifacts with xenon, limitations of tomography in studying the cortex, and approaches to data analysis. The possibility that hypofrontality is a result of medication is also critically examined. The medication factor is still unclear, but most studies of patients before and after neuroleptic medication find that cerebral metabolism goes up, not down, after treatment. The role of patient behavior and experience during an rCBF or PET procedure is an important variable that has not been adequately controlled in most studies. We suggest that this has been the most important variable in interpreting cerebral metabolic data in schizophrenia. Studies of patients examined during a behavior that normally activates prefrontal cortex have consistently found hypofrontality. One theoretical mechanism that could account for hypofrontality as well as many clinical and research findings in schizophrenia is dysfunction of dopaminergic neural transmission at the level of the prefrontal cortex.

This prospective research investigated the occurrence and persistence of depression during the longitudinal course of schizophrenia. The research goals were to (1) compare depression in schizophrenia with that in schizoaffective and major depressive disorders, (2) assess whether some schizophrenia patients are vulnerable to depression, and (3) assess the relationship of depression to posthospital adjustment in schizophrenia. A total of 70 schizophrenia, 31 schizoaffective depressed, 17 psychotic unipolar major depressed, and 69 nonpsychotic unipolar major depressed patients were assessed during hospitalization and prospectively assessed for depression, psychosis, and posthospital functioning at 4.5- and 7.5-year followups. A large number (30% to 40%) of schizophrenia patients evidenced full depressive syndromes at each followup, including a subgroup of patients who evidenced repeated depression. Even when considering the influence of psychosis on outcome, depression in schizophrenia was associated with poor overall outcome, work impairment, lower activity, dissatisfaction, and suicidal tendencies. During the post-acute phase assessed, neither the rates nor the severity of depressive syndromes differentiated depression in schizophrenia from schizodepressive or major depressive disorders. However, the depressed schizophrenia patients showed poorer posthospital adjustment in terms of less employment, more rehospitalizations, and more psychosis than the patients with primary major depression. The high prevalence of depression in schizophrenia warrants its incorporation into theory about the disorder. A continuum of vulnerability to depression contributes to the heterogeneity of schizophrenia, with some schizophrenia patients being prone to depression even years after the acute phase. Depression in schizophrenia is one factor, in addition to psychosis, associated with poor outcome and requires specific attention to the treatment strategies by psychiatrists.

Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val108/158Met on executive attention, using ANT. We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val108/158Met genotype on executive attention as assessed by the ANT. Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val108/158Met on cognitive performance.