Effects of childhood trauma on left inferior frontal gyrus function during response inhibition across psychotic disorders.

BACKGROUND: Childhood trauma is a risk factor for psychosis. Deficits in response inhibition are common to psychosis and trauma-exposed populations, and associated brain functions may be affected by trauma exposure in psychotic disorders. We aimed to identify the influence of trauma-exposure on brain activation and functional connectivity during a response inhibition task. METHODS: We used functional magnetic resonance imaging to examine brain function within regions-of-interest [left and right inferior frontal gyrus (IFG), right dorsolateral prefrontal cortex, right supplementary motor area, right inferior parietal lobule and dorsal anterior cingulate cortex], during the performance of a Go/No-Go Flanker task, in 112 clinical cases with psychotic disorders and 53 healthy controls (HCs). Among the participants, 71 clinical cases and 21 HCs reported significant levels of childhood trauma exposure, while 41 clinical cases and 32 HCs did not. RESULTS: In the absence of effects on response inhibition performance, childhood trauma exposure was associated with increased activation in the left IFG, and increased connectivity between the left IFG seed region and the cerebellum and calcarine sulcus, in both cases and healthy individuals. There was no main effect of psychosis, and no trauma-by-psychosis interaction for any other region-of-interest. Within the clinical sample, the effects of trauma-exposure on the left IFG activation were mediated by symptom severity. CONCLUSIONS: Trauma-related increases in activation of the left IFG were not associated with performance differences, or dependent on clinical diagnostic status; increased IFG functionality may represent a compensatory (overactivation) mechanism required to exert adequate inhibitory control of the motor response.

Pervasive influence of maternal and paternal criminal offending on early childhood development: a population data linkage study.

BACKGROUND: Parental criminal offending is an established risk factor for offending among offspring, but little evidence is available indicating the impact of offending on early childhood functioning. We used data from a large Australian population cohort to determine associations between exposure to parental offending and a range of developmental outcomes at age 5 years. METHOD: Multi-generation data in 66 477 children and their parents from the New South Wales Child Development Study were combined using data linkage. Logistic and multinomial regressions tested associations between any and violent offending histories of parents (fathers, mothers, or both parents) obtained from official records, and multiple measures of early childhood developmental functioning (social, emotional-behavioural, cognitive, communication and physical domains) obtained from the teacher-reported 2009 Australian Early Development Census. RESULTS: Parental offending conferred significantly increased risk of vulnerability on all domains, particularly the cognitive domain. Greater risk magnitudes were observed for offending by both parents and by mothers than by fathers, and for violent than for any offending. For all parental offending exposures, vulnerability on multiple domains (where medium to large effects were observed) was more likely than on a single domain (small to medium effects). Relationships remained significant and of comparable magnitude following adjustment for sociodemographic covariates. CONCLUSIONS: The effect of parental offending on early childhood developmental outcomes is pervasive, with the strongest effects on functioning apparent when both parents engage in violent offending. Supporting affected families in early childhood might mitigate both early developmental vulnerability and the propensity for later delinquency among these offspring.

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

How much do we know about schizophrenia and how well do we know it? Evidence from the Schizophrenia Library.

BACKGROUND: True findings about schizophrenia remain elusive; many findings are not replicated and conflicting results are common. Well-conducted systematic reviews have the ability to make robust, generalizable conclusions, with good meta-analyses potentially providing the closest estimate of the true effect size. In this paper, we undertake a systematic approach to synthesising the available evidence from well-conducted systematic reviews on schizophrenia. METHOD: Reviews were identified by searching Medline, EMBASE, CINAHL, Current Contents and PsycINFO. The decision to include or exclude reviews, data extraction and quality assessments were conducted in duplicate. Evidence was graded as high quality if reviews contained large samples and robust results; and as moderate quality if reviews contained imprecision, inconsistency, smaller samples or study designs that may be prone to bias. RESULTS: High- and moderate-quality evidence shows that numerous psychosocial and biomedical treatments are effective. Patients have relatively poor cognitive functioning, and subtle, but diverse, structural brain alterations, altered electrophysiological functioning and sleep patterns, minor physical anomalies, neurological soft signs, and sensory alterations. There are markers of infection, inflammation or altered immunological parameters; and there is increased mortality from a range of causes. Risk for schizophrenia is increased with cannabis use, pregnancy and birth complications, prenatal exposure to Toxoplasma gondii, childhood central nervous system viral infections, childhood adversities, urbanicity and immigration (first and second generation), particularly in certain ethnic groups. Developmental motor delays and lower intelligence quotient in childhood and adolescence are apparent. CONCLUSIONS: We conclude that while our knowledge of schizophrenia is very substantial, our understanding of it remains limited.

Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia.

Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.

Childhood adversity in schizophrenia: a systematic meta-analysis.

BACKGROUND: Childhood adversity is a putative risk factor for schizophrenia, although evidence supporting this suggestion is inconsistent and controversial. The aim of this review was to pool and quality assess the current evidence pertaining to childhood adversity in people with schizophrenia compared to other psychiatric disorders and to non-psychiatric controls. METHOD: Included were case-control, cohort and cross-sectional studies. Medline, EMBASE and PsycINFO databases were searched. Study reporting was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and pooled evidence quality was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twenty-five studies met inclusion criteria. Moderate to high quality evidence suggests increased rates of childhood adversity in schizophrenia compared to controls [odds ratio (OR) 3.60, p < 0.00001]. Increased childhood adversity was also reported in schizophrenia compared to anxiety disorders (OR 2.54, p = 0.007), although the effect was not significant in the subgroup analysis of five studies assessing only sexual abuse. No differences in rates of childhood adversity were found between schizophrenia and affective psychosis, depression and personality disorders whereas decreased rates of childhood adversity were found in schizophrenia relative to dissociative disorders and post-traumatic stress disorder (OR 0.03, p < 0.0001). CONCLUSIONS: This is the first meta-analysis to report a medium to large effect of childhood adversity in people with schizophrenia and to assess specificity for schizophrenia. Further research is required that incorporates longitudinal design and other potentially causal variables to assess additive and/or interactive effects.

Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis.

Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=-0.458, 95% confidence interval=-0.770 to -0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results.

Systematic review of global functioning and quality of life in people with psychotic disorders.

AimsPeople with psychotic disorders face impairments in their global functioning and their quality of life (QoL). The relationship between the two outcomes has not been systematically investigated. Through a systematic review, we aim to explore the presence and extent of associations between global functioning and QoL and establish whether associations depend on the instruments employed. METHODS: In May 2016, ten electronic databases were searched using a two-phase process to identify articles in which associations between global functioning and QoL were assessed. Basic descriptive data and correlation coefficients between global functioning and QoL instruments were extracted, with the strength of the correlation assessed according to the specifications of Cohen 1988. Results were reported with reference to the Meta-analysis of Observational Studies in Epidemiology guidelines and PRISMA standards. A narrative synthesis was performed due to heterogeneity in methodological approaches. RESULTS: Of an initial 15 183 non-duplicate articles identified, 756 were deemed potentially relevant, with 40 studies encompassing 42 articles included. Fourteen instruments for measuring global functioning and 22 instruments for measuring QoL were used. Twenty-nine articles reported linear associations while 19 assessed QoL predictors. Correlations between overall scores varied in strength, primarily dependent on the QoL instrument employed, and whether QoL was objectively or subjectively assessed. Correlations observed for objective QoL measures were consistently larger than those observed for subjective measures, as were correlations for an interviewer than self-assessed QoL. When correlations were assessed by domains of QoL, the highest correlations were found for social domains of QoL, for which most correlations were moderate or higher. Global functioning consistently predicted overall QoL as did depressive and negative symptoms. CONCLUSIONS: This review is the first to explore the extent of associations between global functioning and QoL in people with psychotic disorders. We consistently found a positive association between global functioning and QoL. The strength of the association was dependent on the QoL instrument employed. QoL domains strongly associated with global functioning were highlighted. The review illustrates the extensive array of instruments used for the assessment of QoL and to a lesser extent global functioning in people with psychotic disorders and provides a framework to understand the different findings reported in the literature. The findings can also inform the future choice of instruments by researchers and/or clinicians. The observed associations reassure that interventions for improving global functioning will have a positive impact on the QoL of people living with a psychotic disorder.

Clozapine users in Australia: their characteristics and experiences of care based on data from the 2010 National Survey of High Impact Psychosis.

AIMS: Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables. METHODS: Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n = 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators. RESULTS: One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups. CONCLUSIONS: Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.

Effects of maltreatment and parental schizophrenia spectrum disorders on early childhood social-emotional functioning: a population record linkage study.

AIMS: Childhood maltreatment and a family history of a schizophrenia spectrum disorder (SSD) are each associated with social-emotional dysfunction in childhood. Both are also strong risk factors for adult SSDs, and social-emotional dysfunction in childhood may be an antecedent of these disorders. We used data from a large Australian population cohort to determine the independent and moderating effects of maltreatment and parental SSDs on early childhood social-emotional functioning. METHODS: The New South Wales Child Development Study combines intergenerational multi-agency data using record linkage methods. Multiple measures of social-emotional functioning (social competency, prosocial/helping behaviour, anxious/fearful behaviour; aggressive behaviour, and hyperactivity/inattention) on 69 116 kindergarten children (age ~5 years) were linked with government records of child maltreatment and parental presentations to health services for SSD. Multivariable analyses investigated the association between maltreatment and social-emotional functioning, adjusting for demographic variables and parental SSD history, in the population sample and in sub-cohorts exposed and not exposed to parental SSD history. We also examined the association of parental SSD history and social-emotional functioning, adjusting for demographic variables and maltreatment. RESULTS: Medium-sized associations were identified between maltreatment and poor social competency, aggressive behaviour and hyperactivity/inattention; small associations were revealed between maltreatment and poor prosocial/helping and anxious/fearful behaviours. These associations did not differ greatly when adjusted for parental SSD, and were greater in magnitude among children with no history of parental SSD. Small associations between parental SSD and poor social-emotional functioning remained after adjusting for demographic variables and maltreatment. CONCLUSIONS: Childhood maltreatment and history of parental SSD are associated independently with poor early childhood social-emotional functioning, with the impact of exposure to maltreatment on social-emotional functioning in early childhood of greater magnitude than that observed for parental SSDs. The impact of maltreatment was reduced in the context of parental SSDs. The influence of parental SSDs on later outcomes of maltreated children may become more apparent during adolescence and young adulthood when overt symptoms of SSD are likely to emerge. Early intervention to strengthen childhood social-emotional functioning might mitigate the impact of maltreatment, and potentially also avert future psychopathology.

Recovery from schizophrenia: a review of patterns of psychosis.

The literature describing symptomatic recovery in schizophrenic psychosis is reviewed. The dimensional and categorical models which have been used in this context are examined separately, and the phenomena of postpsychotic depression and style of recovery are also discussed. A model is then suggested in which the process of recovery is related to five dimensions of psychopathology. Such a model may be of use in efficiently describing the short-term course of psychosis in which symptom patterns or states, having relevance for clinical practice and research, could be defined.

Patterns of current and lifetime substance use in schizophrenia.

A structured interview and standardized rating scales were used to assess a sample of 194 outpatients with schizophrenia in a regional Australian mental health service for substance use, abuse, and dependence. Case manager assessments and urine drug screens were also used to determine substance use. Additional measurements included demographic information, history of criminal charges, symptom self-reports, personal hopefulness, and social support. The sample was predominantly male and showed relative instability in accommodations, and almost half had a history of criminal offenses, most frequently drug or alcohol related. The 6-month and lifetime prevalence of substance abuse or dependence was 26.8 and 59.8 percent, respectively, with alcohol, cannabis, and amphetamines being the most commonly abused substances. Current users of alcohol comprised 77.3 percent and current users of other nonprescribed substances (excluding tobacco and caffeine) comprised 29.9 percent of the sample. Rates of tobacco and caffeine consumption were high. There was a moderate degree of concordance between case manager determinations of a substance-use problem and research diagnoses. Subjects with current or lifetime diagnoses of substance abuse/dependence were predominantly young, single males with higher rates of criminal charges; however, there was no evidence of increased rates of suicide attempts, hospital admissions, or daily doses of antipsychotic drugs in these groups compared with subjects with no past or current diagnosis of substance abuse or dependence. Subjects with a current diagnosis of substance use were younger at first treatment and currently more symptomatic than those with no past or current substance use diagnosis. The picture emerging from this study replicates the high rate of substance abuse in persons with schizophrenia reported in North American studies but differs from the latter in finding a slightly different pattern of substances abused (i.e., absence of cocaine), reflecting relative differences in the availability of certain drugs.

A generalised deficit can account for problems in facial emotion recognition in schizophrenia.

Neuroimaging research has shown localised brain activation to different facial expressions. This, along with the finding that schizophrenia patients perform poorly in their recognition of negative emotions, has raised the suggestion that patients display an emotion specific impairment. We propose that this asymmetry in performance reflects task difficulty gradations, rather than aberrant processing in neural pathways subserving recognition of specific emotions. A neural network model is presented, which classifies facial expressions on the basis of measurements derived from human faces. After training, the network showed an accuracy pattern closely resembling that of healthy subjects. Lesioning of the network led to an overall decrease in the network's discriminant capacity, with the greatest accuracy decrease to fear, disgust and anger stimuli. This implies that the differential pattern of impairment in schizophrenia patients can be explained without having to postulate impairment of specific processing modules for negative emotion recognition.

Preattentive visual search and perceptual grouping in schizophrenia.

To help determine whether patients with schizophrenia show deficits in the stimulus-based aspects of preattentive processing, we undertook a series of experiments within the framework of feature integration theory. Thirty subjects with a DSM-III-R diagnosis of schizophrenia and 30 age-, gender-, and education-matched normal control subjects completed two computerized experimental tasks, a visual search task assessing parallel and serial information processing (Experiment 1) and a task which examined the effects of perceptual grouping on visual search strategies (Experiment 2). We also assessed current symptomatology and its relationship to task performance. While the schizophrenia subjects had longer reaction times in Experiment 1, their overall pattern of performance across both experimental tasks was similar to that of the control subjects, and generally unrelated to current symptomatology. Predictions from feature integration theory about the impact of varying display size (Experiment 1) and number of perceptual groups (Experiment 2) on the detection of feature and conjunction targets were strongly supported. This study revealed no firm evidence that schizophrenia is associated with a preattentive abnormality in visual search using stimuli that differ on the basis of physical characteristics. While subject and task characteristics may partially account for differences between this and previous studies, it is more likely that preattentive processing abnormalities in schizophrenia may occur only under conditions involving selected 'top-down' factors such as context and meaning.

Illusory conjunctions and perceptual grouping in a visual search task in schizophrenia.

This report describes part of a series of experiments, conducted within the framework of feature integration theory, to determine whether patients with schizophrenia show deficits in preattentive processing. Thirty subjects with a DSM-III-R diagnosis of schizophrenia and 30 age-, gender-, and education-matched normal control subjects completed two computerized experimental tasks, a visual search task assessing the frequency of illusory conjunctions (i.e. false perceptions) under conditions of divided attention (Experiment 3) and a task which examined the effects of perceptual grouping on illusory conjunctions (Experiment 4). We also assessed current symptomatology and its relationship to task performance. Contrary to our hypotheses, schizophrenia subjects did not show higher rates of illusory conjunctions, and the influence of perceptual grouping on the frequency of illusory conjunctions was similar for schizophrenia and control subjects. Nonetheless, specific predictions from feature integration theory about the impact of different target types (Experiment 3) and perceptual groups (Experiment 4) on the likelihood of forming an illusory conjunction were strongly supported, thereby confirming the integrity of the experimental procedures. Overall, these studies revealed no firm evidence that schizophrenia is associated with a preattentive abnormality in visual search using stimuli that differ on the basis of physical characteristics.

Serum testosterone levels are related to cognitive function in men with schizophrenia.

BACKGROUND: Sex steroids such as oestrogen and testosterone are potent neurodevelopmental hormones that also play a role in neuromodulation and neuroprotection of the mature brain. Sex steroid hormones may also be involved in the pathophysiology of schizophrenia as reduced circulating sex steroid levels and changes in brain sex steroid receptors are found in people with schizophrenia compared to controls. In men with schizophrenia, recent studies have documented an inverse correlation between serum testosterone and negative symptoms. Our study sought to confirm whether men with schizophrenia had lower levels of testosterone relative to controls and to determine whether lower testosterone levels were related to higher symptom severity and impaired cognition. METHOD: Circulating serum hormone levels (testosterone, oestrogen, and prolactin), cognitive function and symptoms were assessed in 29 chronically ill men with schizophrenia or schizoaffective disorder. Twenty healthy men were recruited as a comparison group. A series of regression analyses were performed to determine the extent to which circulating sex steroid hormone levels predict cognition and symptoms in men with schizophrenia. RESULTS: We did not find a significant difference in serum testosterone levels between groups. However, circulating testosterone levels significantly predicted performance on verbal memory, processing speed, and working memory in men with schizophrenia. With the exception of an effect of oestrogen on verbal memory, circulating sex steroid levels did not predict cognitive function in healthy men. Testosterone levels were not related to positive or negative symptom severity, but testosterone influenced excitement/hostility levels in our schizophrenia sample. CONCLUSIONS: The results suggest that circulating sex steroids may modulate cognitive deficits associated with schizophrenia.

Quality assessment and comparison of evidence for electroconvulsive therapy and repetitive transcranial magnetic stimulation for schizophrenia: a systematic meta-review.

BACKGROUND: Randomized studies directly comparing the effects of electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) for depression generally favour ECT. ECT and rTMS have also been investigated for chronic symptoms of schizophrenia although there are no direct comparisons available. AIMS: We sought to determine the relative benefits and adverse outcomes of ECT and rTMS by comparing effect sizes reported in systematic reviews and to quality assess this evidence using GRADE and QUOROM guidelines. METHOD: Included are systematic reviews with meta-analysis published since 2000, reporting results for people with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder or first episode schizophrenia. Medline, Embase, CINAHL, Current Contents, PsycINFO and the Cochrane library were searched and hand searching was conducted. Data extraction and quality assessment were completed by two independent reviewers. RESULTS: Fifty-three of 58 reviews were excluded as they did not meet inclusion criteria. The remaining five have a low probability of reporting bias and show that high quality evidence suggests a short-term, medium to large treatment effect of rTMS for auditory hallucinations (d=0.88) but not other symptoms, for people treated with concurrent antipsychotics. For ECT, high quality evidence suggests a short-term small, significant effect for improvement in global symptoms, for people with or without concurrent antipsychotics (RR=0.76). There is no evidence for longer-term therapeutic or adverse effects of either treatment. CONCLUSIONS: It is worthwhile considering rTMS in cases where auditory hallucinations have not responded to antipsychotic medications and ECT where overall symptoms have not responded to antipsychotic medications.

The role of the general practitioner in the treatment of schizophrenia: specific issues.

This article provides practical guidelines for general practitioners in treating schizophrenia. Specific areas include pharmacological treatment, supportive therapy, depression and suicide, alcohol and drug abuse, sexuality, and physical health.

The role of the general practitioner in the treatment of schizophrenia: general principles.

In light of the emphasis on community care for schizophrenia and the increasing role likely to be played by general practitioners, this paper describes some of the general principles involved in the treatment of this disorder and provides a set of practical guidelines to assist general practitioners.