The potential effects of antipsychotic drugs on brain structure represent a key factor in understanding neuroanatomical changes in psychosis. This review addresses two issues: (1) do antipsychotic medications induce changes in total or regional human brain volumes and (2) do such effects depend on antipsychotic type?

A systematic review of studies reporting structural brain magnetic resonance imaging (MRI) measures: (1) directly in association with antipsychotic use; and (2) in patients receiving lifetime treatment with antipsychotics in comparison with drug-naive patients or healthy controls. We searched Medline and EMBASE databases using the medical subject heading terms: ‘antipsychotics’ AND ‘brain’ AND (MRI NOT functional). The search included studies published up to 31 January 2007. Wherever possible, we reported the effect size of the difference observed.

Thirty-three studies met our inclusion criteria. The results suggest that antipsychotics act regionally rather than globally on the brain. These volumetric changes are of a greater magnitude in association with typical than with atypical antipsychotic use. Indeed, there is evidence of a specific effect of antipsychotic type on the basal ganglia, with typicals specifically increasing the volume of these structures. Differential effects of antipsychotic type may also be present on the thalamus and the cortex, but data on these and other brain areas are more equivocal.

Antipsychotic treatment potentially contributes to the brain structural changes observed in psychosis. Future research should take into account these potential effects, and use adequate sample sizes, to allow improved interpretation of neuroimaging findings in these disorders.

Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis.

A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family.

The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes.

Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present.

Verbal memory is frequently and severely affected in schizophrenia and has been implicated as a mediator of poor clinical outcome. Whereas encoding deficits are well demonstrated, it is unclear whether retention is impaired. This distinction is important because accelerated forgetting implies impaired consolidation attributable to medial temporal lobe (MTL) dysfunction whereas impaired encoding and retrieval implicates involvement of prefrontal cortex.

We assessed a group of healthy volunteers (n=97) and pre-morbid IQ- and sex-matched first-episode psychosis patients (n=97), the majority of whom developed schizophrenia. We compared performance of verbal learning and recall with measures of visuospatial working memory, planning and attentional set-shifting, and also current IQ.

All measures of performance, including verbal memory retention, a memory savings score that accounted for learning impairments, were significantly impaired in the schizophrenia group. The difference between groups for delayed recall remained even after the influence of learning and recall was accounted for. Factor analyses showed that, in patients, all variables except verbal memory retention loaded on a single factor, whereas in controls verbal memory and fronto-executive measures were separable.

The results suggest that IQ, executive function and verbal learning deficits in schizophrenia may reflect a common abnormality of information processing in prefrontal cortex rather than specific impairments in different cognitive domains. Verbal memory retention impairments, however, may have a different aetiology.

There is increasing evidence that the frequently reported working memory impairments in schizophrenia might be partly due to an alteration in the functional connectivity between task-relevant areas. However, little is known about the functional connectivity patterns in schizophrenia patients during learning processes. In a previous study, Koch et al. [Neuroscience (2007) 146, 1474–1483] have demonstrated stronger exponential activation decreases in schizophrenia patients during overlearning of short-term memory material. The question arises whether these differential temporal patterns of activation in schizophrenia patients and controls are going along with changes in task-related functional connectivity.

Therefore, in the current study, 13 patients with schizophrenia and 13 controls were studied while performing a short-term memory task associated with increasing overlearning of verbal stimulus material. Functional connectivity was investigated by analyses of psychophysiological interactions (PPI).

Results revealed significant task-related modulation of functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and a network including the right DLPFC, left ventrolateral prefrontal cortex, premotor cortex, right inferior parietal cortex, left and right cerebellum as well as the left occipital lobe in patients during the course of overlearning and practice. No significant PPI results were detectable in controls.

Activation changes with practice were associated with high functional connectivity between task-relevant areas in schizophrenia patients. This could be interpreted as a compensatory resource allocation and network integration in the context of cortical inefficiency and may be a specific neurophysiological signature underlying the pathophysiology of schizophrenia.

Cognitive biases, especially jumping to conclusions (JTC), are ascribed a vital role in the pathogenesis of schizophrenia. This study set out to explore motivational factors for JTC using a newly developed paradigm.

Twenty-seven schizophrenia patients and 32 healthy controls were shown 15 classical paintings, divided into three blocks. Four alternative titles (one correct and three lure titles) had to be appraised according to plausibility (0–10). Optionally, participants could decide for one option and reject one or more alternatives. In random order across blocks, anxiety-evoking music, happy music or no music was played in the background.

Patients with schizophrenia, particularly those with delusions, made more decisions than healthy subjects. In line with the liberal acceptance (LA) account of schizophrenia, the decision threshold was significantly lowered in patients relative to controls. Patients were also more prone than healthy controls to making a decision when the distance between the first and second best alternative was close. Furthermore, implausible alternatives were judged as significantly more plausible by patients. Anxiety-evoking music resulted in more decisions in currently deluded patients relative to non-deluded patients and healthy controls.

The results confirm predictions derived from the LA account and assert that schizophrenia patients decide hastily under conditions of continued uncertainty. The fact that mood induction did not exert an overall effect could be due to the explicit nature of the manipulation, which might have evoked strategies to counteract their influence.

The role of the brain-derived neurotrophic factor (BDNF) in the pathogenesis of affective disorders such as depression has been controversial. Mounting evidence comes from structural imaging, that the functional BDNF Val66Met polymorphism influences the hippocampal volume with carriers of the 66Met allele (Val/Met and Met/Met group) having smaller hippocampi. Given that stress-induced atrophy of the hippocampus is associated with the pathogenesis of affective disorders, the functional BDNF Val66Met polymorphism could be an incremental risk factor.

Eighty-seven healthy Caucasian participants underwent structural imaging and were genotyped for the BDNF Val66Met polymorphism. Data were analysed by means of voxel-based morphometry (VBM).

Region of interest (ROI) analyses revealed an association between the 66Met allele and smaller parahippocampal volumes and a smaller right amygdala. In addition, the whole-brain analysis showed that the thalamus, fusiformus gyrus and several parts of the frontal gyrus were smaller in 66Met allele carriers.

This study demonstrates that the impact of the BDNF Val66Met polymorphism is not confined to the hippocampus but also extends to the parahippocampal gyrus and the amygdala.

Clinical depression involves persistent dysphoria, implicating impaired affect regulation or mood repair failure. However, there is comparatively little information about the mood repair repertoires of individuals with histories of clinical depression, how their repertories differ from that of never-depressed people, and whether particular types of mood repair responses differentially contribute to depression risk.

Adult probands who had childhood-onset depressive disorder (n=215) and controls with no history of major mental disorder (n=122) reported which specific (cognitive, behavioral, interpersonal and somatic-sensory) responses they typically deploy when experiencing sad affect, including responses known to appropriately attenuate dysphoria (‘adaptive’ responses) and those known to exacerbate dysphoria in the short or long run (‘maladaptive’ responses). Subjects were longitudinally followed and evaluated.

Remitted probands and probands in depressive episodes both reported a greater number of maladaptive responses and fewer adaptive responses to their own sadness than did controls, although probands did not have an absolute deficiency of adaptive responses. Maladaptive (but not adaptive) mood repair responses predicted future increases in depression symptoms and an increased probability of a recurrent depressive episode among probands (even after controlling for several clinical predictors of course). Post-hoc analyses revealed that maladaptive non-cognitive and maladaptive cognitive mood repair response sets each predicted depression outcomes.

Individuals with past and present episodes of depressive disorder report an array of cognitive and non-cognitive responses to their own sadness that are likely to exacerbate that affect, and this pattern predicts a worse course of the disorder.

Many people suffering from mental disorders do not seek appropriate help. We have examined attitudes that further or hinder help-seeking for depression with an established socio-psychological model, the Theory of Planned Behaviour (TPB), comparing models for respondents with and without depressive symptoms.

A qualitative preparatory study (n=29) elicited salient behavioural (BB), normative (NB) and control beliefs (CB) that were later included in the TPB questionnaire. Telephone interviews with a representative population sample in Germany (n=2303) started with a labelled vignette describing symptoms of a major depression, followed by items covering the components of the TPB. Intention to see a psychiatrist for the problem described was elicited at the beginning and at the end of the interview. We screened participants for current depressive symptoms using the mood subscale of the Patient Health Questionnaire (PHQ-9).

In non-depressed respondents (n=2167), a TPB path model predicted 42% of the variance for the first and 51% for the second question on intention. In an analogous model for depressed respondents (n=136), these values increased to 50% and 61% respectively. Path coefficients in both models were similar. In both depressed and non-depressed persons, attitude towards the behaviour was more important than the subjective norm, whereas perceived behavioural control was of minor influence.

Willingness to seek psychiatric help for depression can largely be explained by a set of attitudes and beliefs as conceptualized by the TPB. Our findings suggest that changing attitudes in the general population are likely to effect help-seeking when people experience depressive symptoms.

Poisoning with weak analgesics is a major public health problem because of easy accessibility of the compounds; however, few studies have investigated their influence on subsequent suicide in the context of subjects' psychiatric status and other factors.

This nested case-control study was based on the entire Danish population including all 21 169 suicide cases and 423 128 matched population controls. Data on hospital admissions for poisoning and confounding factors were retrieved from national medical and administrative registries. Conditional logistic regression was used to compute relative risk.

A prior hospital admission for poisoning with weak non-opioid analgesics significantly increased the risk of subsequent suicide [crude incidence rate ratio (IRR) 24.7, 95% confidence interval (CI) 22.1–27.6], and the effect of paracetamol poisoning was substantially stronger than that of poisoning with salicylates or non-steriodal anti-inflammatory drugs (NSAIDs). This association could not be explained by confounding from socio-economic or psychiatric factors. The elevated risk was extremely high during the first week following the overdose (adjusted IRR 738.9, 95% CI 173.9–3139.1), then declined over time but still remained significantly high 3 years later (adjusted IRR 4.2, 95% CI 3.5–5.0). Moreover, a history of weak analgesic poisoning significantly interacted with a person's psychiatric history, increasing the risk for subsequent suicide substantially more for persons with no history of psychiatric hospitalization than did it for those with such a history.

A history of non-fatal poisoning with weak analgesics is a strong predictor for subsequent suicide. These results emphasize the importance of intensive psychiatric care of patients following overdose.

Most mortality studies of psychiatric patients published to date have been conducted in hospital-based systems of care. This paper describes a study of the causes of death and associated risk factors among psychiatric patients who were followed up over a 20-year period in an area where psychiatric care is entirely provided by community-based psychiatric services.

All subjects in contact with the South Verona Community-based Mental Health Service (CMHS) over a 20-year period with an ICD-10 psychiatric diagnosis were included. Of these 6956 patients, 938 died during the study period. Standardized mortality ratios (SMRs) and Poisson multiple regressions were used to assess the excess of mortality in the sample compared with the general population.

The overall SMR of the psychiatric patients was 1.88. Mortality was significantly high among out-patients [SMR 1.71, 95% confidence interval (CI) 1.6–1.8], and higher still following the first admission (SMR 2.61, 95% CI 2.4–2.9). The SMR for infectious diseases was higher among younger patients and extremely high in patients with diagnoses of drug addiction (216.40, 95% CI 142.5–328.6) and personality disorders (20.87, 95% CI 5.2–83.4).

This study found that psychiatric patients in contact with a CMHS have an almost twofold higher mortality rate than the general population. These findings demonstrate that, since the closure of long-stay psychiatric hospitals, the physical health care of people with mental health problems is often neglected and clearly requires greater attention by health-care policymakers, services and professionals.

Whether autism spectrum maps onto a spectrum of brain abnormalities and whether Asperger's syndrome (ASP) is distinct from high-functioning autism (HFA) are debated. White-matter maldevelopment is associated with autism and disconnectivity theories of autism are compelling. However, it is unknown whether children with ASP and HFA have distinct white-matter abnormalities.

Voxel-based morphometry mapped white-matter volumes across the whole brain in 91 children. Thirty-six had autism spectrum disorder. A history of delay in phrase speech defined half with HFA; those without delay formed the ASP group. The rest were typically developing children, balanced for age, IQ, gender, maternal language and ethnicity. White-matter volumes in HFA and ASP were compared and each contrasted with controls.

White-matter volumes around the basal ganglia were higher in the HFA group than ASP and higher in both autism groups than controls. Compared with controls, children with HFA had less frontal and corpus callosal white matter in the left hemisphere; those with ASP had less frontal and corpus callosal white matter in the right hemisphere with more white matter in the left parietal lobe.

HFA involved mainly left hemisphere white-matter systems; ASP affected predominantly right hemisphere white-matter systems. The impact of HFA on basal ganglia white matter was greater than ASP. This implies that aetiological factors and management options for autism spectrum disorders may be distinct. History of language acquisition is a potentially valuable marker to refine our search for causes and treatments in autism spectrum.

Children with attention deficit/hyperactivity disorder (ADHD) are at risk of negative academic outcomes. However, relatively few studies in this area have been based on long-term longitudinal designs and community-based settings. This study examined the link between childhood hyperactivity-inattention symptoms (HI-s) and subsequent academic achievement in a community setting, controlling for other behavioural symptoms, socio-economic status (SES) and environmental factors at baseline.

The sample consisted of 1264 subjects (aged 12 to 26 years at follow-up) recruited from the longitudinal GAZEL Youth study. Psychopathology, environmental variables and academic outcomes were measured through self-reports. Multivariate modelling was performed to evaluate the effects of childhood HI-s and other risk factors on academic achievement 8 years later.

HI-s independently predicted grade retention [adjusted odds ratio (OR) 3.58, 95% confidence interval (CI) 2.38–5.39], failure to graduate from secondary school (adjusted OR 2.41, 95% CI 1.43–4.05), obtaining a lower-level diploma (adjusted OR 3.00, 95% CI 1.84–4.89), and lower academic performance. These results remained significant even after accounting for school difficulties at baseline. Negative academic outcomes were also significantly associated with childhood symptoms of conduct disorder (CD), even after accounting for adjustment variables.

This longitudinal survey replicates, in a general population-based setting, the finding of a link between HI-s and negative academic outcomes.

We aimed to compare the rate of cognitive decline in patients with early and late onset Alzheimer's disease (AD) and to investigate the potentially modifying influence of the apolipoprotein E (APOE) genotype.

We included 99 patients with early onset AD (age ⩽65 years) and 192 patients with late onset AD (age >65 years) who had at least two scores on the Mini-Mental State Examination (MMSE) (range 2–14) obtained at least 1 year apart. Linear mixed models were performed to investigate the rate of cognitive decline dependent on age at onset (AAO) and APOE genotype.

The mean (s.d.) age for patients with early onset AD was 57.7 (4.5) years, and 74.5 (5.1) years for patients with late onset AD. AAO was not associated with baseline MMSE [β (s.e.)=0.8 (0.5), p=0.14]. However, patients with early onset showed a faster decline on the MMSE [β (s.e.)=2.4 (0.1) points/year] than those with late onset [β (s.e.)=1.7 (0.1) points/year, p=0.00]. After stratification according to APOE genotype, APOE ε4 non-carriers with early onset showed faster cognitive decline than non-carriers with late onset [2.4 (0.3) v. 1.3 (0.3) points/year, p=0.01]. In APOE ε4 carriers, no difference in rate of cognitive decline was found between patients with early and late onset [β (s.e.)=0.2 (0.2), p=0.47].

Patients with early onset AD show more rapid cognitive decline than patients with late onset, suggesting that early onset AD follows a more aggressive course. Furthermore, this effect seems to be most prominent in patients with early onset who do not carry the genetic APOE ε4 risk factor for AD.

Fatigue syndromes and irritable bowel syndrome (IBS) often occur together. Explanations include being different manifestations of the same condition and simply sharing some symptoms.

A matched case-control study in UK primary care, using data collected prospectively in the General Practice Research Database (GPRD). The main outcome measures were: health-care utilization, specific symptoms and diagnoses. Risk markers were divided into distant (from 3 years to 1 year before diagnosis) and recent (1 year before diagnosis).

A total of 4388 patients with any fatigue syndrome were matched to two groups of patients: those attending for IBS and those attending for another reason. Infections were specific risk markers for both syndromes, with viral infections being a risk marker for a fatigue syndrome [odds ratios (ORs) 2.3–6.3], with a higher risk closer to onset, and gastroenteritis a risk for IBS (OR 1.47, compared to a fatigue syndrome). Chronic fatigue syndrome (CFS) shared more distant risk markers with IBS than other fatigue syndromes, particularly other symptom-based disorders (OR 3.8) and depressive disorders (OR 2.3), but depressive disorders were a greater risk for CFS than IBS (OR 2.4). Viral infections were more of a recent risk marker for CFS compared to IBS (OR 2.8), with gastroenteritis a greater risk for IBS (OR 2.4).

Both fatigue and irritable bowel syndromes share predisposing risk markers, but triggering risk markers differ. Fatigue syndromes are heterogeneous, with CFS sharing predisposing risks with IBS, suggesting a common predisposing pathophysiology.