Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample.

Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10(-8). We observed interesting trends for rs9346455 (P=6.49x10(-6)) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10(-5)) and rs1012650 (P=1.47 × 10(-5)), and rs1059778 (P=1.49x10(-5)) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10(-7). Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59.

Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis.

BACKGROUND: A meta-analysis of the serotonin1A (5-HT1A) receptor partial agonist of the azapirone class as an anxiolytic drug for the treatment of major depressive disorder (MDD) has not previously been reported. METHOD: We carried out a systematic review of the literature available in PubMed, the Cochrane Library database and PsycINFO up to 12 October 2013, and conducted a meta-analysis of randomized controlled trials (RCTs) comparing 5-HT1A agonists with placebo and RCTs of 5-HT1A agonist augmentation therapies for MDD treatment. We calculated the risk ratio (RR), number needed to treat (NNT)/number needed to harm (NNH) and 95% confidence intervals (CIs). RESULTS: Fifteen RCTs comparing 5-HT1A agonists with placebo (total n = 2469, four studies with buspirone, seven with gepirone, three with ipsapirone and one with zalospirone) were identified. Pooled 5-HT1A agonists had significantly more responders (RR 0.74, 95% CI 0.65-083, p < 0.00001, NNT = 6, 12 trials, n = 1816) than placebo. Pooled 5-HT1A agonists were superior to placebo in discontinuation due to inefficacy (RR 0.49, p = 0.02, NNH = 16, p = 0.03, 10 trials, n = 1494) but were inferior to placebo in discontinuation due to side-effects (RR 1.88, p < 0.0001, NNH = 17, p = 0.001, 13 trials, n = 2196). However, all-cause discontinuation was similar in both groups (RR 0.99, p = 0.85, 14 trials, n = 2402). Four 5-HT1A agonist augmentation studies were identified (total n = 365, three buspirone studies and one tandospirone study). There were no statistically significant effects of 5-HT1A agonist augmentation therapies on response rate (RR 0.98, p = 0.85, four trials, n = 341). 5-HT1A agonist-related side-effects including gastrointestinal symptoms, dizziness, insomnia, palpitation, paresthesia and sweating were greater than with placebo (p < 0.00001 to p = 0.03). CONCLUSIONS: Our results suggest that 5-HT1A agonist has a more beneficial effect on MDD than placebo, but has several side-effects.

Trends in suicidal ideation in England: the national psychiatric morbidity surveys of 2000 and 2007.

BACKGROUND: Recent falls in suicide rates should be accompanied by a decline in the prevalence of suicidal ideation. METHOD: We used a pseudo-cohort analytic strategy to examine trends in suicidal ideation measured identically in 2000 and 2007, in nationally representative English probability samples of adults aged ≥ 16 years. Suicidal ideation included tiredness of life, death wishes and thoughts of suicide. Logistic regression models were fitted to estimate trends in age-specific prevalence of suicidal ideation in the past year and past week between 2000 and 2007. RESULTS: There were 6799 participants aged 16-71 years in 2000, and 6815 participants aged 16-78 years in 2007. There was little evidence of trends in prevalence of suicidal ideation, with the exception of women aged 44-50 years in 2007, whose prevalence was unusually high. Prevalence of suicidal ideation in the past year followed a W-shaped profile with age, with peaks at the transition to adulthood, in the forties, and in the oldest participants. CONCLUSIONS: Despite falling suicide rates, suicidal ideation did not decline overall between 2000 and 2007. This may indicate the success of the National Suicide Prevention Strategy. Women aged 44-50 years in 2007 were, however, particularly prone to suicidal ideation. As they also have the highest age-adjusted prevalence of common mental disorders and the highest female suicide rate, there are clear implications for treatment access, availability and delivery in primary care.

Estimated verbal IQ and the odds of problem gambling: a population-based study.

BACKGROUND: The neurocognitive deficits and other correlates of problem gambling are also observable in individuals with lower cognitive abilities, suggesting that a low IQ may be a determinant of problem gambling. There has been very little research into this possibility. This study aimed to investigate the characteristics associated with problem gambling in a large population-based study in England, with a particular focus on IQ. METHOD: The Adult Psychiatric Morbidity Survey (APMS) 2007 comprised detailed interviews with 7403 individuals living in private households in England. Problem gambling was ascertained using a questionnaire based on DSM-IV criteria. Verbal IQ was estimated using the National Adult Reading Test (NART). Confounders included socio-economic and demographic factors, common mental disorders, impulsivity, smoking, and hazardous drug and alcohol use. RESULTS: More than two-thirds of the population reported engaging in some form of gambling in the previous year, but problem gambling was rare [prevalence 0.7%, 95% confidence interval (CI) 0.5-1.0]. The odds of problem gambling doubled with each standard deviation drop in estimated verbal IQ [adjusted odds ratio (OR) 2.1, 95% CI 1.3-3.4, p = 0.003], after adjusting for other characteristics associated with problem gambling including age, sex, socio-economic factors, drug and alcohol dependence, smoking, impulsivity and common mental disorders. There was no strong relationship observed between IQ and non-problem gambling. CONCLUSIONS: People with lower IQs may be at a higher risk of problem gambling. Further work is required to replicate and study the mechanisms behind these findings, and may aid the understanding of problem gambling and inform preventative measures and interventions.

The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia.

We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 (MIR137) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis across four independently collected samples of patients with schizophrenia (n=510; F1,506=17.7, P=3.1 × 10(-5)). In an imaging-genetics subsample that included additional matched controls (n=213), patients with schizophrenia who had the MIR137 risk genotype had reduced white matter integrity (F3,209=13.6, P=3.88 × 10(-8)) throughout the brain as well as smaller hippocampi and larger lateral ventricles; the brain structure of patients who were carriers of the protective allele was no different from healthy control subjects on these neuroimaging measures. Our findings suggest that MIR137 substantially influences variation in phenotypes that are thought to have an important role in clinical outcome and treatment response. Finally, the possible consequences of genetic risk factors may be distinct in patients with schizophrenia compared with healthy controls.

The dopamine D1 receptor positive allosteric modulator, DETQ, improves cognition and social interaction in aged mice and enhances cortical and hippocampal acetylcholine efflux.

Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response curve. DETQ, [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one] is highly selective for the human D1Rs as shown in humanized D1R knock-in (hD1Ki) mice. Here, we have ascertained the efficacy of DETQ in aged [13-23-month-old (mo)] hD1Ki mice and their corresponding age-matched wild-type (WT; C57BL/6NTac) controls. We found that in aged mice, DETQ, given acutely, subchronically, and chronically, rescued both novel object recognition memory and social behaviors, using novel object recognition (NOR) and social interaction (SI) tasks, respectively without any adverse effect on body weight or mortality. We have also shown, using in vivo microdialysis, a significant decrease in basal DA and norepinephrine, increase in glutamate (Glu) and gamma-amino butyric acid (GABA) efflux with no significant changes in acetylcholine (ACh) levels in aged vs young mice. In young and aged hD1Ki mice, DETQ, acutely and subchronically increased ACh in the medial prefrontal cortex and hippocampal regions in aged hD1Ki mice without affecting Glu. These results suggest that the D1PAM mechanism is of interest as potential treatment for cognitive and social behavioral deficits in neuropsychiatric disorders including but not restricted to neurodegenerative disorders, such as Parkinson's disease.

Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene.

Antipsychotic-induced weight gain (AIWG) may result in the metabolic syndrome in schizophrenia (SCZ) patients. Downstream variants of the melanocortin-4 receptor (MC4R) gene have been associated with obesity in various populations. Thus, we examined single-nucleotide polymorphisms (SNPs) in the MC4R region for association with AIWG in SCZ patients. Four SNPs (rs2229616, rs17782313, rs11872992 and rs8087522) were genotyped in 224 patients who underwent treatment for SCZ and were evaluated for AIWG for up to 14 weeks. We compared weight change (%) across genotypic groups using analysis of covariance for three SNPs (r²≤0.8). European-ancestry patients who were rs8087522 A-allele carriers (AG+AA) on clozapine gained significantly more weight than non-carriers (P=0.027, n=69). These observations were marginal after correction for multiple testing. We performed in vitro electrophoretic mobility-shift assay that suggested that the presence of the A-allele may create a transcription factor-binding site. Further investigation is warranted for both these exploratory findings.

The population impact of common mental disorders and long-term physical conditions on disability and hospital admission.

BACKGROUND: Long-term physical conditions (LTCs) consume the largest share of healthcare budgets. Although common mental disorders (CMDs) and LTCs often co-occur, the potential impact of improved mental health treatment on severe disability and hospital admissions for physical health problems remains unknown. Method A cross-sectional study of 7403 adults aged 16-95 years living in private households in England was performed. LTCs were ascertained by prompted self-report. CMDs were ascertained by structured clinical interview. Disability was assessed using questions about problems with activities of daily living. Population impact and potential preventive gain were estimated using population-attributable fraction (PAF), and conservative estimates were obtained using 'treated non-cases' as the reference group. RESULTS: Of the respondents, 20.7% reported at least one LTC. The prevalence of CMDs increased with the number of LTCs, but over two-thirds (71.2%) of CMD cases in people with LTCs were untreated. Statistically significant PAFs were found for CMDs and recent hospital admission [13.5%, 95% confidence intervals (CI) 6.6-20.0] and severe disability (31.3%, 95% CI 27.1-35.2) after adjusting for LTCs and other confounders. Only the latter remained significant when using the most conservative estimate of PAF (21.8%, 95% CI 14.0-28.9), and this was reduced only slightly when considering only participants with LTCs (18.5%, 95% CI 7.9-27.9). CONCLUSIONS: Better treatments for CMDs in people with LTCs could achieve almost the same population health gain in terms of reducing severe disability as those targeted at the entire population. Interventions to reduce the prevalence of CMDs among people with LTCs should be part of routine medical care.

The relationship between happiness and intelligent quotient: the contribution of socio-economic and clinical factors.

BACKGROUND: Happiness and higher intelligent quotient (IQ) are independently related to positive health outcomes. However, there are inconsistent reports about the relationship between IQ and happiness. The aim was to examine the association between IQ and happiness and whether it is mediated by social and clinical factors. Method The authors analysed data from the 2007 Adult Psychiatric Morbidity Survey in England. The participants were adults aged 16 years or over, living in private households in 2007. Data from 6870 participants were included in the study. Happiness was measured using a validated question on a three-point scale. Verbal IQ was estimated using the National Adult Reading Test and both categorical and continuous IQ was analysed. RESULTS: Happiness is significantly associated with IQ. Those in the lowest IQ range (70-99) reported the lowest levels of happiness compared with the highest IQ group (120-129). Mediation analysis using the continuous IQ variable found dependency in activities of daily living, income, health and neurotic symptoms were strong mediators of the relationship, as they reduced the association between happiness and IQ by 50%. CONCLUSIONS: Those with lower IQ are less happy than those with higher IQ. Interventions that target modifiable variables such as income (e.g. through enhancing education and employment opportunities) and neurotic symptoms (e.g. through better detection of mental health problems) may improve levels of happiness in the lower IQ groups.

Occupations, work characteristics and common mental disorder.

BACKGROUND: The present study aimed to assess the prevalence of common mental disorders (CMDs) by occupation in a representative sample of the English adult population. Another aim was to examine whether the increased risk of CMD in some occupations could be explained by adverse work characteristics. Method We derived a sample of 3425 working-age respondents from the Adult Psychiatric Morbidity Survey 2007. Occupations were classified by Standard Occupational Classification group, and CMD measured by the Revised Clinical Interview Schedule. Job characteristics were measured by questionnaire, and tested as explanatory factors in associations of occupation and CMD. RESULTS: After adjusting for age, gender, housing tenure and marital status, caring personal service occupations had the greatest risk of CMD compared with all occupations (odds ratio 1.73, 95% confidence interval 1.16-2.58). The prevalence of adverse psychosocial work characteristics did not follow the pattern of CMD by occupation. Work characteristics did not explain the increased risk of CMDs associated with working in personal service occupations. Contrary to our hypotheses, adding work characteristics individually to the association of occupation and CMD tended to increase rather than decrease the odds for CMD. CONCLUSIONS: As has been found by others, psychosocial work characteristics were associated with CMD. However, we found that in our English national dataset they could not explain the high rates of CMD in particular occupations. We suggest that selection into occupations may partly explain high CMD rates in certain occupations. Also, we did not measure emotional demands, and these may be important mediators of the relationship between occupation type and CMDs.

Consumption of lead-shot cervid meat and blood lead concentrations in a group of adult Norwegians.

Several recent investigations have reported high concentrations of lead in samples of minced cervid meat. This paper describes findings from a Norwegian study performed in 2012 among 147 adults with a wide range of cervid game consumption. The main aim was to assess whether high consumption of lead-shot cervid meat is associated with increased concentration of lead in blood. A second aim was to investigate to what extent factors apart from game consumption explain observed variability in blood lead levels. Median (5 and 95 percentile) blood concentration of lead was 16.6 µg/L (7.5 and 39 µg/L). An optimal multivariate linear regression model for log-transformed blood lead indicated that cervid game meat consumption once a month or more was associated with approximately 31% increase in blood lead concentrations. The increase seemed to be mostly associated with consumption of minced cervid meat, particularly purchased minced meat. However, many participants with high and long-lasting game meat intake had low blood lead concentrations. Cervid meat together with number of bullet shots per year, years with game consumption, self-assembly of bullets, wine consumption and smoking jointly accounted for approximately 25% of the variation in blood lead concentrations, while age and sex accounted for 27% of the variance. Blood lead concentrations increased approximately 18% per decade of age, and men had on average 30% higher blood lead concentrations than women. Hunters who assembled their own ammunition had 52% higher blood lead concentrations than persons not making ammunition. In conjunction with minced cervid meat, wine intake was significantly associated with increased blood lead. Our results indicate that hunting practices such as use of lead-based ammunition, self-assembling of lead containing bullets and inclusion of lead-contaminated meat for mincing to a large extent determine the exposure to lead from cervid game consumption.

Association study of cannabinoid receptor 1 (CNR1) gene in tardive dyskinesia.

Tardive dyskinesia (TD) is a severe, debilitating movement disorder observed in 25-30% of the patients treated with typical antipsychotics. Cannabinoid receptor 1 (CNR1) activators tend to inhibit movement, an effect prevented by rimonabant and other selective CNR1 antagonists. Furthermore, CNR1 receptor is downregulated in Huntington's disease and upregulated in Parkinson's disease. Twenty tagSNPs spanning the CNR1 gene were analyzed in schizophrenia patients of European ancestry (n=191; 74 with TD). Significant genotypic (P=0.012) and allelic (P=0.012) association was observed with rs806374 (T>C). Carriers of the CC genotype were more likely to be TD positive (CC vs TT+TC, odds ratio=3.4 (1.5-7.8), P=0.003) and had more severe TD (CC vs TT+TC; 9.52±9.2 vs 5.62±6.9, P=0.046). These results indicate a possible role of CNR1 in the development of TD in our patient population. However, these observations are marginal after correcting for multiple testing and need to be replicated in a larger patient population.

Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain.

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients.

Age and birth cohort differences in depression in repeated cross-sectional surveys in England: the National Psychiatric Morbidity Surveys, 1993 to 2007.

BACKGROUND: The National Psychiatric Morbidity Survey (NPMS) programme was partly designed to monitor trends in mental disorders, including depression, with comparable data spanning 1993 to 2007. Findings already published from this programme suggest that concerns about increasing prevalence of common mental disorders (CMDs) may be unfounded. This article focuses on depression and tests the hypothesis that successive birth cohorts experience the same prevalence of depression as they age. METHOD: We carried out a pseudo-cohort analysis of a sequence of three cross-sectional surveys of the English household population using identical diagnostic instruments. The main outcome was ICD-10 depressive episode or disorder. Secondary outcomes were the depression subscales of the Clinical Interview Schedule - Revised (CIS-R). RESULTS: There were 8670, 6977 and 6815 participants in 1993, 2000 and 2007 respectively. In men, the prevalence of depression increased between cohorts born in 1943-1949 and 1950-1956 [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.4-4.2], then remained relatively stable across subsequent cohorts. In women, there was limited evidence of change in prevalence of depression. Women born in 1957-1963, surveyed aged 44-50 years in 2007, had exceptionally high prevalence. It is not clear whether this represents a trend or a quirk of sampling. CONCLUSIONS: There is no evidence of an increase in the prevalence of depression in male cohorts born since 1950. In women, there is limited evidence of increased prevalence. Demand for mental health services may stabilize or even fall for men.

The contribution of work and non-work stressors to common mental disorders in the 2007 Adult Psychiatric Morbidity Survey.

BACKGROUND: Evidence for an effect of work stressors on common mental disorders (CMD) has increased over the past decade. However, studies have not considered whether the effects of work stressors on CMD remain after taking co-occurring non-work stressors into account. METHOD: Data were from the 2007 Adult Psychiatric Morbidity Survey, a national population survey of participants 6 years living in private households in England. This paper analyses data from employed working age participants (N=3383: 1804 males; 1579 females). ICD-10 diagnoses for depressive episode, generalized anxiety disorder, obsessive compulsive disorder, agoraphobia, social phobia, panic or mixed anxiety and depression in the past week were derived using a structured diagnostic interview. Questionnaires assessed self-reported work stressors and non-work stressors. RESULTS: The effects of work stressors on CMD were not explained by co-existing non-work stressors. We found independent effects of work and non-work stressors on CMD. Job stress, whether conceptualized as job strain or effort-reward imbalance, together with lower levels of social support at work, recent stressful life events, domestic violence, caring responsibilities, lower levels of non-work social support, debt and poor housing quality were all independently associated with CMD. Social support at home and debt did not influence the effect of work stressors on CMD. CONCLUSIONS: Non-work stressors do not appear to make people more susceptible to work stressors; both contribute to CMD. Tackling workplace stress is likely to benefit employee psychological health even if the employee's home life is stressful but interventions incorporating non-work stressors may also be effective.

Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community.

BACKGROUND: There are no tested methods for conducting epidemiological studies of autism spectrum disorders (ASDs) in adult general population samples. We tested the validity of the Autism Diagnostic Observation Schedule module-4 (ADOS-4) and the 20-item Autism-Spectrum Quotient (AQ-20). METHOD: Randomly sampled adults aged ≥16 years were interviewed throughout England in a general population multi-phase survey. The AQ-20 was self-completed by 7353 adults in phase 1. A random subset completed phase 2, ADOS-4 assessments (n=618); the probability of selection increased with AQ-20 score. In phase 3, informant-based Diagnostic Interview Schedule for Social and Communication Disorders (DISCO) and Autism Diagnostic Interview-Revised (ADI-R) developmental assessments were completed (n=56). Phase 1 and 2 data were presented as vignettes to six experienced clinicians (working in pairs). The probability of respondents having an ASD was compared across the three survey phases. RESULTS: There was moderate agreement between clinical consensus diagnoses and ADOS-4. A range of ADOS-4 caseness thresholds was identified by clinicians: 5+ to 13+ with greatest area under the curve (AUC) at 5+ (0.88). Modelling of the presence of ASD using 56 DISCO assessments suggested an ADOS-4 threshold in the range of 10+ to 13+ with the highest AUC at ADOS 10+ to 11+ (0.93-0.94). At ADOS 10+, the sensitivity was 1 [95% confidence interval (CI) 0.59-1.0] and the specificity 0.86 (95% CI 0.72-0.94). The AQ-20 was only a weak predictor of ADOS-4 cases. CONCLUSIONS: Clinically recommended ADOS-4 thresholds are also recommended for community cases: 7+ for subthreshold and 10+ for definite cases. Further work on adult population screening methods is needed.

Humans seem to produce arsenobetaine and dimethylarsinate after a bolus dose of seafood.

Seafood is the predominant food source of several organoarsenic compounds. Some seafood species, like crustaceans and seaweed, also contain inorganic arsenic (iAs), a well-known toxicant. It is unclear whether human biotransformation of ingested organoarsenicals from seafood result in formation of arsenicals of health concern. The present controlled dietary study examined the urinary excretion of arsenic compounds (total arsenic (tAs), iAs, AB (arsenobetaine), dimethylarsinate (DMA) and methylarsonate (MA)) following ingestion of a single test meal of seafood (cod, 780 µg tAs, farmed salmon, 290 µg tAs or blue mussel, 690 µg tAs or potato (control, 110 µg tAs)) in 38 volunteers. The amount of ingested tAs excreted via the urine within 0-72 h varied significantly among the groups: Cod, 74% (52-92%), salmon 56% (46-82%), blue mussel 49% (37-78%), control 45% (30-60%). The estimated total urinary excretion of AB was higher than the amount of ingested AB in the blue mussel group (112%) and also ingestion of cod seemed to result in more AB, indicating possible endogenous formation of AB from other organoarsenicals. Excretion of iAs was lower than ingested (13-22% of the ingested iAs was excreted in the different groups). Although the ingested amount of iAs+DMA+MA was low for all seafood groups (1.2-4.5% of tAs ingested), the urinary DMA excretion was high in the blue mussel and salmon groups, counting for 25% and 11% of the excreted tAs respectively. In conclusion our data indicate a possible formation of AB as a result of biotransformation of other organic arsenicals. The considerable amount of DMA excreted is probably not only due to methylation of ingested iAs, but due to biotransformation of organoarsenicals making it an inappropriate biomarker of iAs exposure in populations with a high seafood intake.

Predicting outcome of assertive outreach across England.

BACKGROUND: Assertive community treatment for the severely mentally ill is being implemented increasingly internationally. It is unclear whether recommended characteristics of assertive outreach (AO) teams influence care and outcomes. We hypothesised that recommended characteristics of AO teams such as joint health and social care management would predict reduced hospitalisation in the first year of an AO client programme and related outcomes throughout England. METHODS: A two-stage design was used: a stratified sample of 100 of the 186 'stand-alone' AO teams in England and a systematic sample of clients from each team with stratification for black and ethnic minority patients. Team characteristics, treatment and outcomes were collected from teams. Analyses took account of patients' histories, clustering and ethnic minority over-sampling. RESULTS: Under AO the proportion of time spent in hospital following admission decreased. Only 3/1,096 patients went missing in 9 months. Although patient' histories significantly predicted outcomes almost no team characteristics predicted re-admission or other patient outcomes after 1 and 3 years. Ethnic minority clients were more likely to be on compulsory orders only on jointly managed teams (P = 0.030). Multidisciplinary teams and teams not working out of hours significantly predicted that patients received psychological interventions, but only 17% of sampled patients received such treatments. CONCLUSIONS: Characteristics of AO teams do not explain long-term patient outcomes. Since recommended team characteristics are not effective new models of care should be developed and the process of care tested. Managing teams to implement evidence-based psychological interventions might improve outcomes.

Pimavanserin augments the efficacy of atypical antipsychotic drugs in a mouse model of treatment-refractory negative symptoms of schizophrenia.

Negative symptoms are a core, pervasive, and often treatment-refractory phenotype of schizophrenia, one which contributes to poor functional outcome, ability to work, pursue educational goals, and quality of life, as well as caretaker burden. Improvement of negative symptoms in some patients with schizophrenia has been reported with some atypical antipsychotic drugs [AAPDs], but improvement is absent in many patients and partial in others. Therefore, more effective treatments are needed, and better preclinical models of negative symptoms are needed to identify them. Sub-chronic [sc] treatment of rodents with phencyclidine [PCP], a noncompetitive N-methyl-d-aspartate [NMDAR] antagonist, produces deficits in social interactions [SI] that have been widely studied as a model of negative symptoms in schizophrenia. Acute restraint stress [ARS] also provides a model of treatment-refractory negative symptoms [TRS] to AAPDs. By themselves, in sc-PCP mice, the AAPDs, risperidone, olanzapine, and aripiprazole, but not the selective 5-HT2AR inverse agonist, pimavanserin [PIM], rescued the SI deficit in sc-PCP mice, as did the combination of PIM with sub-effective doses of each of these AAPDs. These three AAPDs alone did not rescue SI deficit in sc-PCP+ 2 h-ARS mice, indicating these mice were treatment refractory. However, co-administration of PIM with any of the AAPDs significantly restored SI in these mice. PIM may be an effective adjunctive therapy for treating negative symptoms of schizophrenia in some patients who have failed to respond to AAPDs, but further studies are needed.

The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats.

The role of 5-hydroxytryptamine (serotonin) (5-HT)(7) receptor antagonism in the actions of atypical antipsychotic drugs (APDs), e.g., amisulpride, clozapine, and lurasidone, if any, is uncertain. We examined the ability of 5-HT(7) receptor antagonism alone and as a component of amisulpride and lurasidone to reverse deficits in rat novel object recognition (NOR) produced by subchronic treatment with the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP), and we examined the ability of supplemental 5-HT(7) antagonism to augment the inability of sulpiride, haloperidol, and (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a metabotropic glutamate receptor (mGluR) 2/3 agonist, which lack 5-HT(7) antagonism, to reverse the NOR deficit. The 5-HT(7) receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine (SB269970) (0.1-1 mg/kg) dose-dependently reversed PCP-induced NOR deficits. In addition, the ability of lurasidone (0.1 mg/kg) and amisulpride (3 mg/kg) to reverse this deficit was blocked by cotreatment with the 5-HT(7) receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS19) (5-10 mg/kg), which did not affect NOR in naive rats. Sulpiride, a less potent 5-HT(7) antagonist than amisulpride, did not itself improve the PCP-induced NOR deficit. However, a subeffective dose of SB269970 (0.1 mg/kg) in combination with subeffective doses of lurasidone (0.03 mg/kg), amisulpride (1 mg/kg), or sulpiride (20 mg/kg), also reversed the PCP-induced NOR deficit. Pimavanserin, a 5-HT(2A) inverse agonist, LY379268, and haloperidol did not potentiate the ability of subeffective SB269970 to improve the NOR deficit. Furthermore, the mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495), which blocks the effect of clozapine to reverse the NOR deficit, did not block the SB269970-induced amelioration of the NOR deficit. These results suggest 5-HT(7) antagonism may contribute to the efficacy of some atypical APDs in the treatment of cognitive impairment in schizophrenia and may itself have some benefit in this regard.