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Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = -0.34, 95% CI = [-0.660, -0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity., (© 2024. The Author(s).)

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ&#95;PRS), bipolar disorder (BD&#95;PRS), major depression (MD&#95;PRS), and IQ (IQ&#95;PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean&#95;IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean&#95;IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ&#95;PRS than controls [F(4,1319) = 20.4, P < .001]. Among the clusters, the deteriorating group had lower SCZ&#95;PRS and was likelier to have used high-potency cannabis daily. Patients with FEP clustered according to their premorbid and cognitive abilities. Pronounced premorbid deterioration was not typical of most FEP, including those more strongly predisposed to schizophrenia, but appeared in a cluster with a history of high-potency cannabis use., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 -5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Duration of untreated psychosis (DUP) is associated with clinical outcomes in people with a diagnosis of first-episode psychosis (FEP), but factors associated with length of DUP are still poorly understood. Aiming to obtain insights into the possible biological impact on DUP, we report genetic analyses of a large multi-center phenotypically well-defined sample encompassing individuals with a diagnosis of FEP recruited from 6 countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Genetic propensity was measured using polygenic scores for schizophrenia (SZ-PGS), bipolar disorder (BD-PGS), major depressive disorder (MDD-PGS), and intelligence (IQ-PGS), which were calculated based on the results from the most recent genome-wide association meta-analyses. Following imputation for missing data and log transformation of DUP to handle skewedness, the association between DUP and polygenic scores (PGS), adjusting for important confounders, was investigated with multivariable linear regression models. The sample comprised 619 individuals with a diagnosis of FEP disorders with a median age at first contact of 29.0 years (interquartile range [IQR] = 22.0-38.0). The median length of DUP in the sample was 10.1 weeks (IQR = 3.8-30.8). One SD increases in SZ-PGS, BD-PGS, MDD-PGS or IQ-PGS were not significantly associated with the length of DUP. Our results suggest that genetic variation does not contribute to the DUP in patients with a diagnosis of FEP disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Previously, we established an estimated exposome score for schizophrenia (ES-SCZ) as a cumulative measure of environmental liability for schizophrenia to use in gene-environment interaction studies and for risk stratification in population cohorts. Hereby, we examined the discriminative function of ES-SCZ for identifying individuals diagnosed with schizophrenia spectrum disorder in the general population by measuring the area under the receiver operating characteristic curve (AUC). Furthermore, we compared this ES-SCZ method to an environmental sum score (Esum-SCZ) and an aggregate environmental score weighted by the meta-analytical estimates (Emet-SCZ). We also estimated ORs and Nagelkerke's R2 for ES-SCZ in association with psychiatric diagnoses and other medical outcomes. ES-SCZ showed a good discriminative function (AUC = 0.84) and statistically significantly performed better than both Esum-SCZ (AUC = 0.80) and Emet-SCZ (AUC = 0.80). At optimal cut point, ES-SCZ showed similar performance in ruling out (LR- = 0.20) and ruling in (LR+ = 3.86) schizophrenia. ES-SCZ at optimal cut point showed also a progressively greater magnitude of association with increasing psychosis risk strata. Among all clinical outcomes, ES-SCZ was associated with schizophrenia diagnosis with the highest OR (2.76, P < .001) and greatest explained variance (R2 = 14.03%), followed by bipolar disorder (OR = 2.61, P < .001, R2 = 13.01%) and suicide plan (OR = 2.44, P < .001, R2 = 12.44%). Our findings from an epidemiologically representative general population cohort demonstrate that an aggregate environmental exposure score for schizophrenia constructed using a predictive modeling approach-ES-SCZ-has the potential to improve risk prediction and stratification for research purposes and may help gain insight into the multicausal etiology of psychopathology., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

The ability of the brain to reduce the amount of trivial or redundant sensory inputs is called gating function. Dysfunction of sensory gating may lead to cognitive fragmentation and poor real-world functioning. The auditory dual-click paradigm is a pertinent neurophysiological measure of sensory gating function. This meta-analysis aimed to examine the subcomponents of abnormal P50 waveforms in bipolar disorder and schizophrenia to assess P50 sensory gating deficits and examine effects of diagnoses, illness states (first-episode psychosis vs. schizophrenia, remission vs. episodes in bipolar disorder), and treatment status (medication-free vs. medicated). Literature search of PubMed between Jan 1st 1980 and March 31st 2019 identified 2091 records for schizophrenia, 362 for bipolar disorder. 115 studies in schizophrenia (4932 patients), 16 in bipolar disorder (975 patients) and 10 in first-degree relatives (848 subjects) met the inclusion criteria. P50 sensory gating ratio (S2/S1) and S1-S2 difference were significantly altered in schizophrenia, bipolar disorder and their first-degree relatives. First-episode psychosis did not differ from schizophrenia, however episodes altered P50 sensory gating in bipolar disorder. Medications improve P50 sensory gating alterations in schizophrenia significantly and at trend level in bipolar disorder. Future studies should examine longitudinal course of P50 sensory gating in schizophrenia and bipolar disorder., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases., Methods: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases., Results: PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS., Conclusions: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects., Methods: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects., Results: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects., Conclusions: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Evidence suggests that cannabis use, childhood adversity, and urbanicity, in interaction with proxy measures of genetic risk, may facilitate onset of psychosis in the sense of early affective dysregulation becoming 'complicated' by, first, attenuated psychosis and, eventually, full-blown psychotic symptoms., Methods: Data were derived from three waves of the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). The impact of environmental risk factors (cannabis use, childhood adversity, and urbanicity) was analyzed across severity levels of psychopathology defined by the degree to which affective dysregulation was 'complicated' by low-grade psychotic experiences ('attenuated psychosis' - moderately severe) and, overt psychotic symptoms leading to help-seeking ('clinical psychosis' - most severe). Familial and non-familial strata were defined based on family history of (mostly) affective disorder and used as a proxy for genetic risk in models of family history × environmental risk interaction., Results: In proxy gene-environment interaction analysis, childhood adversity and cannabis use, and to a lesser extent urbanicity, displayed greater-than-additive risk if there was also evidence of familial affective liability. In addition, the interaction contrast ratio grew progressively greater across severity levels of psychosis admixture (none, attenuated psychosis, clinical psychosis) complicating affective dysregulation., Conclusion: Known environmental risks interact with familial evidence of affective liability in driving the level of psychosis admixture in states of early affective dysregulation in the general population, constituting an affective pathway to psychosis. There is interest in decomposing family history of affective liability into the environmental and genetic components that underlie the interactions as shown here.

Background: Psychotic experiences (PEs) are not exclusive to psychotic disorders and highly correlated with mood episodes. In this representative general population-based study, longitudinal bidirectional associations between the extended psychosis phenotype and mood episodes were investigated, accounting for other possible causes., Methods: Households were contacted in a multistage clustered probability sampling frame covering 11 districts and 302 neighbourhoods at baseline (n = 4011) and at 6-year follow-up (n = 2185). Participants were interviewed with the relevant sections of the composite international diagnostic interview both at baseline and at follow-up. Sociodemographic, familial and environmental risk factors associated with the extended psychosis phenotype and mood episodes were assessed. Logistic regression and cross-lagged panel correlation models were used for the associations between the extended psychosis phenotype and mood episodes., Results: PEs were associated with subsequent depressive and manic episodes. There was bidirectionality in that mood episodes were associated with subsequent PEs, and PEs were associated with subsequent mood episodes. The associations occurred in a sub-additive pattern. There were substantial synchronous and cross-lagged correlations between these psychopathology domains, with reciprocally similar cross-lagged correlations. Familial risk and adverse life events were associated with both psychopathology domains, whereas some sociodemographic risk factors and alcohol/cannabis use were associated with only one domain., Conclusion: The sub-additive bidirectional associations between PEs and mood episodes over time and the similarity of cross-lagged correlations are suggestive of mutually causal connections between affective and psychotic domains of psychopathology.

The α7 acetylcholine receptor (AChR) has been linked with the onset of psychotic symptoms and we hypothesized therefore that it might also be an autoimmune target. Here, we describe a new radioimmunoassay (RIA) using iodine 125-labelled α-bungarotoxin and membrane extract from transfected HEK293 cells expressing human α7 AChR. This RIA was used to analyze sera pertaining to a cohort of 711 subjects, comprising 368 patients diagnosed with schizophrenia spectrum disorders, 140 with bipolar disorder, 58 individuals diagnosed of other mental disorders, and 118 healthy comparison subjects. We identified one patient whose serum tested positive although with very low levels (0.2 nM) for α7 AChR-specific antibodies by RIA. Three out of 711 sera contained antibodies against iodine 125-labelled α-bungarotoxin, because they precipitated with it in the absence of α7 AChR. This first evidence suggests that autoantibodies against α7 AChR are absent or very rare in these clinical groups., Competing Interests: The authors have declared that no competing interests exist.

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis., (© 2017 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.)

Objective: Social impairment is a long-recognized core feature of schizophrenia and is common in other psychotic disorders. Still, to date the long-term trajectories of social impairment in psychotic disorders have rarely been studied systematically., Methods: Data came from the Suffolk County Mental Health Project, a 20-year prospective study of first-admission patients with psychotic disorders. A never-psychotic comparison group was also assessed. Latent class growth analysis was applied to longitudinal data on social functioning from 485 respondents with schizophrenia spectrum disorders and psychotic mood disorders, and associations of the empirically derived trajectories with premorbid social adjustment, diagnosis, and 20-year outcomes were examined., Results: Four mostly stable trajectories of preserved (N=82; 59th percentile of comparison group sample distribution), moderately impaired (N=148; 17th percentile), severely impaired (N=181; 3rd percentile), and profoundly impaired (N=74; 1st percentile) functioning best described the 20-year course of social functioning across diagnoses. The outcome in the group with preserved functioning did not differ from that of never-psychotic individuals at 20 years, but the other groups functioned significantly worse. Differences among trajectories were already evident in childhood. The two most impaired trajectories started to diverge in early adolescence. Poorer social functioning trajectories were strongly associated with other real-world outcomes at 20 years. Multiple trajectories were represented within each disorder. However, more participants with schizophrenia spectrum disorders had impaired trajectories, and more with mood disorders had better functioning trajectories., Conclusions: The results highlight substantial variability of social outcomes within diagnoses-albeit overall worse social outcomes in schizophrenia spectrum disorders-and show remarkably stable long-term impairments in social functioning after illness onset across all diagnoses.

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Background: Subthreshold psychotic and bipolar experiences are common in major depressive disorder (MDD). However, it is unknown if effectiveness of psychotherapy is altered in depressed patients who display such features compared with those without. The current paper aimed to investigate the impact of the co-presence of subclinical psychotic experiences and subclinical bipolar symptoms on the effectiveness of psychological treatment, alone or in combination with pharmacotherapy., Method: In a naturalistic study, patients with MDD (n = 116) received psychological treatment (cognitive behavioural therapy or interpersonal psychotherapy) alone or in combination with pharmacotherapy. Depression and functioning were assessed six times over 2 years. Lifetime psychotic experiences and bipolar symptoms were assessed at the second time point., Results: Subclinical psychotic experiences predicted more depression over time (β = 0.20, p < 0.002), non-remission [odds ratio (OR) 7.51, p < 0.016] and relapse (OR 3.85, p < 0.034). Subthreshold bipolar symptoms predicted relapse (OR 1.16, p < 0.037)., Conclusions: In general, subclinical psychotic experiences have a negative impact on the course and outcome of psychotherapy in MDD. Effects of subclinical bipolar experiences were less prominent.

Background: There is a negative association between the use of antipsychotics and cognitive functioning in bipolar patients, which may be mediated by altered dopamine signaling in selected brain areas, and moderation thereof by genetic sequence variation such as COMT Val108/158Met. The interaction between antipsychotic drug use and the COMT Val108/158Met genotype on two-year cognitive functioning in bipolar patients was examined., Methods: Interaction between the COMT Val108/158Met and antipsychotics on a composite cognitive measure was examined in 51 bipolar patients who were assessed 12 times at two-monthly intervals over a period of two years (379 observations)., Results: There was a significant negative effect of the interaction between antipsychotic medications and Val allele load on the composite cognitive measure in bipolar patients (p < 0.001)., Conclusions: The negative effects of antipsychotics on cognitive functioning in bipolar disorder may be moderated by the COMT Val 108/158 Met genotype, with a negative effect of Val allele load. If replicated, the results may be indicative of pharmacogenetic interactions in bipolar disorder.

Background: Research in cognitive processes and attitudes in bipolar disorder is scarce and has provided mixed findings, possibly due to differences in current mood state. It is unclear whether alterations in cognitive processes and attitudes are only related to the depressive mood states of bipolar patients or also represent a vulnerability marker for the development of future (depressive) episodes. This was investigated in the current study., Methods: Both implicit (attentional bias for emotional words) and explicit (dysfunctional attitudes and personality characteristics) measures of cognitive processes and attitudes were assessed in 77 bipolar patients with varying levels of depressive symptoms (depressed=17, euthymic n=60), their healthy first-degree relatives (n=39) and a healthy control group (n=61). Analyses of variance were used to investigate differences between groups., Results: Mildly depressed patients with bipolar disorder demonstrated an attentional bias away from positive emotional words and showed increased dysfunctional attitudes and higher levels of neuroticism. Euthymic patients were largely comparable to healthy controls and only differed from controls in higher levels of neuroticism. Relatives were similar to controls on all measures, although they significantly differed from bipolar patients in displaying less neuroticism and more extraversion., Limitations: No firm conclusions regarding causality can be drawn from the associations that were found between cognitive processes and attitudes and the evolution of mood symptoms in bipolar disorder., Conclusion: Alterations in cognitive processes and attitudes in bipolar patients appear to be mostly related to the expression of mood symptomatology rather than to the vulnerability for bipolar disorder., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The role of inflammation in bipolar disorder has recently emerged as a potential pathophysiological mechanism. Tumor necrosis factor-alpha (TNF-α) modulation may represent a pathogenic molecular target and a biomarker for staging bipolar disorder. In this context, the possible association between lithium response and TNF-α level was examined., Methods: Sixty euthymic bipolar patients receiving lithium therapy were recruited for assessment of TNF-α level. The ALDA lithium response scale (LRS) was used to evaluate longitudinal lithium response in bipolar patients, using cut-offs of poor response, partial response and good response. TNF-α level was assessed using enzyme-linked immunosorbent assay., Results: There was a significant increase in TNF-α level in patients with poor lithium response compared to those with good response, also after controlling for a range of potential confounders (adjusted effect size: 0.47, p=0.011). Partial response showed a directionally similar, but attenuated and statistically inconclusive association (adjusted effect size: 0.16, p=0.326)., Limitations: Assessment of response was retrospective and natural course cannot be separated easily from treatment response in an observational design. Selection of additional inflammatory markers could provide for a better understanding of underlying immune changes., Conclusions: This study strengthens the hypothesis that TNF-α level may mark or mediate lithium response, and that continuous immune imbalance in poor lithium responders may occasion treatment resistance. Further investigation of immune alterations in treatment-resistant bipolar patients may be productive., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Current evidence suggests that high concentrations of pro-inflammatory markers are associated with bipolar disorder characterized by severe impairment during inter-episodic periods, reduced treatment response and persistent subsyndromal symptoms. We tested whether persistent subsyndromal symptoms in euthymic bipolar patients were associated with markers of an ongoing chronic pro-inflammatory process., Methods: Forty-five euthymic bipolar patients (22 with subsyndromal symptoms (BD+) and 23 without subsyndromal symptoms (BD-) and 23 well controls (WC) were recruited for assessment of soluble tumor necrosis factor receptor-1 (sTNF-R1), soluble interleukin-6 receptor (sIL-6R) and soluble interleukin-2 receptor (sIL-2R) concentrations. Soluble cytokine receptor concentrations were assessed using enzyme-linked immunosorbent assay., Results: In comparison to WC, sTNF-R1 concentration was higher in both BD- and BD+ (age and sex adjusted standardized β, respectively: β = 0.34, p = 0.012 and β = 0.41, p = 0.003). Similarly, compared to WC, sIL-6R concentration was higher in both BD- and BD+ (age and sex adjusted standardized β, respectively: β = 0.44, p = 0.001 and β = 0.37, p = 0.008). There was no difference between BD- and BD+ in the concentration of either sTNF-R1 or sIL-6R; plasma concentration of sIL-2R was not analyzed as 75% percent of the samples were non-detectable., Conclusions: Although bipolar patients present with a pro-inflammatory shift compared to well controls, subsyndromal symptoms are not associated with additive increasing effects. Longitudinal studies with larger samples are required to clarify the relationship between illness course and inflammatory markers in bipolar disorder.

Objective: To estimate the lifetime prevalence of 12 DSM-IV disorders with psychotic symptoms in a general population survey., Method: Addresses were contacted in a multistage clustered area probability sampling frame of administrative neighbourhoods and households, covering 9 districts and 302 neighbourhoods in the Izmir metropolitan area between November 2007 and October 2008. One household member aged between 15 and 64 years and available to complete the interview was randomly selected using a within-household sampling method. The primary screening instrument was the Composite International Diagnostic Interview 2.1. A systematic screening procedure was implemented to detect probable cases with any psychotic disorder. Those selected by the screens were re-interviewed with the Structured Clinical Interview for DSM-IV. Diagnoses of individuals who were not available for re-interview were made by combining screening information with case register diagnoses and/or the telephone interviews with relatives or spouse., Results: A total of 4011 individuals were screened for disorders with psychotic symptoms. After screening, 499 respondents were selected as a probable case. 277 of screen positive respondents were available for clinical reappraisal. Initial screening interviews and additional material were used for best estimate diagnoses of the remaining 172 respondents. Total lifetime prevalence of 12 DSM-IV disorders with psychotic symptoms was 2.62%. Lifetime prevalence of each disorder separately were as follows: 0.74% for schizophrenia, 0.20% for schizoaffective disorder, 0.05% for schizophreniform disorder, 0.10% for delusional disorder, 0.12% for brief psychotic disorder, 0.55% for major depressive disorder with psychotic features, 0.37% for bipolar I disorder, 0.20% for substance induced psychotic disorder, and 0.07% for psychotic disorders due to a general medical condition., Conclusion: Total lifetime prevalence of disorders with psychotic symptoms is higher than any previously reported estimates in Turkey; with a prevalence of approximately 2.5%, these disorders can be considered a major public health concern.

Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR)=1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Evidence from clinical patient populations indicates that affective dysregulation is strongly associated with reality distortion, suggesting that a process of misassignment of emotional salience may underlie this connection. To examine this in more detail without clinical confounds, affective regulation-reality distortion relationships, and their clinical relevance, were examined in a German prospective cohort community study. A cohort of 2524 adolescents and young adults aged 14-24 years at baseline was examined by experienced psychologists. Presence of psychotic experiences and (hypo)manic and depressive symptoms was assessed at 2 time points (3.5 and up to 10 years after baseline) using the Munich-Composite International Diagnostic Interview. Associations were tested between level of affective dysregulation on the one hand and incidence of psychotic experiences, persistence of these experiences, and psychotic Impairment on the other. Most psychotic experiences occurred in a context of affective dysregulation, and bidirectional dose-response was apparent with greater level of both affective dysregulation and psychotic experiences. Persistence of psychotic experiences was progressively more likely with greater level of (hypo)manic symptoms (odds ratio [OR] trend=1.51, P<.001) and depressive symptoms (OR trend=1.15, P=.012). Similarly, psychotic experiences of clinical relevance were progressively more likely to occur with greater level of affective dysregulation (depressive symptoms: OR trend=1.28, P=.002; (hypo)manic symptoms: OR trend=1.37, P=.036). Correlated genetic liabilities underlying affective and nonaffective psychotic syndromes may be expressed as correlated dimensions in the general population. Also, affective dysregulation may contribute causally to the persistence and clinical relevance of reality distortion, possibly by facilitating a mechanism of aberrant salience attribution., (© The Author 2009. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.)

Objective: Cognitive alterations in bipolar disorder may reflect genetic influence. However, to what degree mood, medication, thyroid function and other factors impact on longitudinal cognitive functioning remains unclear., Method: A group of patients with bipolar (spectrum) disorder (n = 76) underwent two monthly cognitive assessments over a 2-year period in a prospective, repeated measures design. Regression models were used to investigate associations with predictors, corrected for multiple testing., Results: Patients with bipolar disorder performed worse than healthy controls (n = 61) on all cognitive domains tested. Effect sizes were small, with a maximum of -0.36 for sustained attention. However, cognitive performance varied substantially over the 2-year follow-up, co-varying with subjective cognitive complaints and impacting on functioning. Alterations in sustained attention and motor speed were the only impairments that were invariant over time. Predictors had very limited explanatory power on temporal variation in cognition. Use of second-generation antipsychotics was associated with the largest negative effects on cognition, which were evident in the areas of motor speed and basic information processing (-0.35 < β < -0.5)., Conclusion: Cognitive function in bipolar disorder varies significantly over time, largely independent of clinical factors. The temporal stability of sustained attention is the exception, suggesting it may represent a possible candidate intermediary phenotype., (© 2010 John Wiley & Sons A/S.)

Objective: To examine factors increasing the risk for onset and persistence of subthreshold mania and depression., Method: In a prospective cohort community study, the association between risk factors [a family history of mood disorders, trauma, substance use, attention-deficit/hyperactivity disorder (ADHD) and temperamental/personality traits] and onset of manic/depressive symptoms was determined in 705 adolescents. The interaction between baseline risk factors and baseline symptoms in predicting 8-year follow-up symptoms was used to model the impact of risk factors on persistence., Results: Onset of manic symptoms was associated with cannabis use and novelty seeking (NS), but NS predicted a transitory course. Onset of depressive symptoms was associated with a family history of depression. ADHD and harm avoidance (HA) were associated with persistence of depressive symptoms, while trauma and a family history of depression predicted a transitory course., Conclusion: Different risk factors may operate during onset and persistence of subthreshold mania and depression. The differential associations found for mania and depression dimensions suggest partly different underlying mechanisms.

Objective: Neurocognitive functioning may represent an indicator of genetic risk and poor outcome in both schizophrenia and bipolar disorder. In this study, shared and nonshared characteristics in the cognitive domain in both disorders were analyzed to determine to what degree neurocognitive functioning may represent a predictor of the familial vulnerability and poor functioning that schizophrenia spectrum disorders and bipolar disorder share., Method: Neurocognition, psychopathology, and psychosocial functioning were assessed in samples of patients with a schizophrenia spectrum disorder (n = 345) and bipolar disorder (n = 76) meeting DSM-IV criteria, first-degree relatives of both patient groups (n = 331 and n = 37, respectively), and healthy controls (n = 260 and n = 61, respectively). Multiple regression models were used to investigate the effect of group status on neurocognition and to explore associations between cognition, symptoms, and psychosocial functioning in the 2 groups. The schizophrenia spectrum study sample was recruited between September 2004 and January 2008, and the bipolar study sample was recruited between June 2004 and July 2007., Results: Cognitive deficits were more severe and more generalized in patients with a schizophrenia spectrum disorder compared to patients with bipolar disorder; cognitive alterations were present in relatives of patients with schizophrenia spectrum disorders but not in relatives of bipolar patients. The association between neurocognitive dysfunction and psychosocial functioning was more generalized in schizophrenia spectrum disorders than in bipolar disorder; for both disorders, associations were only partly mediated by symptoms., Conclusions: The evidence for cognitive dysfunction as a marker of familial vulnerability is stronger for schizophrenia than for bipolar disorder. Although the presence of multiple cognitive deficits is shared by the 2 groups, the severity of cognitive deficits and its consequences appear to partly differ between schizophrenia and bipolar disorder, which is in line with a model that implies the specific presence of a neurodevelopmental impairment in the former but not in the latter., (2010 Physicians Postgraduate Press, Inc.)

Background: Although (hypo)manic symptoms are common in adolescence, transition to adult bipolar disorder is infrequent., Aims: To examine whether the risk of transition to bipolar disorder is conditional on the extent of persistence of subthreshold affective phenotypes., Method: In a 10-year prospective community cohort study of 3021 adolescents and young adults, the association between persistence of affective symptoms over 3 years and the 10-year clinical outcomes of incident DSM-IV (hypo)manic episodes and incident use of mental healthcare was assessed., Results: Transition to clinical outcome was associated with persistence of symptoms in a dose-dependent manner. Around 30-40% of clinical outcomes could be traced to prior persistence of affective symptoms., Conclusions: In a substantial proportion of individuals, onset of clinical bipolar disorder may be seen as the poor outcome of a developmentally common and usually transitory non-clinical bipolar phenotype.

Background: Reported rates of bipolar syndromes are highly variable between studies because of age differences, differences in diagnostic criteria, or restriction of sampling to clinical contacts., Method: In 1395 adolescents aged 14-17 years, DSM-IV (hypo)manic episodes (manic and hypomanic episodes combined), use of mental health care, and five ordinal subcategories representing the underlying continuous score of (hypo)manic symptoms ('mania symptom scale') were measured at baseline and approximately 1.5, 4 and 10 years later using the Munich-Composite International Diagnostic Interview (DIA-X/M-CIDI)., Results: Incidence rates (IRs) of both (hypo)manic episodes and (hypo)manic symptoms (at least one DSM-IV core symptom) were far higher (714/105 person-years and 1720/10(5) person-years respectively) than traditional estimates. In addition, the risk of developing (hypo)manic episodes was very low after the age of 21 years [hazard ratio (HR) 0.031, 95% confidence interval (CI) 0.0050-0.19], independent of childhood disorders such as attention deficit hyperactivity disorder (ADHD). Most individuals with hypomanic and manic episodes were never in care (87% and 62% respectively) and not presenting co-morbid depressive episodes (69% and 60% respectively). The probability of mental health care increased linearly with the number of symptoms on the mania symptom scale. The incidence of the bipolar categories, in particular at the level of clinical morbidity, was strongly associated with previous childhood disorders and male sex., Conclusions: This study showed, for the first time, that experiencing (hypo)manic symptoms is a common adolescent phenomenon that infrequently predicts mental health care use. The findings suggest that the onset of bipolar disorder can be elucidated by studying the pathway from non-pathological behavioural expression to dysfunction and need for care.

Background: Research shows that the use of cannabis has a negative impact on the onset and outcome of schizophrenia, but little is known about possible effects on mood disorders., Aim: To study the influence of cannabis use on clinical and social treatment outcomes in patients with bipolar disorders who had been treated for a period of 12 months., Method: 3459 bipolar patients were enrolled in an observational study. The influence of cannabis on various clinical and social treatment outcomes was examined over a period of one year. In addition, tests were applied in order to find out whether third, mediating variables had effects on possible associations between cannabis use and treatment outcomes., Results: During 12 months of treatment cannabis users showed less compliance and higher levels of illness severity, mania and psychosis than did non-users. In addition, cannabis users were less satisfied with their lives and had less chance of forming relationships than non-users. There was little evidence that associations between cannabis use and treatment outcomes were mediated by third variables., Conclusion: Cannabis use clearly had an independent impact on clinical treatment outcomes in patients with bipolar disorder, but the impact on social outcomes was only modest.

In this paper we examined whether manic and depressive dimensions independently contribute to mental health service use and determined the degree of comorbidity between manic and depressive dimensions in individuals with and without mental health service use. If both depressive and manic episodes independently influence help-seeking behaviour, a higher level of comorbidity between these dimensions would be found in clinical as compared to non-clinical samples (i.e. Berkson's Bias). Data were derived from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), a prospective epidemiological survey in a representative sample of the Dutch population (N = 7076). Dimensions of depression and mania and mental health service use (MHSU) were assessed with the Composite International Diagnostic Interview (CIDI) at baseline, and prospectively one and three years later. Logistic regression was used to test whether depressive and manic dimensions both had independent effects on mental health service use. The degree of mania-comorbidity given the presence of depressive dimension was assessed as a function of MHSU, both retrospectively and prospectively. Manic and depressive dimensions contributed independently to mental health service use. Mania-comorbidity given the presence of depressive dimension was significantly higher in individuals with mental health service use than in those without, both retrospectively (16.7% versus 7.1%, p = 0.000) and prospectively (10.8% versus 6.6%, p = 0.017). We conclude that the bipolar phenotype consists of manic and depressive dimensions that may be much more loosely associated than (Berkson) biased clinical observations suggest. A dimension-specific approach may be more productive in clarifying the aetiology of mood dysregulation.

Background: In an effort to group mental disorders on the basis of etiology, five clusters have been proposed. Here we consider the validity of the cluster comprising selected psychotic and related disorders., Method: A group of diagnostic entities classified under schizophrenia and other psychotic disorders in DSM-IV-TR were assigned to this cluster and the bordering disorders, bipolar (BD) and schizotypal personality disorders (SPD), were included. We then reviewed the literature in relation to 11 validating criteria proposed by the DSM-V Task Force Study Group., Results: Relevant comparisons on the 11 spectrum criteria are rare for the included disorders except for schizophrenia and the two border conditions, BD and SPD. The core psychosis group is congruent at the level of shared psychotic psychopathology and response to antipsychotic medication. BD and SPD are exceptions in that psychosis is not typical in BD-II disorder and frank psychosis is excluded in SPD. There is modest similarity between schizophrenia and BD relating to risk factors, neural substrates, cognition and endophenotypes, but key differences are noted. There is greater support for a spectrum relationship of SPD and schizophrenia. Antecedent temperament, an important validator for other groupings, has received little empirical study in the various psychotic disorders., Conclusions: The DSM-IV-TR grouping of psychotic disorders is supported by tradition and shared psychopathology, but few data exist across these diagnoses relating to the 11 spectrum criteria. The case for including BD is modest, and the relationship of BD to other mood disorders is addressed elsewhere. Evidence is stronger for inclusion of SPD, but the relationship with other personality disorders along the 11 criteria is not addressed and the absence of psychosis presents a conceptual problem. There are no data along the 11 spectrum criteria that are decisive for a cluster based on etiology, and inclusion of BD and SPD is questionable.

Background: It has been suggested that dopamine dysfunction may play a role in bipolar disorder (BD). An indirect approach to examine this issue was developed, focusing on associations between dopamine proxy measures observed in BD (dopamine-related clinical traits using tardive movement syndromes as dopamine proxy measure of reference)., Methods: 3459 eligible bipolar patients were enrolled in an observational study. Incidence rates of tardive movement syndromes (tardive dyskinesia and tardive dystonia; TDD) were examined. A priori hypothesized associations between incident TDD and other dopamine proxies (e.g. prolactin-related adverse effects, bipolar symptoms) were tested over a 2 year follow-up period., Results: The incidence rate of tardive syndromes was 4.1 %. Incident TDD was independently associated not only with use of antipsychotics, but also with more severe bipolar symptoms, other extrapyramidal symptoms and prolactin-related adverse effects of medication., Conclusion: Apart from the well-known association with antipsychotics, development of TDD was associated with various other dopamine proxy measures, indirectly supporting the notion of generalised dopamine dysregulation in BD.

Objectives: In schizophrenia, a distinction is made between psychosis with developmental and cognitive impairment on the one hand and psychosis without developmental impairment and positive symptoms on the other. In this study, we investigated whether this model can be extended to bipolar disorder by testing the hypothesis that neurocognitive functioning is inversely related to positive psychotic symptoms in bipolar disorder., Methods: Neurocognitive functioning and psychopathology were assessed in (i) 76 patients with bipolar disorder, (ii) 39 of their healthy first-degree relatives, and (iii) 61 healthy controls. Cognitive performance of bipolar patients and their first-degree relatives was investigated, taking into account the possible moderating effect of the level of expression of psychosis in patients and relatives., Results: Bipolar patients showed impaired cognitive performance on multiple cognitive domains, whereas performance of their relatives was comparable to that of controls. A history of psychotic symptoms in patients was suggestive of less likelihood of cognitive alterations in relatives, and the presence of subclinical psychotic symptoms within the group of relatives predicted better cognitive performance., Conclusions: The finding of similar psychosis-cognition associations in bipolar disorder as implied by the two pathways leading to nonaffective psychotic disorders suggests that this model might be extended to the continuum spanning affective and nonaffective psychosis. This is in line with the idea of a partially overlapping vulnerability to bipolar disorder and schizophrenia and provides an explanation for the apparent differences in cognitive alterations in those at risk for the two disorders.

Research suggests that cannabis use affects negatively on onset and outcome of schizophrenia, but less is known about possible effects in mood disorders. Bipolar in- and outpatients (N = 3459) were enrolled in an observational study. The influence of cannabis exposure on clinical and social treatment outcome measures was examined over the course of 1 year, as well as the effects on these associations of third mediating variables. Over 12 months of treatment, cannabis users exhibited less compliance and higher levels of overall illness severity, mania, and psychosis compared with nonusers. Additionally, cannabis users experienced less satisfaction with life and had a lower probability of having a relationship compared with nonusers. There was little evidence that cannabis-outcome associations were mediated by third variables. An independent impact of cannabis use on psychopathologic outcomes in patients with bipolar disorder was apparent, whereas the impact on social outcomes was modest.

Background: Psychopathological heterogeneity in manic syndromes may in part reflect underlying latent classes with characteristic outcome patterns. Differential treatment course and outcome after 12 weeks of treatment were examined for three distinct classes of patients with acute mania in bipolar disorder., Subjects and Methods: Three thousand four hundred and twenty-five patients with acute mania were divided into three distinct mania classes: 'Typical', 'Psychotic' and 'Dual' (i.e. comorbid substance use) mania. Persistence of class differences and social outcomes were examined, using multilevel regression analyses and odds ratios., Results: The three classes showed substantial stability post-baseline in the pattern of associations with class-characteristic variables. Psychotic and Dual mania predicted poorer outcome in terms of psychosis comorbidity and overall bipolar and mania severity, while Dual mania additionally predicted poorer outcome of alcohol and substance abuse. Worse social outcomes were observed for both Dual and Psychotic mania., Conclusion: The identified distinct classes are stable and associated with differential treatment outcome. Overall, Dual and Psychotic mania show less favourable outcomes compared to Typical mania. These findings additionally give rise to concern on the generalisability of randomized clinical trials RCTs.

Objective: Unconfounded differences in inherent vulnerability to metabolic disturbance may be hypothesized for different diagnostic groups with severe mental illness., Method: A naturalistic cohort of patients diagnosed with DSM-IV bipolar disorder (N = 112), schizophrenia (N = 503), and schizoaffective disorder (N = 92) were assessed for metabolic disturbances. The prospective inclusions started in November 2003 and were concluded in July 2007., Results: Diagnosis was strongly associated with the metabolic syndrome (chi(2) = 14.90, df = 2, p < .001). Compared with bipolar patients, the unadjusted risk for metabolic syndrome was significantly higher for schizoaffective (odds ratio [OR] = 3.51, p < .0001) but not for schizophrenia patients (OR = 1.58, p = .094). Differences were not reducible to confounding factors including treatment. Rather, the difference between bipolar and schizophrenia patients also reached significance after adjustment (OR = 1.97, p = .046). Furthermore, the association between diagnosis and glucose dysregulation was significant (chi(2) = 6.97, df = 2, p = .031), with a significantly higher risk in schizoaffective (unadjusted OR = 2.12, p = .022) but not in schizophrenia patients (unadjusted OR = 1.13, p = .640) compared with bipolar patients. Diagnostic differences in glucose dysregulation were in part mediated by body mass index (BMI)., Conclusions: Schizoaffective patients in particular may be at risk for metabolic disturbances compared with bipolar and schizophrenia patients. Differences were not reducible to known metabolic risk factors and could only be explained in part by higher BMI in schizoaffective patients, suggesting an increased inherent vulnerability in this group.

Background: Previous work suggests that impairments in executive function and verbal memory in particular may persist in euthymic bipolar patients and serve as an indicator of genetic risk (endophenotype)., Method: A systematic review of the literature was undertaken. Effects sizes were extracted from selected papers and pooled using meta-analytical techniques., Results: In bipolar patients, large effect sizes (d>0.8) were noted for executive functions (working memory, executive control, fluency) and verbal memory. Medium effect sizes (0.5

Objective: To describe the course and outcome of patients with prospectively defined chronic mania and to identify predictors of treatment non-response., Method: EMBLEM is a 2-year prospective, observational study of bipolar disorder treatment outcomes conducted in 14 European countries. Patients with a manic/mixed episode were assessed and prospectively followed for 1 year. Clinical scales (Clinical Global Impressions-Bipolar Disorder (CGI-BP) overall, mania, and depression; Young Mania Rating Scale (YMRS); and five-item Hamilton Depression Rating Scale (HAM-D-5)) and medication taken were systemically recorded. Treatment adherence and outcome measures were also captured. Chronic mania (non-response) was defined as not achieving more than one point improvement on CGI-BP mania scale during up to 12-month follow-up. The analysis was conducted with 3373 patients who had at least two CGI-BP mania ratings available., Results: A total of 15% of patients fulfilled criteria for chronic mania. Compared to those who responded to treatment, chronic mania was associated with lower severity of mania symptoms at baseline (OR = 0.44, 95% CI 0.37-0.52), shorter duration of current episode before treatment start (OR = 0.71, 95% CI 0.52-0.96), more delusions/hallucinations at baseline (OR = 1.12, 95% CI 1.03-1.22), less socially active (OR = 0.52, 95% CI 0.39-0.70) and greater occupational impairment (OR = 1.54, 95% CI 1.01-2.35) by multivariate statistical analysis., Conclusions: Rather than severity or duration of manic symptoms, factors associated with chronicity in mania are the presence of psychotic symptoms and issues related to social and occupational functioning.

Background: Knowledge of moderators of symptom improvement over time in acute mania improves predictability of individual patient outcomes. This study attempted to identify such moderators of the rate of symptom improvement., Methods: In 3459 patients with high levels of mania in whom a change in psychotropic treatment was initiated and who were assessed six times over three months, clinical and social moderators of the rate of response were examined. Additionally, moderators of symptom improvement in individuals with high baseline levels of comorbid depression (n = 815) and psychosis (n = 1849) were identified., Results: Within three months, mania symptoms were reduced by 52%, psychotic symptoms by 56% and depressive symptoms by 36%. High levels of baseline depression, greater illness severity in the past year, lower age of onset and rapid cycling reduced the rate of mania symptom improvement by 5-15%. Social variables indicating disadvantage similarly had negative contributions (5%-14%). Several reasons for change of medication involving patient choice, patient compliance, side effects and lack of effectiveness impacted negatively (reductions of 10%, 6%, 14% and 9% respectively). For the psychosis dimension, both low mania scores (22% reduction) and high depression scores (14% reduction) at baseline impacted negatively, whereas rate of reduction in depression was not conditional on baseline psychopathology., Conclusions: The rate of symptom improvement in acute mania is to a large extent conditional on the context as provided by the social, psychopathological and consumer environment. Understanding the context of treatment response offers valuable insights into treatment approaches aimed at moderation of traditional pharmacological interventions.

Background: The high risk of suicide in bipolar disorder is well recognized, but may have been overestimated. There is conflicting evidence about deaths from other causes and little known about risk factors for suicide. We aimed to estimate suicide and mortality rates in a cohort of bipolar patients and to identify risk factors for suicide., Method: All patients who presented for the first time with a DSM-IV diagnosis of bipolar I disorder in a defined area of southeast London over a 35-year period (1965-1999) were identified. Mortality rates were compared with those of the 1991 England and Wales population, indirectly standardized for age and gender. Univariate and multivariate analyses were used to test potential risk factors for suicide., Results: Of the 239 patients in the cohort, 235 (98.3%) were traced. Forty-two died during the 4422 person-years of follow-up, eight from suicide. The standardized mortality ratio (SMR) for suicide was 9.77 [95% confidence interval (CI) 4.22-19.24], which, although significantly elevated compared to the general population, represented a lower case fatality than expected from previous literature. Deaths from all other causes were not excessive for the age groups studied in this cohort. Alcohol abuse [hazard ratio (HR) 6.81, 95% CI 1.69-27.36, p=0.007] and deterioration from pre-morbid level of functioning up to a year after onset (HR 5.20, 95% CI 1.24-21.89, p=0.024) were associated with increased risk of suicide., Conclusions: Suicide is significantly increased in unselected bipolar patients but actual case fatality is not as high as previously claimed. A history of alcohol abuse and deterioration in function predict suicide in bipolar disorder.

Background: In the general population, symptoms of mania and psychosis are more broadly distributed than their associated clinical syndromes. Little is known, however, about how these subclinical population phenotypes co-vary with and impact on each other., Method: In a representative population cohort of 7076 adults, prevalence of mania and psychosis symptoms and syndromes were assessed with the CIDI at baseline, at one (T1) and two years later (T2). The degree of comorbidity between subclinical mania and subclinical psychosis was examined, as well as the impact of subclinical comorbidity on social impairment and transition from subclinical mania to onset of bipolar disorder., Results: The lifetime prevalence of at least one manic and one psychotic symptom was 4.1% and 4.2% respectively. Excluding individuals with any lifetime DSM-III-R bipolar or psychotic disorder (n=218), these prevalences were 2.3% (subclinical mania) and 2.8% (subclinical psychosis). Individuals with subclinical mania had a 17% risk of subclinical psychosis, compared with 2.3% in those without (P<0.000). Comorbid subclinical psychosis in individuals with subclinical mania was much more predictive of a future diagnosis of bipolar disorder (positive predictive values of 3% versus 10% respectively)., Conclusion: Subclinical phenotypes of mania and psychosis are more prevalent than their clinical counterparts and cluster together. The risk factors for psychosis may facilitate the formation of more "toxic" combinations of subclinical mania and subclinical psychosis with a higher probability of transition to bipolar disorder. A better understanding of this pathway is crucial for the development of early interventions.

Background: Cannabis use is common in patients with bipolar disorder, however little is known about cannabis as a risk factor for mania. In order to investigate the association between exposure to cannabis and subsequent development of manic symptoms whilst controlling for psychotic symptoms, a longitudinal population-based study was carried out., Methods: 4815 individuals aged 18 to 64 years were interviewed using the Composite International Diagnostic Interview at baseline, 1 year follow up and 3 year follow up, including assessment of substance use, manic symptoms and psychotic symptoms., Results: Use of cannabis at baseline increased the risk for manic symptoms during follow-up (adjusted OR 2.70, 95% CI: 1.54, 4.75), adjusted for age, sex, educational level, ethnicity, single marital status, neuroticism, use of other drugs, use of alcohol, depressive symptoms and manic symptoms at baseline. The association between cannabis use and mania was independent of the prevalence and the incidence of psychotic symptoms. There was no evidence for reverse causality, as manic symptoms at baseline did not predict the onset of cannabis use during follow-up (OR = 0.35, 95% CI: 0.03, 3.49)., Limitations: As 3 years is a relative short period of follow-up, long-term effects of cannabis use on mania outcomes could not be detected., Conclusion: The results suggest that cannabis use may affect population expression of manic symptoms (and subsequent risk to develop bipolar disorder [Regeer, E.J., Krabbendam, L., R, DE Graaf, Ten Have, M., Nolen, W.A., Van Os, J., 2006. A prospective study of the transition rates of subthreshold (hypo)mania and depression in the general population. Psychol Med, 1-9.]). These findings may not be due to the emergence of psychotic symptoms or the effects of self-medication.

Objectives: High rates of psychotic disorders and psychotic symptoms have been found in urban environments but reports for bipolar affective illness have been inconsistent, possibly due to failure to stratify for comorbid psychotic symptoms. It was hypothesised, therefore, that any effect of urbanicity on the bipolar phenotype would be moderated by comorbid psychotic symptoms., Methods: In a random, representative population cohort of 7049 adults with no history of non-affective psychotic disorder, the cumulative incidence of bipolar and psychotic symptoms and syndromes, assessed with the CIDI, was examined over five levels of population density of place of residence. Similarly, the degree of comorbidity between broadly and narrowly defined bipolar phenotypes on the one hand, and the dichotomous presence of broadly (17.2%) and narrowly defined (3.8%) psychotic symptoms on the other, was examined as a function of population density of place of residence., Results: The rate of bipolar disorder, however defined, was progressively higher in more urbanised areas. However, in models of bipolar phenotypes, a strong interaction between comorbid psychosis and level of urbanicity was apparent, indicating that the greater the degree of psychotic comorbidity, the greater the effect size of the urban environmental factor. For bipolar disorder without psychosis, no effect of urbanicity was apparent., Conclusions: The results suggest differential environmental causal effects on affective and cognitive dimensions of bipolar psychopathology that are nevertheless strongly comorbid within the same categorically defined disorder, possibly due to the effect of shared genetic risk factors.

Background: Previous work suggests that subthreshold depression and subthreshold (hypo)mania are common, although little is known about the prognosis in terms of transition to clinical disorder. This paper presents data on the temporal relationship between subthreshold and clinical expression of mood phenotypes., Method: In a random general population sample of 7076 individuals, symptoms of depression and (hypo)mania were measured with the Composite International Diagnostic Interview (CIDI) at baseline, after 1 year, and 2 years later., Results: At baseline, the lifetime prevalences of depressive and (hypo)manic symptoms were 17.2% and 1.2% respectively. Predictive values of mood symptoms for a DSM-III-R mood disorder ranged from 14.3% to 50%. (Hypo)manic mood symptoms had much higher predictive values than unipolar manifestations, not only for bipolar disorder but also for major depression., Conclusions: The subthreshold expressions of depression and (hypo)mania are prevalent and continuous with more severe clinical states. The cross-prediction of mood symptoms may support a continuum from depressive to (hypo)manic symptoms. The high predictive value of (hypo)manic symptoms for mood disorders suggests that the experience of (hypo)manic symptoms is a stronger indicator of vulnerability for mood dysregulation than the experience of depressive symptoms.

Objective: To describe patients included in the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study and to assess and clinically validate the presence of clinical subtypes of patients with acute mania., Method: The EMBLEM study is a 2-year prospective, observational study on the treatment and outcome of patients who are treated for a manic or mixed episode. Latent Class Analysis was used to define discrete groups of patients at baseline., Results: Three groups were identified: 'typical mania' (59% of patients); 'psychotic mania' (27%) with more severe mania and presence of psychotic symptoms; and 'dual mania' (13%) with a high proportion of substance abuse. Patient groups differed in age of onset, social functioning and service needs., Conclusion: Dual mania represents a distinct and not infrequent subgroup of patients with mania. The exclusion of patients with comorbid substance problems from clinical trials creates a gap in our knowledge on treatment effectiveness.

Objective: To determine the effects of familial loading, birth weight, and family problems on change in parent-reported problems across a 14-month period among children of bipolar parents., Method: Emotional and behavioral problems in a sample of 140 offspring of bipolar parents and familial loading in first- and second-degree relatives were assessed at two measurements. Parents reported the birth weight of their offspring and completed a questionnaire on family problems. Multiple linear regression analyses were performed to assess associations of the three predictors with change in problem scores at follow-up., Results: Familial loading of unipolar disorder was a unique predictor for an increase in problem scores from the first to the second measurement with beta-coefficients ranging from 0.17 to 0.25. Birth weight and family problems were not associated with change in problem scores across the two measurements., Conclusion: Familial loading of unipolar disorder predicted an increase in behavioral and emotional problems across the 14-month follow-up.

Objective: Evidence suggests that cognitive functioning in bipolar disorder may be impaired even in euthymic states, but it is unclear if the pattern of deficits is similar to the deficits found in schizophrenia. The aim of this study was to review quantitatively the studies on cognitive performance in schizophrenia and bipolar disorder., Methods: Articles for consideration were identified through a literature search in MEDLINE and PsycLIT in the period between 1985 and October 2004, using the keywords "schizophrenia" combined with "bipolar disorder", or "manic-depress*" or "manic" combined with "cogniti*" or "neuropsycholog*". Thirty-one studies were included that: i) evaluated cognitive performance using standardized and reliable neuropsychological testing procedures; ii) compared adult patients with schizophrenia and with bipolar disorder; iii) reported test scores of both patient groups, or exact p-values, t-values, or F-values; and iv) were published as an original article in a peer-reviewed English language journal., Results: Meta-analyses of all studies indicated that patients with bipolar disorder generally perform better than patients with schizophrenia, but the distribution of effect sizes showed substantial heterogeneity. Results based on a more homogeneous subset of studies that matched patient groups on clinical and demographic characteristics pointed in the same direction, with effect sizes in the moderate range., Conclusions: Patients with bipolar disorder show better cognitive performance than patients with schizophrenia, even when matched for clinical and demographic characteristics.

Background: Few epidemiological studies have investigated incidence by age or age at onset distributions for mania or bipolar disorder. The current study aimed to determine these in a defined area in south-east London, over a 35-year period., Method: All cases of first-episode mania presenting to psychiatric services in Camberwell, south-east London, between 1965 and 1999 were identified. Incidence rates by age, using 5-year age-at-onset bands, were estimated and the structure of the age-at-onset distribution for first-episode mania was investigated using finite mixture distributions (admixture analysis)., Results: The incidence of DSM-IV bipolar I disorder (BP I), first manic episode peaked in early adult life (16.38/100,000 population per year in the 21-25 years band) with a much smaller peak in mid-life. A two-component normal mixture distribution fitted age at onset better than either a single normal distribution or a three-component mixture, implying the existence of early and later onset subgroups. The early onset group had a stronger family history of bipolar disorder, and showed more acute, severe and atypical symptoms during their first manic episode., Conclusions: The incidence of mania peaks in early adult life but there is clear evidence of early and later onset subgroups which may represent different forms of disorder.

Objective: Despite clear gender differences in the symptoms and course of bipolar affective disorder, studies investigating age at onset by gender have yielded inconsistent results. The authors investigated gender differences in age at onset and incidence of first-episode mania and bipolar disorder in an epidemiological catchment area in southeast London over a 35-year period., Method: All adult cases of first-episode psychosis, mania, or hypomania presenting to services in Camberwell, southeast London (1965-1999), were identified. Computerized diagnoses for these cases were generated by using the Operational Checklist for Psychotic Disorders program. Incidence rates and rate ratios of DSM-IV bipolar I disorder, first manic episode, by gender and age (10-year age-at-onset categories) were calculated. Differences in age at onset of first-episode mania and bipolar disorder by gender were examined by using univariate and multivariate analyses., Results: Men had a significantly earlier onset of first-episode mania and bipolar disorder, with childhood antisocial behavior also being significantly associated, after multivariate analysis. Women had higher incidence rates of bipolar I disorder throughout adult life, except for early life (ages 16-25 years), although gender differences in individual age bands did not reach statistical significance., Conclusions: Men appear to have an earlier onset of mania and bipolar disorder than women. The association of male gender and childhood antisocial behavior with early-onset bipolar disorder raised the possibility of the existence of an early-onset subgroup.

Background: Although high incidence rates of mania have been described in some ethnic minority populations, little is known about any ethnic differences in the early clinical presentation of bipolar disorder., Methods: All cases of operationalised DSM-IV bipolar I disorder (BPI), first manic episode, within a defined epidemiological catchment area over a 35-year period, were identified; sociodemographic data, including ethnicity, and clinical information were then extracted. The proportion of African-Caribbean (n=52), African (n=33) and white European (n=149) cases who experienced a depressive episode before onset of mania and psychotic symptoms at first mania were compared., Results: African-Caribbean and African groups were significantly less likely to have experienced a depressive episode before onset of first mania, at 13.5% and 6.1%, respectively, compared with 28.1% in the white European group. African-Caribbean and African groups also experienced more severe psychotic symptoms at first mania, but there were no differences in mood incongruent or first rank symptoms between ethnic groups., Limitations: Data pertaining to diagnosis and clinical symptoms were extracted by retrospective case note review., Conclusions: Ethnic differences in clinical presentation of bipolar disorder may have implications for assessment and treatment of ethnic minority patients.