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Environmental factors such as adverse childhood experiences (ACEs) may affect neurocognition, an endophenotype for several mental illnesses. This study examines the effect of ACEs on neurocognitive performance in first-degree relatives (FDRs) of patients with severe mental illness to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition. Unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder, or alcohol use disorder) (n = 324) and healthy controls (with no familial risk) (n = 188) underwent neurocognitive tests for processing speed, new learning, working memory and Theory of Mind. ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Score and their interaction (familial risk*ACE-IQ score). The main effect of familial risk predicted poor performance in all domains of neurocognition (p < 0.01), and the interaction had a negative association with global neurocognition (β = -0.093, p = 0.009), processing speed (β = -0.109, p = 0.003) and working memory (β = -0.092, p = 0.01). Among the ACEs sub-domains, only maltreatment (specifically the main effect of physical neglect and the interaction effect of sexual abuse with familial risk) predicted poorer neurocognition. In FDRs of schizophrenia and bipolar disorder, only the main effects of familial risk were significantly associated with poorer neurocognition. We conclude that there is a relationship between ACEs (especially maltreatment) and neurocognitive functioning, which is moderated by the familial risk of mental illnesses. Genetic/familial vulnerability may have a stronger association with neurocognition in schizophrenia and bipolar disorder., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interests to declare with respect to the current study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and it helps in the formation of a functional brain. We studied the migration patterns of induced pluripotent stem cell-derived neural precursor cells (NPCs) from individuals with familial bipolar disorder (BD) in comparison with healthy controls. The BD patients also had morphological brain abnormalities evident on magnetic resonance imaging. Time-lapse analysis of migrating cells was performed, through which we were able to identify several parameters that were abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind the aberrant cellular phenotype identified. Our analysis showed the downregulation of a network of genes, centering on EGF/ERBB proteins. The present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype, which could contribute to the functional and structural changes in the brain reported for bipolar disorder. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth., Methods: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer., Results: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001)., Conclusion: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The association of the Val66Met (rs6265) polymorphism in the brain-derived neurotrophic factor ( BDNF ) gene with bipolar disorder (BD) and response to lithium treatment has been suggested, though inconsistently. The considerable diversity of allele frequency across different populations contributes to this. There is no data from South Asia till date. Hence, we examined the association of this polymorphism in BD cases from India, and its association with lithium treatment response., Methods: BD patients ( N  = 301) were recruited from the clinical services of National Institute of Mental Health and Neurosciences (NIMHANS), India. Lithium treatment response for 190 BD subjects was assessed using Alda scale by NIMH life charts. Patients with total score ⩾7 were defined as lithium responders ( N  = 115) and patients with score <7 were defined as lithium non-responders ( N  = 75). Healthy controls ( N  = 484) with no lifetime history of neuropsychiatric illness or a family history of mental illness were recruited as control set. Genotyping was performed by TaqMan genotyping assay., Results: Genotype and allele frequency of BDNF Val66Met SNP was significantly different (χ2 = 7.78, p  = 0.02) in cases compared to controls, and the Val(G) allele was more frequent (χ2 = 7.08, p  = 0.008) in BD patients. However, no significant difference is noted in genotype or allele frequencies of this polymorphism between the lithium responders and non-responders., Conclusions: The Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but it is not related to response to lithium.

Background: Minor physical anomalies (MPA) are markers of impaired neurodevelopment during the prenatal stage. Assessing MPA across psychiatric disorders may help understand their shared nature. In addition, MPA in family members would indicate a shared liability and endophenotype potential. We examined familial aggregation of MPA and their role as transdiagnostic and disorder-specific markers of 5 major psychiatric/neuropsychiatric conditions (schizophrenia, bipolar disorder, substance dependence, obsessive-compulsive disorder, and Alzheimer's dementia)., Methods: Modified Waldrop's MPA scale was applied on 1321 individuals from 439 transdiagnostic multiplex families and 125 healthy population controls (HC). Stage of fetal development (morphogenetic/phenogenetic)- and anatomical location (craniofacial/peripheral)-based sub-scores were calculated. Familiality and endophenotypic potential of MPA were analyzed with serial negative binomial mixed-effect regression. Cross-diagnostic differences and the effect of family history density (FHD) of each diagnosis on MPA were assessed. Mixed-effects Cox models estimated the influence of MPA on age-at-onset of illness (AAO)., Results: MPA were found to be heritable in families with psychiatric disorders, with a familiality of 0.52. MPA were higher in psychotic disorders after controlling for effects of sex and intrafamilial correlation. Morphogenetic variant MPA was noted to be lower in dementia in comparison to HC. FHD of schizophrenia and bipolar disorder predicted higher, and that of dementia and substance dependence predicted lower MPA. MPA brought forward the AAO [HR:1.07 (1.03-1.11)], and this was more apparent in psychotic disorders., Conclusion: MPA are transmissible in families, are specifically related to the risk of developing psychoses, and predict an earlier age at onset. Neurodevelopmentally informed classification of MPA has the potential to enhance the etiopathogenic and translational understanding of psychiatric disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Severe mental illnesses such as schizophrenia and bipolar disorder have complex inheritance patterns, involving both common and rare variants. Whole exome sequencing is a promising approach to find out the rare genetic variants. We had previously reported several rare variants in multiplex families with severe mental illnesses. The current article tries to summarise the biological processes and pattern of expression of genes harbouring the aforementioned variants, linking them to known clinical manifestations through a methodical narrative review. Of the 28 genes considered for this review from 7 families with multiple affected individuals, 6 genes are implicated in various neuropsychiatric manifestations including some variations in the brain morphology assessed by magnetic resonance imaging. Another 15 genes, though associated with neuropsychiatric manifestations, did not have established brain morphological changes whereas the remaining 7 genes did not have any previously recorded neuropsychiatric manifestations at all. Wnt/b-catenin signaling pathway was associated with 6 of these genes and PI3K/AKT, calcium signaling, ERK, RhoA and notch signaling pathways had at least 2 gene associations. We present a comprehensive review of biological and clinical knowledge about the genes previously reported in multiplex families with severe mental illness. A 'disease in dish approach' can be helpful to further explore the fundamental mechanisms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Syndromes of schizophrenia, bipolar disorder, obsessive-compulsive disorder, substance use disorders and Alzheimer's dementia are highly heritable. About 10-20% of subjects have another affected first degree relative (FDR), and thus represent a 'greater' genetic susceptibility. We screened 3583 families to identify 481 families with multiple affected members, assessed 1406 individuals in person, and collected information systematically about other relatives. Within the selected families, a third of all FDRs were affected with serious mental illness. Although similar diagnoses aggregated within families, 62% of the families also had members with other syndromes. Moreover, 15% of affected individuals met criteria for co-occurrence of two or more syndromes, across their lifetime. Using dimensional assessments, we detected a range of symptom clusters in both affected and unaffected individuals, and across diagnostic categories. Our findings suggest that in multiplex families, there is considerable heterogeneity of clinical syndromes, as well as sub-threshold symptoms. These families would help provide an opportunity for further research using both genetic analyses and biomarkers., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the "Alda scale" and "NIMH Retrospective Life chart method"), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in LCLs, and this was unrelated to clinical lithium response. The higher cell proliferation observed in BD was unaffected by in vitro lithium. Cell death was greater in BD. However, LCLs from clinical lithium responders could be rescued by addition of in vitro lithium. In vitro lithium also enhanced BCL2 and GSK3B expression in these cells. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs.

Objectives: Bipolar disorder (BD) is a neuropsychiatric disorder with a complex pattern of inheritance. Although many genetic studies have been conducted on BD, its genetic correlates remain uncertain. This study was aimed at  identifying the genetic underpinnings of the disorder in an Indian family, which has been under comprehensive clinical evaluation and follow-up for over 12 years., Methods: We analysed a four-generation family with several of its members diagnosed for BD employing a combination of genetic linkage and exome analysis., Results: We obtained suggestive LOD score for a chromosome 1 and a chromosome 6 marker (D1S410; LOD = 3.01, Ө = 0; and D6S289; LOD = 1.58, Ө = 0). Manual haplotyping of the regions encompassing these two markers helped delimit a critical genomic interval of 32.44 Mb (D1S2700-D1S435; chromosome 1p31.1-13.2) and another of 10.34 Mb (D6S470-D6S422; chromosome 6p22.3-22.2). We examined the exomic sequences corresponding to these two intervals and found rare variants, NM&#95;181712.4: c.2461G>T (p.Asp821Tyr) in KANK4 at 1p31.1-13.2; and NM&#95;006366:c.-93G>A, in the 5' UTR of CAP2 at 6p22.3-22.2., Conclusions: Our studysuggests involvement of KANK4 or CAP2 or both in BD in this family. Further analysis of these two genes in BD patients and functional evaluation of the allelic variants identified are suggested., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p < 0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome-wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next-generation sequencing may add to the understanding of the genetic architecture of SMI., Methods: We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole-exome sequencing. Prioritized variants were selected by a three-step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool., Results: We identified 42 rare, non-synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a 'private' mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome., Conclusion: Next-generation sequencing approaches in family-based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI., (© 2018 Institute for Stem Cell Biology and Regenerative Medicine (InStem) Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Bipolar Disorder (BD) is a chronic and disabling psychiatric illness with waxing and waning course. Lithium is the mainstay of treatment for Bipolar disorder (BD). There is limited literature on the clinical markers of Lithium treatment response from south Asia., Methods: Two hundred and ten individuals with BD I and a history of at least 6 months of treatment with Lithium were recruited from the outpatient services of the National Institute of Mental Health and Neurosciences (NIMHANS) after obtaining informed consent. A diagnosis of BD I was made according to the DSM-IV criteria. The characterization of response to lithium prophylaxis was done using NIMH Retrospective Life Chart and "Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder" scale., Results: There were 132 (62.86%) good responders and 78 (37.14%) non-responders. Good responders were noted to have less number of hospitalizations and more onset episode of depression than non-responders. Using continuous phenotype, Lithium response was inversely correlated with total number of episodes, number of episodes of mania/ depression, number of hospitalisations and presence of suicide attempt. Multivariate analysis only revealed number of episodes and hospitalization to be associated with Lithium response., Conclusion: Our Lithium response rates were higher than what have been reported in the few previous studies. Illness severity was the only factor associated with Lithium response. There is a need to examine this question in larger prospective samples and to focus on biological/ molecular markers of treatment response., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder., Method: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density., Results: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001)., Conclusion: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups., Aims: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking., Methods: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data., Results and Conclusions: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Objective: Bipolar disorder (BD) is considered to be a common comorbid condition in subjects with obsessive-compulsive disorder (OCD), but there is limited literature on the prevalence of BD and its clinical correlates in those with a primary diagnosis of OCD., Methods: We studied the prevalence of BD in a sample of consecutively registered outpatients attending a specialty OCD clinic in India over a period of 13 months. One hundred and seventy-one patients with a primary diagnosis of OCD were assessed systematically using structured and semi-structured instruments., Results: The prevalence of lifetime BD in OCD was 4%. The OCD + BD group had an episodic course of OCD and higher rate of lifetime suicide attempts., Conclusions: BD may not be as highly prevalent in OCD as reported in literature. Those with OCD seem to have only a marginally higher risk for developing BD than the general population. A diagnosis of BD seems to have a pathoplastic effect on the course of OCD. Patients with OCD-BD comorbidity have to be specifically assessed for suicide risk.

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: There is an emerging interest in the use of cellular models to study psychiatric disorders. We have systematically reviewed the application of cellular models to understand the biological basis of bipolar disorder (BD)., Method: Published scientific literature in MEDLINE, PsychINFO and SCOPUS databases were identified with the following search strategy: [(Lymphoblastoid OR Lymphoblast OR Fibroblast OR Pluripotent OR Olfactory epithelium OR Olfactory mucosa) AND (Bipolar disorder OR Lithium OR Valproate OR Mania)]. Studies were included if they had used cell cultures derived from BD patients., Results: There were 65 articles on lymphoblastoid cell lines, 14 articles on fibroblasts, 4 articles on olfactory neuronal epithelium (ONE) and 2 articles on neurons reprogrammed from induced pluripotent stem cell lines (IPSC). Several parameters have been studied, and the most replicated findings are abnormalities in calcium signaling, endoplasmic reticulum (ER) stress response, mitochondrial oxidative pathway, membrane ion channels, circadian system and apoptosis related genes. These, although present in basal state, seem to be accentuated in the presence of cellular stressors (e.g. oxidative stress--rotenone; ER stress--thapsigargin), and are often reversed with in-vitro lithium., Conclusion: Cellular modeling has proven useful in BD, and potential pathways, especially in cellular resilience related mechanisms have been identified. These findings show consistency with other study designs (genome-wide association, brain-imaging, and post-mortem brain expression). ONE cells and IPSC reprogrammed neurons represent the next generation of cell models in BD. Future studies should focus on family-based study designs and combine cell models with deep sequencing and genetic manipulations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association., Methods: Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4 N and 70.7 N, and 1.2 S and 41.3 S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation., Results: More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model., Conclusions: Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Limited numbers of studies have examined the prevalence of OCD systematically in consecutively sampled adult bipolar disorder type I (BD-I) patients. We examined the frequency of OCD in a large number (n=396) of consecutively hospitalized patients with BD-I and identified socio-demographic and clinical correlates of BD-I with and without OCD., Method: BD-I patients (n=396) were assessed using the Mini International Neuropsychiatric Interview for Bipolar Disorder Studies, the Structured clinical interview for (Axis II) DSM-IV, the Family interview for genetic studies, the Yale-Brown Obsessive-Compulsive Scale, the Young Mania Rating Scale, the Hamilton Rating Scale for Depression, the Global Assessment of Functioning (GAF) and the Clinical Global Impression scale. Patients with and without OCD were compared in terms of various socio-demographic and clinical variables., Results: Thirty (7.6%) of the 396 inpatients studied had OCD and 15 (3.8%) had subclinical OCD. BD-OCD group had significantly lower GAF scores, higher rates of unemployment, and lower incidence of psychotic symptoms. In addition, BD-OCD group had higher rates of comorbid social anxiety and anxious avoidant personality disorder (AAPD) and OCD in first-degree relatives. Those with clinical and subclinical OCD did not differ on functioning and severity measures., Limitations: Retrospective design and recruitment of patients from inpatient services of a tertiary psychiatric hospital., Conclusion: OCD is not an uncommon comorbid disorder in BD-I and appears to be associated with greater functional disability. BD-I with comorbid OCD is associated with greater family history of OCD, comorbidities of social phobia and AAPD and less of psychotic symptoms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database., Methods: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared., Results: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups., Conclusion: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: It has been debated as to whether the polarity of mood disorder (bipolar versus unipolar) has prognostic significance for electroconvulsive therapy (ECT) outcome. In the treatment guidelines, ECT is recommended more readily for unipolar depression and not so for bipolar depression. This study aims to examine efficacy of bipolar and unipolar depression to ECT in a real life naturalistic setting., Method: We studied the ECT parameters of all consecutive patients with a diagnosis of unipolar depression (recurrent depressive disorder, ≥2 episodes of depression) and bipolar depression referred for ECT between the months of July 2008 and December 2010 (BP-D: n=44) and (UP-D: n=106)., Results: When bipolar depression was compared to unipolar depression, the average motor seizure duration (mean=46.9 and 46.7, t=-0.06, p=0.94), number of ECTs required for improvement (mean=6.4 and 6.5, t=0.17, p=0.86), duration of inpatient stay after ECT initiation in days (mean=16.2 and 16.6, t=0.23, p=0.81) and improvement as assessed using a Likert scale (Mann-Whitney U, Z=-0.09, p=0.92) were not statistically different between the groups., Conclusions: We did not find any difference in efficacy of ECT between the two forms of depression in real life setting. This calls for justification of use of ECT in all patients with depression irrespective of the type of illness polarity and inclusion of ECT as a routine treatment option in bipolar depression guidelines., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode., Methods: Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations., Results: There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California., Limitations: Recall bias for onset and family history data., Conclusions: A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders., (Copyright © 2014 Elsevier B.V. All rights reserved.)