Outcome of a psychosocial health promotion intervention aimed at improving physical health and reducing alcohol use in patients with schizophrenia and psychotic disorders (MINT)

Background: Life expectancy is reduced by 19 years in men and 17 in women with psychosis in Sweden, largely due to cardiovascular disease. Aim: Assess whether a psychosocial health promotion intervention improves cardiometabolic risk factors, quality of life, and severity of illness in patients with psychotic disorders more than treatment as usual. Methods: A pragmatic intervention trial testing a manual-based multi-component health promotion intervention targeting patients with psychosis. The Swedish intervention was adapted from IMPaCT therapy, a health-promotion program based on motivational interviewing and cognitive behavioral therapy, designed to be incorporated into routine care. The intervention group consisted of 119 patients and a control group of 570 patients from specialized psychosis departments. Outcome variables were assessed 6 months before intervention during the run-in period, again at the start of intervention, and 12 months after the intervention began. The control group received treatment as usual. Results: The intervention had no significant effect on any of the outcome variables. However, BMI, waist circumference, systolic BP, heart rate, HbA1c, general health, and Clinical Global Impressions Scale score improved significantly during the run-in period before the start of the active intervention (observer effect). The multi-component design meant that treatment effects could only be calculated for the intervention as a whole. Conclusion: The results of the intervention are similar to those of the U.K. IMPaCT study, in which the modular health-promotion intervention had little effect on cardiovascular risk indicators. However, in the current study, the run-in period had a positive effect on cardiometabolic risk factors

CRY2 Is Associated with Rapid Cycling in Bipolar Disorder Patients

Bipolar disorder patients often display abnormalities in circadian rhythm, and they are sensitive to irregular diurnal rhythms. CRY2 participates in the core clock that generates circadian rhythms. CRY2 mRNA expression in blood mononuclear cells was recently shown to display a marked diurnal variation and to respond to total sleep deprivation in healthy human volunteers. It was also shown that bipolar patients in a depressive state had lower CRY2 mRNA levels, nonresponsive to total sleep deprivation, compared to healthy controls, and that CRY2 gene variation was associated with winter depression in both Swedish and Finnish cohorts.Four CRY2 SNPs spanning from intron 2 to downstream 3'UTR were analyzed for association to bipolar disorder type 1 (n = 497), bipolar disorder type 2 (n = 60) and bipolar disorder with the feature rapid cycling (n = 155) versus blood donors (n = 1044) in Sweden. Also, the rapid cycling cases were compared with bipolar disorder cases without rapid cycling (n = 422). The haplotype GGAC was underrepresented among rapid cycling cases versus controls and versus bipolar disorder cases without rapid cycling (OR = 0.7, P = 0.006-0.02), whereas overrepresentation among rapid cycling cases was seen for AAAC (OR = 1.3-1.4, P = 0.03-0.04) and AGGA (OR = 1.5, P = 0.05). The risk and protective CRY2 haplotypes and their effect sizes were similar to those recently suggested to be associated with winter depression in Swedes.We propose that the circadian gene CRY2 is associated with rapid cycling in bipolar disorder. This is the first time a clock gene is implicated in rapid cycling, and one of few findings showing a molecular discrimination between rapid cycling and other forms of bipolar disorder

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

Mortality in schizophrenia and affective disorder

Patients with psychiatric disorders such as schizophrenia, bipolar disorder and unipolar disorder have a considerably increased mortality compared to the population. To reduce this increased mortality is a major task for clinical psychiatry, and the aim of this study is to improve the knowledge about the increased mortality in order to reduce its effects for the patients. The studies in this thesis are based upon register linkages. Information about diagnosis and time of admission and discharge from the Patient register has been linked with information about cause and time of death from the Cause-of-death register, and information about first-degree relatives from the Second-generation register. First admissions with schizophrenia in Stockholm County during 1978 to 1994 were reduced by 1.3% yearly for males and 1.9% for females, while first admissions with either schizophrenia or paranoid psychosis were unchanged for both sexes, indicating that the reduction of first schizophrenia admissions may be an effect of diagnostic changes during the study period. For schizophrenics in Stockholm County followed-up from the first diagnosis, standardized mortality ratios (SMR:s) for all causes of death were increased to 2.8 for males and 2.4 for females. SMR was most increased in suicide, with 15.7 for males and 19.7 for females, and in unspecified violence, with 11.7 for males and 9.9 for females. SMR:s for suicide were particularly increased for young patients during the first year after the first admission. More excess deaths were caused by natural (somatic) than by unnatural causes of death, although the specific causes of death that caused most extra deaths were suicide in males and cardiovascular disease in females. Time trends in SMR for all causes of death during 1976 to 1995, for patients in Stockholm County diagnosed with schizophrenia for the first time, increased 1.7 times for males and 1.3 times for females. Cardiovascular death increased 4.7 times for males and 2.7 times for females, while all unnatural causes of death increased 1.8 times for males and suicide increased 1.9 times for females. The increase in mortality may be an effect of the concomitant reduction with 64% of days in hospital for schizophrenia. SMR:s for all patients with a hospital diagnosis of bipolar or unipolar disorder in Sweden for all causes of death were 2.5 for males and 2.7 for females in bipolar disorder, and 2.0 for both sexes in unipolar disorder. SMR:s for suicide in bipolar disorder were 15.0 for males and 22.4 for females, and in unipolar disorder 20.9 and 27.0 respectively. In bipolar disorder, most extra deaths were caused by natural causes, while in unipolar disorder, unnatural causes caused most extra deaths. Time trends for suicide mortality increased, both for bipolar and unipolar disorder. SMR:s for suicide for siblings to patients with schizophrenia, bipolar or unipolar disorder were not increased, unless the siblings had a psychiatric diagnosis of their own. Siblings with psychiatric diagnoses had as high suicide mortality as the probands. However, previous suicide in the family increased the suicide risk for patients with schizophrenia and bipolar disorder, but not unipolar disorder

Gender influence on the bipolar disorder inpatient length of stay in Sweden, 2005–2014 : A register-based study

Background: The influence of gender on bipolar disorder is controversial and it is unclear if inpatient care differs between men and women. Here, we investigate for gender differences in the inpatient length of stay for Swedes admitted for bipolar disorder and explore other factors that could explain any observed association. Methods: Admission data were extracted from the Swedish National Patient Register and included all patients first admitted to a psychiatric inpatient unit with a bipolar disorder diagnosis, circa 2005–2014. Patients were then retrospectively followed for subsequent hospitalizations. Diagnostic subtypes were categorized by ICD-10 clusters: depressive, depressive with psychotic features, manic, manic with psychotic features, mixed, and other. Psychotropic therapies preceding the corresponding admissions were attained from the Prescribed Drug Register. Mixed-effects zero-truncated negative binomial regressions were employed to model the length of stay per admission. Results: Analysis included 39,653 admissions by 16,271 inpatients (60.0% women). Overall, when compared to men, women spent 7.5% (95% CI: 4.2–11.0%, p < 0.001) extra days hospitalized per admission. However, upon adjusting for candidate confounders, including the bipolar subtype, and selected comorbidities and psychotropics, the association weakened wherein women then spent 3.7% (95% CI: 0.1–6.9%, p = 0.028) extra days hospitalized per admission. Limitations: The integrity of register data can be variable and the adherence to outpatient dispensed psychotropics could not be validated. Conclusion: Although the influence of gender on the bipolar disorder inpatient length of stay is evident, other factors attenuate and better explain this crude observation