Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.

OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.

Dissecting the impact of complement component 4A in bipolar disorder.

The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.

Recent Secular Trends of Body Mass Index in Individuals With Bipolar Disorders and in the General Population.

OBJECTIVE: The aims of this study were to investigate secular trends and distribution of body mass index (BMI) among individuals with bipolar disorders and the general population between 2008 and 2019. METHODS: Data were from the Swedish National Quality Register for Bipolar Disorder, where 24,423 adults with bipolar disorders were identified, and from the national Swedish Living Conditions Surveys, where 77,485 adults from the general population were identified. Quantile regression was used to compare the 15th, 50th, and 85th percentiles of BMI across age and study years. RESULTS: The study sample included 22,127 individuals with bipolar disorders (mean age, 48 years; 63% women) and 71,894 individuals from the general population (mean age, 52 years; 51% women). BMI percentiles were higher among individuals with bipolar disorders. At the 50th percentile, the BMI group differences were 1.1 (95% CI=0.8-1.14) for men and 1.8 (95% CI=1.5-2.1) for women. The gap was widest at the 85th BMI percentile: men, 2.3 (95% CI=1.8-2.8); women, 4.1 (95% CI=3.7-4.6). BMI increased over time in both study groups, but more in the group with bipolar disorders. The changes per decade in mean BMI were 0.4 (95% CI=0.3-0.5) among men in the general population, 1.1 (95% CI=0.7-1.4) among men with bipolar disorders, 0.6 (95% CI=0.5-0.7) among women in the general population, and 1.4 (95% CI=1.1-1.7) among women with bipolar disorders. Women with bipolar disorders had the highest prevalence and the greatest rate of increase of obesity. In 2019, the obesity prevalence was 33% among women and 29% among men with bipolar disorders, compared with 13% and 15%, respectively, among women and men in the general population. CONCLUSIONS: Adults with bipolar disorders had a higher BMI and a higher prevalence of obesity than the general population, indicating a higher cardiometabolic risk. Annually, BMI increased more in the group with bipolar disorders than in the general population, particularly among women and among those with high BMI.

Alterations in the Serum Proteome Following Electroconvulsive Therapy for a Major Depressive Episode: A Longitudinal Multicenter Study.

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but the biological changes induced by ECT remain poorly understood. Methods: This study investigated alterations in blood serum proteins in 309 patients receiving ECT for a major depressive episode. We analyzed 201 proteins in samples collected at 3 time points (T): just before the first ECT treatment session (T0), within 30 minutes after the first ECT session (T1), and just before the sixth ECT session (T2). Results: Using statistical models to account for repeated sampling, we identified 152 and 70 significantly (<5% false discovery rate) altered proteins at T1 and T2, respectively. The most pronounced alterations at T1 were transiently increased levels of prolactin, myoglobin, and kallikrein-6. However, most proteins had decreased levels at T1, with the largest effects observed for pro-epidermal growth factor, proto-oncogene tyrosine-protein kinase Src, tumor necrosis factor ligand superfamily member 14, sulfotransferase 1A1, early activation antigen CD69, and CD40 ligand. The change of several acutely altered proteins correlated with electric current and pulse frequency in a dose-response-like manner. Over a 5-session course of ECT, some acutely altered levels were sustained while others increased, e.g., serine protease 8 and chitinase-3-like protein 1. None of the studied protein biomarkers were associated with clinical response to ECT. Conclusions: We report experimental data on alterations in the circulating proteome triggered by ECT in a clinical setting. The findings implicate hormonal signaling, immune response, apoptotic processes, and more. None of the findings were associated with clinical response to ECT.

Cardiometabolic risk indicators in individuals with bipolar disorders: a replication study.

OBJECTIVES: We recently conducted the first longitudinal study comparing cardiometabolic risk indicators (CMRIs) between a cohort of individuals with bipolar disorders (BDs) and controls from the general population. Here, we sought to validate the findings in that study using an independent case-control sample. METHODS: We used data from the St. Göran project's Gothenburg cohort. The BDs group and the control group were examined at baseline and after a median of eight and seven years, respectively. Data collection occurred between March 2009 and June 2022. We used multiple imputation to handle missing data and linear mixed effects model to examine the annual change in CMRIs over the study period. RESULTS: The baseline cohort included 407 individuals with BDs (mean age 40 years, 63% women) and 56 controls (mean age 43 years, 54% women). Of those, 63 persons with BDs and 42 controls participated at follow-up. At baseline, individuals with BDs had significantly higher mean values of body mass index (ß = 0.14, p = 0.003) than controls. Over the study period, the difference in average annual change between the patient and the control group indicated an increase in patients relative to controls in waist-to-hip ratio (0.004 unit/year, p = 0.01), diastolic (0.6 mm Hg/year, p = 0.048), and systolic (0.8 mm Hg/year, p = 0.02) blood pressure. CONCLUSIONS: This study replicated the main findings from our previous study and showed that central obesity and measures of blood pressure worsened over a relatively short time in individuals with BDs relative to controls. It is vital for clinicians to monitor CMRIs in persons with BDs and to be proactive in preventing cardiometabolic diseases in this high-risk group.

Ghrelin activates the mesolimbic dopamine system via nitric oxide associated mechanisms in the ventral tegmental area.

Besides enhanced feeding, the orexigenic peptide ghrelin activates the mesolimbic dopamine system to cause reward as measured by locomotor stimulation, dopamine release in nucleus accumbens shell (NAcS), and conditioned place preference. Although the ventral tegmental area (VTA) appears to be a central brain region for this ghrelin-reward, the underlying mechanisms within this area are unknown. The findings that the gaseous neurotransmitter nitric oxide (NO) modulate the ghrelin enhanced feeding, led us to hypothesize that ghrelin increases NO levels in the VTA, and thereby stimulates reward-related behaviors. We initially demonstrated that inhibition of NO synthesis blocked the ghrelin-induced activation of the mesolimbic dopamine system. We then established that antagonism of downstream signaling of NO in the VTA, namely sGC, prevents the ability of ghrelin to stimulate the mesolimbic dopamine system. The association of ghrelin to NO was further strengthened by in vivo electrochemical recordings showing that ghrelin enhances the NO release in the VTA. Besides a GABAB -receptor agonist, known to reduce NO and cGMP, blocks the stimulatory properties of ghrelin. The present series of experiments reveal that ablated NO signaling, through pharmacologically inhibiting the production of NO and/or cGMP, prevents the ability of ghrelin to induced reward-related behaviors.

Time effect on cardiometabolic risk indicators in patients with bipolar disorder: a longitudinal case-control study.

Individuals with bipolar disorder are at increased risk for cardiovascular diseases. Most studies have described increases in cardiometabolic risk indicators (CMRIs) using clinical cut-off values. Further, there are no longitudinal studies on CMRIs. We aimed to investigate continuous measures of CMRIs in individuals with bipolar disorder and controls using both cross-sectional and longitudinal data. We used data from the Swedish St. Göran Bipolar project. Study individuals were examined at baseline and after a median of 6 and 7 years for the control and patient group, respectively. Data were collected December 2005-December 2020. The cohort included 281 individuals with bipolar disorder (mean age 39 years, 59% women) and 114 controls (mean age 38 years, 55% women). Of those, 155 patients and 74 controls also provided follow-up data. At baseline, individuals with bipolar disorder had significantly higher mean values of waist-to-hip ratio (WHR) (ß = 0.142, p = 0.001), body mass index (ß = 0.150, p = 0.006), plasma triacylglycerol (TAG) (ß = 0.218, p < 0.001), total/plasma high-density lipoprotein-cholesterol (TChol/HDL-C) ratio (ß = 0.103, p = 0.03), TAG/HDL-C ratio (ß = 0.151, p = 0.006), and non-HDL-C (ß = 0.168, p = 0.001) than controls. Most CMRIs remained higher in the patient group at follow-up. The difference between patients and controls increased over time for WHR (0.005 unit/year, p < 0.001), and systolic (1.1 mm Hg/year, p = 0.002) and diastolic (0.8 mm Hg/year, p < 0.001) blood pressure. Individuals with bipolar disorder displayed persistently higher levels of nearly all included CMRIs. Over time, a subset of CMRIs worsened in patients relative to controls. This suggests that active measures to counter cardiovascular risk in persons with bipolar disorder should be considered.

Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder.

Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005-2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04-1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05-2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.

Association Between Polygenic Risk Scores and Outcome of ECT.

OBJECTIVE: Identifying biomarkers associated with response to electroconvulsive therapy (ECT) may aid clinical decisions. The authors examined whether greater polygenic liabilities for major depressive disorder, bipolar disorder, and schizophrenia are associated with improvement following ECT for a major depressive episode. METHODS: Between 2013 and 2017, patients who had at least one treatment series recorded in the Swedish National Quality Register for ECT were invited to provide a blood sample for genotyping. The present study included 2,320 participants (median age, 51 years; 62.8% women) who had received an ECT series for a major depressive episode (77.1% unipolar depression), who had a registered treatment outcome, and whose polygenic risk scores (PRSs) could be calculated. Ordinal logistic regression was used to estimate the effect of PRS on Clinical Global Impressions improvement scale (CGI-I) score after each ECT series. RESULTS: Greater PRS for major depressive disorder was significantly associated with less improvement on the CGI-I (odds ratio per standard deviation, 0.89, 95% CI=0.82, 0.96; R2=0.004), and greater PRS for bipolar disorder was associated with greater improvement on the CGI-I (odds ratio per standard deviation, 1.14, 95% CI=1.05, 1.23; R2=0.005) after ECT. PRS for schizophrenia was not associated with improvement. In an overlapping sample (N=1,207) with data on response and remission derived from the self-rated version of the Montgomery-Åsberg Depression Rating Scale, results were similar except that schizophrenia PRS was also associated with remission. CONCLUSIONS: Improvement after ECT is associated with polygenic liability for major depressive disorder and bipolar disorder, providing evidence of a genetic component for ECT clinical response. These liabilities may be considered along with clinical predictors in future prediction models of ECT outcomes.

Proteins associated with future suicide attempts in bipolar disorder: A large-scale biomarker discovery study.

Suicide is a major cause of death worldwide. Several biological systems have been implicated in suicidal behavior but studies of candidate biomarkers have failed to produce clinically relevant biomarkers for suicide prediction. The objective of the present study was to identify novel candidate biomarkers for suicidal behavior. We used a nested case-control study design where a large cohort of patients with bipolar disorder (N = 5 110) were followed up to 8 years after blood sampling. We included patients that attempted suicide during follow-up (N = 348) and matched bipolar disorder patients from the same cohort who did not attempt suicide during the study period (N = 348) and analyzed a total of 92 proteins with a neuro exploratory multiplex panel. Using a multivariate classification algorithm devised to minimize bias in variable selection, we identified a parsimonious set of proteins that best discriminated bipolar disorder patients with and without prospective suicide attempts. The algorithm selected 16 proteins for the minimal-optimal classification model, which outperformed 500 models with permuted outcome (p = 0.0004) but had low sensitivity (53%) and specificity (64%). The candidate proteins were then entered in separate logistic regression models to calculate protein-specific associations with prospective suicide attempts. In individual analyses, three of these proteins were significantly associated with prospective suicide attempt (SCGB1A1, ANXA10, and CETN2). Most of the candidate proteins are novel to suicide research.

A serum proteomic study of two case-control cohorts identifies novel biomarkers for bipolar disorder.

We set out to identify novel protein associations with potential as clinically viable biomarkers for bipolar disorder. To this end, we used proximity extension assay to analyze 201 unique proteins in blood serum from two independent cohorts comprising patients with bipolar disorder and healthy controls (total n = 493). We identified 32 proteins significantly associated with bipolar disorder in both case-control cohorts after adjusting for relevant covariates. Twenty-two findings are novel to bipolar disorder, but 10 proteins have previously been associated with bipolar disorder: chitinase-3-like protein 1, C-C motif chemokine 3 (CCL3), CCL4, CCL20, CCL25, interleukin 10, growth/differentiation factor-15, matrilysin (MMP-7), pro-adrenomedullin, and TNF-R1. Next, we estimated the variance in serum protein concentrations explained by psychiatric drugs and found that some case-control associations may have been driven by psychiatric drugs. The highest variance explained was observed between lithium use and MMP-7, and in post-hoc analyses and found that the serum concentration of MMP-7 was positively associated with serum lithium concentration, duration of lithium therapy, and inversely associated with estimated glomerular filtration rate in an interaction with lithium. This is noteworthy given that MMP-7 has been suggested as a mediator of renal tubulointerstitial fibrosis, which is characteristic of lithium-induced nephropathy. Finally, we used machine learning to evaluate the classification performance of the studied biomarkers but the average performance in unseen data was fair to moderate (area under the receiver operating curve = 0.72). Taken together, our serum biomarker findings provide novel insight to the etiopathology of bipolar disorder, and we present a suggestive biomarker for lithium-induced nephropathy.

Cohort profile: the Swedish National Quality Register for bipolar disorder(BipoläR).

PURPOSE: The Swedish National Quality Register for bipolar affective disorder, BipoläR, was established in 2004 to provide nationwide indicators for quality assessment and development in the clinical care of individuals with bipolar spectrum disorder. An ancillary aim was to provide data for bipolar disorder research. PARTICIPANTS: Inclusion criteria for registration in BipoläR is a diagnosis of bipolar spectrum disorder (ICD codes: F25.0, F30.1-F30.2, F30.8-F31.9, F34.0) and treatment at an outpatient clinic in Sweden. BipoläR collects data from baseline and annual follow-up visits throughout Sweden. Data is collected using questionnaires administered by healthcare staff. The questions cover sociodemographic, diagnostic, treatment, outcomes and patient reported outcome variables. The register currently includes 39 583 individual patients with a total of 75 423 baseline and follow-up records. FINDINGS TO DATE: Data from BipoläR has been used in several peer-reviewed publications. Studies have provided knowledge on effectiveness, side effects and use of pharmacological and psychological treatment in bipolar disorder. In addition, findings on the diagnosis of bipolar disorder, risk factors for attempted and completed suicide and health economics have been reported. The Swedish Bipolar Collection project has contributed to a large number of published studies and provides important information on the genetic architecture of bipolar disorder, the impact of genetic variation on disease characteristics and treatment outcome. FUTURE PLANS: Data collection is ongoing with no fixed end date. Currently, approximately 5000 new registrations are added each year. Cohort data are available via a formalised request procedure from Centre of Registers Västra Götaland (e-mail: registercentrum@vgregion.se). Data requests for research purposes require an entity responsible for the research and an ethical approval.

Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder.

The etiopathology of bipolar disorder is largely unknown. We collected cerebrospinal fluid (CSF) samples from two independent case-control cohorts (total n = 351) to identify proteins associated with bipolar disorder. A panel of 92 proteins targeted towards central nervous system processes identified two proteins that replicated across the cohorts: the CSF concentrations of testican-1 were lower, and the CSF concentrations of C-type lectin domain family 1 member B (CLEC1B) were higher, in cases than controls. In a restricted subgroup analysis, we compared only bipolar type 1 with controls and identified two additional proteins that replicated in both cohorts: draxin and tumor necrosis factor receptor superfamily member 21 (TNFRSF21), both lower in cases than controls. This analysis additionally revealed several proteins significantly associated with bipolar type 1 in one cohort, falling just short of replicated statistical significance in the other (tenascin-R, disintegrin and metalloproteinase domain-containing protein 23, cell adhesion molecule 3, RGM domain family member B, plexin-B1, and brorin). Next, we conducted genome-wide association analyses of the case-control-associated proteins. In these analyses, we found associations with the voltage-gated calcium channel subunit CACNG4, and the lipid-droplet-associated gene PLIN5 with CSF concentrations of TNFRSF21 and CLEC1B, respectively. The reported proteins are involved in neuronal cell-cell and cell-matrix interactions, particularly in the developing brain, and in pathways of importance for lithium's mechanism of action. In summary, we report four novel CSF protein associations with bipolar disorder that replicated in two independent case-control cohorts, shedding new light on the central nervous system processes implicated in bipolar disorder.

[Bipolar disorder type 1 was the most stable bipolar subdiagnosis]. / Bipolär sjukdom typ 1 ­ den mest stabila bipolära underdiagnosen.

DSM-IV subcategorises bipolar disorders into type 1, type 2, and a third not otherwise specified (NOS) category. Although previous works suggest that these subtypes remain reasonably stable over time, it is unclear if subdiagnoses endure over time or if patients are commonly recategorized within the spectrum in a real-world clinical setting. We assessed subdiagnostic stability in 6,374 individuals with bipolar disorder using data from the Swedish national quality assurance register for bipolar disorders (BipoläR). Diagnoses at baseline registration - that could occur at any time point during the course of illness - were compared with diagnoses at follow-up registration 3 years later. Changes in subdiagnoses were analysed in relation to clinical setting, diagnostic procedure, and patient features. We found that 74 %, 67 %, and 47 % of patients diagnosed with bipolar disorder type 1, type 2, and NOS, respectively, retained the same subdiagnosis at the 3-year follow-up. The following factors were associated with higher rate of subdiagnostic transitions: previous suicide attempts, unemployment or low psychosocial function, treatment with antidepressants, and comorbid anxiety, neuropsychiatric, or personality disorder. Conversely, use and duration of mood stabilizer treatment, the use of structured diagnostic instruments, and treatment at an outpatient unit specialized in managing affective disorders were associated with lower likelihood of subdiagnostic transitions. Our findings confirm that bipolar disorder type 1 is the most stable subdiagnostic group, but findings also indicate a significant degree of subdiagnostic instability, particularly in the NOS group.

Long-term trajectory of cognitive performance in people with bipolar disorder and controls: 6-year longitudinal study.

BACKGROUND: Cross-sectional studies have found impaired cognitive functioning in patients with bipolar disorder, but long-term longitudinal studies are scarce. AIMS: The aims of this study were to examine the 6-year longitudinal course of cognitive functioning in patients with bipolar disorder and healthy controls. Subsets of patients were examined to investigate possible differences in cognitive trajectories. METHOD: Patients with bipolar I disorder (n = 44) or bipolar II disorder (n = 28) and healthy controls (n = 59) were tested with a comprehensive cognitive test battery at baseline and retested after 6 years. We conducted repeated measures ANCOVAs with group as a between-subject factor and tested the significance of group and time interaction. RESULTS: By and large, the change in cognitive functioning between baseline and follow-up did not differ significantly between participants with bipolar disorder and healthy controls. Comparing subsets of patients, for example those with bipolar I and II disorder and those with and without manic episodes during follow-up, did not reveal subgroups more vulnerable to cognitive decline. CONCLUSIONS: Cognitive performance remained stable in patients with bipolar disorder over a 6-year period and evolved similarly to healthy controls. These findings argue against the notion of a general progressive decline in cognitive functioning in bipolar disorder.

Regional lithium prescription rates and recurrence in bipolar disorder.

BACKGROUND: Lithium is the best documented maintenance treatment in bipolar disorder, but its use varies considerably across and within countries. It is not known whether regional differences in lithium prescription rates translate to differing regional outcomes. AIMS: To estimate associations between county specific lithium prescription rates and county specific recurrence odds of bipolar disorder in Sweden. METHOD: Data from 14,616 patients with bipolar I disorder, bipolar II disorder, or bipolar disorder not otherwise specified were extracted from the Swedish national quality assurance register for bipolar disorders (BipoläR). Lithium prescription frequencies were calculated for 21 counties. Logistic regression analyses were run adjusted for confounders, with any type of recurrence as primary outcome, and incident elated and depressive episodes as secondary outcomes. Subsets of patients with bipolar I, II and not otherwise specified disorder were also analysed separately. RESULTS: Lithium prescription rates for populations with all bipolar subtypes ranged across counties from 37.7 to 84.9% (mean 52.4%). Higher regional prescription rates were significantly associated with lower rate of any type of recurrence. The association was stronger when bipolar I disorder was analysed separately. CONCLUSIONS: The advantages for lithium use long acknowledged for bipolar I disorder are also seen for the rest of the bipolar spectrum. Results suggest that population level outcomes of bipolar disorder could be improved by increasing the number of patients using lithium.

Patient educational level and management of bipolar disorder.

BACKGROUND: Socioeconomic factors can affect healthcare management. AIMS: The aim was to investigate if patient educational attainment is associated with management of bipolar disorder. METHOD: We included patients with bipolar disorder type 1 (n = 4289), type 2 (n = 4020) and not otherwise specified (n = 1756), from the Swedish National Quality Register for Bipolar Disorder (BipoläR). The association between patients' educational level and pharmacological and psychological interventions was analysed by binary logistic regression. We calculated odds ratios after adjusting for demographic and clinical variables. RESULTS: Higher education was associated with increased likelihood of receiving psychotherapy (adjusted odds ratio 1.34, 95% CI 91.22-1.46) and psychoeducation (adjusted odds ratio 1.18, 95% CI 1.07-1.46), but with lower likelihood of receiving first-generation antipsychotics (adjusted odds ratio 0.76, 95% CI 0.62-0.94) and tricyclic antidepressants (adjusted odds ratio 0.76, 95% CI 0.59-0.97). Higher education was also associated with lower risk for compulsory in-patient care (adjusted odds ratio 0.79, 95% CI 0.67-0.93). CONCLUSIONS: Pharmacological and psychological treatment of bipolar disorder differ depending on patients' educational attainment. The reasons for these disparities remain to be explained.

Serum profiling of anorexia nervosa: A 1H NMR-based metabolomics study.

Our understanding of pathophysiological mechanisms underlying anorexia nervosa (AN) is incomplete. The aim was to conduct a metabolomics profiling of serum samples from women with AN (n = 65), women who have recovered from AN (AN-REC, n = 65), and age-matched healthy female controls (HC, n = 65). Serum concentrations of 21 metabolites were measured using proton nuclear magnetic resonance (1H NMR). We used orthogonal partial least-squares discriminant analysis (OPLS-DA) modeling to assign group classification based on the metabolites. Analysis of variance (ANOVA) was used to test for metabolite concentration differences across groups. The OPLS-DA model could distinguish between the AN and HC groups (p = 9.05 × 10-11 R2Y = 0.36, Q2 = 0.37) and between the AN-REC and HC groups (p = 8.47 × 10-6, R2Y = 0.36, Q2 = 0.24,), but not between the AN and AN-REC groups (p = 0.63). Lower methanol concentration in the AN and AN-REC group explained most of the variance. Likewise, the strongest finding in the univariate analyses was lower serum methanol concentration in both AN and AN-REC compared with HC, which withstood adjustment for body mass index (BMI). We report for the first time lower serum concentrations of methanol in AN. The fact that low methanol was also found in recovered AN suggests that low serum concentration of methanol could either be trait marker or a scar effect of AN.

Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy.

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

Central levels of tryptophan metabolites in subjects with bipolar disorder.

The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites such as kynurenic acid (KYNA), quinolinic acid (QUIN), and picolinic acid (PIC) thought to be involved in the pathophysiology of psychosis, major depression, and suicidal behavior. Here, we analyzed cerebrospinal fluid (CSF) concentrations of tryptophan, kynurenine, KYNA, QUIN, and PIC utilizing ultra-performance liquid chromatography - tandem mass spectrometry system (UPLC-MS/MS) in persons with bipolar disorder (n = 101) and healthy controls (n = 80) to investigate if the metabolites correlated with depressive symptoms or to the history of suicidal behavior. Furthermore, we analyzed if genetic variants of the enzyme amino-ß-carboxymuconate-semialdehyde-decarboxylase (ACMSD) were associated with the CSF concentrations of PIC and QUIN. We found that CSF KYNA and PIC concentrations, as well as the kynurenine/tryptophan ratio were increased in bipolar disorder compared with controls. CSF PIC concentrations were lower in subjects with a history of suicidal behavior than those without, supporting the hypothesis that low CSF PIC is a marker of vulnerability for suicidality. Bipolar subjects taking antidepressants had higher CSF concentrations of kynurenine and KYNA than subjects not given these medications. A negative association was found between a genetic variant of ACMSD and the ratio of PIC/QUIN, indicating that a polymorphism in ACMSD is associated with excess of QUIN formation at the expense of PIC. The present results confirm that the kynurenine pathway is activated in bipolar disorder, and suggest that shifting the activity of the kynurenine pathway away from QUIN production towards a production of KYNA and PIC might be a beneficial therapeutic strategy.