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Background: Bipolar disorder (BD) is a severe psychiatric condition with unclear etiology and no established biomarkers. Here, we aimed to characterize the cerebrospinal fluid (CSF) proteome in euthymic BD individuals to identify potential protein biomarkers., Methods: We employed nano-flow liquid chromatography coupled to high-resolution mass spectrometry to quantify over 2,000 CSF proteins in 374 individuals from two independent clinical cohorts (n=164+89 and 66+55 cases and controls, respectively). A subset of the cases was followed longitudinally and reexamined after a median of 6.5 years., Results: Differential abundance analysis revealed 41 proteins with robust case-control association in both cohorts. These included lower levels of synaptic proteins (e.g., APP, CLSTN1, NPTX2, NRXN1), axon guidance and cell adhesion molecules (e.g., NEO1, NCAM1, SEMA7A), higher levels of blood-brain-barrier integrity proteins (e.g., VTN, SERPIN3), and complement components (e.g., C1RL, C3, C5). The findings were consistently driven by the BD type 1 subtype. Comparing BD type 1 with controls increased discoverability, revealing 86 replicated associations despite a loss of statistical power. Moreover, longitudinal analyses of co-expression modules revealed dynamic changes in the CSF proteome composition that correlated with clinical outcomes, including disease severity, future manic episodes, and symptom improvement. Finally, we conducted association analyses of CSF proteins with genetic risk loci for bipolar disorder and schizophrenia., Conclusions: This study represents the first large-scale untargeted profiling of the CSF proteome in BD, unveiling potential biomarkers and providing in vivo support for altered synaptic and brain connectivity processes, impaired neurovascular integrity, and complement activation in the pathology of BD., (Copyright © 2025. Published by Elsevier Inc.)

Introduction: The St. Göran Bipolar Project (SBP) is a longitudinal outpatient study investigation aimed at identifying predictive factors associated with long-term outcomes in individuals with bipolar disorder. These outcomes include cognitive function, relapse rate, treatment responses, and functional outcomes. The study employs a multifaceted approach, integrating brain imaging, biochemical analyses of cerebrospinal fluid and blood, and genetics. This paper provides an overview of the research methods used in the SBP, along with a summary of the main findings to date., Methods: SBP is a collaborative effort between academia and healthcare, enrolling study participants from bipolar outpatient clinics in Stockholm (SBP-S) and Gothenburg (SBP-G), Sweden. Healthy controls were recruited through Statistics Sweden. Data and samples were collected using structured interviews, self-rated questionnaires, blood and cerebrospinal fluid samples, magnetic resonance imaging, and neuropsychological tests. Follow-up visits are conducted 7 and 14 years after baseline., Conclusion: The SBP has generated numerous original findings and has contributed to advancing knowledge on cognitive function, personality, cerebrospinal and blood biomarkers, neuroimaging, and genetics. Further, as data collection nears completion, new research questions can be addressed. The study's strengths include detailed, multimodal information from each study visit and a long follow-up period. The naturalistic setting ensures that findings are relevant to real-world scenarios. However, variability in data completeness can introduce selection bias. Additionally, the control population, while randomly selected, may not be fully representative due to the voluntary nature of participation. Future projects will focus on longitudinal analyses and novel methods to exploit the study's multifaceted approach., (© 2025 The Author(s). Published by S. Karger AG, Basel.)

Despite electroconvulsive therapy (ECT) being recognized as an effective treatment for major depressive episodes (MDE), its application is subject to controversy due to concerns over cognitive side effects. The pathophysiology of these side effects is not well understood. Here, we examined the effects of ECT on blood-based biomarkers of neuronal injury and astrocytic reactivity. Participants with a major depressive episode (N = 99) underwent acute ECT. Blood was sampled just before (T0) and 30 min after (T1) the first ECT session, as well as just before the sixth session (T2; 48-72 h after the fifth session). Age- and sex-matched controls (N = 99) were recruited from the general population. Serum concentrations of neurofilament light chain (NfL), total tau protein, and glial fibrillary acidic protein (GFAP) were measured with ultrasensitive single-molecule array assays. Utilizing generalized least squares regression, we compared baseline (T0) biomarker concentrations against those of our control group, and calculated the shifts in serum biomarker concentrations from baseline to immediately post-first ECT session (T1), and prior to the sixth session (T2). Baseline analysis revealed that serum levels of NfL (p < 0.001) and tau (p = 0.036) were significantly elevated in ECT recipients compared with controls, whereas GFAP levels showed no significant difference. Relative to T0, serum NfL concentration neither changed at T1 (mean change 3.1%, 95%CI -0.5% to 6.7%, p = 0.088) nor at T2 (mean change -3.2%, 95%CI -7.6% to 1.5%, p = 0.18). Similarly, no change in total tau was observed (mean change 3.7%, 95%CI -11.6% to 21.7%, p = 0.65). GFAP increased from T0 to T1 (mean change 20.3%, 95%CI 14.6 to 26.3%, p < 0.001), but not from T0 to T2 (mean change -0.7%, 95%CI -5.8% to 4.8%, p = 0.82). In conclusion, our findings suggest that ECT induces a temporary increase in serum GFAP, possibly reflecting transient astrocytic activation. Importantly, we observed no indicators of neuronal damage or long-term elevation in any assessed biomarker., (© 2024. The Author(s).)

The diagnostic criteria of bipolar disorder (BD) have changed over time. To test if these changes are reflected in the polygenic profile in BD, we studied the association between first BD diagnosis year (during 1972-2016) and polygenic scores (PGS) for psychiatric disorders in BD patients (N = 3,818). We found significant associations between diagnosis year and PGS for BD, depression, and attention deficit hyperactivity disorder (ADHD). The PGS remained largely stable over time in BD type 1, while changes were observed in BD type 2. These findings bear significance not only for genetic research but also for clinical practise, as shifts in patient characteristics can influence treatment response., Competing Interests: Declaration of competing interest ML declares that he has received lecture honoraria from Lundbeck pharmaceutical outside the scope of this work. EJ is currently employed at IQVIA, Mölndal, Sweden., (Copyright © 2024. Published by Elsevier B.V.)

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., Competing Interests: Dr. Ian Jones has received grant support from Akrivia Health and Takeda. Dr. Sullivan has served as a consultant for and is a shareholder in Neumora Therapeutics. Dr. Landén has received lecture honoraria from Lundbeck Pharmaceutical and has served as a consultant for AstraZeneca. The other authors report no financial relationships with commercial interests.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

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) (β = 0.142, p = 0.001), body mass index (β = 0.150, p = 0.006), plasma triacylglycerol (TAG) (β = 0.218, p < 0.001), total/plasma high-density lipoprotein-cholesterol (TChol/HDL-C) ratio (β = 0.103, p = 0.03), TAG/HDL-C ratio (β = 0.151, p = 0.006), and non-HDL-C (β = 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., (© 2022. The Author(s).)

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 (β = 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., (© 2023. The Author(s).)

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 GABA B -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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)