Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Evaluating the effect of exercise-based interventions on functioning in people with transdiagnostic depressive symptoms: A systematic review of randomised controlled trials.

BACKGROUND: Depressive symptoms are associated with various conditions and can exacerbate the outcome of somatic diseases. Transdiagnostic symptom-based approaches provide treatment flexibility, and exercise has demonstrated benefits beyond clinical symptoms. This work aimed to synthesise and establish the effects of exercise-based interventions on global functioning and quality of life in adults with transdiagnostic depressive symptoms, as well as their impact on clinical symptoms. METHODS: A systematic review was conducted following PRISMA guidelines. PubMed, Scopus and PsycINFO databases were searched from inception to April 2023. Eligibility criteria included randomised controlled trials involving adults with transdiagnostic depressive symptoms who received exercise-based interventions and provided details of the interventions. Comparators included treatment as usual or other active control groups. The Cochrane quality assessment tool was used for quality assessment. RESULTS: Fifteen articles involving 2064 participants were included. Data on study design, sample, intervention characteristics, and outcomes were extracted. Several trials demonstrated the expected positive effects of exercise on functioning (7/15). Most results supported the benefits of adjunctive exercise interventions on illness outcomes. LIMITATIONS: The studies had methodological limitations, including small sample sizes and an underrepresentation of somatic diseases. CONCLUSIONS: The functional consequences of exercise-based interventions targeting depressive symptoms are often understudied. Incorporating exercise routinely as an add-on treatment for transdiagnostic depressive symptoms could improve overall functioning, quality of life, and symptom severity. There is a need to expand the focus of exercise-based interventions to incorporate functional outcomes. Future research should address the methodological limitations and include a wider range of participants, including those with somatic diseases.

Exploring the genetics of lithium response in bipolar disorders.

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Y-chromosome in the olfactory neuroepithelium as a potential biomarker of depression in women with male offspring: an exploratory study.

The persistence of fetal cells in the mother (fetal microchimerism (FMc)) has been described in maternal tissues essential to the newborn. FMc is associated with several diseases that start or worsen in pregnancy or postpartum. This exploratory study reports-for the first time-the presence of FMc in the olfactory neuroepithelium (ON) of both healthy and depressed women with male offspring. However, depressed women had fewer microchimeric cells (digital PCR). The existence of FMc in the ON could facilitate mother-child bonding. These findings open new pathways to study FMc in the ON, female depression, and mother-child bonding.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3ß. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Real-world Implementation of a Smartphone-Based Psychoeducation Program for Bipolar Disorder: Observational Ecological Study.

BACKGROUND: SIMPLe is an internet-delivered self-management mobile app for bipolar disorder (BD) designed to combine technology with evidence-based interventions and facilitate access to psychoeducational content. The SIMPLe app was launched to the real world to make it available worldwide within the context of BD treatment. OBJECTIVE: The main aims of this study are as follows: to describe app use, engagement, and retention rates based on server data; to identify patterns of user retention over the first 6-month follow-up of use; and to explore potential factors contributing to discontinuation of app use. METHODS: This was an observational ecological study in which we pooled available data from a real-world implementation of the SIMPLe app. Participation was open on the project website, and the data-collection sources were a web-based questionnaire on clinical data and treatment history administered at inclusion and at 6 months, subjective data gathered through continuous app use, and the use patterns captured by the app server. Characteristics and engagement of regular users, occasional users, and no users were compared using 2-tailed t tests or analysis of variance or their nonparametric equivalent. Survival analysis and risk functions were applied to regular users' data to examine and compare use and user retention. In addition, a user evaluation analysis was performed based on satisfaction, perceived usefulness, and reasons to discontinue app use. RESULTS: We included 503 participants with data collected between 2016 and 2018, of whom 77.5% (n=390) used the app. Among the app users, 44.4% (173/390) completed the follow-up assessment, and data from these participants were used in our analyses. Engagement declined gradually over the first 6 months of use. The probability of retention of the regular users after 1 month of app use was 67.4% (263/390; 95% CI 62.7%-72.4%). Age (P=.002), time passed since illness onset (P<.001), and years since diagnosis of BD (P=.048) correlate with retention duration. In addition, participants who had been diagnosed with BD for longer used the app on more days (mean 97.73, SD 69.15 days; P=.002) than those who had had a more recent onset (mean 66.49, SD 66.18 days; P=.002) or those who had been diagnosed more recently (mean 73.45, SD 66 days; P=.01). CONCLUSIONS: The user retention rate of the app decreased rapidly after each month until reaching only one-third of the users at 6 months. There exists a strong association between age and app engagement of individuals with BD. Other variables such as years lived with BD, diagnosis of an anxiety disorder, and taking antipsychotics seem relevant as well. Understanding these associations can help in the definition of the most suitable user profiles for predicting trends of engagement, optimization of app prescription, and management.

The Effectiveness of Mindfulness-Based Cognitive Therapy in Primary Care and the Role of Depression Severity and Treatment Attendance.

Objectives: Evidence suggests the efficacy of mindfulness-based cognitive therapy (MBCT) to prevent depression relapse and decrease depressive symptoms during the acute phase. However, the effectiveness of MBCT in real-world heterogeneous samples treated in clinical health settings, including primary care, has received little attention. This study had two aims: (1) to evaluate the effectiveness of MBCT delivered in primary care considering pre-treatment depression scores and (2) to explore the role of participants' characteristics on symptom improvement. Methods: Data were obtained from 433 individuals who received MBCT. Participants completed the Personality Inventory for ICD-11 (PiCD) pretreatment and the Beck Depression Inventory (BDI-II) pre- and post-treatment. Results: Sixty percent presented moderate-to-severe depression according to scores on the BDI-II, 18.1% presented mild depression, and 21.7% were in the non-depressed range. The severity of pre-treatment depressive symptoms was associated with outcomes. Most individuals who lacked depressive symptoms at baseline remained in the non-clinical range after the treatment. Those in the severe group benefited the most from the intervention, since 35.6% were considered recovered. Rates of deterioration ranged from 2.1 to 2.7%, depending on the depression-baseline scores. Depression severity at the entrance, attendance, and age, but not personality traits, appear to be related to symptom improvement. Conclusions: According to our results, MBCT can be effectively and safely delivered in primary care.

Improving Depressive Symptoms through Personalised Exercise and Activation (IDEA): Study Protocol for a Randomised Controlled Trial.

Individuals who suffer from depressive symptoms experience a substantial impact on psychosocial functioning, physical health, mortality, and quality of life. In the search for therapeutic strategies, exercise has been found to play a relevant part in its treatment. However, the promotion of exercise entails adherence difficulties that arose out of the tendency towards sedentarism led by symptomatology. Personalised exercise plans on top of usual care have the potential to enhance behavioural changes and mental health. The present study aims at evaluating the changes in functioning deriving from a blended intervention merging a psychological intervention with a personalised exercise programme based on medical assessment. We will conduct a three-arm randomised controlled trial in which 172 participants suffering from mild-moderate depressive symptoms will be allocated to Intervention A (personalised exercise group programme + app with motivational messages), B (personalised exercise group programme + app with no motivational messages) or control group (app with no motivational messages). Data regarding global functioning, well-being, symptoms, physical activity, and exercise capacity will be collected at baseline, 4, 12, and 36 weeks. The results of this trial will provide information about whether this physical activity support programme may be efficient for improving mental and physical health outcomes. Trial registration: ClinicalTrials.gov NCT04857944 (accessed on 15 April 2021). Registered April 2021.

Clinical Features, Neuropsychology and Neuroimaging in Bipolar and Borderline Personality Disorder: A Systematic Review of Cross-Diagnostic Studies.

Background: Bipolar Disorder (BD) and Borderline Personality Disorder (BPD) have clinically been evolving as separate disorders, though there is still debate on the nosological valence of both conditions, their interaction in terms of co-morbidity or disorder spectrum and their distinct pathophysiology. Objective: The objective of this review is to summarize evidence regarding clinical features, neuropsychological performance and neuroimaging findings from cross-diagnostic studies comparing BD and BPD, to further caracterize their complex interplay. Methods: Using PubMed, PsycINFO and TripDataBase, we conducted a systematic literature search based on PRISMA guidelines of studies published from January 1980 to September 2019 which directly compared BD and BPD. Results: A total of 28 studies comparing BD and BPD were included: 19 compared clinical features, 6 neuropsychological performance and three neuroimaging abnormalities. Depressive symptoms have an earlier onset in BPD than BD. BD patients present more mixed or manic symptoms, with BD-I differing from BPD in manic phases. BPD patients show more negative attitudes toward others and self, more conflictive interpersonal relationships, and more maladaptive regulation strategies in affective instability with separate pathways. Impulsivity seems more a trait in BPD rather than a state as in BD. Otherwise, BD and BPD overlap in depressive and anxious symptoms, dysphoria, various abnormal temperamental traits, suicidal ideation, and childhood trauma. Both disorders differ and share deficits in neuropsychological and neuroimaging findings. Conclusion: Clinical data provide evidence of overlapping features in both disorders, with most of those shared symptoms being more persistent and intense in BPD. Thus, categorical classifications should be compared to dimensional approaches in transdiagnostic studies investigating BPD features in BD regarding their respective explanatory power for individual trajectories. Systematic Review Registration: The search strategy was pre-registered in PROSPERO: CRD42018100268.

Does cognitive impairment in bipolar disorder impact on a SIMPLe app use?

BACKGROUND: Smartphone apps are becoming increasingly used by service users in mental health care and research for diverse aims. However, it is well-known the high prevalence of cognitive impairment in some people suffering from severe mental illnesses such as bipolar disorder (BD), which impacts on their psychosocial functioning and quality of life. In this context, the main aim of this paper is to investigate through exploratory analyses the role of specific cognitive deficits in the retention, engagement, and usability of a psychoeducational smartphone app in a group of patients with BD. METHODS: 51 remitted BD patients were asked to use the app for 3 months. Baseline and 3-months follow-up clinical and usability assessments were conducted. Twenty-seven independent results from a comprehensive neurocognitive test of the same participants were retrieved separately of the 2 years before or after the use of the app. Post-hoc exploratory analyses were carried out using Spearman correlations to identify significant cognitive deficits domains influencing the usability and retention with the app. RESULTS: There were no statistically significant cognitive variables associated with the use, reported usability or retention with the app. Some variables associated with executive functions, verbal and visual memory correlated significantly with previous use of smartphones. LIMITATIONS: Post-hoc analysis with a limited sample size. CONCLUSION: These preliminary results suggests that patients with BD and mild cognitive deficits do not present any limitation in using mental health apps. In our case, the adoption of a user-centred design in the development process of the app could have mitigated the participants' difficulties when using the app.

The Prevalence and Clinical and Sociodemographic Factors of Problem Online Gambling: A Systematic Review.

The emergence and spread of new technologies have allowed for the introduction of new forms of gambling. Problem online gambling has specific characteristics, and its prevalence may differ from traditional forms of gambling. This paper systematically reviews studies that include data relevant to problem online gambling and to the sociodemographic and comorbidity variables related to it. A systematic literature search was conducted from Medline database. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, preliminary search resulted in 427 articles, from which 20 were included in this systematic review based on pre-determined criteria. The reported prevalence of problem online gambling varied widely across the different studies. This heterogeneity is due to large variations in settings, instruments, and definitions of problem online gambling, which rules out a meta-analytic approach to the results. The sources of variability in the prevalence, the sociodemographic and comorbidity factors, and the implications for future research are discussed.

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (ß = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (ß = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

A multicenter, observational study of pain and functional impairment in individuals with major depressive disorder in partial remission: the DESIRE study.

BACKGROUND: The study explores the association between pain and functional impairment in patients with partially remitted MDD, considering both clinician and patient reported outcomes. METHODS: Multicenter, observational, and cross-sectional study, with 583 outpatients with partially remitted MDD. Measures of pain intensity (VAS), functional impairment (SOFAS), depressive symptomatology (HAM-D6), and remission from MDD and functional status from a patient-centered perspective (RDQ) were collected. VAS scores (cut-off: 30) were used to divide the sample in two groups: no pain (n = 274) and pain (n = 309). Descriptive data, correlation and regression analyses were obtained. RESULTS: Functional impairment (SOFAS) and pain (VAS) were negatively and significantly correlated in the total sample, and in the group with pain. Lower pain predicted higher functioning. The pain sub-sample was older, less educated, with higher medical comorbidities, higher HAM-D6 scores, and lower functionality (SOFAS). In the RDQ, the pain group showed significantly higher scores in the symptom-related subscales, and lower scores in the subscales related to positive mental health, functioning and wellbeing. LIMITATIONS: Correlational and observational design. The criteria and instruments used to measure pain and to define a threshold might limit the generalizability of findings. CONCLUSIONS: Pain and functionality should be assessed and treated in patients with MDD in partial remission. Our results indicate that functionality should be assessed with a broader perspective, that also considers positive mental health features.

An evidence map of actigraphy studies exploring longitudinal associations between rest-activity rhythms and course and outcome of bipolar disorders.

BACKGROUND: Evidence mapping is a structured approach used to synthesize the state-of-the-art in an emerging field of research when systematic reviews or meta-analyses are deemed inappropriate. We employed this strategy to summarise knowledge regarding longitudinal ecological monitoring of rest-activity rhythms (RAR) and disease modifiers, course of illness, treatment response or outcome in bipolar disorders (BD). STRUCTURE: We had two key aims: (1) to determine the number and type of actigraphy studies of in BD that explored data regarding: outcome over time (e.g. relapse/recurrence according to polarity, or recovery/remission), treatment response or illness trajectories and (2) to examine the range of actigraphy metrics that can be used to estimate disruptions of RAR and describe which individual circadian rhythm or sleep-wake cycle parameters are most consistently associated with outcome over time in BD. The mapping process incorporated four steps: clarifying the project focus, describing boundaries and 'coordinates' for mapping, searching the literature and producing a brief synopsis with summary charts of the key outputs. Twenty-seven independent studies (reported in 29 publications) were eligible for inclusion in the map. Most were small-scale, with the median sample size being 15 per study and median duration of actigraphy being about 7 days (range 1-210). Interestingly, 17 studies comprised wholly or partly of inpatients (63%). The available evidence indicated that a discrete number of RAR metrics are more consistently associated with transition between different phases of BD and/or may be predictive of longitudinal course of illness or treatment response. The metrics that show the most frequent associations represent markers of the amount, timing, or variability of RAR rather than the sleep quality metrics that are frequently targeted in contemporary studies of BD. CONCLUSIONS: Despite 50 years of research, use of actigraphy to assess RAR in longitudinal studies and examination of these metrics and treatment response, course and outcome of BD is under-investigated. This is in marked contrast to the extensive literature on case-control or cross-sectional studies of actigraphy, especially typical sleep analysis metrics in BD. However, given the encouraging findings on putative RAR markers, we recommend increased study of putative circadian phenotypes of BD.

A prospective longitudinal study searching for predictors of response to group psychoeducation in bipolar disorder.

BACKGROUND: The efficacy of adjunctive group psychoeducation in bipolar disorder has been proven although treatment response differ among individuals. The aim of this study was to characterize responders and non-responders to group psychoeducation in order to identify baseline variables that could predict treatment response. METHODS: The sample was composed of 103 medicated euthymic patients with bipolar disorder referred to 21 sessions of group psychoeducation (6 months). Sociodemographic and clinical variables, temperament, circadian rhythms, BDNF, cognitive and psychosocial functioning were collected. At the 18-month endpoint, the patients were split in two groups on the basis of having suffered any recurrence. Significant group differences were included in a logistic regression analysis. RESULTS: Ninety patients out of 103 engaged in group psychoeducation, 47 of whom (52.2%) responded to psychoeducation and 43 (47.8%) did not. Recurrences occurred more often in the follow-up, the most common being depression. Responders and non-responders differed in gender, age at diagnosis, latency of diagnosis, temperament, attention composite score and BDNF. Lower age at diagnosis of bipolar disorder, lower cyclothimic temperament scores and being male -which was associated with bipolar type I and a trend to more previous manic episodes- were significantly related to a better response to psychoeducation in the regression analysis. LIMITATIONS: No control group. CONCLUSIONS: This study identifies age at diagnosis as a significant modifiable risk factor of treatment response, highlighting the need for early identification of bipolar disorder. Existing programs should be adjusted to the characteristics of specific subpopulations in the framework of a personalized approach.

The Catalonia Suicide Risk Code: A secondary prevention program for individuals at risk of suicide.

BACKGROUND: Suicide prevention is an emerging priority for public health systems. Here, we present the Catalonia Suicide Risk Code (CSRC), a secondary suicide prevention program that provides a systematic approach to follow-up care for patients at risk. We describe the care pathway of the CSRC and characteristics of the patients enrolled in the program. METHODS: Observational study based on data extracted from the Catalan health care system between the years 2014 and 2019. The following patient-related data were obtained: sociodemographic and clinical characteristics, characteristics of suicidal behaviour, and pathway of care. RESULTS: A total of 12,596 individuals (64.1% women) were screened for suicide risk and 8,403 (66.7%) were subsequently enrolled in the CSRC. Adherence data show that most patients (81.9%) attended a face-to-face appointment and most (67.1%) were successfully contacted by telephone afterwards. Most face-to-face appointments were performed within 10 days of enrolment for adults and 72 h for minors. Psychiatric disorders were significant risk factors for both men and women. Females were significantly more likely to report stressful life events, while males were more likely to report social problems. Compared to men, women were more likely to use poisoning. LIMITATIONS: Adherence to the CSRC care pathway might reflect obstacles to its implementation. Due to the observational study design, it is not possible to determine the effectiveness of the CSRC to reduce suicide re-attempts. CONCLUSIONS: Although the CSRC successfully provided follow-up care for many individuals at high risk of suicide, greater adherence to the CSRC care pathway is needed.

Psychoeducation for bipolar disorder and risk of recurrence and hospitalization - a within-individual analysis using registry data.

BACKGROUND: The efficacy of psychoeducation for bipolar disorder has been demonstrated in clinical trials, but it is not known if the results translate into effectiveness in routine clinical practice. The aim was to determine the effectiveness of psychoeducation for bipolar disorder in a routine clinical setting. METHOD: We identified 2819 patients with at least three registrations in the Swedish Quality Assurance Register for Bipolar Disorder. Among those, 402 had not been exposed to psychoeducation at the first visit, but received psychoeducation during any of the following registrations. Using within-individual analyses, the risk of recurrence after having received psychoeducation was compared with the risk prior to psychoeducation. RESULTS: In adjusted within-individuals comparisons, periods after psychoeducation was associated with decreased risks of any recurrence [odds ratio (OR) 0.57, 95% CI 0.42-0.78], (hypo-)manic or mixed episodes (OR 0.54, 95% CI 0.39-0.76), depressive episodes (OR 0.63, 95% CI 0.47-0.86), and inpatient care (OR 0.54, 95% CI 0.33-0.86) relative to periods prior to psychoeducation. There was no association with rates of involuntary sectioning or suicide attempts. CONCLUSIONS: The results suggest that psychoeducation for bipolar disorder reduces the risk of mood episodes and inpatient care also when implemented in routine clinical practice.