This in memoriam honours Professor Jules Angst, MD, and reflects on his major contributions to mood disorder research, psychiatric classification, longitudinal clinical studies, and lithium prophylaxis. It also commemorates his enduring influence on IGSLi, clinical psychiatry, and generations of researchers and clinicians.
Abstract Background With limited evidence-based options, treatment of depressive episodes in bipolar disorder (BD-DE) remains challenging. This study examines the trajectories of psychotropic drug use and polypsychopharmacy in psychiatric inpatients with acute BD-DE. Methods Using data from the German pharmacovigilance program “Arzneimittelsicherheit in der Psychiatrie” (AMSP), the pharmacological treatment of 1,902 psychiatric inpatients with BD-DE between 2007–2024 was analyzed. Temporal changes in drug use between early (T1: 2007–2010) and late (T2: 2021–2024) periods were calculated using prevalence ratios (PR) with 95% confidence intervals (CI) and Welch’s t-test. Results Overall, 98.5% of inpatients with acute BD-DE were treated with psychotropic drugs. Antipsychotic drugs (APD) were the most used psychotropic drug group (76.2%), followed by antidepressant (ADD; 70.3%) and antiepileptic drugs (AED; 44.3%) during the entire study period. Over time, APD use increased from 70.1% in T1 to 80.7% in T2 (PR 1.15, CI 1.06–1.25), attributable to the increased use of second-generation APD (PR 1.19, CI 1.07–1.32), especially quetiapine and aripiprazole. ADD (T1: 78.1% vs T2: 67.6%; PR 0.87, CI 0.79–0.95) and AED (T1: 56.7% vs T2: 34.6%; PR 0.61, CI 0.51–0.73) use significantly declined, while lithium use remained stable (31.7% from 2007–2024). Although the mean number of psychotropic drugs per patient decreased (T1: 3.85 vs T2: 3.34, p < 0.001, d =−0.30), complex polypsychopharmacy consisting of ≥3 psychotropic drugs remained prevalent (66.1% of patients during the entire study period). Combination strategies involving APD, especially use of two APD, significantly increased (T1: 15.6% vs T2: 31.5%; PR 2.01, CI 1.51–2.69). Conclusion Pharmacological treatment of BD-DE has shifted towards an increased use of second-generation APD while AED are less utilized. ADD use and complex polypsychopharmacy continue to be prevalent, indicating a persistent gap between guideline recommendations and real-world practice.
Sleep disturbances persist during euthymia in bipolar disorder (BD) and may contribute to cognitive impairment. While subjective sleep complaints have been linked to cognition, associations between objective sleep parameters and objective cognitive performance are under-explored. In this exploratory cross-sectional study, 40 euthymic individuals with BD underwent 21 days of actigraphy to assess objective sleep parameters, including sleep duration, sleep onset latency, sleep efficiency, wake time after sleep onset (WASO), and fragmentation index. Cognitive performance was assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP). Associations between sleep parameters and cognitive outcomes were examined using Spearman correlations, then using multivariable linear regression models, including a stepwise selection of potential confounding factors and a false discovery rate correction for multiple testing. Assumed sleep duration was negatively associated with the SCIP total score (β = −0.38, p = 0.011), with age retained as a covariate (p = 0.011). Total sleep time was negatively associated with delayed verbal learning (β = −0.48, p = 0.003), with no covariate retained. Sleep onset latency was negatively associated with working memory (β = −0.41, p = 0.014), with no covariate retained. Sleep onset latency was negatively associated with processing speed (β = −0.38, p = 0.002), with age (p < 0.001) and sex (p = 0.022) retained as covariates. WASO was negatively associated with verbal fluency (β = −0.39, p = 0.016), with no covariate retained. In euthymic individuals with BD, objective measures of sleep duration, sleep initiation, and sleep continuity were associated with distinct cognitive domains. These findings highlight the relevance of sleep continuity and sleep initiation, beyond sleep duration alone, as correlates of cognitive functioning in BD. Due to methodological limitations, these results should be considered hypothesis-generating and require replication in larger, longitudinal cohorts. This study was conducted as part of a larger research protocol entitled GAN (Genetics, Actimetry, and Neuropsychology in Bipolar Disorders). The protocol has been registered on ClinicalTrials.gov on November 13, 2015 (NCT02627404).
Bipolar disorder (BD) is a severe, chronic psychiatric illness defined by profound and recurrent fluctuations in mood, energy, and function. Treatment is generally limited by both the efficacy and safety of available agents. Thyroid augmentation has been found to be useful to treat depression and rapid cycling in BD. Herein, we provide a narrative review of adjunctive use of thyroid hormone in BD with a specific focus on its potential mechanism of action. Ion dysregulation with mood-state-related reduced sodium pump activity and increased intracellular sodium and calcium are among the most reproduced biologic findings in manic and depressed bipolar patients. Thyroid hormone directly increases sodium pump expression and activity, and indirectly improves energy utilization in bipolar patients. Across the reviewed literature, approximately 300–350 patients received supraphysiologic doses of thyroid hormone (T3 or T4), with the majority comprising individuals with BD and yielding generally very positive outcomes and minimal harm. Thyroid hormone augmentation can improve depression and reduce rapid cycling, and while never studied to treat mania, it does not increase the risk of manic episodes in all of the studies. Inconsistencies in data are related to different dosing regimens in different studies. Thyroid hormone appears to directly correct known pathophysiologic abnormalities in patients with bipolar disorder. While additional studies are needed to confirm these findings, sufficient data are available to warrant the use of supertherapeutic thyroid hormone augmentation in selected patients.
This network meta-analysis evaluates the efficacy and safety of pharmacological and physical treatments for depressive episodes in adolescents with bipolar disorder (BD), incorporating evidence from six randomized controlled trials (RCTs), total N = 879. Due to the absence of shared comparators, pharmacological treatments and non-invasive brain stimulation (NIBS) were analyzed in separate evidence networks rather than being directly compared.Pharmacological treatments included lurasidone, olanzapine-fluoxetine combination (OFC), and quetiapine, while NIBS consisted of transcranial direct current stimulation (tDCS) and intermittent theta-burst stimulation (iTBS). P-scores probabilities showed lurasidone as the most effective for reducing depressive symptoms (CDRS-R SMD: -0.41, 95
Life lessons from a civilization’s most consequential individuals are hard to come by and, certainly, rarely find their way into a medical journal. However, such investigations can repay study—as Plutarch’s continued popularity demonstrates. Our subjects lived before the era of medications and might today be diagnosed, not coincidentally, as having bipolar temperaments, and possibly bipolar disorder as well, and suffered severe depressions. We consider Robert Burton, Samuel Johnson, Meriwether Lewis, Winston Churchill, William Osler, and Jacques Barzun with an eye toward understanding how they were able to get the best from themselves and stimulate the most intense expression of their remarkable gifts—all the while escaping crippling depressions to which they were prone. Their insights were forged in the harsh crucible of life experience. Five of them (there appears no record of how Lewis understood his temperament) sought to pass on what they had learned, even writing about their discovered truths in similar fashion. Each found salvation in total commitment to a creative and spiritually satisfying challenge of an all-encompassing sort. Such a technique proved to be both palliative and prophylactic for reasons that, scientifically, are unclear. Some of the questions that their distinguished lives suggest are discussed.
This Swedish nationwide cohort study used large-scale data to investigate the associations between bipolar disorder and somatic disorders and whether these risks differ by subtype, sex, or exposure to compulsory care. 61,071 individuals diagnosed with bipolar disorder in inpatient (from 1973) or outpatient care (from 2001) care were compared with the general population without bipolar disorder. The cohort included individuals born in 1932 or later, with follow-up from 1973 to 2020. Cox regression models estimated associations with a range of somatic conditions, including cardiovascular, endocrine, neurological, and infectious diseases. Subtype-specific analyses were conducted in individuals with type 1 (n = 8,352) or type 2 (n = 9,674), and in those with a history of compulsory care (n = 6,748). Bipolar disorder was associated with significantly increased risks for most examined somatic conditions. The highest hazard ratios (HRs) were observed for sleep disorders (HR 3.79; 95
Studies examining the effect of mania on cognition in Bipolar Disorders (BD) have yielded contradictory results. Koenders and collaborators showed in 2014 that, among 189 adults with BD, adults with subclinical manic symptoms perform a task measuring divided attention significantly better than adults with less or more severe manic symptoms. We aimed to replicate this finding in a larger sample. We included adults from the FACE-BD cohort with a BD diagnosis based on the DSM-IV-R criteria. We excluded adults with a current characterized depressive or manic episode or with other possible sources of cognitive impairment. We assessed the associations between the YMRS score and cognitive functions involved in divided attention using linear regression models, adjusting for the same covariates as the original study. We found no significant linear or quadratic associations between the YMRS total score and attention, working memory, and executive performance in the bivariable models nor after adjusting for covariates in 2,739 adults with BD. We were unable to replicate the findings reported by Koenders and collaborators. The low variance and mean severity of manic symptoms in our sample may partly explain the absence of significant associations. Our results suggest that subclinical hypomanic symptoms neither enhance nor impair cognitive performance in adults with BD, calling into question the benefit of residual hypomanic symptoms on patients’ cognitive functioning.
Bipolar disorder (BD) is a heterogeneous psychiatric disorder that is increasingly recognized as having immune-inflammatory pathogenesis. Previous studies have shown thyroid autoimmunity, in particular, thyroid peroxidase antibody (TPO-Ab), is associated with rapid cycling and antidepressant-induced mania in BD. We examined the relationship between TPO-Ab seropositivity and BD clinical sub-phenotypes and lithium response. In this cross-sectional study, adult patients with BD enrolled in the Mayo Clinic BD Biobank were stratified into TPO-Ab positive versus negative groups using all available information (research data and electronic health records). Multivariable logistic regression analyses were conducted to assess associations between TPO-Ab status and clinical sub-phenotypes, including early age at onset, history of psychosis, rapid cycling, suicide attempt, and antidepressant-induced mania. Linear regression was used to examine associations with lithium treatment response (Alda A score). All models were adjusted for age, sex, BMI, and laboratory data source for TPO-Ab values. Among 339 individuals (mean age = 43.8 ± 15.2 years, 61.1
Abstract Background The temporal relationship between sleep and mood changes in bipolar disorder (BD) has been investigated before, and this paper aims to replicate results from previous analyses while adding new details to the understanding of the relationship between fluctuations of sleep and mood. Furthermore, we comment on the use of sleep changes as a prodrome to mood changes in BD, which could improve clinical outcomes. Methods BD outpatients in remission (N = 29) recorded daily their sleep of the past 24 h and rated their mood on a visual analogue scale for 1 year (total of 9,433 days). Cross-correlation functioning was employed to identify potential relationships between self-reported sleep values and mood scores, for both the days before and after a change in mood. Results 41% of participants reported a negative relationship between changes in total time spent in bed and mood the following day, e.g. spending more time in bed before a shift towards depressive symptoms. Additionally, 21%-28% of all participants experienced an increase (or decrease) in their 7-day sleep average (sleep duration and awake in bed duration) in the week before a change in mood towards a lower (or higher) score. Only a few participants showed any relationship between changes in the 7-day variability of sleep and mood change. Conclusion Our findings align with and support those of earlier studies with similar designs. The duration of sleep and time in bed may serve as early indicators of mood changes in BD for about two-fifths of patients, and integrating these symptoms into clinical practice may help anticipate critical clinical shifts.
This scoping review synthesized evidence on vitamin D, parathyroid hormone (PTH), and serum calcium in bipolar disorder (BD) to evaluate their potential clinical utility. A systematic PubMed search identified original studies examining calcium metabolism biomarkers (vitamin D, PTH, serum calcium) exclusively in BD populations. Findings were synthesized narratively due to substantial methodological heterogeneity. Fourteen studies met inclusion criteria, with small sample sizes (median n = 55) and predominantly cross-sectional designs. Vitamin D comparisons between BD patients and controls yielded contradictory results: three studies reported significantly lower levels in BD patients, two found significantly higher levels, and three found no differences. Vitamin D deficiency definitions varied widely (< 25 to < 50 nmol/L), precluding meaningful comparisons. Four cognition studies showed inconsistent associations with vitamin D, with negative correlations, age-dependent effects, or no associations reported. Two small vitamin D supplementation studies in bipolar spectrum disorders yielded contradictory results in distinct populations, with one in youth and the other in adults. Data on PTH and calcium were sparse and inconsistent. Study limitations included a single database search, substantial study heterogeneity, and inadequate control for confounders, including seasonal variation. Evidence on calcium metabolism biomarkers in BD is contradictory and methodologically limited. Fundamental inconsistencies in vitamin D status between BD patients and controls, combined with conflicting supplementation data, preclude clinical recommendations. Routine vitamin D screening specifically for BD management cannot be supported. Large-scale, standardized studies are needed before clinical application.
A substantial proportion of patients with bipolar disorder experience daily variability in mood that seems associated with poor prognostic factors, including impaired functioning, and increased risk of hospitalisation and relapse. The present SmartBipolar randomised controlled trial (RCT) investigated whether group (1) daily smartphone-based outpatient monitoring and treatment including CBT elements with clinical feedback (intervention group) versus group (2) daily smartphone-based monitoring and treatment with CBT elements without clinical feedback (content was the same as intervention group but without clinical feedback) (control group) or group (3) daily smartphone-based mood monitoring only without CBT elements or other smartphone content (control group), improved mood instability and other clinically relevant patient-related outcomes in patients who have had a bipolar disorder for more than two years, and typically many years. This study was a pragmatic, randomised controlled trial with a follow-up period of 6 months. The outcomes were (1) mood instability (primary), (2) questionnaire-based evaluations of quality of life, depressive symptoms, manic symptoms, perceived stress, as well as smartphone-based measures of mood, activity, stress, anxiety, irritability, and sleep. Group differences were quantified using linear mixed models. A total of 201 patients with progressed bipolar disorder were included as part of their specialised outpatient treatment in the Mental Health Services in the Capital Region of Denmark. The trial began in March 2021 with last patient follow-up in July 2025. Intention-to-treat analyses showed no differences in the primary outcome mood instability (difference: 0, 95
Mood disorders are characterized by considerable cognitive heterogeneity. However, little is known about high cognitive performance and its associations with relevant clinical outcomes. High cognitive performance in persons with mood disorders and high-risk unaffected relatives (UR) may be an expression of resilience to illness-related neuropathology. Cross-sectional data from persons with mood disorders (n = 212), unaffected relatives (UR) (n = 96), and healthy controls (HC) (n = 152) were pooled from two cohort studies, during which participants completed neuropsychological test batteries comprising both non-emotional and emotional cognition. Participants were grouped into ‘high’ or ‘normal cognitive performance’ subgroups based on their global cognitive performance. Groups were compared to investigate high-performing persons with mood disorders and relatives, respectively, in demographic and clinical variables and emotional cognition. Resulting subgroups were persons with mood disorders with high (P-HP = 67) and normal cognitive performance (P-NP = 135), UR with high (UR-HP = 41) and normal cognitive performance (UR-NP = 52) and HC with high (HC-HP = 86) and normal cognitive performance (HC-NP = 66). P-HP were characterized by fewer experiences of physical abuse, fewer mood episodes and improved functioning compared to P-NP. Both P-HP and UR-HP experienced more overall childhood trauma, compared to HC-HP. All cognitively high-performing subgroups exhibited faster recognition of emotional faces compared to their corresponding normally performing group. High cognitive performance was associated with favorable clinical outcomes and improved functioning in persons with mood disorders and high-risk UR. Given this association, above-average enhancement of cognition beyond normalization may aid functional recovery.
BackgroundData on factors that influence patient and caregiver preference for long-acting injectable (LAI) formulations of antipsychotics are limited in bipolar I disorder (BP-I), particularly regarding longer dosing intervals. The objective of this study was to explore healthcare experiences, preferences for LAI dosing frequency, and factors influencing preferences for a hypothetical LAI administered once every 2 months, in people living with BP-I, caregivers, and prescribers.MethodsThis qualitative interview study recruited people living with BP-I currently treated with a once-monthly LAI, caregivers, and prescribers from the USA and Canada. In semi-structured interviews, participants were asked about their treatment experiences, views on an ideal treatment, and preferences on LAI dosing frequency. Interview transcripts were analyzed descriptively for key themes.ResultsTwelve people living with BP-I currently treated with a once-monthly LAI, five caregivers, and five prescribers were interviewed. All three participant groups perceived frequency of administration and remaining on the same antipsychotic as key features of an LAI; prescribers also considered previous responses to treatment, treatment access, and the need to maintain control of medication important when prescribing. Participants were positive about an LAI administered once every 2 months compared with LAIs in general due to improved convenience, reduced patient and caregiver impact, and the potential to feel well and stable for longer.ConclusionsParticipants were positive about a potential transition to an LAI given once every 2 months. As each participant group has unique preferences for LAIs and treatment goals, these should be discussed during healthcare interactions to ensure that targeted disease management goals are met.
BACKGROUND:Bipolar Disorder (BD) is a class of mood disorders that poses a significant diagnostic challenge for clinicians. With its unknown etiology and the increasing disability burden it contributes to, BD necessitates further study to improve patient outcomes. Our study aimed to characterize the demographic trends in BD-related mortality using the CDC WONDER database. METHODS:The CDC WONDER database was utilized to collect data on the mortality burden from 1999 to 2023. Data was stratified by race or ethnicity, sex, age, rural or urban designation, and census region. Data analysis was performed using Joinpoint analysis to help determine trends as well as statistical significance. RESULTS:Our study found that the rate at which BD was mentioned in death certificates increased throughout the study period and mortality associated with BD increased with age. Additionally, the study found statistically significant increases in age adjusted mortality rate when analyzed in groups. Not only was mortality rate determined to be higher amongst females than their male counterparts, variation by race and ethnicity also persisted, with mortality being highest among the Non-Hispanic White cohort. Mortality burden varied by region, with higher mortality rates in rural areas than in urban areas and in the Midwest United States, compared to other census regions. CONCLUSIONS:Our study expands on prior research related to trends in mortality of BD and aims to highlight the disproportionate mortality burdens related to BD as a potential guide towards future management strategies. Further studies related to how the increased utilization of mental health resources, including telehealth, and focus on earlier treatment initiation can be useful to guide mental health practices in the future.
Ambulatory assessment uses digital technology to capture real-time data on mood, mental state and behaviour. It has the potential to enhance traditional clinical outcome measures, but the practical application of these tools fundamentally depends on their performance. This systematic review aimed to assess the performance of active and passive ambulatory assessment and mood monitoring outcome measures in non-randomised and randomised studies in bipolar disorder over 3 months or longer. We aimed to evaluate their performance against established clinical measures and through inter-ambulatory assessment comparisons. Systematic review (PROSPERO: CRD42023396473) of performance of mood monitoring and ambulatory assessment protocols in RCTs and non-randomised studies in bipolar disorder. Identified studies were assessed for risk of bias. Due to the very high heterogeneity in included studies and performance metrics we were not able to aggregate the data via meta-analysis. The review included 42 studies with a combined sample of 7,813 participants. We included 28 distinct ambulatory assessment protocols which reported 487 different smartphone-based performance metrics. The considerable variability and inconsistency across these metrics limited our ability to make definitive comparisons of performance. Overall, some active ambulatory assessment approaches showed good performance when compared with established clinical measures. There was a paucity of data examining the performance of passive ambulatory assessment measures. Most studies were rated as having low to moderate risk of bias. While ambulatory assessment holds significant promise, current evidence fails to establish the validity and reliability of passive ambulatory assessment to measure mood. The substantial methodological variation—particularly in how performance metrics are defined and reported—limits meaningful comparison and replication. Greater consistency in ambulatory assessment design and reporting standards is essential to support reliable evaluation and broader adoption of these behavioural assessment tools.
BACKGROUND:Bipolar disorder (BD) is a severe mental illness associated with marked functional impairment and reduced life expectancy. Early indicators such as mood instability, circadian rhythm disturbance, and anxiety symptoms often precede the first manic or depressive episode, providing a potential window for preventive intervention. Currently, no structured early intervention program exists for individuals at risk for BD who do not yet meet diagnostic criteria. This study aims to evaluate the feasibility and acceptability of a novel, personalized early intervention program combining light therapy, lifestyle psychoeducation, and imagery-focused cognitive therapy (ImCT) for individuals at risk for BD. METHODS:The study employs a single-case experimental A-B-A design with staggered baseline and multiple daily assessments. Fifty participants aged 16-35 years identified as being at risk for BD by a specialized early detection team will be included. The intervention consists of three core components: (1) a chronotherapeutic intervention (bright light therapy or blue-light blocking glasses) tailored to individual symptom profiles; (2) one session of lifestyle-focused psychoeducation targeting sleep, nutrition, and physical activity; and (3) six sessions of ImCT to address mood instability and maladaptive mental imagery. Feasibility and acceptability will be assessed through drop-out rates, adherence, and participant feedback. Secondary outcomes include changes in depressive, hyperactive, anxiety, and imagery-related symptoms, as well as sleep quality and activity levels, measured through validated questionnaires and actigraphy. DISCUSSION:By combining chronotherapeutic, psychological, and lifestyle components, this intervention targets multiple mechanisms implicated in BD risk. Findings will inform the development of preventive strategies for individuals in an at-risk mental state for BD. The study will also provide data on the feasibility of integrating early interventions within routine mental health services and guide the design of future randomized controlled trials. TRIAL REGISTRATION:Medical Ethical Committee Brabant (METC Brabant; identifier P2314); ClinicalTrials.gov Identifier: NCT06282250. Registered 20 February 2024.
This study aimed to explore and understand the experiences of patients with bipolar disorder type I who underwent magnetic resonance imaging (MRI) brain scans as part of lithium treatment assessment in the European R-LiNK study. All participants underwent brain imaging at baseline and three months after starting lithium treatment. 1 H-MRI scans (structural, diffusion-weighted, and single voxel proton spectroscopy) were conducted on both occasions, with 7Li-MRI at the second visit, all at 3T. The study used a qualitative, inductive approach to explore patients’ subjective experiences. Eight participants were included, four males and four females, aged 22 to 52 years. This group was selected from the R-LiNK study based on s having completed the imaging component before and after lithium treatment initiation. Seven themes were identified: Motivations for Participation, Experiences with MRI Scans, Psychological Impact of MRI Scans, Patient Reflections on Lithium Use, Integration of Technology in Treatment, Evaluating Combined Treatment Strategies, and Implications for Future Research. Participants commonly described lithium as contributing to mood stabilisation, while the MRI scans provided several individuals with a tangible sense of the biological underpinnings of their illness. Conversely, some participants reported anxiety and discomfort with the MRI procedure and particularly in relation to lithium’s side effects, emphasizing the importance of supportive and empathetic communication throughout the treatment process to encourage trust and understanding. This qualitative study revealed that adding 7Li-MRI scans to the early stages of lithium treatment subjectively validated the diagnosis, increased participants’ confidence in the treatment process, and highlighted the importance of integrating patient experiences when incorporating advanced technology to monitor treatment response.
