Association of childhood trauma, social support, cognition, and suicidality in females with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a severe mental disorder with heavy disease burden. Females with BD are special populations who suffer a lot from childhood trauma, social support, cognitive deficits, and suicidality. In this study, the relationship among childhood trauma, social support, and clinical symptoms of BD was investigated and the risk factors for suicidality were explored in female patients with BD. METHODS: This study included 57 drug-naive female BD patients, 64 female BD patients with long-term medication, and 50 age-matched female healthy controls. Childhood trauma, social support, clinical symptoms, cognition, and suicidality (suicide ideation, suicide plan, suicide attempt, suicide frequency) were measured with scales. RESULTS: Compared with healthy controls, females with BD showed higher levels of childhood trauma and suicidality, and lower levels of social support and cognitive deficits. In the drug-naïve BD group, social support mediated the relationship between childhood trauma and insomnia symptoms (indirect effect: ab = 0.025). In the BD with long-term medication group, mania symptom was associated with suicide plan (OR = 1.127, p = 0.030), childhood trauma was associated with suicide attempt (OR = 1.088, p = 0.018), and years of education (OR = 0.773, p = 0.028), childhood trauma (OR = 1.059, p = 0.009), and delayed memory (OR= 1.091, p= 0.016) was associated with suicide frequency (OR = 1.091, p = 0.016). CONCLUSIONS: This study provides initial evidence that social support partially explains the relationship between childhood trauma and clinical symptoms in females with BD. Additionally, mania symptoms, childhood trauma, and delayed memory were risk factors for suicidality. Interventions providing social support and improving cognitive function may be beneficial for females with BD who are exposed to childhood trauma and with high suicide risk.

Identifying tripartite relationship among cortical thickness, neuroticism, and mood and anxiety disorders.

The number of young adults seeking help for emotional distress, subsyndromal-syndromal mood/anxiety symptoms, including those associated with neuroticism, is rising and can be an early manifestation of mood/anxiety disorders. Identification of gray matter (GM) thickness alterations and their relationship with neuroticism and mood/anxiety symptoms can aid in earlier diagnosis and prevention of risk for future mood and anxiety disorders. In a transdiagnostic sample of young adults (n = 252;177 females; age 21.7 ± 2), Hypothesis (H) 1:regularized regression followed by multiple regression examined relationships among GM cortical thickness and clinician-rated depression, anxiety, and mania/hypomania; H2:the neuroticism factor and its subfactors as measured by NEO Personality Inventory (NEO-PI-R) were tested as mediators. Analyses revealed positive relationships between left parsopercularis thickness and depression (B = 4.87, p = 0.002), anxiety (B = 4.68, p = 0.002), mania/hypomania (B = 6.08, p ≤ 0.001); negative relationships between left inferior temporal gyrus (ITG) thickness and depression (B = - 5.64, p ≤ 0.001), anxiety (B = - 6.77, p ≤ 0.001), mania/hypomania (B = - 6.47, p ≤ 0.001); and positive relationships between left isthmus cingulate thickness (B = 2.84, p = 0.011), and anxiety. NEO anger/hostility mediated the relationship between left ITG thickness and mania/hypomania; NEO vulnerability mediated the relationship between left ITG thickness and depression. Examining the interrelationships among cortical thickness, neuroticism and mood and anxiety symptoms enriches the potential for identifying markers conferring risk for mood and anxiety disorders and can provide targets for personalized intervention strategies for these disorders.

[A clinical case of the new-onset bipolar affective disorder in the postcovid period]. / Klinicheskii sluchai vpervye voznikshego v postkovidnyi period bipolyarnogo affektivnogo rasstroistva.

A large number of people who have had COVID-19 have developed mental symptoms and mood disorders. Anxiety and depression prevail among affective pathology. Evidence is accumulating that the Sars-CoV-2 virus can induce mania or hypomania in people with no personal psychopathological history. Some clinical, anamnestic and paraclinical patterns of new-onset mania and hypomania have been found. In cases of severe manic symptoms, it is possible to quickly assume the occurrence of bipolar affective disorder. The predominance of depressive and anxiety syndromes in the long-term disease and the presence of vivid vegetative symptoms can mask brief and syndromally incomplete episodes of hypomania, which distorts the understanding of the disease as a bipolar disorder. This article presents such a clinical case of the occurrence of bipolar affective disorder in a patient who had COVID-19 with an asymptomatic course. Approaches to rational diagnosis and treatment are discussed.

Bipolar symptoms, somatic burden and functioning in older-age bipolar disorder: A replication study from the global aging & geriatric experiments in bipolar disorder database (GAGE-BD) project.

OBJECTIVES: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset. DESIGN/METHODS: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601). RESULTS: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning. CONCLUSIONS: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning.

Echocardiographic evaluation of myocardial strain in bipolar disorder across different phases: A comparative study with healthy controls.

This study aims to investigate the relationship between different phases of bipolar disorder (depressive, manic, and euthymic) and myocardial deformation, assessed by echocardiography, compared to healthy controls. It seeks to elucidate whether these phases of bipolar disorder are associated with different myocardial strain patterns, thus contributing to the understanding of cardiovascular implications in bipolar disorder. A cross-sectional design was employed at Dursun Odabas Medical Centre, Psychiatry Clinic of Van Yüzüncü Yl University. The study enrolled 200 participants, divided into 4 groups: 50 in a depressive phase, 50 in a manic phase, 50 in an euthymic phase of bipolar disorder, and 50 healthy volunteers. Participants underwent detailed electrocardiographic and ECG evaluations, focusing on myocardial strain patterns and cardiac function. Statistical analyses, including ANOVA and chi-square tests, were used to compare the groups. Significant differences in global longitudinal strain (GLS) values were observed between the groups. The manic phase group exhibited the highest GLS (21.51), followed by the euthymic (20.75), depressive (20.25), and healthy control groups (19.0). The E/A ratio of the mitral valve also varied, with the manic group displaying the highest ratio (1.21). Other echocardiographic parameters such as left atria size and Ejection Fraction also differed significantly between the groups. The study concluded that the phases of bipolar disorder are associated with distinct myocardial strain patterns, as evidenced by the variation in GLS values. The findings underscore the importance of cardiac monitoring in bipolar disorder, suggesting potential cardiac risks, particularly during the manic phase. This study advocates integrated care approaches, combining psychiatric and cardiac evaluations for patients with bipolar disorder.

An initial test of the contrast avoidance model in bipolar spectrum disorders.

The Contrast Avoidance Model suggests that individuals sensitive to negative emotional shifts use prior increases in negative affect to prevent further escalation in response to adverse situations, while the heightened negative affect amplifies positive emotional contrasts when encountering unexpected positive events. Individuals with bipolar spectrum disorders (BSDs), characterized by shifts between (hypo)manic and depressive episodes, may undergo more salient emotional contrasts. Drawing from the Contrast Avoidance Model, the shifts from depression to (hypo)mania can be conceptualized as positive emotional contrasts, potentially heightening the perceived pleasure during (hypo)manic episodes. On the other hand, the shifts from (hypo)manic to depressive episodes can be viewed as negative emotional contrasts, contributing to the challenges associated with depressive states. Despite the intriguing potential of this interplay, the link between the Contrast Avoidance Model and BSDs has never been empirically tested. Our study addressed this gap by examining group differences in contrast avoidance traits between individuals with BSDs, unipolar depression, and healthy controls in a large cohort study (N = 536). Results indicated that individuals with BSDs exhibited significantly higher scores in the total, and Discomfort with Negative Emotional Shifts and Avoidance of Negative Emotional Contrasts/Enhancement of Positive Emotional Contrasts factors, as well as separate item scores on the Contrast Avoidance Questionnaire-General Emotion (CAQ-GE), compared to those with unipolar depression and healthy controls. Although marginal, the BD II subtype demonstrated a stronger inclination to avoid negative emotional contrasts compared to BD I. These findings suggest that contrast avoidance may be a psychological mechanism implicated in BSDs.

Molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania based on network pharmacology and molecular docking: Evidence from computational biology.

BACKGROUND: Quetiapine monotherapy is recommended as the first-line option for acute mania and acute bipolar depression. However, the mechanism of action of quetiapine is unclear. Network pharmacology and molecular docking were employed to determine the molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania. METHODS: Putative target genes for quetiapine were collected from the GeneCard, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and bipolar mania were identified from the DisGeNET and GeneCards databases. A protein-protein interaction (PPI) network was generated using the String database and imported into Cytoscape. DAVID and the Bioinformatics platform were employed to perform the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the top 15 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the interactions between quetiapine and potential targets. RESULTS: Targets for quetiapine actions against bipolar depression (126 targets) and bipolar mania (81 targets) were identified. Based on PPI and KEGG pathway analyses, quetiapine may affect bipolar depression by targeting the MAPK and PI3K/AKT insulin signaling pathways via BDNF, INS, EGFR, IGF1, and NGF, and it may affect bipolar mania by targeting the neuroactive ligand-receptor interaction signaling pathway via HTR1A, HTR1B, HTR2A, DRD2, and GRIN2B. Molecular docking revealed good binding affinity between quetiapine and potential targets. LIMITATIONS: Pharmacological experiments should be conducted to verify and further explore these results. CONCLUSIONS: Our findings suggest that quetiapine affects bipolar depression and bipolar mania through distinct biological core targets, and thus through different mechanisms. Furthermore, our results provide a theoretical basis for the clinical use of quetiapine and possible directions for new drug development.

Mapping prodromal symptoms in patients with bipolar disorder: A network perspective.

Bipolar disorder (BD) is a major mental disorder that significantly impairs behavior and social functioning. This study assessed the network structure of prodromal symptoms in patients with BD prior to their index mood episode. Semi-structured interviews were conducted with the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R) to examine patients' prodromal symptoms. Network analysis was conducted to elucidate inter-relations between prodromal symptoms. A total of 120 eligible patients participated in this study. Network analysis indicated that the observed model was stable. The edge Mania3-Depression9 ('Racing thoughts' - 'Thinking about suicide', edge weight = 14.919) showed the strongest positive connection in the model, followed by the edge Mania1-depression1 ('Extremely energetic/active' - 'Depressed mood', edge weight = 14.643). The only negative correlation in the model was for Mania7-depression2 ('Overly self-confident' - 'Tiredness or lack of energy', edge weight = -1.068). Nodes Mania3 ('Racing thoughts'), Depression9 ('Thinking about suicide'), Mania1 ('Extremely energetic/active'), and Depression1 ('Depressed mood') were the most central symptoms. Both depressive and manic or hypomanic symptoms appeared in the prodromal phase. Symptoms reflecting 'Racing thoughts', 'Thinking about suicide', 'Extremely energetic/active', and 'Depressed mood' should be thoroughly assessed and targeted as crucial prodromal symptoms in interventions to reduce the risk of BD episodes.

A case report of LAI two injection start in a 16-year-old adolescent with severe manic episode and comorbid cannabinoid use disorder.

There is a lack of randomized clinical trials and few studies regarding long-acting injectable antipsychotics (LAIs) in adolescents. Non-adherence, aggressiveness, comorbid substance use disorder and lack of insight may represent the main reasons for starting LAIs. Hereby we describe a 16-year-old male adolescent subject with bipolar type I disorder and comorbid cannabinoid use disorder, successfully treated with two-injection start regimen of LAI aripiprazole. Two-injection start regime of aripiprazole could represent an effective and safe therapeutic option for adolescents with early onset bipolar disorder.

Spanish validation of the short version of the racing and crowded thoughts questionnaire (RCTQ-13).

BACKGROUND: The Racing and Crowded Thoughts Questionnaire (RCTQ-13) is the most widely used specific scale for the measurement of racing thoughts, but there is currently no Spanish version that allow the evaluation in Spanish-speaking patients. The objective of this study is to translate, adapt, and validate the RCTQ-13 in a Colombian population with affective disorders. METHODS: The questionnaire was translated and back-translated, and corrections were implemented following a pilot test to improve comprehensibility. We included patients with Bipolar I Disorder and with Major depressive disorder seen in three centers in the city of Medellín, Colombia. We evaluate structural validity with confirmatory factor analysis, internal consistency, and test-retest reliability. Construct validity was also assessed with the comparison between euthymic, maniac, and depressive episodes and the correlation with worry, rumination, and mania scales. Responsiveness was measured 1 month after the first evaluation. Based on item response theory (IRT), we also estimated item difficulty, discrimination, and fit using a generalized partial credit model. RESULTS: Two hundred fifty subjects were included. Confirmatory factor analysis revealed that the three-factor structure of the scale was appropriate. Internal consistency was adequate for the entire scale (Cronbach's alpha = 0.95, 95% CI: 0.94-0.96) and for each factor. Test-retest reliability was good (intraclass correlation coefficient = 0.82, 95%IC: 0.70-0.88). For construct validity, we observed differences between patients with different types of affective episodes, a moderate positive correlation with the Penn State Worry Scale (r = 0.55) and the Ruminative Response Scale (r = 0.42), and a low negative correlation with the Young Mania Rating Scale (r = - 0.10). Responsiveness was proved to be adequate. Under IRT, the response thresholds for the response options are organized for all items. The infit was adequate for all items and the outfit was acceptable. CONCLUSIONS: The Spanish version of the RCTQ-13 is a reliable, valid, and responsive scale and can be used for the clinical assessment of the construct of racing and crowded thoughts in patients with the spectrum of affective disorders in whom this experience can be expressed with different nuances. Further research is needed to expand the relationship with rumination and worry.

Antibiomania: A Case Report of a Manic Episode Potentially Induced by the Interaction of Clarithromycin and Amoxicillin during H. Pylori Eradication Therapy.

Antibiomanic episodes, or as the DSM-5 refers to them, drug-induced manic episodes, pose a clinical challenge that is still poorly understood. There is insufficient information on the most common clinical presentation, patient profile, or underlying aetiopathogenic mechanisms. We present the clinical case of a 67-year-old woman who, after starting treatment (clarithromycin and amoxicillin) for the eradication of Helicobacter pylori, bacteria presented with a brief manic episode, which resolved after withdrawal of both drugs and with antipsychotic treatment. The possible interaction of both drugs, as GABA antagonists, in the generation of such episodes is discussed, and the clinical importance of such episodes in psychiatric emergency departments and liaison and interconsultation psychiatry, is highlighted.

Fourteen-year trends in prescribing patterns for patients with bipolar mania discharged from a public psychiatric hospital in Taiwan.

Bipolar disorder is a complex mental illness. Pharmacological therapy, including antipsychotics and mood stabilizers, is the primary treatment approach for manic episode. The study aimed to analyze prescribing patterns over a 14-year period for patients with bipolar mania discharged from a psychiatric hospital in Taiwan. Patients with bipolar mania discharged from the study hospital between 2006 and 2019 (n = 2956) were included in the analysis. Prescribed drugs for the treatment of manic episode, included mood stabilizers (i.e., lithium, valproate, carbamazepine) and any antipsychotics (i.e., second- and first-generation antipsychotics; SGAs & FGAs). Monotherapy, simple polypharmacy, and complex polypharmacy were also examined. Simple polypharmacy was defined as being prescribed 2 different bipolar drugs (lithium, valproate, carbamazepine, and any antipsychotics), while complex polypharmacy at least 3 bipolar drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. The prescription rates of valproate, SGAs, and complex polypharmacy significantly increased over time, whereas the prescription rates of any mood stabilizers, FGAs, and simple polypharmacy significantly decreased. Prescription rates of lithium and monotherapy did not significantly change. The study highlights the shifts in prescribing practices for bipolar mania. SGAs were prescribed more while FGAs declined, likely due to SGAs' favorable properties. Complex polypharmacy increased, reflecting the complexity of treating bipolar disorder. Long-term outcomes of these changes require further research.

Neural markers of mania that distinguish inpatient adolescents with bipolar disorder from those with other psychopathology.

Pediatric bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders, a challenge which can result in delayed or incorrect interventions. Using neuroimaging we aimed to identify neural measures differentiating a rarified sample of inpatient adolescents with BD from other inpatient psychopathology (OP) and healthy adolescents (HC) during a reward task. We hypothesized reduced subcortical and elevated cortical activation in BD relative to other groups, and that these markers will be related to self-reported mania scores. We examined inpatient adolescents with diagnosis of BD-I/II (n = 29), OP (n = 43), and HC (n = 20) from the Inpatient Child and Adolescent Bipolar Spectrum Imaging study. Inpatient adolescents with BD showed reduced activity in right thalamus, left thalamus, and left amygdala, relative to inpatient adolescents with OP and HC. This reduced neural function explained 21% of the variance in past month and 23% of the variance in lifetime mania scores. Lower activity in regions associated with the reward network, during reward processing, differentiates BD from OP in inpatient adolescents and explains >20% of the variance in mania scores. These findings highlight potential targets to aid earlier identification of, and guide new treatment developments for, pediatric BD.

The influence of acute dopamine transporter inhibition on manic-, depressive-like phenotypes, and brain oxidative status in adult zebrafish.

Functional changes in dopamine transporter (DAT) are related to various psychiatric conditions, including bipolar disorder (BD) symptoms. In experimental research, the inhibition of DAT induces behavioral alterations that recapitulate symptoms found in BD patients, including mania and depressive mood. Thus, developing novel animal models that mimic BD-related conditions by pharmacologically modulating the dopaminergic signaling is relevant. The zebrafish (Danio rerio) has been considered a suitable vertebrate system for modeling BD-like responses, due to the well-characterized behavioral responses and evolutionarily conservation of the dopaminergic system of this species. Here, we investigate whether GBR 12909, a selective inhibitor of DAT, causes neurobehavioral alterations in zebrafish similar to those observed in BD patients. Behaviors were recorded after a single intraperitoneal (i.p.) administration of GBR 12909 at different doses (3.75, 7.5, 15 and 30 mg/kg). To observe temporal effects on behavior, swim path parameters were measured immediately after the administration period during 30 min. Locomotion, anxiety-like behavior, social preference, aggression, despair-like behavior, and oxidative stress-related biomarkers in the brain were measured 30 min post administration. GBR 12909 induced prominent effects on locomotor activity and vertical exploration during the 30-min period. Hyperactivity was observed in GBR 30 group after 25 min, while all doses markedly reduced vertical drifts. GBR 12909 elicited hyperlocomotion, anxiety-like behavior, decreased social preference, aggression, and induced depressive-like behavior in a behavioral despair task. Depending on the dose, GBR 12909 also decreased SOD activity and TBARS levels, as well as increased GR activity and NPSH content. Collectively, our novel findings show that a single GBR 12909 administration evokes neurobehavioral changes that recapitulate manic- and depressive-like states observed in rodents, fostering the use of zebrafish models to explore BD-like responses in translational neuroscience research.

Correlates to Improvement in Sleep Duration in Acute Mania and Depression.

Objective: To examine sleep duration at admission and discharge and change in sleep duration during hospitalization in patients experiencing a manic episode and compare these parameters to patients hospitalized for major depressive disorder (MDD) during the same time frame. The correlation between sleep duration parameters in those with mania and MDD with length of hospital stay, after accounting for possible confounders, was also examined.Methods: This retrospective study examined patients admitted to an acute care psychiatric unit from 2018 to 2021 with an episode of mania or MDD. Sleep duration was determined based on nursing observer report.Results: The study included 41 patients with mania (32.9 ± 1.7 years) and 38 patients with MDD (32.7 ± 1.8 years). Mania patients had longer hospitalization and received higher antipsychotic and benzodiazepine doses, but fewer hypnotics (all P < .005). No differences were found in sleep duration at admission (P = .109) and discharge (P = .623) in the mania and MDD groups. Change in sleep duration was 1.14 ± 0.27 and 0.37 ± 0.28 hours (P = .05) in the groups, respectively. In those with mania, sleep duration at admission negatively correlated with length of stay (r = -0.033; P = .03). Sleep duration parameters were not correlated with length of stay in patients with MDD.Conclusion: There was a trend toward greater improvement in sleep duration in inpatients with mania versus MDD. Sleep duration at admission correlated with length of hospitalization in patients with mania. Future studies should examine whether attempts to increase sleep duration can improve patient outcomes.Prim Care Companion CNS Disord 2024;26(1):23m03620. Author affiliations are listed at the end of this article.

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder.

There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania.

Corticosteroids and mania: A systematic review.

OBJECTIVES: Corticosteroids are widely prescribed for a variety of medical conditions. Accumulating evidence suggests that their use may be associated with adverse psychiatric effects, including mania. In this systematic review, we aim to critically evaluate the existing literature on the association between corticosteroid use and the emergence of mania. METHODS: We conducted a comprehensive search of major electronic databases (PubMed, Embase, Cochrane Library) for relevant studies published up to the date of the search (12th January 2023). Inclusion criteria involve studies that investigate the association between corticosteroid use and the emergence of mania in adult patients. The primary outcome is the prevalence of (hypo)mania following corticosteroid administration. Secondary outcomes include potential risk factors, dose-response relationships, and differences among various corticosteroid formulations. RESULTS: The identified studies were subjected to a systematic selection process and data extraction by an independent reviewer. A total of 47 articles met the inclusion criteria for our systematic review. CONCLUSION: Our findings suggest that mania is a common side-effect of corticosteroid use, particularly in prednisone equivalent doses above 40 mg. These findings hold practical significance for clinicians and provide insights into potential interventions, including careful monitoring, dose adjustments, and consideration of psychotropic medications when managing corticosteroid-induced mania.

Mortality and Lithium-Protective Effects after First-Episode Mania Diagnosis in Bipolar Disorder: A Nationwide Retrospective Cohort Study in Taiwan.

INTRODUCTION: This study aimed to estimate all-cause mortality in patients after a first-episode mania (FEM) and examine whether six guideline-recommended medications can reduce mortality. METHODS: The cohort included population-based FEM samples and matched controls from Taiwan, spanning 2007 to 2018. The primary outcomes assessed were all-cause/suicide-related mortality, while the secondary outcome focused on mortality associated with pharmacological treatments. We compared mortality in post-FEM patients and age-/sex-matched controls without any diagnosed bipolar disorders and patients with and without psychopharmacological treatment using Cox regression analysis, respectively. Statistics were presented with time-to-event adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). RESULTS: The study included 54,092 post-FEM patients and 270,460 controls, totaling 2,467,417 person-years of follow-up. Post-FEM patients had higher risks of all-cause mortality (AHR 2.38, 95% CI: 2.31-2.45) and suicide death (10.80, 5.88-19.84) than controls. Lithium (0.62, 0.55-0.70), divalproex (0.89, 0.83-0.95), and aripiprazole (0.81, 0.66-1.00) were associated with reduced all-cause mortality compared to non-users. There were no significant all-cause mortality differences for quetiapine (0.95, 0.89-1.01), risperidone (0.92, 0.82-1.02), and paliperidone (1.24, 0.88-1.76) users. When accounting for drug action onset times in sensitivity analyses, only lithium significantly reduced all-cause mortality (AHR range 0.65-0.72). There were 35 and 16 suicide deaths in post-FEM patients and controls, respectively. No drug had a significant effect on suicide deaths (lithium: 6; divalproex: 7; aripiprazole: 0; quetiapine: 10; risperidone: 4; paliperidone: 1). CONCLUSION: Post-FEM patients had a higher risk of all-cause/suicide-related mortality, and lithium treatment might reduce all-cause mortality.