ISBD 2026 Vancouver Abstracts

SGLT2 Inhibitors Associated With Reduced Suicidality, Mortality, and Hospitalization in Adults With Bipolar Disorder: A Cohort Study of 1.23 Million Adults

Submission ID Submission Type Topic
Submitter Affiliation

3002746
Poster Epidemiology Balwinder Singh Mayo Clinic

SUBMISSION DETAILS
Category Selection Application Research and/or Clinical Practices Abstract:

Introduction/Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated promising neuropsychiatric properties in recent research. This study examined whether SGLT2i exposure is associated with reduced incidence of suicidality, all-cause mortality, and hospitalization among adults with bipolar disorder (BD).

Method: This cohort study utilized the TriNetX network (2008–2025) to identify 1,230,821 adults with BD, including 36,092 SGLT2i users and 1,194,729 non-users. Primary outcomes were incident suicidality, all-cause mortality, and hospitalization over 5-years of follow-up. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models, with additional 1:1 propensity score matching (PSM) for survival analysis conducted to control for confounding. Subgroup analyses stratified results by sex, race/ethnicity, concurrent mood stabilizer use, and somatic comorbidities.

Results: SGLT2i exposure was associated with significantly reduced risk of suicidality (aHR 0.75, 95% CI 0.71–0.79), all-cause mortality (aHR 0.55, 95% CI 0.52–0.57), and hospitalization (aHR 0.71, 95% CI 0.69–0.72; all p < 0.001). Protective associations remained consistent across subgroups, including patients receiving lithium, lamotrigine, or valproate. After PSM (31,001 matched pairs), five-year outcomes favored SGLT2i users: suicidality-free survival 94.51% versus 93.56%, overall survival 88.99% versus 79.57%, and hospitalization-free survival 72.39% versus 66.72% (all p < 0.001).

Conclusion: In this large cohort of over 1.2 million adults with BD, SGLT2i therapy was associated with substantially lower risks of suicidality, hospitalization, and all-cause mortality, with consistent benefits across demographic and clinical subgroups. These findings suggest SGLT2is may represent a promising therapeutic strategy to improve psychiatric and survival outcomes in BD. Prospective RCTs are warranted to establish causal relationships and evaluate long-term safety and efficacy.

SGLT2 Inhibitors Lower Risk of Kidney Replacement Therapy and Mortality in Bipolar Disorder With Chronic Kidney Disease

Submission ID Submission Type Topic
Submitter Affiliation

3002747
Poster
Medical Comorbidity Balwinder Singh Mayo Clinic

SUBMISSION DETAILS Category Selection Hot Topics Abstract:

Introduction/Aims: Bipolar disorder (BD) is associated with chronic kidney disease (CKD) progression and high mortality, yet individuals with BD and CKD are less likely to receive kidney replacement therapy (KRT). Sodium-glucose cotransporter-2 inhibitors (SGLT2is) provide renal protection in diabetes, but their long-term effects in this high-risk population remain unknown. We evaluated whether SGLT2i use reduces the risk of KRT and all-cause mortality in adults with BD and mild-to-moderate CKD (stage≤3).

Method: In this retrospective cohort study using TriNetX (2009–2024), 89,369 adults with BD and mild-to-moderate CKD were classified as SGLT2i users (n=12,736) or nonusers (n=76,633). Primary outcomes were progression to KRT and all-cause mortality over 5-years. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models, and 1:1 propensity score matching (PSM) reduced confounding. Subgroup analyses examined sex, race/ethnicity, diabetes status, CKD stage, and mood stabilizer use.

Results: SGLT2i use was associated with lower risk of KRT (aHR 0.47, 95%CI 0.42–0.53) and all-cause mortality (aHR 0.69, 95%CI 0.65–0.73; both p < 0.001). Protective effects were consistent across subgroups, including patients on lithium, lamotrigine, valproate, antipsychotics, and those with CKD ≤2. After PSM (10,967 matched pairs), five-year KRT-free survival was 94.61% versus 90.99%, and all-cause survival was 78.67% versus 67.53% (both p < 0.001).

Conclusion: SGLT2i therapy in individuals with BD and mild-to-moderate CKD is associated with lower risks of KRT and all-cause mortality, with benefits consistent across subgroups, highlighting SGLT2is as a promising strategy to improve renal and survival outcomes and emphasizing the need for prospective trials to assess safety and long-term effects.

as an Independent Predictor of Accelerated Recurrence in Bipolar Disorder: A Survival Analysis

3002876
Poster
Integrative and Holistic Treatments (i.e., pharmacological, somatic,

Eunju Kim
Delaware Department of Health and Social Services

SUBMISSION DETAILS
Category Selection Application Research and/or Clinical Practices Abstract:

Introduction/Aims: Early-onset bipolar disorder (BD) is associated with severe illness trajectories and suicidal behavior. However, whether a history of suicide attempts (SA) independently predicts recurrence patterns—regardless of age at onset—remains unclear. This study evaluates whether SA history predicts the time to mood recurrence in stabilized patients with BD.

Method: We analyzed a clinical cohort of 198 euthymic patients with BD from Seoul National University Bundang Hospital. Participants were categorized into those with a history of SA (n=61) and those without (n=137). The primary outcome was time to the next mood episode recurrence. Kaplan–Meier survival curves assessed recurrence risk, and a Cox proportional hazards model identified independent predictors, adjusting for age, gender, and age at onset.

Results: The SA group exhibited a significantly earlier age at onset (21.67 ± 7.94 vs. 25.27 ± 9.07 years, p=0.027) and earlier treatment initiation (p=0.008) compared to the non-SA group. The recurrence rate was significantly higher in the SA group (42.6% vs. 15.3%, p<0.001), with a markedly shorter mean time to recurrence (17.92 vs. 24.02 months, p<0.001). Notably, multivariate Cox regression analysis revealed that a history of SA was the most potent independent predictor of recurrence (Hazard Ratio [HR] = 2.956, 95% CI: 1.633–5.352, p<0.001), even after adjusting for age at onset, gender, and diagnosis.

Conclusion: SA history serves as a distinct phenotypic marker for an accelerated disease course in BD, independent of onset age. Clinicians should prioritize SA history as a critical prognostic indicator, necessitating intensified monitoring during the first year of stabilization.

Structural Brain Alterations in Bipolar Disorder: Updated Analysis From the Enigma Bipolar Disorder Working Group in 11,297 Individuals From 53 Global Sites

3002922
Poster
Big Data and Machine Learning
Melody J.Y. Kang
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and

Informatics Institute, Keck School of Medicine, University of Southern California

SUBMISSION DETAILS
Category Selection Basic Research Abstract:

Introduction/Aims: This study reports updated structural brain findings from the ENIGMA-Bipolar Disorder Working Group (ENIGMA-BD), combining data from 11,297 individuals. We replicate and extend prior findings to determine the most generalizable patterns of bipolar disorder (BD) and associations with clinical variables using global data.

Method: T1-weighted brain MRI from 11,297 participants across 53 international sites (BD=4,271, healthy controls (HC)=7,026, 6-85 years) were processed using the ENIGMA-standard FreeSurfer pipeline to derive subcortical volumes, cortical thickness, and surface area measures. BD vs. HC differences, and associations with BD subtypes, polypharmacy treatment, history of psychosis, and age of onset were tested using linear regression, with FDR correction (q<0.05). Site effects were modeled as a random effect, linear ComBat, and ComBat-GAM.

Results: BD diagnosis was associated with a widespread pattern of smaller subcortical volumes, thinner cortex, and altered surface area. Compared to BD2, BD1 showed smaller subcortical volumes and thinner cortex. Lithium was associated with larger volumes, and thicker cortex, whereas antiepileptics showed opposite patterns. History of psychosis was associated with larger pallidum and putamen volumes. Earlier age of BD onset was associated with smaller subcortical volumes, and thinner cortex. The small-to-/moderate effect sizes (Cohen’s d 0.04-0.3) were in line with our prior work, and consistent across site modeling strategies.

Conclusion: We report new structural brain signatures related to BD in the largest study to date. The expanded ENIGMA-BD sample extended prior findings, and identified novel associations with clinical features. Ongoing work is combining multimodal neuroimaging measures, symptoms, and genetic/environmental risk factors to support more clinically-relevant predictions.

A Systematic Review of Adjunctive Antidepressant Maintenance Treatment in Bipolar Disorder

Submission ID Submission Type Topic
Submitter Affiliation

3002849
Poster
Updates on Treatment Guidelines
Thales Almeida
Santa Casa de São Paulo School of Medical Sciences

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Category Selection Application Research and/or Clinical Practices Abstract:

Introduction/Aims: Depression is often the predominant polarity in the course of bipolar disorder and is associated with functional impairment and disease burden. The use of antidepressants (AD) in both acute and maintenance treatment remains debated. However, some evidence suggests that adjunctive AD therapy may confer benefits during maintenance.

Method: We conducted a systematic review of observational and interventional studies published between January 1995 and August 2025 using MEDLINE (PubMed) and Web of Science. A predefined protocol assessed four primary outcomes: (1) sustained response or remission following an acute depressive episode; (2) time to depressive relapse; (3) risk of manic or hypomanic switch during maintenance AD treatment; and (4) prevention of psychiatric hospitalization. Risk of bias was evaluated using ROBINS-I and RoB 2 tools. Certainty of evidence was rated according to the GRADE framework.

Results: Fifteen studies met inclusion criteria. Adjunctive AD was consistently associated with longer time to depressive relapse and reduced recurrence rates, particularly among patients who demonstrated an initial response to acute AD treatment. Across studies, no consistent increase in manic or hypomanic switching was observed during the maintenance phase. Evidence regarding prevention of psychiatric hospitalization was heterogeneous. Most studies presented at least moderate risk of bias, limiting the overall certainty of findings.

Conclusion: Adjunctive AD during maintenance may provide clinically benefits in prolonging remission and reducing depressive recurrences in bipolar disorder, especially among acute responders, without a clear signal of increased mood switching. These findings support a more individualized, evidence-informed approach to maintenance treatment while highlighting the need for higher-quality trials.

Efficacy of Add-On Transcranial Alternating Current Stimulation (tACS) in Bipolar Depression: A Randomized Controlled Trial

Submission ID Submission Type Topic
Submitter Affiliation

3002853
Poster
Innovation in Therapeutics Jinjie Xu
Beijing Anding Hospital

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Category Selection Application Research and/or Clinical Practices Abstract:

Introduction/Aims: Bipolar depression is a major public health burden, and effective neuromodulatory treatments remain limited. Transcranial alternating current stimulation (tACS) can modulate neural oscillations, but its efficacy in bipolar depression is unclear.

Method: In this randomized, double-blind, sham-controlled trial, we evaluated the efficacy, safety, and electrophysiological effects of adjunctive tACS in individuals with bipolar depression. Sixty participants were randomized to receive either 2 weeks of active 10-Hz tACS or sham stimulation, administered twice daily (2 mA, 20 minutes per session, 70-minute intersession interval; 20 total sessions) bilaterally over the dorsolateral prefrontal cortices, in addition to standardized lithium therapy. Participants were followed for 6 weeks after treatment. The primary endpoint was antidepressant response at week 2, defined as a ≥50% reduction in the 17-item Hamilton Depression Rating Scale (HAMD-17) score. Secondary outcomes included changes in anxiety, sleep, and functional measures, as well as electroencephalography (EEG).

Results: Active tACS produced significantly higher response rates than sham at week 2 (46.7% vs. 20.0%) and week 4 (70.0% vs. 43.3%). Across multiple secondary outcomes, active tACS also yielded greater reductions in anxiety and sleep-related symptoms. No serious adverse events occurred, and tolerability was comparable between groups. EEG analyses showed that lithium monotherapy increased delta power in frontal and parietal regions, whereas adjunctive tACS prevented this elevation. In the sham group, increased parietal delta power was negatively correlated with improvement in depressive symptoms.

Conclusion: Adjunctive 10-Hz tACS enhances antidepressant efficacy in bipolar depression and modulates aberrant low-frequency neural activity, supporting its safety, tolerability, and mechanistic relevance.

NOT IN

The Evaluation of the Serum Interleukin-6 and Cognitive Changes in Patients With Bipolar Disorder in Manic and Euthymic

Submission ID Submission Type Topic
Submitter Affiliation

3003039
Poster
Cognition
Niloufar Mahdavi Hezaveh
Behavioral Sciences Research Center of Imam Hossein Educational Hospital,

Shahid Beheshti University of Medical Sciences

SUBMISSION DETAILS
Category Selection Basic Research Abstract:

Introduction/Aims: The remarkable role of immune system in pathogenesis of different mood disorders has been the center of attention during the past two decades; however, the results of the studies have been accompanied by contradictions. We aimed to assess the changes in serum interleukin-6 levels and the cognitive performance in different states of mood in patients with bipolar disorder.

Method: The cross-sectional study was performed on 40 patients with the diagnosis of bipolar one disorder according to DSM-5. The severity of the disease was measured by the Young Mania Rating Scale (YMRS). All patients were examined for interleukin-6 and cognitive tests in both the manic phase and after treatment, in their euthymic state.

Results: The value of interleukin-6 in manic phase was 9.08 ± 4.72 that significantly reduced to 2.41 ± 1.30 after recovery (p<0.001). The changes in interleukin-6 levels were in line with the improving results of Trail Making Test A (r=0.698, p<0.001) , TMT-B (r=0.675, p<00.001), Stroop B score (r=0.531, p<00.001) , and Stroop C score (r=0.725, P<0.001).

Conclusion: Changes in the serum level of interleukin-6 following the treatment of bipolar disorder are consistent with changes in cognitive performance in patients with bipolar disorder.

Novelty/Unique Data The assessment of biomarkers and cognitive performances at the same time in different phases of psychological disorder.

Clinical Characteristics and Mental Health Service Use Before a First Diagnosis of Bipolar Disorder Among Adolescents and Young Adults

Submission ID Submission Type Topic
Submitter Affiliation

3003060
Poster
Developmental Psychopathology, Prodromes, Early Recognition Kathleen Miley
HealthPartners Institute

SUBMISSION DETAILS
Category Selection Population Health/Analysis Abstract:

Introduction/Aims: Little is known about the patterns of care preceding an initial BD diagnosis. Understanding these care patterns could inform risk identification and early detection of emerging BD.

Method: Electronic health record and administrative data from a large United States healthcare system were used to identify 2,060 patients aged 15-35 years with an incident diagnosis of BD between 2017-2023, matched 2:1 on key demographics to patients with an incident diagnosis of MDD. Mental health service utilization, prescribed medications, and comorbid psychiatric diagnoses up to 2 years prior to index were compared between groups using logistic and Poisson regression, adjusted for demographics. A random forest model was employed and variable importance was quantified to identify characteristics associated with receiving a BD diagnosis.

Results: Compared to MDD, BD patients had significantly more outpatient mental health specialty services (aOR 8.94 [7.87-10.16], inpatient hospitalizations (aOR 47.85 [29.81-82.78]), and emergency room visits (aOR 13.77 [10.79-17.79]). BD patients were more likely to have diagnoses of ADHD, anxiety, personality disorders, psychotic disorders, PTSD, self-harm, and substance use disorders and were more likely to have any psychiatric medication prescription in the 2 years prior to index (aOR 4.73 [4.22-5.31]. The most predictive variables of a BD diagnosis were an outpatient mental health visit, anxiety disorder, antipsychotic medication, and substance use disorder.

Conclusion: Individuals later diagnosed with BD have mental health service use, psychiatric comorbidity, and medication exposure in the 2 years preceding diagnosis at levels exceeding those with MDD. These distinct pre-diagnosis patterns may inform approaches to earlier identification of emerging BD.

Alcohol Use Disorder in Bipolar Disorder: Meta-Analytic Evidence on Prevalence and Clinical Correlates

Submission ID Submission Type Topic
Submitter Affiliation

3003135
Poster
Psychiatric Comorbidity
Camila Zimmer
Federal University of Rio Grande Do Sul

SUBMISSION DETAILS

Category Selection Application Research and/or Clinical Practices

Abstract:

Introduction/Aims: Aims: To estimate the prevalence of alcohol use disorder (AUD) in bipolar disorder and to identify clinical and sociodemographic correlates associated with this comorbidity.

Method: Methods: A systematic review, meta-analysis, and meta-regression were conducted following PRISMA guidelines. Ninety observational studies were included. Random-effects models were used to estimate pooled prevalence and effect sizes for clinical correlates, and meta-regression explored sources of heterogeneity.

Results: Results: The pooled prevalence of AUD among individuals with bipolar disorder was 26%, increasing to approximately 30% after adjustment for publication bias. AUD was significantly associated with male sex, bipolar II subtype, rapid cycling features, earlier age at illness onset, a higher number of psychiatric hospitalizations, and multiple psychiatric and substance-related comorbidities. Importantly, individuals with BD and AUD showed significantly higher odds of lifetime suicide attempts. Despite robust associations, substantial heterogeneity was observed, and meta-regression explained only a limited proportion of between-study variance.

Conclusion: Conclusion: The pooled prevalence of AUD among individuals with bipolar disorder was 26%, increasing to approximately 30% after adjustment for publication bias. AUD was significantly associated with male sex, bipolar II subtype, rapid cycling features, earlier age at illness onset, a higher number of psychiatric hospitalizations, and multiple psychiatric and substance-related comorbidities. Importantly, individuals with BD and AUD showed significantly higher odds of lifetime suicide attempts.  AUD is highly prevalent in bipolar disorder and consistently associated with greater illness severity and suicidal behavior. These findings underscore the importance of systematic alcohol use assessment in BD and support substance-specific approaches to prognosis and clinical management.

Symposium: Linking Immunity, Metabolism, and Brain Function in Bipolar Disorder: From Cellular Mechanisms to Clinical Phenotypes

Inflammatory and Oxidative Stress Markers (IOSM) in Bipolar I Disorder (BD I): The Potential for Early Identification of Bd I in Combination With Other Biomarkers

Submission Type

Topic

Submitter

Affiliation

Participant(s)

Symposia
Biomarkers
Muralidharan Kesavan
National Institute of Mental Health and Neuro Sciences
Bartholomeus C.M. Haarman (Chair), Bartholomeus C.M. Haarman (Presenter),

Muralidharan Kesavan (Presenter), Jennifer Kruse (Presenter)

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Individual Abstract: Background: Increased oxidative stress markers (IOSM) and the disruption of antioxidant defenses play an important role in the neurobiology of BD I. Elevated inflammatory markers, including pro-inflammatory cytokines like IL-6 and TNF-α, and C-reactive protein (CRP), are reported in BD I.

Aim of the study: Studying IOSM as biomarkers in individuals early in the course of the disorder (BD I-first episode mania [FEM] in remission) and in currently healthy individuals who are high-risk (HR; family history of BD) compared to healthy subjects (HS). Combining IOSM with other markers may help with early identification of BD.

Methods: In study 1, Plasma IL-6 levels were assayed in 28 FEM, 21 HR and 18 HS. All subjects were evaluated on cortical inhibition measures using TMS. In study 2, serum biomarkers related to IOSM were investigated across the stages of BD i.e., FEM (n=43), HR (n=43), and HS (n=43). These subjects were also evaluated on neurocognitive domains.

Results: There was a statistically significant difference in plasma IL-6 levels between the groups [(F=6.98, p<0.05); Post-hoc FEM>HS]. sTNFR-2 showed significant group differences, mainly between FEM and HS. Oxidative stress markers were different between FEM and HC in GPX levels and nitrate levels (p<0.05). On linear discriminant analysis combining these markers, the ability to accurately classify the subjects into the groups was > 80%.

Conclusions: Combining IOSM with other biomarkers could enhance the diagnostic utility of these markers as potential endophenotypes and aid in the early diagnosis of BD.

Inflammation and Metabolic Risk Show Distinct Cognitive and White Matter Microstructural Signatures in Bipolar I Disorder

Jennifer Kruse
David Geffen School of Medicine at UCLA
Bartholomeus C.M. Haarman (Chair), Bartholomeus C.M. Haarman (Presenter),

Muralidharan Kesavan (Presenter), Jennifer Kruse (Presenter)

SUBMISSION DETAILS

Individual Abstract: Aims: Bipolar I disorder (BD-I) involves cognitive impairment linked to inflammation and metabolic dysfunction, yet brain mechanisms mediating these relationships remain unclear. We examined whether peripheral inflammation and metabolic dysregulation show distinct cognitive signatures and investigated white matter microstructural correlates.

Methods: BD-I participants from the UCLA BD2 cohort (n=103; 42±14 years; 56% female) completed neuropsychological assessment, fasting biomarker collection (hsCRP; lipid and insulin-triglyceride profiles), and multi-shell diffusion MRI (n=74). Metabolic principal components were derived via PCA. Hierarchical regressions tested biomarker associations with global and domain-specific cognition, adjusting for demographics, mood symptoms, and BMI. NODDI-derived neurite density index (NDI) associations with cognition were examined in white matter tracts.

Results: Higher hsCRP independently predicted worse global cognition (β=-0.24, p=0.04), working memory (β=-0.25, p=0.04), and greater cognitive discrepancy (current - estimated premorbid; β=0.27, p=0.03). Metabolic PC2 (insulin resistance/triglycerides) selectively predicted slower processing speed (β=-0.26, p=0.03) including impaired verbal fluency (β=-0.39, p=0.002). Preliminary diffusion analyses revealed higher global cognition associated with increased NODDI-derived neurite density index (NDI) in bilateral medial lemniscus, left cingulum, and corpus callosum (FDR-corrected p < 0.05), indicating neurite density, not inflammation-related free-water, correlates with cognitive performance.

Conclusions: Inflammation and metabolic dysfunction demonstrate distinct cognitive signatures in BD-I. White matter neurite density provides a neural substrate linking peripheral biomarkers to cognitive outcomes. Findings support multi-targeted therapeutic approaches addressing both inflammatory and metabolic pathways to preserve cognitive function, with ongoing longitudinal data collection enabling examination of temporal dynamics.

How Does Stress Impact Health Outcomes in Bipolar Disorder and Depression? The Role of Affective Responsivity, Inflammation and Oxidative Stress

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Everyday Emotional Dynamics in the Depression–Inflammation Link

Submission Type

Topic

Submitter

Affiliation

Participant(s)

Symposia
Physiological, Molecular, Cellular Markers and Models
David Almeida
Pennsylvania State University, College of Medicine
Erika Saunders (Chair), Georgina Hosang (Presenter), David Almeida

(Presenter), Jody Greaney (Presenter)

SUBMISSION DETAILS

Individual Abstract: This cohort panel study examined whether daily affective dynamics serve as mechanisms underlying bidirectional and longitudinal associations between depressive symptoms and inflammation. Data were drawn from the second and third waves of the Midlife in the United States (MIDUS) study and included 563 adults who participated in both the Daily Diary and Biomarker Projects (Mage = 52.4; 57% female; 84% White). Depressive symptoms were assessed using the CESD-20. Inflammatory markers included C-reactive protein (CRP) and four cytokines (IL-6, IL-8, TNF-α, IL-10), combined into a composite index for primary analyses. Daily affect and stress were assessed across eight consecutive days, from which two affect dynamics indicators were derived: affective variability and affective reactivity to daily stressors. Multilevel structural equation models simultaneously estimated person-level autoregressive and cross-lagged associations between depressive symptoms and inflammation, along with day-level mediated pathways involving daily affect dynamics. Results indicated that affective variability and stress reactivity mediated the autoregressive stability of depressive symptoms across waves. Positive affective variability mediated the pathway from higher baseline depressive symptoms to elevated CRP at follow-up, whereas negative affective reactivity to daily stressors mediated the pathway from higher baseline CRP to increased subsequent depressive symptoms. These findings identify daily affective processes as key mechanisms linking depressive symptoms and inflammation over time, highlighting the importance of promoting affective stability and adaptive stress responses in everyday life to support long-term mental and physical health.

Clozapine and Bipolar Disorder

Experts by Experience Symposium
Innovation in Therapeutics
Trisha Suppes
Stanford University and Palo Alto VA
Trisha Suppes (Chair), Trisha Suppes (Presenter), Michael Berk (Presenter),

Kathy O'Connor (Presenter)

SUBMISSION DETAILS

Individual Abstract: In the mid 1980s under a compassionate use license, we were able to offer clozapine to our most ill patients with bipolar I disorder (BDI) – ones who no medication nor combination medication was adequate to allow mood stabilization. What we observed seemed little short of miraculous, many people with BDI “woke up” as though emerging from a coma. They were now able to concentrate, and mood lability and persistent manic symptoms were markedly improved.

This led us to conduct a randomized clinical trial on severely treatment-resistant patients with BDI and Schizoaffective disorder. In this one-year randomized open study clozapine was added to ongoing medication treatment versus not added (TAU). The results of this study will be presented. Among other observations, for the patients with BDI without psychotic symptoms when manic, clozapine was as effective for them as those with psychotic symptoms when manic.

This was the first study to show the possibilities of using a 2nd generation antipsychotic as a mood stabilizer without psychosis present. It is the only study I have ever stopped before completion in the nonclozapine group because we believed it was unethical to continue the trial when we saw such substantial gains in the clozapine add-on group.

While various meta analyses have been done there are few randomized trials, though case series and records review continue to be published. Results from these will be presented. To date there have not any large, controlled trials in patients with treatment resistant bipolar I disorder.

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The Development of Novel Therapies for Psychiatric Disorders: A Bench to Bedside Program From Stem Cells to Clinical Trials

Michael Berk

Individual Abstract: There is a drought in the development of novel therapies for the major mental health disorders. We aim to identify off-patent drugs with known safety profiles that can be rapidly translated to clinical practice. This presentation highlights a bench to bedside programme for the development of novel therapies for mental health disorders, principally bipolar disorder and schizophrenia. It begins with stem cell and cell line models using transcriptomics to detect and repurpose available and tolerable agents in compound libraries. Patient derived peripheral blood mononuclear cells isolated from blood samples are reprogrammed into induced pluripotent cells using episomal vectors. These cells are differentiated into neural progenitor cells, and a gene expression signature of known agents detected. Firstly, detecting drugs that reverse that gene expression signature to levels like a control group “disease reversal screen” and a “drug likeness screens” which examines which novel agents have the same transcriptomic signature as combinations of known effective medications. Compound libraries are explored to detect comparable profiles and detect lead agents. Next, preclinical and epidemiological validation platforms are used to verify the detected signals. Agents that pass these steps are studied in several currently running large scale multicenter clinical trials. In this presentation, data regarding several lead compounds detected through this paradigm including trimetazidine, candesartan, statins and metformin that have progressed to clinical trials will be presented. New clinical trial emulation data regarding the mental health benefits of GLP-1 agents will also be presented.

Keywords

Experts by Experience Symposium Innovation in Therapeutics Michael Berk
Deakin University

Advances in the Molecular and Biological Understanding of Bipolar Disorders

Deciphering the Neuropathology of Bipolar Disorder Using Single-Cell Analysis

Masaki Nishioka
Juntendo University
Alexander Niculescu (Chair), Masaki Nishioka (Presenter), Ma-Li Wong

(Presenter), Martin Schalling (Presenter)

SUBMISSION DETAILS

Individual Abstract: Recent genetic studies have identified multiple risk genes for bipolar disorder (BD) ; however, the molecular and cellular mechanisms underlying this condition in the human brain remain poorly understood. Neuroimaging studies report reduced thalamic volume in BD, and animal models implicate the paraventricular thalamic nucleus (PVT) as a key regulator of mood.

To elucidate the BD core pathology, we performed single-cell transcriptomic analyses of the thalamus and frontal cortex from 21 patients and 20 controls. Both regions were obtained from the same donors, enabling direct intra-individual comparisons. Among all cell types examined, PVT neurons exhibited the most prominent transcriptional alterations, accompanied by an approximately 50% reduction in cell number in BD. Notably, genes involved in synaptic function and ion channel regulation, including SHISA9, CACNA1C, and KCNQ3, were significantly downregulated. These genes are established BD risk loci or have previously been reported to show reduced expression, and network analyses suggest that they act as hubs within disease-related molecular pathways.

In addition, we observed disrupted intercellular communication between PVT neurons and microglia, indicating impaired coordinated regulation of AMPA receptor signaling. In contrast, BD-associated changes in the frontal cortex were comparatively modest, underscoring the central importance of the thalamus.

Together, our findings identify PVT neurons as a potential core cellular substrate of BD and provide new insights into thalamic mechanisms of mood regulation. These results may inform the development of novel diagnostic biomarkers and therapeutic targets. At this symposium, we will discuss future directions in BD research from the perspective of PVT pathology.

Assortative Mating Patterns Among Probands With Mood Disorders and the Increment of the Co-Parent’s Psychiatric Disorder on the Risk of Mood Disorders in Offspring

Martin Preisig
Lausanne University Hospital and University of Lausanne

SUBMISSION DETAILS
Category Selection Special Groups Abstract:

Introduction/Aims: Although the increased risk of mood disorders in offspring of patients with bipolar disorder (BPD) or major depressive disorder (MDD) is well established, particularly when the parental mood disorder had an early onset, the role of co-parental disorders has rarely been addressed. The goals of the present study were to 1) assess the associations of early (<21 years) and later-onset BPD and MDD in patients with mood, anxiety and substance use disorders in the co-parents, 2) test the interaction of the proband's mood disorder with the co-parent's psychiatric disorder regarding the risk of BPD or MDD in offspring, and 3) assess the association between the co-parent’s psychiatric disorder and the risk of BPD or MDD in offspring.

Method: The sample stemmed from a prospective 16-year family study of mood disorders. Information through semi-structured diagnostic interviews was obtained from 222 probands with early or later BPD or MDD and controls, 222 co-parents and their 390 offspring.

Results: 1) Probands with later-onset MDD were more likely to mate with persons exhibiting BPD, and probands with any mood disorder were more likely to mate with persons reporting substance use disorders. 2) There were no interactions between proband and co-parent’s disorders regarding the risk of mood disorders in offspring. 3) The co-parent’s BPD and MDD were respectively associated with BPD and MDD in offspring.

Conclusion: Our data support the specificity of the co-parent’s mood disorder subtype in increasing the risk of the corresponding mood disorder in offspring.

Lithium as Neuroprotective Agent, New Evidence From an Old Drug

Innovation in Therapeutics
Paul Vöhringer
Universidad de Chile
Paul Vöhringer (Chair), Nassir Ghaemi (Presenter), Barbara Palma (Presenter),

Ariel Gildengers (Presenter)

SUBMISSION DETAILS
Category Selection Application Research and/or Clinical Practices

Overall Abstract Details Lithium has long been established as the cornerstone pharmacological treatment for mood disorders, with robust evidence supporting its efficacy in relapse prevention and suicide risk reduction. Beyond symptomatic control, a growing body of translational and clinical research suggests that lithium may exert disease-modifying effects, influencing the long-term trajectory of mood disorders through neuroprotective and neurotrophic mechanisms. These effects are thought to involve, among others, modulation of glycogen synthase kinase-3 (GSK-3), enhancement of neurogenesis, mitochondrial stabilization, anti-inflammatory actions, and preservation of synaptic plasticity. Within this framework, lithium has emerged as a promising neuroprotective agent across affective and neurocognitive conditions.

This scientific symposium will examine lithium’s neuroprotective potential through an integrated clinical and mechanistic perspective. The opening session will review lithium’s historical and contemporary role as a first-line mood stabilizer, emphasizing its distinctive capacity to modify illness progression rather than merely addressing acute symptomatology.

The second presentation will report findings from a randomized controlled trial conducted in Chile involving patients with mood disorders, evaluating the neuroprotective effects of trace-dose lithium. This study explores whether sustained exposure to subtherapeutic lithium levels can enhance neural resilience while minimizing adverse effects, potentially expanding lithium’s clinical applicability to preventive and maintenance strategies.

The third presentation will describe a randomized controlled trial carried out in Pittsburgh, focusing on patients with mild cognitive impairment treated with 300 mg of lithium. This trial examines lithium’s effects on cognitive trajectories, neuroimaging biomarkers, and progression toward dementia. These presentations aim to advance understanding of lithium as a neuroprotective agent in psychiatry

Novelty/Unique Data The novelty of this symposium lies in the integration of new empirical 1

2026 ISBD Annual Conference

evidence with a reconceptualization of lithium’s clinical role that extends beyond its traditional use as a mood stabilizer. Central to the program is the presentation of unpublished data from a randomized controlled trial conducted in Chile examining the neuroprotective effects of trace-dose lithium in patients with mood disorders. This study represents one of the first clinical attempts to translate epidemiological and preclinical observations of lithium’s neuroprotective properties into a rigorously designed trial using subtherapeutic dosing, with the explicit aim of enhancing neural resilience while minimizing adverse effects. Importantly, this presentation goes beyond reporting trial outcomes by proposing a broader conceptual framework in which lithium is viewed as a preventive and disease-modifying agent capable of influencing the longitudinal course of mood disorders, rather than solely as a treatment for acute affective episodes or relapse prevention. This reconceptualization has implications for earlier intervention, long-term maintenance strategies, and personalized risk–benefit assessments across the lifespan. Complementing these unpublished findings, the symposium will also discuss results from a randomized controlled trial conducted in Pittsburgh in patients with mild cognitive impairment treated with 300 mg of lithium, which is currently in press. This study provides timely, high-quality evidence supporting lithium’s potential to slow cognitive decline and alter neurobiological markers associated with progression toward dementia, thereby extending lithium’s relevance into the neurocognitive domain. Together, the combination of unpublished randomized data, newly published evidence, and novel theoretical perspectives offers a unique and forward-looking contribution that reframes lithium as a transdiagnostic, neuroprotective intervention and situates it within emerging models of preventive psychiatry and long-term brain health.

Lithium for Alzheimer's Disease Prevention: Mechanistic Rationale and Results From the Lattice Trial

Ariel Gildengers
University of Pittsburgh
Paul Vöhringer (Chair), Nassir Ghaemi (Presenter), Barbara Palma (Presenter),

Ariel Gildengers (Presenter)

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Individual Abstract: Alzheimer's disease (AD) affects over 55 million people worldwide, with global costs exceeding $1.3 trillion annually. Recent discoveries reveal that lithium deficiency, resulting from sequestration by amyloid plaques, may underlie AD's multisystem neurodegeneration. This presentation reviews converging evidence for lithium's neuroprotective properties and presents findings from the LATTICE (Lithium as a Treatment to Prevent Impairment of Cognition in Elders) trial.

Mechanistic studies reveal that lithium inhibits GSK-3β, a key enzyme that phosphorylates both β-catenin and tau protein. By blocking GSK-3β, lithium preserves synaptic proteins critical for memory and learning while reducing tau hyperphosphorylation and neurofibrillary tangle formation. Lithium also increases brain-derived neurotrophic factor (BDNF) expression, contributing additional neuroprotective effects.

While prior randomized trials have examined lithium in MCI and AD, no study has combined cognitive assessment, advanced neuroimaging, and plasma biomarkers in a single investigation. LATTICE was a two-year, double-blind, placebo-controlled pilot trial in 80 older adults with mild cognitive impairment. The study employed ultra-high field 7T MRI for precise brain volume measurements, amyloid PET imaging for biomarker stratification, and comprehensive cognitive testing including verbal and visual memory measures.

This presentation will review the mechanistic and epidemiological rationale for lithium in AD prevention, describe the LATTICE study design and methodology, present trial results across cognitive and neuroimaging outcomes, and discuss implications for future confirmatory trials.

Detection and Help-Seeking in the Early Course of Bipolar Disorder: New Advances and International Consensus

Symposia
Developmental Psychopathology, Prodromes, Early Recognition
Jacob Crouse
University of Sydney
Jacob Crouse (Chair), Aswin Ratheesh (Presenter), Kamyar Keramatian

(Presenter), Jacob Crouse (Presenter)

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Category Selection Application Research and/or Clinical Practices

Overall Abstract Details The peak age of onset of bipolar disorder (BD) is 15-25, however there is evidence that diagnosis and guideline-recommended interventions are likely to be delayed until age 25-35 in most cases (Scott et al., 2022; PMID:36018259). Accordingly, there is a need to improve the detection of BD, encourage help-seeking, and refine definitions about early intervention to reduce the latency to effective treatment. In this symposium, Dr. Ratheesh (University of New South Wales, Australia) will present unpublished data from an international Delphi study on behalf of the ISBD Taskforce on Early Intervention; a series of expert consensus recommendations about definitions of key parameters, interventions, and outcomes to support early intervention of BD will be presented. Next, Dr. Keramatian (University of British Columbia, Canada) will present data that demonstrates that a novel manualized telehealth-based group intervention for individuals at high risk of BD has excellent feasibility (100% sign-up rate, 76.2% completion rate) and has a strong and positive effect on improving help-seeking intention. Finally, Dr. Crouse (University of Sydney, Australia) will present unpublished data on a prediction model of the onset of hypo/mania or mania in a prospective sample of community-residing twins; the model demonstrates that a combination of demographic, clinical, familial, and molecular genetic predictors can correctly classify 86.7% of cases of new-onset BD. Together, these complementary studies provide new definitions, interventions, and predictive models that will help improve the field’s capacity to detect at-risk individuals, encourage them to seek help, and provide timely and effective early interventions.

Novelty/Unique Data The data presented by Dr. Crouse and Dr. Ratheesh are unpublished, and while the primary data presented by Dr. Keramatian are published, he will supplement this by introducing unpublished data about the digitization and implementation of the PREP-BD intervention. Moreover, the study by Dr. Ratheesh represents the first international consensus study by the Early Intervention Task Force and the first consensus study on the topic of early intervention for BD more generally.

Significance This symposium will present new evidence about: (a) the predictive and potential

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2026 ISBD Annual Conference

clinical utility of polygenic risk scores (a contested area) in a developmentally-sensitive cohort of youth passing through the peak phase of onset; (b) a novel intervention that may reduce the lag time between the onset of symptoms and help-seeking for BD (a major global priority); and (c) refined consensus definitions for early intervention for BD which will guide future clinical trial targets and designs (e.g., influence trial/cohort inclusion criteria) and improve consistency of international research efforts.

Novel Program to Enhance Help-Seeking Intentions in Individuals at High Risk for Bipolar Disorder: A Feasibility Trial and Implications for Digital Scale-Up

Symposia
Developmental Psychopathology, Prodromes, Early Recognition Kamyar Keramatian
The University of British Columbia
Jacob Crouse (Chair), Aswin Ratheesh (Presenter), Kamyar Keramatian

(Presenter), Jacob Crouse (Presenter)

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Individual Abstract: Aims: Bipolar disorder (BD) often goes unrecognized and untreated for several years leading to negative outcomes. We have recently developed a manualized telehealth-based group Psychoeducational and Resilience Enhancement Program for individuals at high risk for BD (PREP-BD). The primary objective of this study was to assess the feasibility of implementing PREP-BD to enhance help-seeking intentions among high-risk individuals, and to inform future digital adaptation and scale-up of the intervention.

Methods: The intervention consisted of eight weekly, 60-minute group psychoeducation sessions conducted via Zoom. Participants (N = 21), aged 17 to 24 years, who met the Bipolar At-Risk criteria, were assigned to one of four cohorts. Semi-structured interviews were conducted with participants, their family members, and group facilitators to gather insights into their experiences and perspectives on the intervention. Participants also completed the Help-Seeking Intentions Questionnaire in response to a hypomanic scenario both pre- and post-intervention.

Results: Our findings indicate excellent feasibility as evidenced by efficient recruitment, 100 percent sign-up rate, and 76.19% percent completion rate (defined as attending at least 75% of group sessions). Help-seeking intentions showed a significant increase from pre- to post-intervention (Mean difference = 8.50, SD = 7.36); paired samples t-test: t(15) = 4.62, p < 0.001.

Conclusion: A telehealth-based group psychoeducational intervention can be feasibly implemented to improve help-seeking in individuals at high risk for BD. These findings support the next phase of PREP-BD development, including digitalization into scalable, self-guided format to increase accessibility, reach, and implementation across diverse settings.

Mental Health Service in the Year Following a First Diagnosis of Bipolar Disorder Among Adolescents and Young Adults

Symposia
Illness Course, Staging
Kathleen Miley
HealthPartners Institute
Aswin Ratheesh (Chair), Aswin Ratheesh (Presenter), Muralidharan Kesavan

(Presenter), Kathleen Miley (Presenter)

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Individual Abstract: Aims: To investigate mental health service utilization, prescribed psychiatric medications, and comorbid psychiatric diagnoses in the year following an incident bipolar disorder (BD) diagnosis.

Methods: Electronic health record and administrative data from a large healthcare system in the Midwestern USA were used to identify 2,060 patients age 15-35 with an incident diagnosis of BD between 2017-2023, matched 2:1 on key demographics to patients with an incident diagnosis of depression (MDD). Mental health service utilization, psychiatric medications, and psychiatric diagnoses in the year following index were compared between groups using logistic and Poisson regression models, adjusted for demographics.

Results: Compared to those with MDD, significantly more patients with BD had inpatient hospitalizations (17.8% of BD vs 2% of MDD; aOR 10.01 [95% CI 7.83-12.93]), and mental health emergency department visits (17.5% vs 3.2%; aOR 5.51 [4.47-6.83]). Patients with BD had frequent outpatient mental health contacts (Mean 26.1 (SD 35.8)/year) and 76.4% were prescribed psychiatric medications, with 51.5% prescribed antidepressants, 45.2% prescribed antipsychotics, 14% prescribed stimulants, 9.1% prescribed lithium, and 36% prescribed other mood stabilizers. BD patients had significantly higher rates of ADHD, anxiety disorders, personality disorders, psychosis, and substance use disorders than those with MDD.

Conclusions: Mental health service use is high in the early course of BD with rates of hospitalization and emergency department visits exceeding those for patients with MDD. Medication patterns, including low lithium use and frequent antidepressant prescribing, suggest potential gaps in guideline-concordant care. High psychiatric comorbidity underscores clinical complexity of early-stage BD and informs treatment needs.