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Clinical trials landscape

TL;DR — The active bipolar-disorder pipeline spans new mechanisms for mania and depression, psychedelic feasibility studies, lithium comparisons, device-based treatment, metabolic interventions and biomarker validation. As of live ClinicalTrials.gov v2 API retrievals on 2026-08-31 and 2026-09-03, with all 28 records cited on this page re-fetched and re-verified on 2026-09-03, phase 3 programs included xanomeline/trospium for mania (acute plus open-label extension), lumateperone for pediatric bipolar depression, azetukalner for bipolar depression and a small brexpiprazole study, while phase 2 programs included adjunctive brenipatide for time-to-relapse, ALTO-100, ABX-002 and tightly controlled psilocybin studies (NCT06951711; NCT07140913; NCT06929273; NCT06372964; NCT07217860; NCT04569448; NCT07286175; NCT06656416; NCT06869187; NCT06706232). The frontier is not only pharmacologic: active studies test accelerated theta-burst stimulation, magnetic seizure therapy, open- and closed-loop deep-brain stimulation, vocal prediction and composite blood-marker algorithms (NCT05849402; NCT04080778; NCT06599099; NCT07127913; NCT07298278; NCT07031817). Registry status is a snapshot, not evidence of efficacy; completion, posted results and peer-reviewed outcome reporting must be tracked separately. Every record cited here was re-fetched directly on 2026-09-03: all resolved, and none has posted results.

Methods and snapshot boundary

The registry sweep used the ClinicalTrials.gov API v2 condition query for “Bipolar Disorder,” restricted to recruiting, not-yet-recruiting, active-not-recruiting and enrolling-by-invitation records, followed by direct /api/v2/studies/{NCT} retrieval for every ID listed below. Access date: 2026-08-31. Direct re-fetch of the 20 previously cited identifiers found no overall-status change and no posted results. Newly retained records were limited to programs that change the described pipeline (KarXT mania extension, pediatric lumateperone depression, adjunctive brenipatide relapse prevention). Incidental uses of the word “bipolar” in surgery and electrophysiology were excluded by reading title, condition and intervention. Status and enrollment are registry-reported and can change.

API source: https://clinicaltrials.gov/api/v2/studies?query.cond=Bipolar%20Disorder&filter.overallStatus=RECRUITING%7CNOT_YET_RECRUITING%7CACTIVE_NOT_RECRUITING%7CENROLLING_BY_INVITATION&pageSize=50, accessed 2026-08-31.

Pharmacologic pipeline

Trial Phase; enrollment Status at 2026-08-31 Intervention Scientific question
Brexpiprazole Treatment for Bipolar I Depression (NCT04569448) Phase 3; 58 Recruiting; verified Aug 2026 Brexpiprazole Antidepressant efficacy and tolerability in bipolar I depression
BALSAM-2 mania study (NCT06951711) Phase 3; 274 Recruiting; verified Aug 2026 KarXT vs placebo Muscarinic mechanism for manic episodes
Adjunctive KarXT for mania with/without mixed features (NCT07140913) Phase 3; 424 Recruiting; verified Jun 2026 Xanomeline/trospium vs placebo added to lithium, valproate or lamotrigine Adjunctive antimanic efficacy
BALSAM-3 mania open-label extension (NCT06929273) Phase 3; 450 Recruiting; verified Aug 2026 KarXT; lithium, valproate or lamotrigine permitted Long-term safety after mania/mixed-mania treatment
Lumateperone for pediatric bipolar depression (NCT06372964) Phase 3; 384 Recruiting; verified Aug 2026 Lumateperone vs placebo Efficacy and safety of a major-depressive-episode treatment in ages 10–17
X-CEED open-label extension (NCT07217860) Phase 3; 400 Enrolling by invitation; verified Jun 2026 Azetukalner Longer-term exposure after bipolar-depression trials
Brenipatide adjunctive relapse prevention (NCT07286175) Phase 2; 400 Recruiting; verified Aug 2026 Brenipatide vs placebo added to standard of care Time to relapse over ≥6 months of adjunctive treatment
ALTO-100 in bipolar depression (NCT06656416) Phase 2; 200 Recruiting; verified Jul 2025 ALTO-100 vs placebo Novel adjunctive antidepressant mechanism
ABX-002 adjunctive bipolar depression (NCT06869187) Phase 2; 35 Active, not recruiting; verified May 2026 ABX-002 Early efficacy/safety signal
Lithium vs lamotrigine in bipolar II (NCT06184581) Phase 4; 200 Recruiting; verified Mar 2026 Lithium carbonate vs lamotrigine Pragmatic comparative treatment in bipolar II
Psilocybin in bipolar II depression and suicidality (NCT06706232) Phase 2; 10 Recruiting; verified Jul 2026 Two psilocybin doses plus therapeutic support Feasibility and safety in a population commonly excluded from psychedelic trials
Psilocybin neurobiology in treatment-resistant bipolar depression (NCT06506019) Phase 1; 30 Active, not recruiting; verified Aug 2026 Psilocybin plus functional MRI Mechanism and early safety

The new-mechanism pipeline should be read against a high attrition baseline. Network meta-analyses can establish average efficacy for completed interventions, but they cannot validate registry optimism or substitute for posted results (Kishi 2021, PMID 33177610). Mixed-feature and rapid-cycling eligibility also matters because broad diagnostic labels can conceal populations with different benefit-risk profiles (Roosen 2022, PMID 35545157).

Neuromodulation and device trials

Trial Enrollment Status at 2026-08-31 Intervention / comparator Key design issue
Accelerated iTBS for treatment-resistant bipolar II depression (NCT05849402) 60 Active, not recruiting Active vs sham aiTBS Blinding integrity and durability
Magnetic seizure therapy in bipolar and treatment-resistant depression (NCT04080778) 60 Recruiting MST vs ECT Noninferiority, cognitive burden and diagnosis-specific effects
Deep-brain stimulation for treatment-resistant bipolar depression (NCT06599099) 10 Recruiting Medtronic Percept RC; blinded discontinuation Invasiveness, tiny sample and within-person signal
Closed-loop DBS for treatment-resistant bipolar depression (NCT07127913) 10 Recruiting Stimulation-on/off/active control Personalized control signal and safety

These studies occupy different development stages. Sham-controlled noninvasive stimulation can estimate short-term symptomatic effects, whereas implanted-device studies at n=10 primarily establish feasibility and individualized physiology. Device novelty should not be confused with comparative effectiveness.

Biomarker and prediction trials

Trial Enrollment Status Measurement Intended context of use
Vocal biomarkers for impending depressive/manic episodes (NCT07298278) 170 Not yet recruiting; verified Dec 2025 Voice interviews, under-mattress sleep sensor, smartwatch activity/sleep/temperature Prospective episode anticipation
Composite blood-marker algorithm plus MDQ (NCT07031817) 623 Recruiting; verified Oct 2025 Venous blood panel plus standardized psychiatric assessment Diagnostic support
Prediction on recurrence of manic and depressive episodes (NCT05828056) 100 Recruiting; directly verified 2026-08-30 Prospective clinical and digital measures Recurrence prediction
mHealth algorithms signaling upcoming recurrence (NCT06204705) 200 Recruiting; directly verified 2026-08-30 Mobile-health estimates and alerts Prospective episode warning

The vocal study directly addresses a major gap in retrospective digital-phenotyping work: prospectively defined episodes and a time-to-warning endpoint. Existing reviews show substantial methodological heterogeneity and overfitting, so external validation and false-alert burden will be more decision-relevant than a high internal AUC (Saccaro 2021, PMID 34488086; Ortiz 2021, PMID 34706433).

The composite blood-marker study is larger than many discovery cohorts, but size alone does not establish clinical utility. It must show incremental discrimination beyond the MDQ and structured clinical assessment, report calibration and predefine how discordant results should be used (Hu 2023, PMID 36347076).

Metabolic, circadian and lifestyle interventions

Trial Enrollment Status Arms Principal outcome domain
Ketogenic-diet mechanism study (NCT06081426) 107 Recruiting; verified Dec 2025 Ketogenic, non-ketogenic and no-diet arms Symptoms, metabolism and neurobiology
Healthy Lifestyles for Bipolar Disorder (NCT06188754) 300 Recruiting; verified Jul 2026 Time-restricted eating vs Mediterranean diet Feasibility, metabolic and mood outcomes

Diet studies face predictable adherence, blinding and co-intervention problems. They are important because cardiovascular mortality is elevated in bipolar disorder, but mechanistic or weight changes must not be described as mood efficacy unless the prespecified mood endpoint supports it (Biazus 2023, PMID 37491460; Paljärvi 2024, PMID 38826056).

Suicide-focused psychosocial trial

The registry lists a 130-participant recruiting trial of four psychosocial approaches for suicidal behavior in bipolar disorder: interpersonal and social rhythm therapy, bipolar-specific CBT, mindfulness-based stress reduction, and psychoeducation/medication understanding (NCT02604277; status verified January 2026). Because the arms are active psychosocial strategies, interpretation should distinguish comparative benefit from absolute change over time.

Suicide outcomes require adequate event counts and careful composite definitions. A prior 519-participant randomized trial of lithium augmentation after a recent suicide-related event stopped for futility and found no reduction in the composite outcome (HR 1.10, 95% CI 0.77-1.55), illustrating why observational protection signals cannot predetermine trial results (Katz 2022, PMID 34787653).

Completed evidence that shapes trial design

Design lesson Quantitative example Implication
Rare events produce imprecision Lithium meta-analysis: 48 RCTs, 6,674 participants; suicide OR 0.13, 95% CI 0.03-0.66 vs placebo (Cipriani 2013, PMID 23814104) Event definitions and follow-up length dominate power
Composite outcomes can dilute a specific effect VA trial: HR 1.10, 95% CI 0.77-1.55 for repeat suicide-related events (Katz 2022, PMID 34787653) Report each component as well as the composite
Digital models need participant-level separation Mood forecast: 15,975 observations from only 84 people, next-day R² 0.51 (Busk 2020, PMID 32234702) Observation count is not participant count
Diagnostic classification remains difficult Smartphone study AUC 0.62 for bipolar vs major depression (Langholm 2023, PMID 38129571) Compare against a strong clinical baseline
Actigraphy effects are heterogeneous Mood-disorder meta-analysis: 38 studies, n=3,758 (Tazawa 2019, PMID 31060012) Harmonize devices and state definitions
Safety can be long-latency Lithium toxicity synthesis screened 5,988 abstracts and included 385 studies (McKnight 2012, PMID 22265699) Trials need registry or cohort follow-up for renal/endocrine outcomes

How to read registry records

Field What it means What it does not mean
Recruiting Site reports current recruitment Participants are necessarily enrolling at every listed site
Active, not recruiting Study continues without open recruitment Primary analysis is complete
Enrollment Planned or actual count, as labeled in the record An analyzable final sample
Phase Regulatory development label Methodological quality
Primary outcome Sponsor-declared endpoint Result or clinical importance
Last update Registry record activity Independent verification

Portfolio gaps

  • Acute mania has major drug development, but fewer trials test service-level approaches to sleep restoration, financial/sexual risk and family-supported crisis planning.
  • Bipolar II depression remains underrepresented relative to bipolar I despite dedicated lithium-versus-lamotrigine and psilocybin feasibility trials (NCT06184581; NCT06706232). Pediatric bipolar depression now has a 384-participant phase 3 lumateperone record (NCT06372964); that does not fill the adult bipolar II gap.
  • The active-record sweep, re-run on 2026-09-03, found prospective prediction and alert studies (NCT05828056; NCT06204705; NCT07298278), but no retrieved protocol clearly randomized an alert-plus-response pathway with hospitalization prevention as the clinical-utility endpoint. The nearest records remain a transitional-care study whose primary outcomes are feasibility and acceptability (NCT07213492) and a probiotic relapse trial (NCT03349528). This is an evidence gap in the retrieved active portfolio, not a claim that no such protocol can exist outside the query scope.
  • Invasive neuromodulation samples are necessarily small; transparent stopping, adverse-event and explant criteria are critical (NCT06599099; NCT07127913).
  • Diet trials create an opportunity to link metabolic and mood outcomes, but causal interpretation requires measured adherence and prespecified mediation (NCT06081426; NCT06188754).
  • Patient-prioritized outcomes such as cognition, sexual function, work and treatment burden are not visible in most brief registry titles and require full-outcome review.

Maturity matrix for this snapshot

Program Current maturity Evidence needed next
Xanomeline/trospium for mania Two acute phase 3 records plus an open-label extension Completed primary outcomes, adverse-event discontinuation and controlled maintenance data
Azetukalner for bipolar depression Phase 3 open-label extension Parent-trial placebo-controlled efficacy plus switch and long-term safety
Brexpiprazole for bipolar I depression Small phase 3 registry record Precision around efficacy and tolerability in a larger representative sample
Brenipatide adjunctive relapse prevention Phase 2, n=400, time-to-relapse primary Prespecified relapse definition, adjunctive standard-of-care composition and adverse-event profile
Lumateperone pediatric bipolar depression Phase 3, ages 10–17 Developmental safety, switch surveillance and whether adult bipolar-depression effects transport
ALTO-100 Phase 2 Replication and validity of any enrichment strategy
ABX-002 Phase 2, active not recruiting Posted results and peer-reviewed report
Psilocybin Phase 1/2, n=10-30 Acute mania/hypomania surveillance, durability and controlled efficacy
aiTBS / MST Sham or active-comparator device trials Blinding, cognitive outcomes and longer follow-up
DBS Feasibility samples of 10 Reproducible target/biomarker logic and multi-site safety
Vocal prediction Prospective multimodal cohort Locked alert threshold and external validation
Blood-marker algorithm Diagnostic-validation study Calibration, incremental value and clinical-utility trial
Diet / timed eating Behavioral-mechanism trials Adherence measurement, metabolic mediation and mood specificity

Trial-tracking fields to preserve

For every future sweep, retain the prior status, status-verification date, enrollment type (anticipated or actual), primary completion date, results-posting state, publication link and reason for any termination. A status transition is evidence about trial conduct, not treatment effect. Direct record endpoints used here follow the reproducible form https://clinicaltrials.gov/api/v2/studies/NCT######## and were fetched on 2026-08-31.

Small signals at the experimental edge

A 60-person bipolar trial randomized omega-3 fatty acids 2 g/day or placebo for two months and reported lower depression scores, TNF-α, IL-6 and hsCRP in the active arm (all P<.001), but the abstract does not provide between-group effect sizes or confidence intervals (Eslahi 2023, PMID 37213459). It is hypothesis-supporting, not sufficient for treatment ranking.

Ketogenic-diet evidence remains earlier. A 2024 review found human psychiatric studies generally small, short, often uncontrolled, heterogeneous and affected by high dropout or unmeasured adherence, despite plausible metabolic and anti-inflammatory mechanisms (Chrysafi 2024, PMID 38892480). A ClinicalTrials.gov v2 query on 2026-09-03 shows that registered bipolar-specific ketogenic trials now exist — a randomized open-label first-episode study (NCT06221852; n=50; recruiting; primary outcomes are brain redox/creatine-kinase metabolites, insulin resistance and symptom change), a single-arm bipolar-depression study (NCT07121894; n=30; recruiting) and an adolescent study (NCT06920940; n=80; recruiting) alongside the mechanistic study already tracked here (NCT06081426). What is still absent is a completed, adequately powered, blinded randomized efficacy trial with a mood-episode endpoint; none of the retrieved records is blinded and all are ongoing.

Ketamine literature demonstrates denominator leakage. A real-world treatment-resistant-depression synthesis pooled 79 studies (n=2,665) and estimated response 45%±10% and remission 30%±5.9%, but it did not provide a bipolar-specific pooled estimate (Alnefeesi 2022, PMID 35688035). Likewise, a 24-trial comparison of racemic ketamine and esketamine combined unipolar and bipolar depression; racemic ketamine showed larger pooled response (RR 3.01 versus 1.38) and remission (RR 3.70 versus 1.47), but formulation and route were confounded with study populations (Bahji 2021, PMID 33022440).

One small psilocybin-assisted psychotherapy trial admitted major depression and bipolar II depression: 30 participants were randomized to immediate or delayed treatment, 29 reached week 2, and the immediate arm showed a MADRS effect size g=1.07 (P<.01) without serious adverse events (Rosenblat 2024, PMID 38359838). The mixed diagnosis, wait-list design and tiny sample leave polarity-switch and durability risks unresolved.

Open questions

  • Will muscarinic treatment improve mania without an offsetting cholinergic tolerability burden in phase 3, and is longer-term exposure tolerable in the open-label extension (NCT06951711; NCT07140913; NCT06929273)?
  • Can adjunctive brenipatide delay syndromal relapse on standard of care, and with what adverse-event profile (NCT07286175)?
  • Can azetukalner or ALTO-100 produce durable bipolar-depression benefit with acceptable switch risk (NCT07217860; NCT06656416)?
  • Does lumateperone separate from placebo on pediatric bipolar-depression ratings without a developmental safety signal that adult trials cannot detect (NCT06372964)?
  • Can vocal and wearable measures provide calibrated, actionable warning rather than retrospective separation (NCT07298278; Saccaro 2021, PMID 34488086)?
  • Which treatment-resistant bipolar-depression phenotype justifies invasive stimulation, and how should n-of-1 signals be combined across participants (NCT06599099; NCT07127913)?
  • Can metabolic interventions improve both cardiometabolic risk and mood without conflating adherence effects with diet mechanism (NCT06081426; NCT06188754)?
  • How often do completed bipolar trials post timely registry results and publish all prespecified outcomes?

References

  1. Kishi T, et al. Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: systematic review and network meta-analysis. Mol Psychiatry. 2021;26:4146-4157. PMID 33177610
  2. Roosen L, et al. Evidence-based treatment strategies for rapid cycling bipolar disorder: a systematic review. J Affect Disord. 2022;311:69-77. PMID 35545157
  3. Saccaro LF, et al. Portable technologies for digital phenotyping of bipolar disorder: A systematic review. J Affect Disord. 2021;295:323-338. PMID 34488086
  4. Ortiz A, et al. Apps and gaps in bipolar disorder: electronic monitoring for episode prediction. J Affect Disord. 2021;295:1190-1200. PMID 34706433
  5. Hu X, et al. Biomarkers and detection methods of bipolar disorder. Biosens Bioelectron. 2023;220:114842. PMID 36347076
  6. Biazus TB, et al. All-cause and cause-specific mortality among people with bipolar disorder: a systematic review and meta-analysis. Mol Psychiatry. 2023;28:2508-2524. PMID 37491460
  7. Paljärvi T, et al. Cardiovascular mortality in bipolar disorder: Population-based cohort study. Acta Psychiatr Scand. 2024;150:56-64. PMID 38826056
  8. Katz IR, et al. Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder. JAMA Psychiatry. 2022;79:24-32. PMID 34787653
  9. Cipriani A, et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. PMID 23814104
  10. Busk J, et al. Forecasting Mood in Bipolar Disorder From Smartphone Self-assessments. JMIR Mhealth Uhealth. 2020;8:e15028. PMID 32234702
  11. Langholm C, et al. Classifying and clustering mood disorder patients using smartphone data. NPJ Digit Med. 2023;6:238. PMID 38129571
  12. Tazawa Y, et al. Actigraphy for evaluation of mood disorders: A systematic review and meta-analysis. J Affect Disord. 2019;253:257-269. PMID 31060012
  13. McKnight RF, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721-728. PMID 22265699
  14. Eslahi H, et al. Effects of omega-3 fatty acids on inflammatory cytokines and depression status in bipolar disorder: a randomized double-blind controlled trial. J Res Med Sci. 2023;28:36. PMID 37213459
  15. Chrysafi M, et al. Potential effects of the ketogenic diet in prevention and co-treatment of psychiatric disorders. Nutrients. 2024;16:1546. PMID 38892480
  16. Alnefeesi Y, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review and meta-analysis. J Psychiatr Res. 2022;151:693–709. PMID 35688035
  17. Bahji A, et al. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542–555. PMID 33022440
  18. Rosenblat JD, et al. Psilocybin-assisted psychotherapy for treatment-resistant depression: a randomized clinical trial evaluating repeated doses. Med (N Y). 2024;5:190–200.e5. PMID 38359838