Summary
Valproic Acid has reached the approved stage (maximum clinical phase 4) for at least one indication, so its use in Bipolar Disorder would be drug repurposing rather than first-in-human development. This does not mean it is approved for Bipolar Disorder. ClinicalTrials.gov lists 8 registered trials linking Valproic Acid to Bipolar Disorder: 6 have completed; 2 are terminated, withdrawn, suspended or of unknown status. The most advanced is Phase 4 (NCT00667745). The largest enrolment is 3416 participants (NCT01064297). Registration activity spans 2001 to 2008. The literature layer holds 20 publications for this pair: 5 Cochrane reviews, 3 meta-analyses, 5 systematic reviews, 2 randomised controlled trial publications and 5 clinical trial publications. Publication years run from 2013 to 2026. Because at least one synthesis-level source exists (systematic review, meta-analysis or Cochrane review), this pair has been assessed beyond single studies, although the synthesis may concern a different indication.
The RepurpOS disease-intelligence file for Bipolar Disorder ranks 389 candidate therapeutics from Open Targets, ChEMBL, DGIdb and PubMed; only a minority carry direct clinical evidence, and this page covers one of those. Spontaneous remission context recorded for the condition: Natural episodic pattern: untreated, median episode length 3-6 months; recurrence in 90% within 5 years; functional impairment between episodes in 30-60%; suicide risk 20-30x general population.
Evidence table
| Evidence tier | A · Strong |
|---|---|
| Evidence score | 73.0 (trials 23.0, literature 30.0, tier 15, approved bonus 5.0) |
| Registered trials | 8 total: 0 recruiting, 0 active / not yet recruiting, 6 completed, 2 other |
| Linked publications | 20 (5 Cochrane reviews, 5 systematic reviews, 5 clinical trial publications, 3 meta-analyses, 2 randomised controlled trial publications) |
| Agent type | Drug (Small molecule) |
| Development stage (any indication) | Approved |
| Mechanism / class | inhibitor |
| Data sources | DGIdb |
| Linked via biomarker / target | ALDH5A1 |
How the evidence score is calculated
- Each registered trial scores by status (recruiting / active / enrolling 3, completed 2.5, not yet recruiting 2, unknown 1, terminated / withdrawn / suspended 0.5) plus a phase bonus (phase 3-4 +2, phase 2 +1, phase 1 +0.5). The trial component is capped at 30.
- Each literature item scores by design (Cochrane review 5, meta-analysis 4, systematic review 3, RCT 3, clinical trial publication 2, curated reference 1.5, other PubMed record 1). The literature component is capped at 30.
- The existing evidence tier adds 15 (A / Strong), 10 (B / Moderate), 5 (C / Preliminary) or 0 (D / Anecdotal).
- Agents approved for any indication (max clinical phase 4) add 5, because an approved agent has an established safety profile that lowers the barrier to repurposing trials.
- The score ranks what has been studied, not what works. It does not read effect sizes or directions of effect.
Registered clinical trials
| NCT ID | Title | Status | Phase | Enrolment |
|---|---|---|---|---|
| NCT00177567 | Treatment of Geriatric Bipolar Mood Disorders: A Pilot Study 2001 | completed | Phase 4 | 60 |
| NCT00667745 | Effectiveness of Lithium Plus Optimized Medication in Treating People With Bipolar Disorder 2008 | completed | Phase 4 | 283 |
| NCT00332098 | Effectiveness of Family-Focused Treatment Plus Pharmacotherapy for Bipolar Disorder in Adolescents 2006 | completed | Phase 3 | 145 |
| NCT00204503 | Open-Label Depakote ER in Patients With Bipolar I or II Depression and Alcohol Abuse or Dependence 2003 | withdrawn | Phase 2 | — |
| NCT00562861 | Treatment for Bipolar Depression: Acute & Prophylactic Efficacy With Citalopram 2007 | completed | PHASE2, PHASE3 | 119 |
| NCT01064297 | Lamotrigine Pregnancy Registry (LAM05) 2001 | completed | Not applicable | 3,416 |
| NCT00240110 | Valproate Efficacy in Cocaine-Bipolar Comorbidity 2006 | completed | PHASE1, PHASE2 | 152 |
| NCT00451542 | Divalproex vs. Lamotrigine for Bipolar Disorder 2006 | terminated | Not applicable | 1,000 |
Published literature
- Clinical trial publication Neuroprotective, cognitive, and immunomodulatory effects of Valproic acid combined with dextromethorphan in bipolar disorderHuang CC, Tzeng NS, Chang YH et al. · Journal of psychiatric research · 2026 · PMID 41774971
- Cochrane review Therapeutic Overlap Between Bipolar Disorder and Migraine: A Systematic Review of Pharmacological TrialsHaddad M, Dieckmann LHJ, Rodrigues da Silva N et al. · Pharmaceuticals (Basel, Switzerland) · 2026 · PMID 42356466
- Cochrane review Mechanisms of weight gain associated with valproic acid: a scoping reviewPopkova D, Fellendorf F, Vinberg M et al. · European archives of psychiatry and clinical neuroscience · 2026 · PMID 42334569
- Systematic review Lamotrigine-induced Stevens-Johnson syndrome: a systematic review of case reports and case seriesSaxena A, Chaudhary V, Kumari S et al. · Clinical toxicology (Philadelphia, Pa.) · 2026 · PMID 41843406
- Systematic review Clozapine-induced cardiac toxicity and successful rechallenge in children and adolescents: a systematic review and new case reportBiagetti R, Caiazza L, Giuva T et al. · Psychiatry research · 2025 · PMID 40780116
- Systematic review Evaluating the efficacy of valproic acid in alcohol use disorder: a systematic analysis of clinical trials from ClinicalTrials.govAlshehri FS · Frontiers in pharmacology · 2025 · PMID 40351441
- Systematic review Exploring accelerated aging as a target of bipolar disorder treatment: A systematic reviewCourtes AC, Jha R, Topolski N et al. · Journal of psychiatric research · 2024 · PMID 39476539
- Systematic review [Effects of lithium, valproic acid, carbamazepine and antipsychotic agents on cognition in bipolar disorders-A systematic review]Leopold S, Quante A · Der Nervenarzt · 2023 · PMID 36922444
- Clinical trial publication Fixed Dose Combination Tablets of Aripiprazole and Divalproex Sodium: a Pilot Pharmacokinetic Study in Human VolunteersAhmed Z, Subhan F, Ahmed S · AAPS PharmSciTech · 2022 · PMID 35986197
- Cochrane review [Lamotrigine in bipolar disorder: preventing depression to treat the disease]Cuomo A, Amore M, Vampini C et al. · Rivista di psichiatria · 2021 · PMID 33560270
- Clinical trial publication A randomized controlled trial comparing lithium plus valproic acid versus lithium plus carbamazepine in young patients with type 1 bipolar disorder: the LICAVAL studyMissio G, Moreno DH, Demetrio FN et al. · Trials · 2019 · PMID 31655626
- Clinical trial publication Bipolar Disorder Mixed Episodes: A Pragmatic Trial of a Public Health Treatment EffectivenessMiguel SRPS, Lima AFBS, Cruz LN et al. · Value in health regional issues · 2018 · PMID 30316147
- Clinical trial publication Add-On Memantine Treatment for Bipolar II Disorder Comorbid with Alcohol Dependence: A 12-Week Follow-Up StudyLee SY, Wang TY, Chen SL et al. · Alcoholism, clinical and experimental research · 2018 · PMID 29656414
- Cochrane review A Review of the Pharmacological and Clinical Profile of Newer Atypical Antipsychotics as Treatments for Bipolar Disorder: Considerations for Use in Older PatientsVasudev A, Chaudhari S, Sethi R et al. · Drugs & aging · 2018 · PMID 30187288
- Cochrane review [The effects of pharmacological and psychotherapeutic treatment of comorbid anxiety disorders in patients with bipolar disorder]van der Veen WAM, Renes JW, Kupka RW et al. · Tijdschrift voor psychiatrie · 2018 · PMID 29943796
- Meta-analysis [The use of anticonvulsants and the levels of folate, vitamin B12 and homocysteine]Dinç D, Schulte PFJ · Tijdschrift voor psychiatrie · 2018 · PMID 29341053
- Meta-analysis Maintenance therapy with second generation antipsychotics for bipolar disorder - A systematic review and meta-analysisLindström L, Lindström E, Nilsson M et al. · Journal of affective disorders · 2017 · PMID 28222360
- Randomized controlled trial A randomized, double-blind, placebo- and risperidone-controlled study on valnoctamide for acute maniaWeiser M, Levi L, Levine SZ et al. · Bipolar disorders · 2017 · PMID 28605109
- Randomized controlled trial Comparing clinical responses and the biomarkers of BDNF and cytokines between subthreshold bipolar disorder and bipolar II disorderWang TY, Lee SY, Chen SL et al. · Scientific reports · 2016 · PMID 27270858
- Meta-analysis Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorderCipriani A, Reid K, Young AH et al. · The Cochrane database of systematic reviews · 2013 · PMID 24132760
Mechanism and notes
Recorded mechanism or class: inhibitor.
OSMF's existing evidence tier for this pair is A (Strong), derived from the strength of the disease association recorded in DGIdb, in this case via the biomarker or target ALDH5A1. The tier describes how well the drug-disease link is documented, not how well the drug works.
Frequently asked questions
Is Valproic Acid approved for Bipolar Disorder?
Valproic Acid has reached the approved stage (maximum clinical phase 4) for at least one indication, so its use in Bipolar Disorder would be drug repurposing rather than first-in-human development. This does not mean it is approved for Bipolar Disorder. Approval status for the specific indication should always be confirmed with the relevant regulator and prescribing information.
Is Valproic Acid in clinical trials for Bipolar Disorder?
ClinicalTrials.gov lists 8 registered trials linking Valproic Acid to Bipolar Disorder: 6 have completed; 2 are terminated, withdrawn, suspended or of unknown status. The most advanced is Phase 4 (NCT00667745). The largest enrolment is 3416 participants (NCT01064297). Registration activity spans 2001 to 2008.
What does the evidence show for Valproic Acid in Bipolar Disorder?
Valproic Acid has both completed registered trials and synthesis-level publications linked to Bipolar Disorder. That is the strongest profile in this database, but the summaries here do not extract effect sizes, so read the linked reviews for direction and magnitude of benefit. OSMF's existing evidence tier for this pair is A (Strong), derived from the strength of the disease association recorded in DGIdb, in this case via the biomarker or target ALDH5A1. The tier describes how well the drug-disease link is documented, not how well the drug works.
Cite this page
Data: ClinicalTrials.gov, PubMed, Open Targets, ChEMBL, DGIdb and the OSMF therapeutic agent database. Last updated 2026-07-05. Page built 2026-10-07.