Ziprasidone
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
- Ziprasidone
- Ziprasidone: From Bipolar Mania to Major Affective Disorder (MDD/Bipolar Depression Augmentation)
Ziprasidone: From Bipolar Mania to Major Affective Disorder (MDD/Bipolar Depression Augmentation)
One-Sentence Summary
Ziprasidone is an atypical antipsychotic historically established for bipolar mania and mixed episodes. The TxGNN model predicts it may be effective for Major Affective Disorder (bipolar depression and treatment-resistant MDD augmentation), with 30 clinical trials and 21 publications currently supporting this direction — by far the strongest evidence base among all ten predicted indications in this evidence pack.
Note: TxGNN’s top-ranked prediction (trichotillomania, score 99.83%) and several other high-ranked candidates (hydranencephaly, congenital glycosylation disorder, X-linked myopia, retinal dystrophy, polymicrogyria syndrome) have zero supporting clinical trials or literature and are flagged “Hold” in the scoring. This report focuses on the highest-evidence candidate, Major Affective Disorder (rank 3), which is the only indication reaching decision stage S3.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available from India regulatory licenses (drug not marketed locally); per literature evidence in this pack, ziprasidone is a globally approved atypical antipsychotic for bipolar mania/mixed episodes |
| Predicted New Indication | Major Affective Disorder (bipolar depression / MDD augmentation) |
| TxGNN Prediction Score | 99.66% |
| Evidence Level | L1 |
| India Market Status | Not marketed |
| Number of Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
The original_moa field in this evidence pack is a data gap, but the repurposing rationale and literature evidence together describe ziprasidone’s mechanism: it is a D2/D3 dopamine receptor antagonist and 5-HT2A/5-HT2C serotonin receptor antagonist, with additional partial agonism at 5-HT1A and moderate serotonin/norepinephrine reuptake inhibition (PMID 19040553). This multi-target monoamine profile distinguishes it from purely dopaminergic first-generation antipsychotics.
Ziprasidone’s established use in bipolar mania and mixed episodes shares direct pharmacological and diagnostic overlap with bipolar depression and treatment-resistant major depressive disorder (MDD) — both fall under the same “affective disorder” spectrum. The serotonergic component (5-HT1A partial agonism, 5-HT2A antagonism) in particular provides a mechanistic rationale for antidepressant/augmentation effects, consistent with the broader class effect seen with other second-generation antipsychotics (quetiapine, aripiprazole, olanzapine) already approved for MDD augmentation or bipolar depression.
This is reflected in the evidence: eight Grade-A Phase 3 RCTs directly test ziprasidone in bipolar I depression and adjunctive mania treatment, and a further cluster of Phase 2 RCTs (led by Papakostas/Fava, Mass General) specifically test ziprasidone augmentation of SSRIs in MDD. A known trade-off is QTc interval prolongation, a class-wide antipsychotic risk that must be actively monitored as a guardrail rather than a contraindication.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00107939 | Phase 3 | Completed | 453 | Licarbazepine adjunctive to atypical antipsychotics (incl. ziprasidone) in bipolar I manic episodes; RCT, placebo-controlled |
| NCT00141271 | Phase 3 | Completed | 536 | Fixed-flexible dose oral ziprasidone in outpatients with Bipolar I Depression, 6-week RCT |
| NCT00312494 | Phase 3 | Completed | 680 | Add-on ziprasidone with lithium/divalproex in acute mania, 3-week placebo-controlled RCT |
| NCT00282464 | Phase 3 | Completed | 392 | Flexible-dose oral ziprasidone in outpatients with Bipolar I Depression, 6-week RCT |
| NCT00483548 | Phase 3 | Completed | 298 | Ziprasidone as add-on to lithium/valproate/lamotrigine in Bipolar I Depression, 6-week placebo-controlled RCT |
| NCT00633399 | Phase 2 | Completed | 458 | Ziprasidone combined with SSRIs for MDD non-responders; 3-phase efficacy/safety trial |
| NCT00555997 | Phase 2 | Completed | 120 | 12-week ziprasidone monotherapy vs placebo for MDD, sequential parallel design |
| NCT00340379 | Phase 2/3 | Completed | 72 | Ziprasidone monotherapy vs sertraline+haloperidol for psychotic major depression |
| NCT01168674 | Phase 4 | Completed | 49 | Predictors of response to ziprasidone augmentation in MDD, 13-week crossover RCT |
| NCT00667745 | Phase 4 | Completed | 283 | LiTMUS effectiveness trial, lithium-based optimized treatment with ziprasidone as a comparator arm |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 26085041 | 2015 | RCT | Am J Psychiatry | Ziprasidone augmentation of escitalopram significantly improved efficacy in nonpsychotic unipolar MDD non-responders |
| 27835715 | 2017 | RCT | J Clin Psychiatry | Ziprasidone augmentation of escitalopram in MDD: characterized cardiac, endocrine, metabolic, motoric safety profile |
| 24815673 | 2014 | RCT | Int Clin Psychopharmacol | 12-week ziprasidone monotherapy improved psychomotor and depressive symptoms in MDD |
| 28749091 | 2018 | RCT | J Clin Psychiatry | Adjunctive ziprasidone improved cognitive symptoms in MDD patients with residual symptoms after SSRI |
| 22999893 | 2013 | RCT/Analysis | J Affect Disord | Adjunctive ziprasidone (with lithium/valproate) significantly lowered relapse risk in bipolar disorder |
| 26619770 | 2015 | Review (ziprasidone-specific) | Am J Psychiatry | Reviews adjunctive ziprasidone data in MDD and status of adjunctive atypical antipsychotics |
| 19040553 | 2008 | Review | CNS Neurosci Ther | Ziprasidone’s unique serotonergic/dopaminergic/NE-reuptake profile reviewed for affective disorder use |
| 34986373 | 2022 | Network Meta-analysis | J Affect Disord | Compares augmentation agents (incl. antipsychotics) for treatment-resistant depression |
| 35510505 | 2023 | Systematic Review/Meta-analysis | Psychol Med | Efficacy/safety of antipsychotics as monotherapy and adjunctive therapy in MDD |
| 35993319 | 2022 | Systematic Review/NMA | Psychol Med | Efficacy and acceptability of second-generation antipsychotics as antidepressant augmentation in unipolar depression |
India Market Information
Ziprasidone is currently not marketed and has no registered authorizations in the India regulatory dataset (0 licenses on file). No product name, dosage form, or approved indication text is available in this evidence pack.
Safety Considerations
Drug Interactions: Of 305 total interactions on record (DDInter), several are flagged Major:
- Hydrocortisone
- Amphotericin B / Amphotericin B (lipid complex)
- Bupropion
- Morphine
Other safety note (from repurposing rationale, not a formal warning field): QTc interval prolongation is a known class-related risk for ziprasidone and should be treated as a guardrail requiring ECG monitoring in any repurposing pathway.
Key warnings and contraindication fields are not populated in this evidence pack (TFDA/India label data is flagged as a Blocking data gap — see Conclusion).
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Major Affective Disorder is the only predicted indication reaching decision stage S3 (L1 evidence), backed by multiple completed Phase 2/3 RCTs directly testing ziprasidone in bipolar I depression and MDD augmentation, plus consistent supportive network meta-analyses. However, the known QTc prolongation risk and total absence of local (India) labeling/regulatory data require guardrails before advancing.
To proceed, the following is needed:
- TFDA/India-equivalent package insert warnings and contraindications (Blocking data gap, DG001)
- Formal DrugBank MOA documentation to corroborate the mechanistic rationale (High priority gap, DG002)
- Cardiac (QTc) monitoring protocol for any repurposing trial or off-label use
- India market entry/registration pathway assessment, since the drug currently has zero local licenses
Note: The remaining eight predicted indications (trichotillomania, hydranencephaly, congenital glycosylation disorder, X-linked myopia variants, retinal dystrophy, polymicrogyria syndrome) have no supporting clinical or literature evidence and are correctly scored “Hold” — these should not be pursued without independent mechanistic or preclinical validation. Tourette syndrome (rank 7, L3/S2, “Research Question”) has limited pilot-study support and may warrant a separate, lower-priority evaluation.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.