Ziprasidone
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Ziprasidone: From Schizophrenia and Bipolar Disorder to Major Affective Disorder
One-Sentence Summary
Ziprasidone is an atypical antipsychotic originally used to treat schizophrenia and bipolar disorder (manic and mixed episodes). The TxGNN model predicts it may be effective for Major Affective Disorder, with 7 clinical trials and 19 publications currently supporting this direction. The strongest evidence comes from several Phase 2 placebo-controlled trials, but no completed Phase 3 RCT confirms efficacy.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Schizophrenia; bipolar disorder (manic bipolar affective disorder) |
| Predicted New Indication | Major affective disorder |
| TxGNN Prediction Score | 99.66% |
| Evidence Level | L2 |
| US Market Status | Cancelled only (all licenses cancelled) |
| Number of NDAs | 7 (1 NDA and 6 ANDAs) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on the supplied analysis, ziprasidone antagonizes 5-HT2A and D2 receptors, partially activates 5-HT1A, and inhibits serotonin and norepinephrine reuptake. This profile gives a plausible rationale for use in depression.
Ziprasidone is already used for bipolar disorder (mania and mixed states), which is closely related to major affective disorder. Several second-generation antipsychotics are approved as add-ons to antidepressants for major depression, and systematic reviews and network meta-analyses address this strategy in treatment-resistant depression.
This is partly an extension of an existing bipolar indication rather than a fully new repurposing. Evidence for add-on use in unipolar depression appears mixed, and tolerability concerns (somnolence, QTc prolongation) must be weighed.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00633399 | Phase 2 | Completed | 458 | Three-phase study of ziprasidone added to an SSRI in MDD patients with inadequate SSRI response |
| NCT00555997 | Phase 2 | Completed | 120 | 12-week randomized, double-blind, placebo-controlled trial of ziprasidone in MDD, primary outcome HAM-D-17 change |
| NCT00490542 | Phase 2 | Completed | 73 | Double-blind, placebo-controlled trial in depressive mixed state |
| NCT00340379 | Phase 2/3 | Completed | 72 | Ziprasidone monotherapy vs. sertraline plus haloperidol in psychotic major depression |
| NCT01168674 | Phase 4 | Completed | 49 | Predictors of response to ziprasidone augmentation in MDD (13-week cross-over) |
| NCT00237666 | Phase 4 | Completed | 30 | Open-label, flexible-dose study in bipolar II major depression |
| NCT00421954 | Phase 3 | Completed | 8 | Open-label feasibility study in adolescents with psychotic disorder; too small to judge efficacy |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 34986373 | 2022 | Systematic review/NMA | Journal of Affective Disorders | Compares augmentation agents for treatment-resistant depression (efficacy and discontinuation) |
| 35510505 | 2023 | Systematic review/Meta-analysis | Psychological Medicine | Efficacy and tolerability of antipsychotics as monotherapy and adjunct in adult MDD |
| 34238049 | 2021 | Systematic review/Meta-analysis | Journal of Psychopharmacology | Antidepressants plus second-generation antipsychotics vs. esketamine vs. lithium in major depression |
| 40808264 | 2025 | Systematic review | Bipolar Disorders | Pharmacological treatments for MDD and bipolar depression with mixed features |
| 27835715 | 2017 | Randomized controlled trial | Journal of Clinical Psychiatry | Cardiac, endocrine, metabolic and motor effects of ziprasidone added to escitalopram in MDD |
| 27306192 | 2016 | Post-hoc analysis of RCT | International Clinical Psychopharmacology | Ziprasidone augmentation in anxious vs. non-anxious depression |
| 26619770 | 2015 | Review | American Journal of Psychiatry | Adjunctive ziprasidone in major depression and the status of adjunctive atypical antipsychotics |
| 19040553 | 2008 | Review | CNS Neuroscience & Therapeutics | Ziprasidone in affective disorders; acts on serotonin and dopamine receptors and inhibits norepinephrine reuptake |
| 25963405 | 2016 | Review | Asia-Pacific Psychiatry | Antipsychotics as antidepressants; effective for depression only at subantipsychotic doses |
| 32512768 | 2020 | Review | Pharmaceuticals (Basel) | Pharmacological options for treatment-resistant depression |
US Market Information
All seven authorizations are listed as cancelled; none is currently valid.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA020825 | Geodon (Roerig) | Capsule | Not listed |
| ANDA077561 | Ziprasidone Hydrochloride (American Health Packaging) | Capsule | Not listed |
| ANDA090348 | Ziprasidone (Chartwell RX) | Capsule | Not listed |
| ANDA204375 | Ziprasidone Hydrochloride (Macleods) | Capsule | Not listed |
| ANDA211908 | Ziprasidone mesylate (Dr. Reddy’s) | Lyophilized powder for injection | Not listed |
Safety Considerations
- Contraindications suggested by the knowledge graph (graph-derived associations, not label text): long QT syndrome, torsades de pointes, heart conduction disease, sudden cardiac arrest, myocardial infarction, orthostatic hypotension, liver failure, kidney disease, epilepsy, diabetes mellitus and diabetic ketoacidosis, hyperglycemia, neutropenia and agranulocytosis, hyperlipidemia, obesity, potassium deficiency and others.
- Drug Interactions: 100 interactions were found. Major-level examples include hydrocortisone, amphotericin B (including the lipid complex), bupropion and morphine. Moderate-level examples include metformin, pioglitazone, famotidine, epinephrine, atropine and acarbose.
- Literature notes: QTc prolongation and somnolence are tolerability issues raised in the supplied literature, along with pediatric cardiac safety.
Package insert warnings and contraindications were not available for this report; please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: Several Phase 2 placebo-controlled trials and meta-analyses address ziprasidone in major depression, so the prediction has real support (evidence level L2). However, no completed Phase 3 RCT confirms efficacy, results for unipolar augmentation appear mixed, cardiac (QTc) risk is significant, and all US licenses are cancelled. The model’s other top-ranked predictions (such as trichotillomania and Tourette syndrome) have little or no supporting evidence.
To proceed, the following is needed:
- Outcome data from the Phase 2 trials (especially NCT00633399 and NCT00555997) and a review of their efficacy results
- FDA package insert warnings and contraindications, to complete the safety screening
- Detailed mechanism of action data
- A cardiac risk assessment (QTc monitoring plan) and a review of the QT-related and other contraindications
- Clarification of market and regulatory feasibility given the cancelled licenses
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.