Trazodone
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Trazodone: From Unipolar Depression to Obsessive-Compulsive Disorder
One-Sentence Summary
Trazodone is a serotonergic antidepressant, originally used to treat depression (unipolar depression, major depressive disorder) and anxiety disorders. The TxGNN model predicts it may be effective for Obsessive-Compulsive Disorder (OCD), but the supporting evidence consists of no registered clinical trials and 20 publications, mostly small, dated (1984–1996) case reports, open-label studies and reviews, with one double-blind placebo-controlled study.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Unipolar depression, major depressive disorder (the US license entries contain no indication text) |
| Predicted New Indication | Obsessive-compulsive disorder |
| TxGNN Prediction Score | 99.95% |
| Evidence Level | L3 |
| US Market Status | Cancelled only (all 9 listed licenses are cancelled) |
| Number of NDAs | 9 (all ANDA generic applications, none currently valid) |
| Recommended Decision | Hold (research question only) |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. Based on general pharmacology, trazodone acts as a 5-HT2A receptor antagonist with weak serotonin reuptake inhibition, and its active metabolite mCPP has serotonergic effects. Serotonergic modulation is the established pharmacological basis of OCD treatment, so the link is plausible.
Depression and OCD frequently co-occur, and several reports describe OCD patients with comorbid depression responding to trazodone. However, the clinical literature is mixed. Trazodone’s own serotonin reuptake inhibition is weak compared with the agents that are established in OCD (clomipramine and the SSRIs). It is not a standard first-line OCD drug, and one review notes that its use in OCD is off-label.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 1629380 | 1992 | RCT | J Clin Psychopharmacol | Double-blind, placebo-controlled study of trazodone in OCD (the only controlled trial in the data compiled for this report) |
| 2119885 | 1990 | Case series / open-label | Clin Neuropharmacol | Nine clomipramine-resistant OCD patients: mild overall improvement; three responded well, with symptoms returning on withdrawal |
| 3501130 | 1987 | Observational | Psychopathology | Responders to trazodone showed changes in caudate glucose metabolism on PET |
| 3571943 | 1986 | Open-label pilot | Int Clin Psychopharmacol | Trazodone plus tryptophan in 11 patients: marginal benefit and poor tolerability |
| 8434675 | 1993 | Case series | Am J Psychiatry | Trazodone in OCD and trichotillomania |
| 4009160 | 1985 | Case report | J Nerv Ment Dis | Two treatment-resistant OCD patients with depression improved on trazodone |
| 26088119 | 2015 | Review | Curr Pharm Des | Off-label trazodone use, including OCD: evidence, benefits and risks |
| 27744763 | 2017 | Review | Postgrad Med | Review of trazodone in psychiatric and medical conditions, including non-approved uses |
| 8993077 | 1996 | Review | Psychopharmacol Bull | OCD responds mainly to potent serotonin reuptake inhibitors, relevant to where trazodone fits |
| 6703152 | 1984 | Case report | Am J Psychiatry | Early report of trazodone in OCD |
The 1992 placebo-controlled study is the strongest item, but the data compiled for this report do not include its full result, and the other literature is largely small, uncontrolled and old.
US Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ANDA205253 | Trazodone Hydrochloride (Cardinal Health 107) | Tablet | Not stated (cancelled) |
| ANDA071524 | Trazodone Hydrochloride (Vangard Labs) | Tablet | Not stated (cancelled) |
| ANDA202180 | Trazodone Hydrochloride (Torrent) | Tablet | Not stated (cancelled) |
| ANDA071196 | Trazodone Hydrochloride (RemedyRepack) | Tablet | Not stated (cancelled) |
| ANDA204852 | Trazodone Hydrochloride (Bryant Ranch Prepack) | Tablet | Not stated (cancelled) |
Nine licenses are listed in total, all cancelled, and all are oral tablets.
Safety Considerations
- Disease-level cautions from the knowledge graph (these are not package insert text): cardiac and haemodynamic conditions (long QT syndrome, familial long QT syndrome, torsades de pointes, heart disease, cardiovascular disease, orthostatic hypotension, postural orthostatic tachycardia syndrome, multiple system atrophy), potassium deficiency, blood coagulation disease, benign prostatic hyperplasia, priapism, and inappropriate ADH syndrome (including nephrogenic syndrome of inappropriate antidiuresis).
- Drug interactions: 100 interactions were recorded. Those flagged Major in the sample reviewed include bupropion, lorcaserin, dolasetron, palonosetron, cisapride, dexfenfluramine and fenfluramine, which are mostly QT-prolonging or serotonergic agents. Moderate examples include famotidine, loperamide, aprepitant, morphine, clarithromycin and dronabinol.
Please refer to the package insert for formal warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic link is plausible and one placebo-controlled study exists, but there are no registered trials, the literature is old and mostly uncontrolled, and trazodone is not an established OCD agent. The US licenses are all cancelled, and the package insert safety data are missing.
To proceed, the following is needed:
- Full results and critical appraisal of the 1992 placebo-controlled study (PMID 1629380)
- Detailed mechanism-of-action data
- FDA package insert warnings and contraindications for safety screening
- A modern, adequately powered controlled trial, ideally compared with or added to standard serotonin reuptake inhibitors
- Cardiac (QT) and serotonergic interaction risk assessment, since OCD patients often take SSRIs
Other Predicted Indications (Brief Notes)
| Predicted Indication | Score | Evidence Level | Note | |——|——|——|——| | Dysthymic disorder | 99.48% | L3 | Close to the original depression indication, but direct evidence is limited to a 1992 open-label study and insomnia-focused work | | Agoraphobia | 99.81% | L3 | Small 1980s panic disorder studies; efficacy appears inferior to standard agents | | Phobic disorder | 99.45% | L3 | Rests on the same two panic and agoraphobia studies | | Paranoid and histrionic personality disorders | 99.92% | L5 | Only a drug-interaction case report and a 1975 hysteria report, with no efficacy evidence | | Schizoid and schizotypal personality disorders, benign paroxysmal torticollis of infancy, Ohdo syndrome | 99.92% / 99.92% / 99.83% / 99.28% | L5 | No trials, no literature, no plausible mechanism; likely graph artifacts |
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.