A Review of the Use of Stimulants and Stimulant Alternatives in Treating Bipolar Depression and Major Depressive Disorder
Abstract
OBJECTIVE: Prescribers often consider the off-label use of stimulants or stimulant alternatives as adjunctive antidepressants. The authors reviewed the available literature on the efficacy of these agents for treatment of refractory unipolar and bipolar depression. DATA SOURCES: PubMed, MEDLINE, and relevant English-language literature from 1988-2013 were searched. Keywords were dopaminergic, stimulant, augmentation, treatment refractory depression, dextroamphetamine, methylphenidate, modafinil, atomoxetine, and cardiovascular safety. STUDY SELECTION: All randomized controlled trials (RCTs) published during this time period were included. When RCTs were unavailable, open studies were summarized. DATA EXTRACTION: Data on the efficacy of stimulants and stimulant alternatives as treatment augmentation for unipolar and bipolar depression were extracted. RESULTS: Three open studies showed positive findings for dopaminergic stimulants, and, although 2 RCTs showed negative findings, a recent RCT revealed positive results for lisdexamfetamine as an adjunctive agent. To date, dopaminergic stimulants have not been tested in bipolar depression RCTs. Four completed RCTs suggested that modafinil/armodafinil were beneficial as treatment adjuncts for unipolar and bipolar depression, with very low rates of mood switch in bipolar depression. One study was stopped prematurely due to safety concerns of increased suicidality. CONCLUSIONS: Modafinil and armodafinil are recommended treatment adjuncts for refractory unipolar and bipolar depression. Until recently, RCT data on dopaminergic stimulants were too limited to warrant their use as first-line treatment adjuncts. However, the promising results of 1 recent lisdexamfetamine RCT, when considered in the context of the deleterious effect of subsyndromal depression, suggest consideration of dopaminergic medications in treatment-refractory unipolar or bipolar depression when modafinil is cost prohibitive or otherwise contraindicated.
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Modafinil has been shown in several randomized trials to be effective for symptoms of MDD as adjunctive treatment.
“Modafinil, thought primarily to act as a weak dopamine reuptake inhibitor, has been shown in several randomized trials to be effective for symptoms of MDD as adjunctive treatment (reviewed in ref. 106).”
From Paying attention to attention in depression (2019) · cites this paper as [106]
Psychostimulants remain the first-line treatment for ADHD and have been used as adjunctive therapy in MDD despite limited support from high-quality randomized controlled trials that examined mood-related symptom improvement alone.
“Psychostimulants, which increase levels of both NE and DA in the striatum and cortex, remain the first-line treatment for ADHD and have also been used as an adjunctive therapy in MDD despite limited support from high quality, randomized, controlled trials that examined mood-related symptom improvement alone106.”
From Paying attention to attention in depression (2019) · cites this paper as [106]
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- Authors
- Corp, S. A., Gitlin, M. J., & Altshuler, L. L.
- Affiliations
- University of California, Los Angeles (US)
- ORCID
- Gitlin, Michael J.
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2014-09-25
- Volume
- 75
- Issue
- 09
- Pages
- 1010-1018
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2109747167
- Cited by
- 56
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 10 · 2016: 9 · 2015: 12
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Keywords
- bipolar depression, major depressive disorder, treatment-resistant depression, stimulants, modafinil, armodafinil, lisdexamfetamine, methylphenidate, d-amphetamine, atomoxetine, mood switching, antidepressant augmentation, off-label drug use, cardiovascular safety, suicidality
- MeSH terms
- Central Nervous System Stimulants, Antidepressive Agents, Bipolar Disorder, Major Depressive Disorder, Drug Synergism, Drug Therapy, Combination, Humans, Treatment Outcome
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