A Review of the Use of Stimulants and Stimulant Alternatives in Treating Bipolar Depression and Major Depressive Disorder

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.