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Unipolar major depression in adults: Augmentation of antidepressants with stimulants and stimulant-like drugs

Andrew Nierenberg, MD
Section Editor
Peter P Roy-Byrne, MD
Deputy Editor
David Solomon, MD


Stimulants (eg, methylphenidate) are primarily used to treat attention deficit hyperactivity disorder (ADHD), and stimulant-like drugs such as modafinil are used for narcolepsy, obstructive sleep apnea, and sleep shift work disorder [1]. However, stimulants have also been used for decades as add-on treatment in patients with unipolar major depression who have not responded adequately to antidepressant monotherapy. In a retrospective study of patients with unipolar major depression who were treated with an antidepressant and then received augmentation therapy (n >3200), stimulants were used in 5 percent of the patients [2].

This topic reviews the efficacy of stimulants and stimulant-like drugs for augmentation of antidepressants in treatment-resistant, unipolar major depression. Choosing a drug regimen for treatment-resistant depression is discussed separately. (See "Unipolar depression in adults: Treatment of resistant depression".)  


Adjunctive therapy for unipolar major depression is often required because initial treatment with a single antidepressant leads to remission in only 30 to 50 percent of patients [3-5]. Options for add-on treatment include second-generation antipsychotics, lithium, triiodothyronine, a second antidepressant, and psychotherapy (eg, cognitive-behavioral therapy). It is also thought that stimulants and stimulant-like drugs may be useful for patients with treatment-resistant depression because these drugs may ameliorate symptoms such as anergia, fatigue, hypersomnia, and impaired concentration, which are often initial or residual symptoms of major depression as well as side effects of some antidepressants [6,7].

In addition, it is biologically plausible that stimulants may be of value for treating depression when combined with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The pathophysiology of major depression may involve insufficient monoaminergic neurotransmission, and SSRIs initially increase serotonergic activity and SNRIs increase serotonergic and noradrenergic activity. However, major depression may also be associated with diminished dopaminergic transmission, and stimulants, modafinil, and pramipexole increase dopaminergic activity [8-10].


Stimulants (eg, methylphenidate) are indicated for late-life, treatment-resistant unipolar major depression. In addition, stimulant-like drugs (eg, modafinil and pramipexole) have limited evidence for efficacy in the general population of patients with treatment-resistant major depression. The use of stimulants and stimulant-like drugs is consistent with multiple treatment guidelines [11-13]. Based upon our clinical experience, we are more inclined to use stimulants and stimulant-like drugs for patients who lack energy, drive, motivation, interest, optimism, pleasure, and the ability to initiate activities [14].

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Literature review current through: Nov 2017. | This topic last updated: Jun 09, 2017.
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