Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.
Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life. 1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes. 2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression. 4
Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission. 5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration. 7
Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of 2 or more antidepressants with different mechanisms of action for sufficient duration. 5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility. 8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.
Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied. 9-12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs). 10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well. 12,14-23 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.
A literature search was conducted following an algorithmic approach in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for depression) and pemoline as the sole augmenting stimulant as well as studies of patients with comorbid mental health diagnoses and studies that initiated stimulants and antidepressants simultaneously