Drs. Pary, Jijakli, and Tobias are psychiatrists at the Robley Rex VAMC in Louisville, Kentucky. Dr. Scarff is a psychiatrist at the William Jennings Bryan Dorn Veterans Affairs Community Based Outpatient Clinic in Spartanburg, South Carolina. Dr. Lippmann is professor emeritus in the Department of Psychiatry and Behavioral Sciences at the University of Louisville School of Medicine in Kentucky.
References
but not overall depression. 36 Although OROS methylphenidate similarly failed to demonstrate statistically significant efficacy in another study, more responders were documented in the treatment group. 37
Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the limited number of studies evaluating stimulants’ effect on depression in patients with traumatic brain injury. This observation is of concern, as these conditions are frequently comorbid in returning veterans. One study noted that methylphenidate was an effective monotherapy for depression; whereas another study found that methylphenidate monotherapy reduced depression as well as sertraline, was better tolerated, and improved fatigue and cognition. 38,39
Modafinil and Armodafinil
Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder by modulating glutamate, gamma amino-butyric acid, and histamine. 40,41 Although they increase extracellular dopamine concentrations, they do not cause an increase in dopamine release and may have less misuse potential than that of dextroamphetamine and methylphenidate. 40,41 In a study of 7 patients with unipolar or bipolar depression, all patients achieved full or partial remission with minimal adverse effects (AEs). 42 In a prospective study, 41% of patients reported only mild depression or full remission with modafinil augmentation. 43
Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants. 44-49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue. 50-54 However, in one study, modafinil did not demonstrate efficacy compared with placebo. This result was attributed to premature study termination after 2 modafinil-treated patients developed suicidal ideation. 55 A post hoc analysis found no difference in frequency of suicidal ideation between groups.
Two DBPC studies evaluated armodafinil in patients with bipolar depression. In both studies it was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions in depression. 56,57
Atomoxetine
Atomoxetine is a norepinephrine reuptake inhibitor indicated for the treatment of ADHD and is considered to have no misuse potential due to lack of dopamine modulation. 58 In one study, 15 patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction. 59 A chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline. 60 However, in a DBPC trial, atomoxetine did not lead to significant changes in depression. 61
Discussion
There is a limited amount of high-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, most of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar depression, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both depression types. Collectively,
