A Cochrane review included 24 studies with a total of 1 557 subjects. The level of depression of included patients ranged from mild to severe. Five drugs were evaluated; dexamphetamine, methylphenidate, methylamphetamine, pemoline and modafinil. Modafinil was evaluated separately as its pharmacology is different to that of the other PS. PS were administered as a monotherapy, adjunct therapy, in oral or intravenous preparation and in comparison with a placebo or an active therapy. Most effects were measured in the short term (up to four weeks). Thirteen trials had some usable data for meta-analyses.
Three trials (62 participants) demonstrated that oral PS, as a monotherapy, significantly reduced short term depressive symptoms in comparison with placebo (SMD -0.87, 95% CI -1.40 to -0.33). A similar effect was found for fatigue. In one small short term trial of PS with a total of 20 participants, there was no significant difference in depression scores between the PS and antidepressant groups (WMD -4.30, 95% CI -8.79 to 9.19). In one short term trial of PS with a total of 50 participants, there was no significant difference in the mean depression score between PS versus placebo as adjunct to antidepressant treatment (WMD -1.60, 95% CI -5.96 to 2.76). In two short term trials of modafinil with a total of 411 participants, there was no statistical difference in depression scores between modafinil and placebo (WMD -0.09, 95% CI -1.07 to 0.89). In the short term PS were acceptable and well tolerated. Tolerance and dependence were under evaluated. No statistically significant difference in depression symptoms was found between modafinil and placebo.
Comment: The quality of evidence is downgraded by study quality (inadequate or unclear allocation concealment, lack of blinding, short follow-up time), indirectness (few patient-related outcomes) and by imprecise results (few patients and wide confidence intervals).