Why do stimulants not work in typical depression?

Stimulants have been suggested as therapeutics in depression for 80 years now, but there is still no evidence from randomized controlled trials that stimulants, in general, possess specific antidepressant effects. Also, several recent large randomized controlled trials which tried to establish an indication for stimulants as add-on in depression failed, and the companies no longer proceed with regulatory filings. One reason why the common belief of an antidepressant effect has survived over decades is a lack of clarity in psychopathology. Tiredness in the sense of sleepiness (downregulation of arousal) and lack of drive are mixed up with tiredness in the sense of exhaustion with high inner tension (upregulation of arousal) and inhibition of drive. The latter is found in typical depression, and according to the recently introduced arousal regulation model of affective disorders, upregulation of arousal is considered to be an important pathogenetic factor. Psychostimulants are unlikely to have beneficial effects in those patients with upregulated arousal. However, there might be subgroups of depressed patients, such as atypical depression, which suffer from sleepiness and lack of drive and might respond to stimulants. Arousal, a dimension included in the Research Domain Criteria project of the National Institute of Mental Health, can be assessed with an electroencephalography-based algorithm (the Vigilance Algorithm Leipzig) and is a promising biomarker to identify subgroups of patients, which might respond to stimulants.