As parts of the pharmaceutical industry are withdrawing from psychiatric drug development, drug repurposing has become one of the main techniques of innovative drug development in the field. Based on human neuropsychopharmacological studies, we aim to identify neurobiological mechanisms of action and clinical effects of potential new treatments for depression or other stress-related disorders. In this respect, we focus on targeting the GABAergic, noradrenergic and glutamatergic neurotransmitter systems, sleep physiology, memory consolidation, hedonic and social functions, neuroprotection and -degeneration, as well as neuroendocrine and neuroinflammatory mechanisms. Our approach includes various state-of-the-art techniques such as functional magnet resonance imaging (fMRI), electroencephalography (EEG), blood sampling, behavioural and neuropsychological testing, and assessment of subjective drug effects. Substances under current investigation are gamma-hydroxybutyrate (GHB), trazodone, dexmedetomidine, and ketamine/esketamine. As part of a research program investigating the effects of GHB on stress- and depression-related subjective, behavioural, and neurobiological parameters, we currently perform a study on the effects of GHB and trazodone on sleep, memory consolidation and neuroinflammatory parameters in healthy subjects and patients with depression.