For economic reasons, the generic substitution of branded medications is common and welcome. These replacements are based on the concept of bioequivalence, which is considered equal to therapeutic equivalence. Regulatory standards for bioequivalence require the 90 % confidence intervals of group averages of pharmacokinetic measures of a generic and the original drug to overlap within ±20 %. However, therapeutic equivalence has been challenged for several psychotropic agents by retrospective studies and case reports. To evaluate the degree of bioequivalence and therapeutic equivalence of branded and generic psychotropic drugs, we performed an electronic search (from database inception until 24 May 2012 and without language restrictions) in PubMed/MEDLINE, Cochrane Library, and Web of Science. Search terms were "(generic) AND (psychotropic OR psychoactive OR antipsychotic OR antiepileptic OR antidepressant OR stimulant OR benzodiazepine)" or the respective individual substances. We included clinical studies, regardless of design, comparing branded with generic psychotropic drug formulations, identifying 35 such studies. We also included case reports/series reporting on outcomes after a switch between brand and generic psychotropics, identifying 145 clinical cases. Bioequivalence studies in healthy controls or animals, in-vitro studies, and health economics studies without medical information were excluded. An overview of the few randomized controlled studies supports that US FDA regulations assure clinically adequate drug delivery in the majority of patients switched from brand to generic. However, with a growing number of competing generic products for one substance, and growing economic pressure to substitute with the currently cheapest generic, frequent generic-generic switches, often unbeknownst to prescribing clinicians, raise concerns, particularly for antiepileptics/mood stabilizers. Generic-generic switches may vary by more than ±20 % from each other in individual patients since the pharmacokinetic properties of each generic may differ from the innovator drug in opposing directions. Ideally, therapeutic equivalence studies in addition to pharmacokinetic equivalence studies would be performed for each generic, reflecting the full variability of clinical responses due to changes of pharmacokinetic properties related to age, sex, ethnicity, genetic factors, and body mass index. This is particularly relevant, as bioequivalence studies are based on single-dose studies in healthy controls who are likely not representative of the patients who are prescribed the psychotropic medications. Additionally, individual case reports suggest potential clinical effects during brand-generic switches. Knowledge and consideration of intra-individual variations can help guide the clinical management during brand-generic or generic-generic switch periods. To optimize outcomes, clinicians need to consider that when using generic psychotropic medications, a change in the patient's clinical status can be related to psychological, interactional, physiological, and pharmacological factors that may or may not be related to the change to a generic drug. In addition, throughout all treatment periods, clinicians need to be aware of the currently dispensed product (i.e., branded or exact generic formulation), particularly when evaluating clinical changes in efficacy, tolerability, and adherence. If clinical problems occur, the first response should be an assessment of adherence and a careful dose adjustments of the generic drug rather than an immediate switch back to the originator.