OBJECTIVE: Isotretinoin (13-cis-retinoic acid), approved by the US Food and Drug 
Administration for the treatment of acne, carries a black box warning related to 
the risk of depression, suicide, and psychosis. Retinoic acid, the active form 
of vitamin A, regulates gene expression in the brain, and isotretinoin is its 
13-cis isomer. Retinoids represent a group of compounds derived from vitamin A 
that perform a large variety of functions in many systems, in particular the 
central nervous system, and abnormal retinoid levels can have neurologic 
effects. Although infrequent, proper recognition and treatment of psychiatric 
side effects in acne patients is critical given the risk of death and 
disability. This article reviews the evidence for isotretinoin's relationships 
with depression and suicidality.
DATA SOURCES: The PsycINFO, MEDLINE, and PubMed searchable database indexes were 
searched for articles published in the English language from 1960 to June 2010 
using the key words isotretinoin, retinoids, retinoic acid, depression, 
depressive disorders, and vitamin A. Evidence examined includes (1) case 
reports; (2) temporal association between onset of depression and exposure to 
the drug; (3) challenge-rechallenge cases; (4) class effect (other compounds in 
the same class, like vitamin A, having similar neuropsychiatric effects); (5) 
dose response; and (6) biologically plausible mechanisms.
STUDY SELECTION: All articles in the literature related to isotretinoin, 
depression, and suicide were reviewed, as well as articles related to class 
effect, dose response, and biologic plausibility.
DATA EXTRACTION: Information from individual articles in the literature was 
extracted, including number of episodes of depression, suicidality, suicide, 
psychosis, violence and aggression, past psychiatric history, time of onset in 
relation to isotretinoin usage, medication dosage, duration of treatment, and 
dechallenge and challenge history.
RESULTS: The literature reviewed is consistent with associations of isotretinoin 
administration with depression and with suicide in a subgroup of vulnerable 
individuals.
CONCLUSIONS: The relationship between isotretinoin and depression may have 
implications for a greater understanding of the neurobiology of affective 
disorders.