Psychological effects
Rare psychological side effects may include depression, worsening of pre-existing depression, aggressive tendencies, irritable mood and anxiety. Very rare effects include abnormal behaviour, psychosis, suicidal ideation, suicide attempts and suicide.[4][34][35][36] In a total of 5577 adverse reactions reported to the UK's MHRA up to 31 March 2017, the plurality (1207, or 22%) concerned psychiatric effects.[37] There were 85 reports of suicidal ideation, 56 of completed suicide and 43 of suicide attempts.[37]
The association between isotretinoin use and psychopathology has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use.[38] A number of studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects.[38]
Depression and suicidality
Isotretinoin is the only non-psychiatric drug on the FDA's top 10 list of drugs associated with depression[35][39] and is also within the top 10 for suicide attempts.[40] A black box warning for suicide, depression and psychosis has been present on isotretinoin's packaging in the United States since 2005.[39]
In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression and suicide, as well as articles related to class effect, dose response, and biologic plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals.[34] Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin.[41] However, whether isotretinoin use is causally associated with mental illness remains controversial.[41]
Evidence for depression being causally associated with isotretinoin use includes 41 reports of positive challenge/dechallenge/rechallenge with isotretinoin, involving administering isotretinoin, withdrawing the drug and then re-administering it.[34] The majority of these cases had no psychiatric history.[34] There is also a temporal relationship between development of depression and initiation of isotretinoin treatment, with most cases developing after 1–2 months of treatment.[34] Further, higher doses of isotretinoin increases the risk of developing depression, with 25% of people showing depression on a dose of 3 mg/kg/day as compared with 3–4% at normal doses.[34] Studies have uncovered several biological processes which may credibly explain the affective changes induced by isotretinoin.
Psychosis
Isotretinoin has also been linked to psychosis.[21] Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms.[34] The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms.[42]
It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia.[43][44] The evidence for this is threefold - Transcriptional activation of the dopamine D2 receptor, in addition to serotonin and glutamate receptors, is regulated by retinoic acid,[43] schizophrenia and the retinoid cascade have been linked to the same gene loci[43] and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia.[43] Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid.[45][46]