Genetic vulnerability and isotretinoin-induced psychiatric adverse events.

isotretretinoin (positive de-challenge) and re-emerged whenever the drug was re-administered (positive re-challenges); the remaining cases scored 3 on the Naranjo scale (“possible” ADR). In all four cases, however, the temporal relationship (1- or 2-month interval) between isotretinoin administration and the appearance of psychiatric symptoms shows that the drug was the most probable triggering factor.The multiformity of isotretinoin-induced psy-chiatric adverse events is only partly accounted for by the multiplicity of the drug’s effects on various neurotransmitter systems and brain structures (Goodman 1998; Bremner and McCaffery 2008). In this case series, we speculate a potential role for the various types of genetic vulnerability of the exposed individuals in the emergence of diverse psychiatric symptoms, an effect that has scarcely been investi-gated to date (Barak et al. 2005). For example, in cases #1 and #3 each of which had a family history loading for both psychosis and affective disorder, isotretinoin induced a mixed clinical syndrome with both psychotic and depressive features (“schizo-affective disorder”, “psychotic depression”). In cases #2 and #4 which had a loading for affective disor-der or psychosis, the induced syndrome was (non-psychotic) “major depression” or “schizophrenia”, respectively. We suggest that isotretinoin-induced psychiatric symptoms might be generated through a gene–environment interaction, with isotretinoin as an undifferentiated environmental stressor and its effects being modulated by the various types of genetic vulnerability of the exposed individuals.In conclusion, cases reported add to a few pre-vious similar reports of isotretinoin-induced psychi-atric manifestations in individuals with a positive To the Editors,Isotretinoin, a synthetic retinoid that is used against severe, recalcitrant nodulocystic acne, has been asso-ciated in several case-series and some retrospective and uncontrolled studies with various psychiatric side-effects (depression, violent behaviour, suicidality and psychotic symptoms) (Ng et al. 2001; Hull and d’Arcy 2003; Kontaxakis et al. 2009). Depressive symptoms are most often reported at 1 month after isotretinoin initiation at an estimated incidence of 1–11% (Bremner and McCaffery 2008). The first controlled study to find a statistically significant asso-ciation between isotretinoin and depression (relative risk 2.68) was recently published (Azoulay et al. 2008). However, the causal link between isotretinoin use and psychiatric adverse events remains controver-sial mainly due to poor quality of existing evidence (Strahan and Raimer 2006). We present four patients consecutively hospital-ized in our department during 2008 whose psychi-atric symptoms (depression, suicidality, psychotic symptoms) were possibly induced by isotretinoin administration. All patients had a positive family his-tory for psychiatric disorders. In Table I, clinicode-mographic characteristics of the four patients are presented. Determining the likelihood of whether a symptom is actually an adverse drug reaction (ADR) is often quite complicated (Naranjo et al. 1981; Mann et al. 2008). It is obvious that an association of isotretinoin use with psychopathology is not equally demonstrated by all cases presented. The strongest association can be established for case #3 (Naranjo score 5: “probable” ADR), whose psychi-atric symptoms remitted upon discontinuation of