Isotretinoin, Depression and Suicide Ideation in an Adolescent Boy

Isotretinoin [13-cis-retinoic acid, trade name: (ro)accutane], is a common, effective pharmacological substance in the treatment of severe acne. There has been a long history of controversial discussion as to whether or not treatment with isotretinoin may induce depressive symptoms, suicide ideation or even suicide (for review, see [1]).

The studies performed until now do not support an association between isotretinoin and the aforementioned symptoms; however, some studies underlie several methodological limitations, e.g., retrospective or uncontrolled study design.

We here report the case of a 16-year-old boy who experienced two depressive episodes which were strongly associated with isotretinoin treatment.

The boy was presented in our hospital in April 2006 with depressed mood, insomnia, headache, loss of energy, anxiety and pondering about the future, social withdrawal, feeling of worthlessness and reduced appetite, thus fulfilling clinical criteria for a major depressive episode (DSM-IV-TR). The severity of symptoms including suicide ideation required closed ward care. Psychological examination showed an average intelligence (HAWIK-III: IQ=99) and a markedly increased score for depression in the Beck's Depression Inventory (T=78). Apart from pronounced acne conglobata (face, back), there were no pathological results in the physical and neurological examination or laboratory tests.

The boy's medication history revealed that he had received acne treatment with isotretinoin monotherapy (60 mg per day) from November 2005 to March 2006. The boy and his parents reported onset of depressive symptoms immediately after initiation of isotretinoin therapy. In March 2006, four weeks prior to admission, isotretinoin had been replaced by minocycline (200 mg per day), leading to a mild improvement of the depressive symptoms. Further enquiry revealed there had been a previous course of isotretinoin treatment three years prior to that date: Soon after drug initiation, the boy had developed depressive symptoms and had discontinued medication. After that, the depressive symptoms had improved.

Based on the assumption of a drug-induced depression and due to a mild improvement of psychopathology after isotretinoin discontinuation, we first speculated whether the depressive symptoms would again resolve spontaneously. However, due to the severity of his depression, we decided to start anti-depressive therapy with fluoxetin (20 mg per day) two weeks after admission. The depressive symptoms disappeared completely within 4 weeks and the patient could be discharged. The 3 month follow-up did not reveal any remaining depressive symptoms.

To estimate the link between isotretinoin treatment and depression, we used the adverse drug reaction (ADR) scale by Naranjo et al. (“Naranjo Probability Scale”, [2]) as an objective causality assessment. The scale consists of 10 items asking, e.g., about a possible ADR/dose relation, other possible causes for ADR and objective measures for ADR. The items can be answered with “yes”, “no”, and “unknown”, scoring -1 to 2 points, resulting in a total score of 13 points maximum. Dependent of the total score, the probability of a causative link between drug and ADR is attributed as “definite”, “probable”, “possible” or “doubtful”.

According to the best estimate procedure, based on the review of all available information, the probability of the present and previous depressive episodes as isotretinoin-induced were rated as “definite” and “probable”, respectively. Hence, we classified the symptomatology as “mood disorder due to isotretinoin treatment (DSM-IV-TR 293.83) with major depressive-like episode”.

To our knowledge, this is the first case report using an objective causality assessment to support the link between isotretinoin treatment and depression. Especially the positive dechallenge and rechallenge are persuasive references indicating a link between drug and ADR. The pharmacological mechanisms underlying the psychiatric symptomatology remain unclear; it may be speculated that retinoid receptors play a role, as they are widely distributed in the brain. From a pharmacological point of view, it seems reasonable that the clinical symptomatology of isotretinoin treatment may not only be a result from the specific pharmacological properties of the drug, but also from pharmacogenetic influences [3].

The current case report strongly indicates that isotretinoin may induce depression in idiosyncratic patients. Hence, prescribers of isotretinoin should be aware of this ADR and, if necessary, refer patients to psychiatric institutions.

The authors state that patient's and patient's parents’ consent for publication has been given.

References

• 1 Magin P, Pond D, Smith W. Isotretinoin, depression and suicide: a review of the evidence.  Br J Gen Pract. 2005;  55 134-138
• 2 Naranjo CA, Busto U, Sellers EM. et al . A method for estimating the probability of adverse drug reactions.  Clin Pharmacol Ther. 1981;  30 239-245
• 3 Rodondi N, Darioli R, Ramelet AA. et al . High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study.  Ann Intern Med. 2002;  136 582-589

Correspondence