Acute psychosis induced by isotretinoin.

Isotretinoin is used for the treatment of severe acne. Psychiatric side-effects, particularly depression, have been well-documented. This dramatic case report is about a young male patient who developed acute psychosis within a few days of starting isotretinoin. Due to his persecutory delusions, the patient, who was an Indian engineer working in Germany, decided to immediately return to India fearing for his life in Germany. Careful history taking established the cause of the psychosis. Isotretinoin was stopped; patient showed rapid improvement, within a week, on a low dose of risperidone. Risperidone was continued as a precaution for 3 months. After a further 8 months, the patient remains well without any psychotropic medication.

INTRODUCTION

Isotretinoin is an oral medication used to treat severe acne. Isotretinoin is the 13-cis isomer of retinoic acid, the active form of vitamin A. Isotretinoin works in acne by reducing sebaceous gland size, inhibiting the formation of new comedones, reducing growth of Propionibacterium acnes, and decreasing inflammation. Improvement usually takes at least 2 months, and treatment needs to be continued for at least 4 months. Although it is indicated only for severe, treatment-resistant cystic or nodular acne, in practice, it is being increasingly prescribed even for mild or moderately severe acne.[1] In the US, isotretinoin carries a so-called “Black Box” prescription warning of potential psychiatric side-effects including depression, suicide, and psychosis. It ranks in the top 10 drugs with respect to the number of reports of depression and suicide attempts.[2] Between 1982 and 2000, 37 patients on isotretinoin committed suicide, while 110 patients needed inpatient treatment for depression.[2] It is also highly teratongenic. While depression has been the most common psychiatric side-effect, psychosis has been occasionally documented.[3] In this report, I present a patient who developed acute psychosis after being prescribed isotretinoin for acne.

CASE REPORT

Mr. M was a 27-year-old single male, who had been working as an engineer in Germany for 15 months. He attended my outpatients’ clinic in Chennai with his brother and mother. He had returned suddenly from Germany the previous day, as he was convinced that his life was under threat from his work colleagues. When asked why he was being targeted, he said that he had developed a software tool at work recently, which because of its effectiveness was able to do the job of several people; consequently, some of his colleagues were angry with him as they were at risk of losing their jobs. He believed that his drinks and food in Germany were being contaminated to harm him. He felt he was being used as a “human sample.” He was convinced that his mobile phone calls were hacked, his internet activity was being monitored, and that he was being followed. He had written to his company management about his perceived persecution, and he had even lodged a complaint with the local German police who visited him at home to reassure him that he was safe. Even though he felt safer in Chennai than in Germany, he was concerned about potential harm to himself and his family from his German colleagues. He was adamant that he would never return to Germany.

He denied any hallucinations. He reported disturbed sleep over the previous few nights. He denied any suicidal ideas or ideas of wanting to harm others. There were no incidents of aggression.

He reported that he was started on isotretinoin by a dermatologist in Germany for acne (which by his account and on appearance did not seem particularly severe) about 2 weeks previously. The psychiatric symptoms started about 5 days later, increasing in severity gradually.

He had no previous psychiatric history or family psychiatric history. He reported no history of any major medical illnesses and was not on any regular medication apart from the recently started isotretinoin. He had one older brother. He was born of a full-term normal delivery and his mother said that his developmental milestones were normal. Patient reported no neglect or abuse as a child. He held a Master's degree in engineering, and had work experience for 4 years in an Indian company before going to Germany. He was a nonsmoker and denied any abuse of illicit drugs. In Germany, he used to drink beer occasionally.

During the assessment, he appeared tense but was cooperative and there was no formal thought disorder. He reported feeling “heavy” in his head. He had a slightly blunted affect, although he was able to smile at times. On testing his cognition, he was oriented in time and place, his immediate and delayed recall were normal, his concentration (serial 7s test) was preserved and he was able to interpret a proverb correctly. With respect to insight, he did not think he had a psychiatric problem and was more concerned about potential harm to his physical health due to deliberate “contamination” of food and drink in Germany. Nevertheless, he was willing to cooperate with the plan I suggested.

A provisional diagnosis of an acute psychotic episode (International Classification of Diseases-10 category F23.3 – “other predominantly delusional psychotic disorders”) was made, on the basis of acute onset of delusions (mainly of a persecutory nature) within a period of <2 weeks. Isotretinoin was considered the likely precipitant as the onset of the symptoms followed its initiation. Although a functional origin of symptoms was possible (i.e. first episode of a functional mental illness like schizophrenia), absence of any prodromal symptoms, previous psychiatric history, or family psychiatric history made this unlikely.

Mr. M was advised to stop isotretinoin. He was started on a low dose of risperidone 1 mg at night. In addition he was prescribed clonazepam 0.25 mg twice a day and zolpidem 5 mg at night. Some routine investigations were ordered. He was reviewed 3 days later, accompanied by his mother. He showed remarkable improvement. His sleep had improved, the “heaviness” in the head was much less, he no longer believed he or his family were under threat, and he was even open to the possibility of returning to Germany (an option he was vehemently against just 3 days previously!). His investigations (complete blood count, thyroid function test, liver function test, glucose, cholesterol, creatinine, and electrocardiography) were within normal limits. He was advised to continue risperidone 1 mg at night and zolpidem 5 mg at night. The dosage of clonazepam was reduced to 0.25 mg once daily.

Mr. M was reviewed again 4 days later (7 days after his first presentation). He felt he was fully back to his normal self, and this was corroborated by his mother. There were no psychotic, affective, or anxiety symptoms. He was keen to return to Germany as soon as possible, and I provided him a certificate of fitness to return to work. Clonazepam and zolpidem were stopped. As he was going to be living on his own in Germany, I advised him to take risperidone 1 mg at night for a further 3 months, mainly as a precautionary measure. He returned to Germany about 10 days later to resume his previous employment. He continues to remain well 11 months after his original presentation (8 months without medication).

The Naranjo adverse drug reaction probability scale[4] is sometimes helpful in determining whether a particular side-effect is due to a specific medication. The aggregate score from 10 items falls under four possible categories: “Doubtful” if the score is 0, “possible” if 1-4, “probable” if 5-8 and “definite” if the score is 9 or more. In this patient, the score was 7 (which falls in the “probable” category – i.e. that his psychosis was probably due to isotretinoin).

DISCUSSION

This is one more case highlighting the potential psychiatric consequences of a medication used to treat a physical condition. Isotretinoin has been in the international market since 1982 and is considered superior to other anti-acne treatments[5] (a position similar to that of clozapine among antipsychotics). However, considering its wide range of side-effects, it is officially recommended only for recalcitrant severe acne (similar to clozapine being given only for treatment-resistant schizophrenia). Due to its effectiveness, there has been an increasing tendency for isotretinoin to be prescribed even for less severe forms of acne (as was the case in this patient). As a result, psychiatric side-effects due to isotretinoin are likely to occur more frequently.

The exact mechanisms by which isotretinoin causes psychiatric side-effects are not known. While sufficient levels of vitamin A and its derivate, the retinoids, are important for central nervous system functioning, excess vitamin A can be harmful. Depression due to isotretinoin may be caused by decreased neurogenesis and impaired serotonin signalling.[6] Aetiology of psychosis due to isotretinoin is poorly understood and there do not seem to be any hypotheses yet.

There have been only a handful of previous reports of psychosis: A case series of five cases of manic psychosis[7] and three individual case reports of affective psychosis.[8910] Those cases have been mainly in those with a past history or family history of mental illness. The patient presented here had no prominent affective symptoms, and neither did he have a past psychiatric or family psychiatric history. The duration between initiation of isotretinoin and onset of psychotic symptoms was only 5 days in this patient, while in the previous case reports it has varied from 2 weeks to up to 11 months.[3]

This case reminds us of the importance of taking a full history, including medical history, during the initial assessment. If the use of isotretinoin had not been elicited in history, the patient would have got a label of a functional psychotic illness (such as schizophrenia), would probably have been prescribed antipsychotics for much longer, and would have had to live with the stigma of being labelled mentally ill. Furthermore, isotretinoin may have been continued by the patient and it would have interfered with the effectiveness of the antipsychotic, necessitating higher doses of the antipsychotic.

The general principles of treatment in drug-induced (including prescribed medication) psychosis should be: Stop the offending drug, prescribe lowest effective dose of antipsychotic, and adjunct sedative/hypnotic for the shortest possible time. These simple strategies helped the patient get better very quickly and return to his previous level of functioning.

CONCLUSION

Psychiatrists in addition to being aware of physical side-effects of the psychotropic drugs they prescribe (such as extra-pyramidal side-effects and metabolic syndrome) should also consider the possibility that typical psychiatric symptoms can be caused by medication prescribed for physical disorders.