A manic episode associated with efavirenz therapy for HIV infection

We report the case of a 40-year-old HIV-infected man who presented with the classic symptoms of a manic episode. Recent behavioural changes prompted a friend to bring the patient to the emergency department at St Michael's Hospital (Toronto, Canada). The previously antiretroviral-naive patient had been started on a treatment regimen one month earlier that consisted of lopinavir/ritonavir (400/100 mg twice a day) and efavirenz (600 mg a day). Upon speaking with the patient and his friend, it became evident that there had been a 2-week history of mood lability and disinhibition, mild grandiosity, decreased need for sleep, and an increase in activity level, spending and alcohol consumption. The friend also described pressured speech and flight of ideas, although the patient did not display these signs when examined in the emergency department. The patient was oriented to person and place but not to the day or date. He denied any other psychiatric symptoms and explained that he stopped taking both antiretroviral agents one week before his presentation because he felt ‘confused'. The patient denied any symptoms to suggest systemic or neurological disease and a complete physical examination was within normal limits. Bloodwork (complete blood count, prothrombin time/partial thromboplastin time, electrolytes, liver and renal function tests) and a computed tomography scan of the head were normal. He denied experiencing psychiatric symptoms in the past and reported no family history of psychiatric illness. The patient also denied any substance use other than occasional alcohol consumption – this was supported by a negative urine toxicology screen. Before starting antiretroviral therapy, the patient's CD4 lymphocyte count was 10 × 106 cells/l and his viral load was greater than 500 000 copies/ml. The patient had also recently been started on azithromycin (Mycobacterium avium intracellulare prophylaxis), dapsone (Pneumocystis carinii pneumonia prophylaxis), and fluconazole (treatment for oral candidiasis). Treatment of this patient's mania involved admission to the psychiatry ward and the administration of olanzapine (5 mg a day) for control of his mood symptoms. The patient showed progressive improvement in his symptoms over 5 days; however, the symptoms had not resolved completely and he was started on divalproex sodium (500 mg twice a day). He continued to improve and was discharged home one day later. On follow-up at 2 weeks and one month, the patient reported complete resolution of all his symptoms. Plans were made to discontinue the olanzapine and to continue follow-up for eventual discontinuation of divalproex sodium. Efavirenz, a potent antiretroviral agent used to manage HIV-1 infection, is well known for its neuropsychiatric adverse effects. Studies have shown rates of neuropsychiatric side-effects in patients receiving regimens containing efavirenz of up to 73% compared with 25% of patients on regimens not containing efavirenz [1–3]. The most commonly reported problems are dizziness, insomnia, difficulty concentrating, somnolence, and abnormal dreams. Severe depression, hallucinations, aggressive behaviour, suicidal ideation, or paranoia may also be experienced, although these effects are rare [1,2]. Manic reactions are a rare adverse event associated with the use of the drug; only 0.1% of patients enrolled in two large clinical trials experienced such reactions [1]. The manufacturer of efavirenz warns that the risk of mania and severe depression is higher in those with a history of psychiatric illness and substance abuse [1]. However, a recent review of the current literature that addresses this issue concluded that a lifetime history of psychiatric illness and substance abuse is not an independent risk factor for the development of neuropsychiatric adverse effects associated with efavirenz [4]. Only a single case report was found on MEDLINE that described a manic episode secondary to efavirenz therapy [5]. In that case, the patient took an overdose of 90 tablets and quickly developed the classic symptoms of mania. These symptoms resolved completely within 5 days of the discontinuation of efavirenz and treatment with low-dose risperidone. In this case, although it is impossible to rule out an underlying psychiatric illness without long-term follow-up, it appears likely that the manic symptoms were caused by efavirenz, and at a therapeutic dose. The temporal relationship of the symptoms and the initiation of efavirenz therapy, the patient's lack of a past personal or family history of psychiatric illness, and the improvement of some of the symptoms, such as the pressured speech and flight of ideas, when the patient stopped taking the efavirenz all support a causative role by efavirenz. In addition, the patient responded relatively rapidly to a low dose of olanzapine, and his symptoms had resolved completely on follow-up. Physicians prescribing efavirenz for the management of HIV-1 infection should be aware that the development of mania is a possible adverse effect of the medication, and that the effect may be delayed from the onset of therapy. Therefore, when evaluating patients who present with manic episodes, physicians should consider efavirenz as an aetiological agent in addition to the possible underlying psychiatric and organic aetiologies.

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