Portal de Periódicos da CAPES

Psychiatric disorders after starting dolutegravir

2015; Lippincott Williams & Wilkins; Volume: 29; Issue: 13 Linguagem: Inglês

10.1097/qad.0000000000000789

1473-5571

Farid Kheloufi, Julie Allemand, Saadia Mokhtari, Anne Default,

Biochemical and Molecular Research

Dolutegravir is an integrase inhibitor with an excellent safety profile and antiviral activity. We report here four cases of patients who experienced psychiatric disorders. Symptoms resolved in three patients after stopping dolutegravir and in one patient who continued treatment. HIV healthcare professionals should pay attention to psychiatric disorders when beginning dolutegravir. Integrase inhibitors have demonstrated an excellent safety profile and antiviral activity. The last one is dolutegravir displaying an excellent tolerability and a high genetic barrier [1]. We report four patients who experienced psychiatric troubles or an exacerbation of psychiatric troubles after starting dolutegravir (Table 1).Table 1: Characteristics of patients.Patient 1 is a 56-year-old man treated with raltegravir/etravirine/darunavir/ritonavir. Raltegravir twice daily was switched to dolutegravir 50 mg once daily for treatment simplification. One week after beginning dolutegravir, he complained to his physician about dizziness, uneasiness feeling, and unusual fatigue. Sensations of being drunk were also felt by the patient. Treatment was continued but after 1 month, the patient decided to stop treatment because of his symptoms. Dolutegravir was switched back to raltegravir and symptoms quickly disappeared. There was not any past history of psychiatric troubles. Patient 2 is a 43-year-old woman treated with abacavir/lamivudine/atazanavir. Atazanavir was switched to dolutegravir because of metabolic adverse effects. After 1 month of treatment, she presented headaches, and felt mentally depressed with a sensation of angriness and irritability. Treatment was continued for one more month and then the patient decided to stop dolutegravir because the symptoms were still ongoing. Symptoms resolved within 2 weeks after dolutegravir discontinuation and switch to lopinavir/ritonavir. Patient 3 is a 51-year-old woman with an anxiodepressive and toxicomania history. She was treated with abacavir/lamivudine/atazanavir for HIV but atazanavir was switched to dolutegravir because of dyslipidemia. A few days after starting dolutegravir, she experienced a sensation of feeling ‘high’ and did not feel the outside world in the same way. One month after, she complained of anxiety and after 3 months of treatment, she consulted her physician because of severe depressive syndrome including an important sensation of craziness and psychological distress. Dolutegravir was stopped, treatment was switched back to atazanavir, and symptoms disappeared. Patient 4 is a 63-year-old man with severe anxiodepressive troubles background without any psychiatric medication. He was treated by emtricitabine/tenofovir/atazanavir/ritonavir but presented dyslipidemia. Atazanavir/ritonavir was stopped and switched to dolutegravir 50 mg once daily. A few days after beginning treatment, he complained about intense headaches that spontaneously resolved. He consulted his physician 1 month after starting dolutegravir because he experienced an exacerbation of his anxiodepressive troubles associated with suicidal ideation. Dolutegravir was continued and a few months after symptoms slowly decreased and the patient felt better. These four cases were reported to the local pharmacovigilance center. To the best of our knowledge, these are the first cases describing anxiodepressive troubles or exacerbation of psychiatric disorders after starting dolutegravir. For all patients, symptoms appeared quickly from 1 week to 1 month after beginning dolutegravir. Two patients had a past history of depression. Three patients recovered from their psychiatric troubles after stopping dolutegravir and symptoms slowly disappeared without stopping dolutegravir in one patient. Dolutegravir was the only new medicine introduced for all patients. None of the two patients with past treatment including raltegravir had experienced psychiatric adverse effect while treated with raltegravir. Psychiatric adverse effects such as depression were described during clinical trials but were not in excess compared with the control arms of SPRING-1 [2], SPRING-2 [3], SINGLE [4], FLAMINGO [5], VIKING [6], and VIKING-3 [7] studies. The fact that patients with a history of psychiatric disorders might be excluded from studies must be considered. Although common psychiatric adverse effects such as abnormal dreams are mentioned in the the summary of product characteristics of the three integrase inhibitors, an exacerbation of preexisting psychiatric troubles or depression in patients with past history of depression have been described only for raltegravir and elvitegravir in postmarketing studies [8,9]. The summary of product characteristics of dolutegravir does not mention any psychiatric adverse effect of that kind until April 2015 [10]. In 2008, Harris et al.[11] described an exacerbation of depression symptoms after starting raltegravir. The hypothesis of a drug–drug interaction between psychoactive drugs and antiretroviral was raised but does not apply here because none of the four patients were taking psychoactive drugs. Dolutegravir consistently penetrate central nervous system (CNS) as high levels of dolutegravir in CNS displaying antiviral activity were recently reported [12]. Considering that fact, the hypothesis of a direct CNS toxicity might explain depressive disorders after beginning dolutegravir. The psychiatric tolerability profile of the three integrase inhibitors might suggest the hypothesis of a class effect. Risk management plan of dolutegravir includes the analysis of psychiatric adverse reactions through pharmacovigilance reports. HIV healthcare professionals should pay attention to psychiatric adverse effects when beginning dolutegravir, especially in patients with past history of psychiatric disorders and report any adverse drug reaction to their pharmacovigilance center. Acknowledgements Conflicts of interest There are no conflicts of interest.