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Case reports of severe dolutegravir-related depression
Michael Carter, 2017-09-05 10:50:00

Severe depression can be a side-effect of treatment with the anti-HIV drug dolutegravir. In HIV Medicine, clinicians from the Netherlands report two cases of rapid onset of serious depression after initiation of therapy with the drug. The authors are persuaded that dolutegravir was the cause. In neither case did the patients have factors pre-disposing them to the rapid on-set of depression, symptoms rapidly resolved after dolutrgravir was discontinued, and neither patient was treated with antidepressants. “This strongly suggests a causal relationship,” they comment.

Dolutegravir belongs to a class of antiretrovirals known as integrase inhibitors. It has been coformulated with abacavir/lamivudine providing potent HIV treatment in a single pill (Triumeq).

Severe dolutegravir-associated neuropsychiatric side-effects were rare in the clinical trials that led to the licensing of the drug. However, higher than expected rates of neuropsychiatric adverse events have been reported in routine clinical settings. In the past year, clinicians have reported discontinuation rates of up to 14%, with older patients and women especially likely to develop neuropsychiatric side-effects and stop taking the drug.

The latest cases both involve middle-aged men in the Netherlands.

The first patient was 58-year-old man newly diagnosed with HIV. His mental and physical health was good and he had no co-infections or co-morbidities. A month after diagnosis, the patient initiated therapy with Triumeq, which he took before going to bed. Depressive symptoms soon appeared. Within a week, the patient reported feeling gloomy, followed shortly by the emergence of severe depression. The patient developed paranoia and became very short tempered. Laboratory tests did not identify a cause. Therapy with Triumeq was discontinued and replaced with elvitegravir/cobicistat/emtricitabine/tenofovir. Within a week, his symptoms had improved and had completely disappeared after 20 days. Three months after the treatment change, the man was emotionally stable and had not experienced a recurrence of the depressive symptoms.

The second case involved a 52-year-old man who switched to Triumeq from an efavirenz-based regimen after complaining of tiredness. At the time of the change, his viral load was undetectable, his CD4 cell count was normal. He did not have a history of any psychiatric illnesses, co-infections or significant co-morbidities. Two months after initiating Triumeq the patient became mildly depressed but did not tell his doctor. Therapy with dolutegravir continued for four months, the patient developing suicidal thoughts. On the verge of a serious suicide attempt, the man was admitted to a psychiatric unit. Laboratory tests revealed no abnormalities and no other causes could be identified. On the day of admission, he switched antiretroviral therapy to darunavir/tenofovoir/emtricitabine. After five days, he was sufficiently stable to be discharged. Two weeks later, his depressive symptoms had almost resolved and three months after he was fully active without any psychiatric symptoms.

The investigators are persuaded that the absence of pre-existing mental health problems, the rapid onset of symptoms after initiation of dolutegravir therapy and the improvement in their patients after the drug was discontinued suggest a causal relationship between the drug and serious depression. They note that their patients are far from unique and that other case-series have been reported of patients discontinuing dolutegravir due to neuropsychiatric side effects.

Nonetheless these high rates of discontinuation are unexpected. In clinical trials, fewer than 2% of patients stopped dolutegravir because of serious side-effects of any kind and only 0.1-0.6% of patients discontinued the drug because of suicidal thoughts. 

They note that in 50 spontaneously reported cases of discontinuation reported to the manufacturer, a detailed psychiatric history was only available for 20 patients. In 16 of the 20, the patient had a prior history of mental health problems. Four of the five patients who committed suicide within six months of starting dolutegravir had a history of depression. In contrast, in the two cases newly reported, there was no history of poor mental health.

The authors suggest that the elevated concentrations of the drug could be linked to the occurrence of neuropsychiatric side-effects.

“We are in need of clinical and pharmacokinetic studies to precisely define the overall performance of dolutegravir in clinical practice with regard to neuropsychiatric adverse events, particularly in populations usually underrepresented in clinical trials,” write the authors.