Does Raltegravir (Isentress) Worsen Depression in HIV Patients with a History of Treatment for Depression?

Exacerbation of depression associated with starting raltegravir: a report of four cases

Raltegravir is an HIV integrase inhibitor that has demonstrated excellent antiviral activity, safety and tolerability in clinical trials. We report four cases of treatment-experienced HIV-infected patients who experienced significant exacerbation of pre-existing depression temporally related to the start of raltegravir therapy.

Patient 1 is a 54-year-old man with a long-standing history of bipolar disorder. His HIV treatment included efavirenz [Sustiva] since 2004, without apparent adverse psychiatric effects. On 5 June 2007, he was doing well and his bipolar disorder was stable. He discontinued enfuvirtide [Fuzeon] and started raltegravir, 400 mg twice daily, on 20 June 2007. He was seen by his family doctor on 27 June reporting increased depression. His dose of valproic acid [an anticonvulsant and mood-stabilizing drug] was increased by his psychiatrist. For the next month, he experienced severe depression to the point where he did not have "the strength to get out of bed". The symptoms resolved gradually and, by 24 August 2007, he felt better. As of 14 March 2008, his mood was stable while still receiving raltegravir.

Patient 2 is a 44-year-old man diagnosed with depression in 2006. Symptoms were exacerbated by efavirenz starting 2 June 2006 and improved after efavirenz was discontinued on 22 May 2007. On 26 June 2007, he discontinued enfuvirtide and started raltegravir, 400 mg twice daily. When he presented to his family doctor on 23 July 2007, he was very depressed, tearful, suicidal, and had paranoid ideation and psychomotor slowing. He was admitted to hospital on 30 July 2007 with psychosis, depression with suicidal risk, and anxiety. His doses of risperidone [Risperdal], bupropion [Wellbutrin], and clonazepam [Klonopin] were increased, citalopram [Celexa] was continued, quetiapine [Seroquel, Ketipinor] was discontinued, and he commenced zopiclone [Imovane, Zimovane]. Psychiatric symptoms improved after discharge on 28 August 2007 and he remains stable on raltegravir as of 22 May 2008. The exacerbation of depression in this case was previously reported with regard to the strategy of switching from enfuvirtide to raltegravir.

Patient 3 is a 55-year-old man diagnosed with depression and bipolar disorder in 2002. He discontinued lopinavir/ritonavir [Kaletra] due to gastrointestinal intolerance and started raltegravir, 400 mg, and darunavir/ritonavir [boosted Prezista], 600/100 mg twice daily, on 8 November 2007. In February 2008, he reported the onset of profound depression shortly after changing his antiretrovirals. Doses of his psychiatric medications were decreased and his symptoms improved. As of 6 May 2008, he remains stable on raltegravir.

Patient 4 is a 40-year-old man with a history of depression with psychotic features. On 28 January 2008, he discontinued atazanavir [Reyataz], nevirapine [Viramune], and stavudine [d4T; Zerit] because of gastrointestinal intolerance and started raltegravir, 400 mg twice daily. On 25 February 2008, he reported a depressed mood, lack of energy, lack of motivation, and feeling sad since starting raltegravir. On 10 March 2008, he had an ongoing severe depressed mood, increasing auditory hallucinations, poor sleep, lack of energy, and was irritable and angry. Citalopram was discontinued and he started venlafaxine [Effexor] extended release, 75 mg daily. By 31 March, he reported his depressed mood was resolved. On 26 May 2008, his depression and psychotic symptoms were stable and raltegravir was continued.

Depression and other psychiatric adverse events in excess of those seen in the control arms have not been reported with raltegravir in clinical trials; however, patients with a history of such disorders may be excluded from participation. No post-marketing reports of depression appear in the product information as of May 2008. To our knowledge, these are the first cases to describe an association between starting raltegravir and exacerbation of depression. The association is compelling in terms of the temporal association and the fact that the patients started no new drugs other than raltegravir, except one who concomitantly started darunavir (which is not known to be associated with depression). Two patients had simply replaced enfuvirtide with raltegravir, a strategy that has demonstrated virological success.

Of note, all patients had ongoing depression and were under treatment with antidepressants and other psychotropic medications. One potential cause of the observed psychiatric decompensation would be an as yet unidentified interaction between raltegravir and one or more of the psychotropic medications.

Raltegravir is neither an inducer nor an inhibitor of cytochrome P450 3A4, and no clinically significant interactions are expected with drugs metabolized by this system, including the psychiatric medications received by these patients; however, another mechanism may be affecting drug levels in this situation. At this time, the mechanism by which raltegravir may have contributed to the observed psychiatric decompensation remains unknown.

In addition, it is not currently known whether this is a class effect of the integrase inhibitors or a specific attribute of raltegravir. Pending further study, caution and close monitoring is advised when starting raltegravir in patients with a history of depression who are currently under treatment with antidepressant and other psychotropic medications.