Venlafaxine Treatment of Interferon-α Induced Depression

Director of Outpatient Services, Tisch Hospital’s Department of Psychiatry, New York University Medical Center

Interferon (IFN)-α, a highly purified protein product manufactured by recombinant deoxyribonucleic acid technology, is approved for the treatment of chronic hepatitis C virus (HCV) and for several types of cancer. Its antiviral/antitumor activity is believed to result from direct inhibition of viral replication, antiproliferative action against tumor cells, and modulation of the host immune response. Common adverse events (AEs) caused by this drug include flu-like manifestations and psychiatric symptoms. In particular, depression and suicidality,¹ psychosis,^2-6 and mania^7,8 have been reported. Case reports have indicated the efficacy of several types of antidepressants for IFN-α induced depression, including selective serotonin reuptake inhibitors (SSRIs),^9-12 nortriptyline,¹³ imipramine,¹⁴ trazodone,¹⁵ and bupropion.^16,17 The following is the first published report on the effectiveness of the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine for the treatment of IFN-α-induced depression.¹⁸

A 41-year-old man with chronic HCV was started on pegylated IFN-α2a 180 µg self-injected weekly and ribavirin 1,000 mg/day approximately 6 months after diagnosis. His other medications consisted of phenytoin, levothyroxine, hydrochlorothiazide, and diltiazem. Three weeks later, the patient experienced an unusual symptom combination of mood-incongruent visual hallucinations and depression. His history was significant for substance abuse—with the patient refusing drug testing—as well as for epilepsy, hypothyroidism, and well-controlled hypertension. While he reported no prior history of depression or hallucinations, a sibling was being treated for depression and anxiety.

Two weeks after his initial evaluation, the patient denied hallucinations but did report a worsening of depression. Escitalopram 10 mg/day was not tolerated. Sertraline 50 mg/day for 2 weeks improved the depression. Four weeks later, due to complaints of irritability, sertraline was increased to 75 mg/day. Two months later, his depression worsened; however, he declined to take a higher dose of sertraline. At this point, venlafaxine 37.5 mg/day was initiated, then titrated to 150 mg/day. He tolerated venlafaxine well without any AEs. His blood pressure remained unchanged. His depression remitted 2 weeks later. Throughout the course of treatment, the dosages of venlafaxine and interferon remained constant. After completion of the course of interferon therapy, venlafaxine was gradually withdrawn without recurrence of depression.

Given the patient’s substance-abuse history and noncompliance with drug testing, it is possible that ongoing substance abuse may have been the cause of his symptoms. Even if he was abstinent, IFN may have triggered flashbacks associated with past use of drugs. The temporal sequence of events presented in this case is consistent with IFN-α-induced depression and with resolution attributable to venlafaxine. At a dosage of 150 mg/day, venlafaxine is almost exclusively a serotonin reuptake inhibitor, as norepinephrine reuptake inhibition begins at doses higher than 150 mg/day. Interestingly, milnacipran, an SNRI, has also been reported to be efficacious for the treatment of IFN-α-induced depression in a patient with renal malignancy.¹⁹

The pathophysiology of IFN-α-induced depression may involve several different mechanisms. In rats, IFN-α decreases the concentrations of serotonin and norepinephrine in the frontal cortex²⁰ while in humans it increases serotonin transporter messenger ribonucleic acid²¹ and induces indoleamine 2,3-dioxygenase, the enzyme that converts tryptophan to kynurenine.²² As a result, the conversion of tryptophan to serotonin may be decreased, which would portend a higher likelihood of depression. In fact, recent research by Bonacorrso and colleagues²³ in a group of 18 patients with chronic HCV treated with IFN-α has shown a negative correlation between serotonin plasma levels and depression.

While during short-term treatment IFN-α appears to act as a dopaminergic agonist, after prolonged administration it binds to opiate receptors that seem to modulate presynaptic dopamine release, thereby eliciting a decrease in central dopaminergic activity.²⁴

Thus, deficiencies of serotonin, norepinephrine, and dopamine may all occur in IFN-α-induced depression supporting a role for SSRIs, SNRIs, bupropion, and other antidepressants that enhance serotonin, norepinephrine, and dopamine in the treatment of this AE. Clinicians prescribing IFN-α ought to be aware of its potential for precipitating depression and of the utility of the various antidepressants described here in the amelioration of this AE.

Disclosure: Dr. Ginsberg is a speaker for AstraZeneca, Bristol-Myers Squibb, Cyberonics, Forest, and GlaxoSmithKline; and has received research support from Cyberonics.

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