Strategies for treating depression in patients with hepatitis C
Psychiatric symptoms can precede infection or be caused by HCV treatments
Altered serotonin metabolism has been linked to depression in hepatitis C virus (HCV) patients treated with interferon-α (IFN-α). Tryptophan can be metabolized towards serotonin via tryptophan hydroxylase and niacin via indoleamine-2,3-dioxygenase (IDO) with kynurenine (KYN) and quinolinic acid (QUIN) as intermediaries. Introduction of IFN-α activates IDO, causing preferential conversion of tryptophan towards the niacin arm away from serotonin and leads to elevated levels of KYN and QUIN. KYN and QUIN are available centrally, are neurotoxic, and have been correlated with increased depressive symptoms in IFN-α-treated patients.a,b A tryptophan-deficient state is created, with less tryptophan being converted to serotonin and subsequently to its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Decreased levels of 5-HIAA in cerebrospinal fluid have been associated with higher depressive symptoms and higher rates of suicide.a,b
Several genetic polymorphisms may help identify patients at risk for developing IFN-α-induced depression. Genes for the 5’ promoter of the serotonin transporter (5-HTTLPR) have been investigated for roles in depression development in patients undergoing immunotherapy. Studies have found that persons with the short allele in the 5-HTTLPR gene are more likely to develop depression than those with the long allele. However, this has not been consistent across racial or ethnic groups.a,b Research also has associated the serotonin (5-HT) transporter, interferon receptor-A1, apolipoprotein ε4 allele, cyclooxygenase 2, and phospholipase A2 with development of a specific subgroup of symptoms.a
References
a. Smith KJ, Norris S, O’Farrelly C, et al. Risk factors for the development of depression in patients with hepatitis C taking interferon-α. Neuropsychiatr Dis Treat. 2011;7:275-292.
b. Sockalingam S, Links PS, Abbey SE. Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update. J Viral Hepat. 2011;18(3):153-160.
Treating depressed HCV patients
Antidepressants are the treatment of choice for IFN-α-induced depression. Most currently used antidepressants are effective22 and selective serotonin reuptake inhibitors are considered first choice.16 Antidepressant choice should be guided by principles similar to those used for patients without HCV: using side effects profiles to target specific symptoms and being mindful of pharmacokinetic properties.
Two treatment approaches have been investigated: prophylactic and symptomatic. A 2012 study23 of 181 HCV patients with no history of mental illness determined escitalopram, 10 mg/d, effectively reduced the incidence and severity of interferon-associated depression. Other studies examining prophylactic treatment of all patients who were to undergo interferon treatment found this approach did not prevent depressive episodes.24,25 However, antidepressants have been beneficial for patients with subsyndromal depressive symptoms at baseline26 and after clinically significant depressive symptoms emerge.27 Electroconvulsive therapy also has been reported to effectively treat depression in HCV patients undergoing antiviral therapy.28
CASE CONTINUED: Lingering symptoms
Mr. P responds to citalopram with an improvement in mood, anhedonia, and appetite, but he continues to complain of low energy and poor concentration. In an effort to target these symptoms, methylphenidate, titrated to 30 mg/d in divided doses, is added to his regimen, which rapidly improves his symptoms. Insomnia is treated successfully with trazodone, 50 mg/d. Mr. P frequently visits his psychiatrist, who monitors his depressive symptoms using the BDI-II. Mr. P completes HCV treatment without recurrence of depressive symptoms or relapse to heroin use.
Although antidepressants are effective for treating affective and cognitive symptoms, they are not as effective for fatigue and other neurovegetative symptoms.16,29 The psychostimulants methylphenidate and dextroamphetamine and the nonstimulant modafinil have been studied for treating depressive symptoms in medically ill patients and can be used to treat IFN-α-induced fatigue.16,22,29
IFN-α’s effect on serotonin metabolism leads to a tryptophan-deficient state because of increased catabolism as a result of activation of indoleamine-2,3-dioxygenase (IDO). This has led to use of tryptophan supplementation, either as augmentation or monotherapy, for managing depressive symptoms in patients treated with IFN-α. Schaefer et al30 reported 3 cases where tryptophan supplementation significantly decreased depressive symptoms. Other researchers have argued that supplementing tryptophan in the context of IDO activation can lead to greater production of kynurenine and quinolinic acid, which have been linked to increased depressive symptoms in patients receiving IFN-α.31 They argue that supplementation of 5-HTP, which is available as a dietary supplement without a prescription, can lead to increased serotonin levels and improvement in depressive symptoms.31
IFN-α treatment also is associated with mania and psychosis. The incidence, pathophysiology, and management of these treatment-emergent symptoms are not as well studied as IFN-α-induced depression. Mania and hypomania have been reported with interferon treatment, discontinuation of interferon, and use of antidepressants for interferon-induced depression.29,32 Psychosis, in association with mood symptoms or alone, has been reported to occur in <1% of treated patients.33 Treatment for mania and psychosis consists of decreasing or discontinuing immunotherapy and adding mood stabilizers and antipsychotics. Once immunotherapy is discontinued, mania and psychosis usually resolve, but prolonged duration of symptoms has been reported.29,32,33
