April Bonus Edition 2005
Hepatitis C infection (HCV) is a common cause of chronic liver disease and is frequently managed with immunosuppressive therapy (Scott and Perry, 2002). This illness is of great interest to the consultation-liaison psychiatrist because of the high risk of depression both from the underlying condition and its usual treatment. The risk of depressive disorders in people with HCV infection (even without interferon/ribavirin [IFN/RBV] treatment) has been reported as high as 37% (Dieperink et al., 2000; Yovtcheva et al., 2001). The risk of HCV is higher in patients with pre-existing psychiatric illness (Yovtcheva et al., 2001). Treatment-emergent depression after IFN/RBV treatment is common, as most studies report a risk of 10% to 40% (Dieperink et al., 2000). Proposed mechanisms for IFN-associated mood symptoms reflect possible effects on several neurotransmitter systems (Dieperink et al., 2000). Interferon increases plasma cortisol, and may also increase levels of norepinephrine and epinephrine, eventually leading to a downregulation of adrenergic receptors (Dieperink et al., 2000). It may also interfere with the production of tryptophan, decreasing the relative amount of serotonin available for neurotransmission, induce the activity of secondary cytokines and have a central dopamine agonist effect via an opioid mechanism (Dieperink et al., 2000).
Depressive disorders with IFN/RBV commonly feature prominent insomnia and fatigue. Depression attributable to IFN/RBV may be seen within two weeks of beginning treatment, with onset most common within 12 weeks (Crone et al., 2004; Loftis and Hauser, 2003b). The psychiatric side effects of IFN are so concerning that uncontrolled substance use and severe psychiatric symptoms (e.g., severe depression or psychosis) are strong contraindications to starting IFN, and may necessitate discontinuation of immunosuppressive treatment (Crone and Gabriel, 2003; Loftis and Hauser, 2003b).
Psychiatric symptoms represent nine of 21 common side effects and six of 24 uncommon side effects (Crone and Gabriel, 2003). Interferon-induced depression appears to be related to duration and dose of IFN more than to personal or family history of mood disorders. Suicidal ideation may also occur (Ademmer et al., 2001). A prospective study revealed that 11 (26%) of 42 patients with chronic HCV were receiving psychiatric treatment at study onset (Dieperink et al., 2003). During the study, 15 (48%) of the 31 patients (74%) not initially treated with psychotropic agents required treatment for psychiatric symptoms, and seven of these patients (23%) had major depression. Schaefer et al. (2003) found that 13 (16%) of 81 patients with HVC developed depression during IFN/RBV treatment. Seventeen (21%) patients were on antidepressants either before or during treatment, and selective serotonin reuptake inhibitors were used in 13 patients.
Kraus et al. (2003) studied 104 patients, 84 of whom received IFN. Increased depression, anger and hostility were found in the IFN group. Clinically relevant emotional distress was evident in 58% of IFN patients, compared to 23% pre-IFN patients. Despite these symptoms, only 8% of IFN patients discontinued treatment due to psychiatric factors. Seven IFN patients were started on paroxetine (Paxil) for IFN-induced depression; and six were subsequently able to complete the IFN treatment. Fontana et al. (2002) used the Brief Symptom Inventory (BSI) in 26 patients being treated with IFN/RBV. Neuropsychiatric symptoms were seen in 15 (58%). Depression, anxiety and somatization symptoms were increased on the BSI. Gochee et al. (2004) analyzed the apolipoprotein E genotypes of 110 patients with chronic HCV being treated with IFN. Patients with the ε-4 allele were more likely to be referred for psychiatric care and have more psychiatric symptoms such as irritability, anger, anxiety and other mood symptoms.
Hoffman et al. (2003) reported four cases of mood disorders with psychotic features associated with IFN/RBV for HCV. All four patients had a prior history of mood and substance use disorders, but no prior history of psychosis. Olanzapine (Zyprexa) was used with other psychotropic agents to manage the psychotic symptoms. Gleason and Yates (1999) treated five cases of HCV/IFN-associated depression with antidepressants, and three had a positive response. Farah (2002) found that citalopram (Celexa) 40 mg qd provided symptomatic relief in HCV/IFN-associated depression and was well tolerated. Gleason et al. (2004) assessed 15 patients treated with citalopram (mean dose=26.67 mg/day). There was a trend toward lower citalopram levels in patients receiving IFN. The authors concluded that citalopram might be used at usual doses to avoid undertreatment of depression in HCV.
The psychiatric effects of IFN have been reported in other systemic conditions. Musselman et al. (2001) randomized 38 patients with melanoma to paroxetine versus placebo before IFN treatment and found subsequent incidence of depression of 11% with paroxetine versus 45% with placebo.