Lorenzo Rossaro, MD

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.

Even without IFN, the risk of depressive disorder in recurrent HCV following liver transplant is high. Reduced quality of life was found, as was decreased physical functioning in liver transplant patients who experienced a recurrence of HCV (Chong et al., 2003; Paterson et al., 2000). Patients with recurrence of HCV following hepatic transplantation and treated with IFN and RBV are at especially high risk for depression (Scott and Perry, 2002).

Mood disorders in patients with HCV (especially in post-transplant recurrent HCV) require aggressive clinical management. Some recommendations are listed in 

. Because worsening of depression may be associated with decreased medication compliance with antiviral and immunosuppressive regimens, it is particularly critical for these patients to minimize the risk of exacerbating mood symptoms during treatment of recurrent HCV. The pre-IFN/RBV psychiatric assessment should examine the patient's emotional and cognitive capacity for medication and other medical compliance; reinforce the need for sobriety and recovery, as necessary; and consider antidepressant prophylaxis and other psychiatric treatment to minimize the level of symptoms (Goldsmith et al., 2003). The use of standardized depression symptom instruments (e.g., Hamilton Rating Scale for Depression [HAM-D], Beck Depression Inventory [BDI]) is encouraged, as serial assessments may reveal trends of increased scores with emerging symptoms. Psychiatric assessment should, in an integrated manner, address social and cultural factors to facilitate compliance (Goldsmith et al., 2003). Loftis and Hauser (2003a, 2003b) cautioned against the routine prophylactic use of SSRIs for IFN-induced depression, citing the reports of increased retinal hemorrhages, cotton wool spots and gastrointestinal bleeding.

Therefore, even if patients are already on antidepressant treatment at the beginning of IFN/RBV therapy, continued vigilance for worsening of depressive symptoms is critical throughout the course of treatment, especially in the first three months. Mood disturbances may be due to a complex series of factors, including serotonin, norepinephrine and thyroid dysregulation (Dieperink et al., 2000). Pretreatment and ongoing monitoring of thyroid status with replacement of thyroid hormone in cases of treatment-emergent hypothyroidism appears warranted.

The SSRI agents, while generally valuable in the treatment of mood disorders, may be limited by their paucity of noradrenergic-modulating activity (Dieperink et al., 2000). It therefore seems prudent to consider two strategies, neither of which is yet validated in clinical studies. First, given the possibility of noradrenergic mechanisms in mood disorders following IFN therapy (which may be reflected in symptoms such as fatigue and mental slowing), the antidepressants of first choice may ultimately prove to be dual-action agents that affect both serotonergic and noradrenergic mechanisms (Dieperink et al., 2000). Some considerations are listed in 

. Currently available examples of dual-action agents include venlafaxine (Effexor), duloxetine (Cymbalta), mirtazapine (Remeron) and tricyclic antidepressants (Gumnick and Nemeroff, 2000). However, TCAs have a high burden of side effects and can increase the risk for delirium. Thus, they are not the antidepressants of choice (Crone and Gabriel, 2003; Gumnick and Nemeroff, 2000).

An alternative is to use SSRIs for initial treatment of depression in HCV and to continue these agents when IFN/RBV is started. It may be more prudent to choose a SSRI with fewer cytochrome P450 drug interactions (e.g., citalopram, escitalopram [Lexapro]) rather than one with more interactions (e.g., fluoxetine [Prozac], paroxetine, fluvoxamine [Luvox], sertraline [Zoloft]) (Hauser et al., 2002). If this strategy is followed, then vigilance for treatment-emergent depression is especially critical in the first three months of IFN/RBV therapy (Loftis and Hauser, 2003b). If mood symptoms worsen, increasing the dose of the SSRI or switching to a dual-action antidepressant such as venlafaxine or mirtazapine should be strongly considered. Care should be taken that adequately high doses of dual action agents are used to assure that the dual action is being obtained. Up to 225 mg/day of venlafaxine or 45 mg/day of mirtazapine may be needed (Crone et al., 2004). More complex psychiatric augmentation strategies, including psychostimulants and/or antipsychotics, may also be needed (Crone and Gabriel, 2003).

Mirtazapine is associated with sedation and increased appetite and thus is valuable in cases of significant insomnia and weight loss. An additional concern with mirtazapine is a low risk of decreased white cell count, which may also be seen as a side effect of IFN/RBV treatment (Ahmed, 2002; Beckebaum et al., 2004; Hartmann, 1999; Ong and Younossi, 2004). In cases of depression with weight gain or hypersomnolence, venlafaxine may be preferred. Another theoretical benefit of venlafaxine is its relatively low level of protein binding, which may be significant in cases with hepatic dysfunction (Gumnick and Nemeroff, 2000). Venlafaxine has, only rarely, been associated with medication-induced hepatitis (Crone and Gabriel, 2003).

Bupropion (Wellbutrin) affects dopamine receptor dynamics and thus may be mildly stimulating. However, it has a risk of provoking seizures, so should not be used in a patient with history of seizure disorder or at other high risk for seizures (Crone and Gabriel, 2003). In addition, seizures are themselves associated with IFN (albeit rarely), which may make bupropion use additionally risky (Dieperink et al., 2000).

For depressed patients with significant lethargy and apathy despite antidepressant therapy, augmentation with psychostimulants (e.g., methylphenidate [Ritalin, Concerta, Metadate], dextroamphetamine [Adderall, Dexedrine]) or the wakefulness-promoting agent modafinil (Provigil) may be considered (Loftis and Hauser 2003b). Caution should be exercised in prescribing psychostimulants to patients with history of substance abuse/dependence. For cases of depression with psychotic features, treatment with an antidepressant and an atypical antipsychotic is preferred (Hoffman et al., 2003). For treatment-refractory cases, electroconvulsive therapy can be considered. Comprehensive multidisciplinary medical and non-medical mental health care is a desirable treatment model, due to the psychiatric illness burden in these patients (Straits-Troster et al., 2003).

Psychiatric comorbidity, particularly depression, is common and may complicate the management of HCV. The risk of depression appears to increase further with the use of IFN/RBV treatment for HCV. Careful attention to comorbid substance abuse and modification of psychopharmacological approaches may be necessary for these patients.

Comanagement with the patient's hepatologist is desirable for coordination and maximization of clinical care.

Dr. Bourgeois is the Alan Stoudemire Professor of Psychosomatic Medicine and director of the psychiatry consultation-liaison service at the University of California at Davis (UCD) Medical Center in Sacramento, Calif.

Dr. Rossaro is chief of hepatology and medical director of liver transplantation in the department of internal medicine at the UCD School of Medicine.

Dr. Canning is a medical psychologist at the California Dept. of Corrections at the California Medical Facility in Vacaville, Calif., where he treats inmates suffering from HIV and other chronic medical conditions.

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