Sanjeev Sockalingam, MD

It is estimated that 130 to 150 million people currently suffer from chronic hepatitis C virus (HCV) infection.

 The prevalence of chronic HCV infection is among the highest in patients with severe underlying mental illness. The treatment of hepatitis C has evolved over the past 2 decades and transitioned from interferon-Î± (IFN-Î±) monotherapy to pegylated IFN-Î± in combination with ribavirin therapy; both are nonspecific immunotherapies.

There has recently been a shift in hepatitis C treatment guidelines with the emergence of a new class of agents: direct-acting antivirals (DAAs) that have revolutionized treatment of the infection. DAAs offer improved rates of HCV infection “cure,” defined as sustained virological response (negative HCV RNA, 24 weeks post treatment). They also require a shorter duration of treatment and have a more favorable adverse-effect profile than previous hepatitis C medication regimens (

). The most common adverse effects associated with DAAs are fatigue and insomnia (

). The reduced psychiatric risks with DAAs are salient developments to hepatitis C therapy, given that up to 50% of patients with untreated chronic HCV infection suffer from psychiatric illness when substance abuse and dependence are excluded.

In the past, patients with severe comorbid psychiatric illnesses had been considered “high risk” for HCV infection treatment primarily because of the neuropsychiatric adverse-effect profile associated with IFN-Î±. Although HCV-infected patients with psychiatric comorbidity can be effectively treated in integrated care models with psychiatric support, the introduction of newer DAAs may further increase access to hepatitis C treatment for these patients.

The focus on hepatitis C treatment adherence with DAAs has redefined psychiatrists’ role in collaborative or integrated care models for HCV infection. This article explores several implications pertaining to the psychiatric care of patients undergoing hepatitis C treatment and sheds some light on the changing role of psychiatrists amid evolving hepatitis C therapies and care models.

A limitation of IFN-Î± therapy has been its adverse neuropsychiatric effects, specifically depression, which can compromise the management of HCV-infected patients who have a preexisting history of psychiatric illness. It is estimated that the rates of IFN-Î±–induced depression range from 25% to 30%; this can result in severe complications, such as patient suicide, if the depression is poorly controlled.

Several proposed mechanisms for IFN-Î±–induced depression have been cited in the literature; however, much of the evidence suggests associated changes in the serotonergic system.

 Reductions in both tryptophan and plasma serotonin concentrations following the administration of IFN-Î± have been reported. It is believed that IFN-Î± transcriptionally activates indoleamine 2,3-dioxygenase, the rate-limiting enzyme of tryptophan conversion into kynurenine, the major (90%) nonprotein pathway of tryptophan metabolism.

 Other studies have identified a deficiency of serotonin production from tryptophan as a risk factor for developing IFN-Î±–induced depression (

 These abnormalities appear to resolve in most cases approximately 6 months after completion of IFN-Î± therapy.

The management of IFN-Î±–induced depression consists of an initial assessment for baseline depressive symptoms before the start of immunotherapy. Standardized depression scales can be used to evaluate the baseline psychopathology and the presence of an MDD before starting hepatitis C treatment. After initiating IFN-Î± therapy, clinicians should monitor patients for potential IFN-Î±–related adverse effects, such as anemia and hypothyroidism, that may cause or contribute to depressive symptoms.

A recent meta-analysis and systematic review found that prophylactic administration of an SSRI, such as paroxetine or escitalopram, before starting antiviral treatment for chronic HCV infection reduces the incidence of a major IFN-Î±–induced depressive episode by 43%.

Antidepressants, such as SSRIs, mirtazapine, and bupropion, have been efficacious in treating IFN-Î±–induced depression when it emerges during hepatitis C treatment.

 Regardless of the approach to antidepressant therapy, monitoring and routine follow-up every 2 weeks for at least the first 3 months after initiation of IFN-Î± therapy is required for all high-risk patients and continuous monitoring thereafter for stable high-risk patients.

Additional neuropsychiatric sequelae may also arise de novo or be exacerbated by immunotherapy with IFN-Î±. Potential neuropsychiatric complications of IFN-Î± therapy include anxiety, mania, psychosis, and cognitive changes. No specific anxiety disorders have been uniquely associated with IFN-Î± therapy; however, the literature shows that IFN-Î±–induced anxiety can be successfully treated with benzodiazepines and antidepressants.

Mania is also a reported complication of IFN-Î± therapy, and some reports suggest that rates of IFN-Î±–induced mania and hypomania may be as high as 19% in some samples.

 IFN-Î±–induced mania may respond to antipsychotic therapy.

 The use of carbamazepine and oxcarbazepine as mood stabilizers should be avoided because of the increased risk of agranulocytosis when they are used in combination with IFN-Î±.

Psychosis is a rare complication in patients undergoing treatment of HCV infection, and the recommended approach is to discontinue IFN-Î± therapy and use a conventional or novel antipsychotic.

 Neurocognitive symptoms have also been reported in patients with hepatitis C who are undergoing IFN-Î± therapy, specifically deficits in processing speed and verbal fluency and disruptions in frontostriatal structures.

 Recent data suggest that neurocognitive symptoms secondary to IFN-Î± therapy, although less common, can persist in select patients for longer periods. Moreover, early neurocognitive symptoms during IFN-Î± therapy may be a risk factor for persistent cognitive adverse effects.

 If neurocognitive complications arise during hepatitis C treatment, the patient should undergo a thorough cognitive assessment and cognitive monitoring should be done during and after treatment.

When a patient has a neuropsychiatric disorder related to hepatitis C treatment, the psychiatrist will need to have adequate knowledge of potential drug-drug interactions based on the pharmacokinetic properties of the DAAs. The risk of associated drug-drug interactions will substantially increase with the use of multiple medications, especially protease inhibitors because of their inhibitory effect on cytochrome P-450 (CYP) 3A4.

Similar challenges have been observed in the treatment of psychiatric disorders in patients with HIV infection. The results of potential drug-drug interactions in the treatment of psychiatric disorders with concurrent DAA therapy have been effectively summarized in a published systematic review.

 The steps to be taken to identify and manage potential drug-drug interactions before proceeding with treatment of HCV infection include but are not limited to the following:

• Ensure up-to-date patient medication records at each patient encounter

• Use a systematic approach to identify areas of potential concern

• Consult with pharmacists and HCV drug interaction resources

This comprehensive approach will help improve patient safety and optimize treatment outcomes.

In general, protease inhibitors, such as telaprevir, boceprevir, and simeprevir, potentially inhibit CYP3A4, which could potentially increase levels of psychotropics metabolized by this isoenzyme. Therefore, an appropriate dose reduction of psychotropics that require this P-450 enzyme may be necessary.

 For example, fluphenazine, pimozide, thioridazine, and ziprasidone are not to be administered with any DAAs because of the increased levels of these antipsychotic medications and increased risk of QTc prolongation. The anticonvulsants car- bamazepine and oxcarbazepine also should not be administered concurrently with DAAs. Carbamazepine and oxcarbazepine can decrease levels of boceprevir, telaprevir, simeprevir, and sofosbuvir through induction of CYP3A4. In patients with bipolar illness, these medications should be reassessed, or avoided, because they may reduce efficacy of DAAs. Because of the high degree of psychiatric comorbidity in HCV-infected patients, ongoing reassessment of psychiatric medications is needed, and psychiatrists will need to be knowledgeable about potential drug-drug interactions with the increasing use of DAAs for HCV infection.

It is imperative that the role of the psychiatrist evolve with changes in treatment guidelines and delivery of care to the patient population. Adherence to hepatitis C treatment is the most significant component in determining potential outcomes. Psychiatrists play a critical role in managing patient adherence to DAA therapy because of the nature of the potential adverse effects.

The emergence of IFN-Î±–sparing therapies or treatment regimens with shorter durations of IFN-Î± exposure should lessen neuropsychiatric concerns and shift psychiatrists toward supporting this therapy for even more patients. However, the introduction of DAAs does not preclude clinicians from continuing to assess and manage comorbid substance use disorders before, during, and after the course of treatment.

Patients with underlying psychiatric illness may have additional barriers that affect adherence to therapy, including potential cognitive deficits, lack of social supports, and limited insight. Therefore, there is a need to optimize supports and treatment within multidisciplinary health care teams to provide marginalized HCV-infected patient populations with appropriate supports and care necessary for successful treatment outcomes.

Interprofessional and peer support models of care for marginalized HCV-infected patients with high rates of substance use who are treated in collaborative care settings can achieve sustained virological response rates comparable to those seen in clinical trial populations.

 This suggests that the integration of mental health care will be a crucial aspect in improving overall patient adherence and engagement in treatment. Finally, it is of utmost importance to provide continual support and aftercare for HCV-infected patients who may not achieve a sustained virological response following treatment.

The following case highlights the shift in the psychiatrist’s role.

Mr B is a 50-year-old single white man with HCV infection. He received the diagnosis in 1998 after elevated alanine aminotransferase and aspartate aminotransferase levels were found on routine blood work. His risk factors for HCV infection included a history of intravenous substance abuse for 3 to 4 years, although he had not used drugs for 7 years before the diagnosis.

Mr B’s psychiatric history is significant for a major depressive episode associated with substance abuse and relationship problems more than 2 decades ago that required psychiatric hospitalization. He also has a history of alcohol dependence-he drank excessively (30 or more drinks a week) for 10 years but has been abstinent for the past 5 years. After the diagnosis, Mr B was treated with citalopram 20 mg/d. In 2007, treatment with weekly IFN-Î± injections and daily oral ribavirin was started. He experienced significant adverse effects, including fevers, worsening depressive symptoms, fatigue, muscle aches, and nausea, during the course of the treatment.

Despite the adverse effects, Mr B was able to continue the 48-week treatment. He was regularly assessed by a psychiatrist who found no worsening of his mood symptoms. Six months after treatment, he continued to have detectable HCV RNA in his blood.

In 2014, combination therapy with simeprevir and sofosbuvir was started. Mr B experienced mild nausea but no other adverse effects. He was followed up weekly to monitor and encourage adherence to the 2 pills daily. He completed the full 12-week course and was confirmed to have a sustained virological response in December 2014.

No adjustments to his psychiatric medications were required during the treatment for HCV infection, and his depressive symptoms remained stable throughout the treatment. Mr B’s psychiatrist continued to follow up with him to support his transition post-HCV eradication, specifically identifying life goals and continuing to support substance use relapse prevention.

As this case illustrates, the evolution of therapy for HCV infection will change the role of psychiatrists in treating HCV-infected patients. As hepatitis C treatment moves away from IFN-Î±–based regimens, more patients with psychiatric and substance use issues will likely receive the treatment because of the reduction of neuropsychiatric effects associated with it.

Psychiatrists can play an instrumental role in screening at-risk populations for the illness. Patient education and information can also have a potential impact on treatment adherence; patients who may have avoided treatment may reconsider treatment with DAAs. In the new era of hepatitis C treatment, psychiatrists will need to support adherence and manage drug-drug interactions to maximize the likelihood of a sustained virological response while minimizing the risk of viral resistance.

The psychiatrist can be an integral part of the patient’s care team; he or she can provide ongoing support and education and can advocate for psychiatric patients living with HCV infection. Adherence in this patient population is improved with collaborative health care that encompasses both hepatologists and psychiatrists as key members of the multidisciplinary health team. Additional efforts, however, are needed to further promote collaborative care models as effective means of increasing patient adherence to therapy as well as providing awareness of treatment changes.

Dr Thiara is Research Assistant in the department of psychiatry at the University Health Network, Toronto; Dr Sackalingam is Deputy Psychiatrist-in-Chief at the University Health Network and Associate Professor in the department of psychiatry at the University of Toronto. The authors report no conflicts of interest concerning the subject matter of this article.

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The prevalence of chronic hepatitis C virus infection is among the highest in patients with severe underlying mental illness. Here: clinical information on the interface of HCV infection and psychiatric disorders.

Author | Sanjeev Sockalingam, MD

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