Medicine Today Internal Medicine Webcast Series

Hepatitis C Management:

Management of Psychiatric Disorders
in HCV-Infected Patients

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Key Points

  • HCV-infected patients have a high prevalence of psychiatric disorders, including depression, bipolar disorder, schizophrenia, and personality disorder.

  • Patients should be screened for depression at every office visit during therapy for HCV infection.

  • Prophylactic use of antidepressants should be considered prior to the initiation of IFN therapy for patients who have a history of depression.

  • De novo depression should be treated with antidepressants. Because there has been no demonstrated superiority of one single antidepressant agent, drug choice should aim to find side effect profiles that provide benefit and cause the least difficulty for patients.

  • If the scope of the patient's psychiatric problem is beyond the capability of the physician who is treating the HCV infection, the patient should be referred.

The prevalence of psychiatric disorders in patients infected with HCV is high. This increased prevalence is most likely related to risk-taking behaviors driven by psychiatric disorders, particularly injection-drug abuse. Behaviors that lead to HCV infection have been implicated in many psychiatric disorders. Furthermore, psychiatric disorders caused by hepatitis C and associated treatments may increase the risk for other psychiatric disorders, resulting in a vicious cycle depicted in Figure 21.

Treating HCV-infected patients is further complicated by the fact that the drugs used to treat them generally have many psychiatric side effects. Before treatment, approximately 20% to 30% of patients have already had an affective disorder such as major depression.148 During the course of IFN therapy, it is estimated that between 30% and 60% of HCV-infected patients will experience a major depressive episode.149 Nevertheless, it is now recognized that depression and other psychiatric illnesses are not a contraindication to the pharmacologic treatment of HCV infection.150

HCV-infected patients who meet the diagnostic criteria for major depression need treatment. Table 16 lists complaints and symptoms that suggest the need for psychiatric consultation or intervention before and during IFN treatment.

Table 16: Symptoms that suggest the need for psychiatric evaluation
Symptom Likely Diagnosis
Suicidal thoughts or feelings Depression
Depression, anhedonia, weeping, paroxysmal sadness Depression
Racing thoughts. insomnia, irritability, euphoria, excitement Bipolar disorder with mania or mixed affective states
Relapsed or ongoing substance abuse Addiction
Abrupt behavioral change Delirium, depression. or bipolar disorder
Rage attacks or loss of temper Delirium, depression. or bipolar disorder

Depression Versus Other Neuropsychiatric States

The complaint of depression in a patient may have many causes. The two most common are major depression, a disease state of the brain that occurs in about 4% to 8% of the general population, and demoralization, the understandable psychological response to loss or adversity that every person experiences from time to time. Major depression is a medical condition associated with poor medical outcomes and poor adherence to treatment. Patients with a complaint of depression usually have one or both of these conditions. Like the distinction between viral upper respiratory tract infection and pneumonia, demoralization is usually responsive to supportive treatment whereas major depression usually requires more aggressive intervention, usually with medications.151

Diagnostic criteria for major depression focus on several cardinal features. The first three are diminished mood, vital sense, and self-attitude.

  • Mood is tied to a patient's baseline state of happiness.

  • Vital sense indicates a patient's sense of well-being, health, energy, alertness, and ability.

  • Self-attitude reflects a patient's sense of doing well, being good, being effective, and being of use to others.

The usefulness of these first three factors is not as great in chronically ill patients, such as those with HCV, because their mood may already be low and their vital sense and self-attitude may already be impaired as a result of their infection.

Two other factors that might help physicians distinguish between depression and demoralization are anhedonia and neurophysiologic disturbances.

  • Anhedonia is defined as a loss of rewards—including pleasure, satiation, and satisfaction—that are associated with behaviors such as sleeping, eating, sex, work, hobbies, and exercise.

  • Neurophysiologic disturbances are characterized by early-morning awakening from sleep, difficulty falling asleep, or disrupted sleep. They also involve changes in appetite, weight loss or gain, variations in immune function, and changes in gastrointestinal function.

Patients with anhedonia will say that they no longer enjoy or benefit from activities such as sleeping, eating, sex, work, hobbies, or exercise. Patients with major depression, on the other hand, will say that their feelings about these activities fluctuate. Early-morning awakening is a strong indicator of major depression.

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Screening for Depression in HCV-Infected Patients

Identification of depression in HCV-infected patients is crucial, as depression has been shown to be the strongest predictor of poor adherence to anti-HCV therapy among a number of demographic factors.

HCV-infected patients should be screened for depression at presentation and at every office visit during the course of anti-HCV therapy, using a reliable screening method. Screening tests such as the Beck Depression Inventory, when used in combination with symptom checklists such as the General Health Questionnaire or the Symptom Checklist-90 (SCL-90), have an overall positive predictive value of 70% to 80% for depression in medical patients. However, effective screening does not require specialist intervention or reliance upon a standardized depression screening test. The key to good depression screening is practice at examining patients. We recommend a simple mental status examination that uses no more than 10 simple questions to assess for the major diagnostic criteria for major depressive disorder, as captured in the mnemonic "SIGECAPS" and detailed in Table 17.152 The nonpsychiatrist physician can pose questions such as "Do you have problems sleeping?" or "Are things not fun for you anymore?" to screen for these criteria and assess for depression. With minimal training, nonpsychiatrist physicians can dramatically improve their detection of major depression with a simple mental status exam of this type.

Table 17: SIGECAPS: A mnemonic for symptoms of major depression and dysthymia*
S Sleep disorder (either increased or decreased sleep)
I Interest deficit (anhedonia)
G Guilt (worthlessness, hopelessness, regret)
E Energy deficit
C Concentration deficit
A Appetite disorder (either decreased or increased)
P Psychomotor retardation or agitation
S Suicidality

*The mnemonic refers to a prescription one might write for a depressed, anergic patient—SIG: Energy CAPSules. Reprinted from Carlat DJ Am Fam Physician. 1998;58:1617-24.

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Depression and IFN

As noted above, major depressive episodes occur in an estimated 30% to 60% of HCV-infected patients during the course of IFN therapy.153 One study suggests that IFN-induced major depression is a predictor of improved viral response to treatment, or at least an indication of optimal IFN dosing.

Patients with IFN-induced major depression have been described as having more liability, more irritability, and less melancholy than other patients with depression. Although some of these patients have energy, they say they are "unable to do anything with it." Depression caused by corticosteroids has been described in similar ways.

Clinicians must be vigilant for signs of depression throughout the full course of therapy, since major depression can develop as late as 10 or more weeks after the start of IFN treatment.154

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Depression and Ribaviran

Ribavirin has not traditionally been thought to increase the risk of depression in HCV-infected patients. In two large randomized trials of IFN alone or in combination with ribavirin found no significant difference in the incidence of depression between patients who received ribavirin and those who did not. However, reports show that the anemia induced by ribavirin may be responsible for some part of treatment based depression.151

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Treatment of IFN-Induced Depression

The goal of treatment for IFN-induced depression includes alleviating symptoms to the extent that the patient is able to complete IFN therapy. However, determining the best treatment for patients with this type of depression can be difficult. Complicating management is the fact that these patients often cope with their depression poorly-that is, by drinking alcohol or abusing drugs.

Numerous studies have shown that IFN-induced depression responds well to therapy with a wide range of antidepressants, with no indication that any one agent is superior to the others. Thus, de novo depression in an HCV-infected patient should be treated with antidepressant therapy.

More controversial is the question of whether all or a subset of HCV-infected patients should be treated prophylactically with antidepressants or whether these patients should not be treated unless they actually develop depression. Studies have shown that prophylactic use of antidepressants155 can lower the rate of depression and decrease the IFN discontinuation. However, although some experts advocate prophylactic use of antidepressants for all patients receiving IFN therapy, we recommend that it be reserved for high-risk patients, particularly those who have had previous depressive episodes and who have responded to a particular antidepressant. We advise against the initiation of antidepressant therapy before IFN therapy in patients who have never had depression until there are better data about the risk-benefit relationship for this practice. Patients who develop major depression should be treated aggressively. Prophylactic treatment is probably reasonable in patients with prior episodes of depression. In the absence of prior treatment, prophylaxis with selective serotonin reuptake inhibitors (SSRIs) has at least been studied and found successful.

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Antidepressant Side Effects and Choice of Agent

Only a small percentage of patients treated with antidepressants experience serious side effects or toxicity.

We have clinical experience with many antidepressants in patients on IFN therapy, and because their side effects tend to vary from patient to patient, we find it best to choose the agent that is most likely to have side effects that might help a particular patient-in other words, to make side effects work for the patient rather than against the patient. Some general guidance along these lines is outlined below.

SSRIs. The SSRIs-citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine-have a good safety profile and are usually well tolerated. All but venlafaxine have a fairly long half-life. Physicians tend to under-dose SSRIs initially and then increase the dosage too rapidly. Patients need time to adjust gradually to the effects of these drugs.

The SSRIs offer a number of opportunities to customize drug selection according to side effects and the patient's individual needs. For example, patients who are thin and do not sleep well might be given paroxetine (which is mildly sedating and may cause weight gain) rather than sertraline (which is somewhat activating and does not cause weight gain). Likewise, patients who sleep excessively may be given fluoxetine or venlafaxine, which are both activating. Although sertraline causes the most gastrointestinal side effects, it may help improve gastric motility in patients with HIV-related gastroparesis.

Tricyclic antidepressants. Although tricyclic antidepressants have a narrower therapeutic index and more severe toxicity than the SSRIs, they are useful in many subsets of patients, particularly those with chronic pain, weight loss, diarrhea, and insomnia, and those in whom monitoring blood levels is useful. The potential for blood level-related cardiotoxicity from these drugs makes it mandatory to monitor blood levels. Overdosage with tricyclic antidepressants may be lethal.

Atypical antidepressants. The atypical antidepressants include bupropion, mirtazapine, nefazodone, and trazodone, among others. Of this group of agents, bupropion is the least sedating and causes the fewest sexual side effects, so it is a good first choice for high-functioning patients. On the other hand, it will worsen the condition of patients who are anxious, restless, jittery, or irritable. Mirtazapine has some SSRI-like properties and some tricyclic-like properties, and it might be useful when a tricyclic antidepressant is not an option. Mirtazapine is somewhat sedating and quite appetite-stimulating, and is therefore useful in patients with weight loss and insomnia.

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HCV Infection in Patients with Bipolar Disorder of Schizophrenia

Both bipolar disorder and schizophrenia are associated with elevated rates of HCV infection, most likely because these disorders are associated with high rates of drug use and risky sexual behaviors. However, they are much less prevalent than depression (eg, bipolar disorder has a lifetime prevalence of 1% to 2%, compared with 4% to 10% for depression). Because mania occurs in younger patients, physicians can generally rule out bipolar disorder on the basis of the patient's history. Some patients with bipolar disorder may develop a "mixed state," with a mixture of symptoms of both depression and mania, and such patients are hard to distinguish from patients with agitated major depression. Patients with agitated depression or mania may benefit from neuroleptics and should generally be referred to an expert for treatment. Patients with mixed states should be treated as having bipolar disorder and probably should be seen by a psychiatrist urgently. In general, physicians who treat HCV infection should promptly seek psychiatric consultation if they encounter a patient with a psychiatric disorder that is beyond their capability to knowledgeably treat.

IFN therapy generally does not appear to exacerbate schizophrenia, although it may exacerbate bipolar disorder in some patients with this disorder. Patients with either of these disorders should be stable on psychopharmacologic treatment before IFN therapy for HCV infection is begun.

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HCV Infection in Patients with Personality Disorders

Although relatively little research has been done on the topic, indirect data show that patients with personality disorders have higher rates of HCV infection. The reason is that these patients manifest increased impulsivity, are more vulnerable to substance abuse disorders, and engage in more risk-taking behaviors. The onset of HCV infection further stresses and demoralizes these patients, which exacerbates their personality vulnerabilities.

Personality traits such as introversion and extroversion may affect whether or not patients adhere to their medication regimen. Introverts will generally adhere to their regimen because they are consequence-avoidant, future-focused, and function-oriented. Extroverts are more likely to discontinue their medications because they are present-directed and reward-directed and their emotional states are often mercurial.

At the onset of treatment, the clinician must counsel patients and reinforce the fact that they might not be able to tolerate IFN treatment if they let their personality direct their behavior. Patients must also be reminded that even though they might feel poorly during treatment, they must continue to take their medication.

Patients who experience problems adhering to their regimen must be encouraged to discuss their problem. When counseling extroverts, the clinician should focus on the rewards of drug adherence rather than on the negatives. For introverts, the focus should be on the consequences of nonadherence.

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HCV Therapy and Substance Abuse

Anti-HCV therapy generally should not be initiated in patients with ongoing substance abuse disorders (IV drug use or alcoholism). Patients who are unlikely to be able to stop their substance use for the full course of anti-HCV therapy are best counseled to get help in ending their drug and alcohol use before coming back for treatment for their hepatitis C.

At the same time, experience in methadone programs has shown that concurrent treatment for HCV infection and drug addiction in HCV-infected drug addicts may result in improved completion of anti-HCV treatment and better retention in methadone treatment compared with treating either condition alone.156,157

Such results underscore the potential of more integrative models of care that better incorporate the assessment of HCV-infected patients with management of psychiatric illness and substance abuse.

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