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Neuropsychiatric side effects associated with interferon-alfa plus ribavirin therapy: Treatment and prevention

Neuropsychiatric side effects associated with interferon-alfa plus ribavirin therapy: Treatment and prevention
Authors:
Charles L Raison, MD
Nezam H Afdhal, MD, FRCPI
Section Editor:
Jonathan M Silver, MD
Deputy Editor:
David Solomon, MD
Literature review current through: Jun 2022. | This topic last updated: Dec 07, 2021.

INTRODUCTION — Few well designed studies are available to provide definitive guidance on preventing or alleviating the many neuropsychiatric side effects associated with interferon-alfa (IFN-alfa) plus ribavirin. Fortunately, several placebo-controlled studies confirm clinical experience by demonstrating that side effects can be managed effectively in many patients. Nonetheless, the recommendations that follow are based mainly upon observational studies and experience in treatment of psychiatric syndromes in other settings.

The guidelines found on product information sheets (ie, dose reduction of IFN-alfa as a treatment for depression) are not sufficiently comprehensive to address the clinical issues that arise during treatment. They do not adequately consider the tradeoff between managing depression and the reduction in efficacy of treatment associated with a dose reduction, especially early in the course of therapy. In addition, the effectiveness of dose-reduction in resolving treatment-emergent neuropsychiatric side effects remains to be conclusively determined.

We believe that a better strategy is to use all techniques at our disposal (pharmacological and psychosocial) to allow patients to tolerate full doses of IFN-alfa/ribavirin for an appropriate period while minimizing negative impact on emotional and physical well-being and daily functioning.

This topic review will summarize the treatment and prevention of neuropsychiatric side effects in patients receiving IFN-alfa plus ribavirin for hepatitis C virus infection.

PSYCHIATRIC CONSULTATION — Patients who are candidates for interferon-alfa (IFN-alfa) are often referred to psychiatrists to evaluate the risk of adverse psychiatric outcomes [1]. The role of the psychiatrist includes:

Diagnosing and treating any preexisting mental disorders – Preexisting disorders should be stable and ideally remitted for several weeks or months (eg, three months) before commencing IFN-alfa.

Discussing adherence with antiviral therapy – It may be possible to enlist family, social, and vocational supports for adherence.

Educating the patient about depression and the use of antidepressants to prevent depressive syndromes. (See "Patient education: Depression in adults (Beyond the Basics)" and "Patient education: Depression (The Basics)" and 'Prophylaxis' below.)

Facilitating communication amongst the members of the treatment team.

PSYCHOSOCIAL CONTEXT OF TREATMENT — Comprehensive mental health services for patients undergoing treatment with interferon-alfa (IFN-alfa) and ribavirin therapy can be helpful but are not widely available [2-4]. Thus, much of the responsibility for assessing and treating neuropsychiatric side effects usually falls to the primary clinical team. Before specific pharmacological treatment strategies are discussed, it is important to discuss an even more fundamental issue, which is the importance of the primary treatment environment in the detection and management of neuropsychiatric side effects.

Much clinical experience suggests that patients are far more likely to cope with IFN-alfa side effects and stay on therapy when they are in an involved, supportive, and organized treatment environment. Patient education prior to treatment is essential and should include a clear description of likely side effects, and their time course. (See "Patient education: Hepatitis C (Beyond the Basics)".)

Behavioral coping strategies should be emphasized. They can provide symptom relief and help patients feel in control of their symptoms. Such strategies include adequate hydration, graded exercise and preparing one's daily schedule to best accommodate the decreased energy that almost always accompanies treatment.

Many treatment centers have found that support groups facilitate the dissemination of this type of information and provide key psychosocial support. Family members should be fully educated on likely side effects of treatment. Educating families can help them anticipate and increase their tolerance to behavioral changes in their family member and help them strategize for ways to maximize the patient's psychosocial support network.

Other characteristics of an optimal treatment environment include:

Use of standardized assessments to identify "at-risk" patients prior to treatment. Self-report scales useful to assess depressive symptoms include the Patient Health Questionnaire 9 item (table 1), Quick Inventory of Depressive Symptoms (QIDS), the Beck Depression Inventory (BDI), and Center for Epidemiologic Studies Depression Scale. Sleep should be specifically assessed because poor sleep prior to IFN-alfa treatment strongly predicts onset of depression by 12 weeks of treatment [5].

Adequate staffing to allow for ongoing close psychosocial/symptom follow-up of patients during treatment (especially in the first eight weeks of treatment).

The clinical expertise to initiate pharmacological interventions in a timely manner by staff with adequate experience in their use.

A close working relationship with mental health providers who are familiar with issues related to IFN-alfa/ribavirin to whom patients can be referred for a rapid evaluation when symptoms escalate beyond the expertise of staff members.

It is very likely that specific psychotherapeutic interventions tailored to the unique situation of patients on IFN-alfa/ribavirin would augment the more nonspecific recommendations given thus far. However, demonstration of efficacy for techniques based on individualized psychotherapies (eg, cognitive-behavioral or interpersonal psychotherapy) awaits results from appropriately designed studies.

WHO CAN BE SAFELY TREATED WITH INTERFERON — Patients with hepatitis C virus who also have significant psychiatric illnesses have often been excluded from treatment with IFN out of concern for the medication's well documented ability to worsen cognitive and emotional functioning. However, clinicians increasingly recognize the need to treat these patients, and accumulating experience suggests that many patients with pre-existing psychiatric disorders can tolerate IFN and obtain viral clearance [2,3]. Even patients with severe mental illnesses, such as schizophrenia, can tolerate and benefit from IFN [4,6]. Thus, a psychiatric history per se should not automatically disqualify a patient for IFN therapy.

However, given evidence that baseline mood symptoms strongly predict depressive symptoms during therapy, it is of great importance that all patients with a psychiatric history be as stable as possible prior to initiation of IFN. This will typically require close collaboration with a treating psychiatrist. Patients who are severely depressed, suicidal, manic, or grossly psychotic are best treated only when these symptoms have been adequately treated.

Data from a large Veteran's Administration population highlight the challenges of optimizing emotional functioning prior to commencing IFN-alfa [7]. Many patients responded poorly to antidepressant treatment, suggesting that patients who require IFN-alfa therapy may enter treatment with psychiatric vulnerabilities despite attempts at antidepressant pretreatment.

WHEN TO TREAT FOR INTERFERON PSYCHIATRIC SIDE EFFECTS — Antidepressants are useful both as a prophylactic strategy for at-risk patients who are starting interferon-alfa (IFN-alfa) for hepatitis C, and as a treatment for symptoms that emerge once antiviral therapy has started (table 2 and algorithm 1) [8,9].

Antidepressants have side effects and safety risks, and only 20 to 40 percent of patients treated with interferon and ribavirin develop significant depression. Thus, pretreating all patients may expose a significant proportion to an additional medication burden that provides no benefit. In addition, antidepressants appear to be effective in treating depression once it has emerged during IFN-alfa/ribavirin therapy, in most cases allowing affected patients to recover sufficiently to continue their antiviral treatment [10-21].

Prophylaxis — Pharmacotherapy should be considered before beginning interferon-alfa in patients with risk factors for a mood disturbance (table 2 and algorithm 1) [8,9], and in patients with significant depressive symptoms or sleep disturbance. In other patients it can be started after symptoms develop, provided that treatment settings permit close follow-up to detect early signs and symptoms. We generally suggest beginning antidepressant treatment in such patients if they have had seven or more days of continuous depressive symptoms of mild or greater severity.

These suggestions are based on the assumption that patients at greatest risk for treatment-emergent symptoms are also those most likely to benefit from antidepressant pretreatment. This approach was supported by at least one placebo-controlled trial, which found a significant benefit to paroxetine pretreatment in patients with depressive symptoms before treatment, but no benefit in patients who did not have depressive symptoms prior to IFN-alfa therapy [6].

Most physicians who treat depression or anxiety disorders play a constant game of "catch-up" with symptoms that are already present and impairing daily life. On the other hand, clinicians can address IFN-alfa-induced neuropsychiatric side effects by pretreating patients before beginning antiviral therapy in hopes of preventing, or at least alleviating, treatment-emergent symptoms.

Based upon multiple meta-analyses of randomized trials, prophylaxis with antidepressants can reduce the incidence of depression in patients with chronic hepatitis C who are treated with IFN-alfa [22-24]. As an example, one meta-analysis of eight randomized trials compared antidepressants (citalopram, escitalopram, or paroxetine) with placebo for preventing depression in patients who were about to start interferon for hepatitis C (n = 549) or malignant melanoma (n = 40) [25]. The findings included the following:

Major depression was less likely to occur during interferon treatment in patients who received antidepressants than patients who received placebo (odds ratio 0.4, 95% CI 0.3-0.7); heterogeneity across studies was low to moderate. A separate analysis limited to the patients with hepatitis C found comparable results.

In the seven trials that included patients with pre-existing or active psychiatric disorders (n = 408), antidepressants reduced the incidence of major depression (odds ratio 0.4, 95% CI 0.2-0.8). In the one trial that excluded patients with pre-existing or active psychiatric disorders (n = 181), antidepressants reduced the incidence of major depression (odds ratio 0.4, 95% CI 0.1-0.9).

Sustained virologic response in patients who received antidepressants and patients who received placebo was comparable.

In addition, pretreatment with selective serotonin reuptake inhibitors is acceptable to patients who are about to commence treatment with IFN-alfa for hepatitis C. A pooled analysis (six trials, 522 patients) found that discontinuation of prophylactic antidepressants and placebo was comparable (19 and 21 percent of patients) [22].

Omega-3 fatty acids may also prevent onset of depression in patients who are initiating IFN-alfa for hepatitis C. A randomized trial compared omega-3 fatty acids with placebo in 152 patients without major depression [26]. Patients were assigned to eicosapentaenoic acid (3500 mg per day), docosahexaenoic acid (1750 mg per day), or placebo (oleic acid) for two weeks before starting IFN-alfa plus ribavirin, and then followed for up to 24 weeks during antiviral therapy. Major depression occurred in fewer patients who were treated with eicosapentaenoic acid than placebo (10 versus 30 percent), and there was a trend for a lower rate of depression with eicosapentaenoic acid than docosahexaenoic acid (10 versus 28 percent of patients). Discontinuation of treatment due to side effects did not occur in any the groups.

Additional information about omega-3 fatty acids, including treatment of depression, is discussed separately. (See "Fish oil: Physiologic effects and administration" and "Unipolar depression in adults and initial treatment: Investigational and nonstandard approaches", section on 'Omega-3 fatty acids'.)

After onset of depression — For patients who are beginning IFN-alfa and are not at risk for a mood disturbance (table 2 and algorithm 1), pharmacotherapy can be started after depressive symptoms develop, provided that treatment settings permit close follow-up to detect early signs and symptoms [8,9]. We generally suggest beginning antidepressant treatment in such patients if they have had seven or more days of continuous depressive symptoms of mild or greater severity.

This approach was supported in a randomized trial that confirmed the effectiveness of antidepressants in reducing depressive symptoms that emerged during treatment with IFN-alfa/ribavirin [27]. Patients randomized to the citalopram had a significant reduction in IFN-alfa induced depressive symptoms within four weeks, whereas no effect was observed for placebo. The lack of an appreciable placebo response was observed in a prior study of high dose IFN-alfa for malignant melanoma and may differentiate IFN-alfa induced depression from other forms of major depression in which a substantial placebo response is typically seen [28].

Symptomatic treatment strategies are most appropriate for patients without pretreatment depressive or anxiety symptoms, and in treatment settings in which routine depression screening is available during IFN-alfa treatment. This latter point is especially important, given the rapidity with which IFN-alfa-induced depressive symptoms often emerge and the typical time lag of four to six weeks for a full therapeutic response to antidepressants.

Only two weeks of symptoms are required to meet criteria for major depression (table 3), according to the American Psychiatric Association’s Diagnostic and Statistical Manual, Fifth Edition [29], emphasizing that even in the context of idiopathic depression, symptoms need not be present for an extended period for treatment to be indicated. This is even truer in the context of IFN-alfa/ribavirin therapy where the known depressogenic factor will continue to adversely affect the patient, often for months or years of treatment.

DEPRESSION — Accumulating data indicate that antidepressants are effective in reducing depressive symptoms, whether initiated before beginning IFN-alfa/ribavirin or after symptoms have emerged on therapy (algorithm 1). Clinical experience and observational studies suggest that antidepressants also effectively diminish treatment-emergent irritability in many patients, although clinicians should be aware of the risk of mania [10,13]. (See 'Mania' below.)

Selective serotonin reuptake inhibitors (SSRIs), especially paroxetine and citalopram, have been most extensively studied [10,11,14,27,30-35]. Based upon meta-analyses, prophylactic treatment with SSRIs is beneficial. (See 'When to treat for interferon psychiatric side effects' above.)

Other antidepressants may be effective. Indeed, agents with norepinephrine activity may have more activity against painful symptoms than do SSRIs, and hence might be especially valuable in the context of antiviral therapy [36]. Combined serotonin-norepinephrine reuptake inhibitors (SNRIs) available in the United States include venlafaxine, desvenlafaxine, and duloxetine. However, the Food and Drug Administration has issued a precaution about the use of duloxetine in patients with chronic liver disease and thus it is probably not a good choice [37].

Other options include bupropion, an agent with norepinephrine and dopamine activity, and mirtazapine, a novel agent with effects on norepinephrine and serotonin. Bupropion may be especially useful for fatigue and has an added benefit in lacking the sexual side effects of serotonergic agents. Mirtazapine promotes sleep and weight gain. Both these agents are also frequently used to augment SSRIs in patients who do are not fully responsive to the initial treatment [38].

Less is known about any potential benefits of older agents such as tricyclic antidepressants or monoamine oxidase inhibitors in patients receiving IFN-alfa/ribavirin, although because of increased side effects and risk of toxicity, these medications are no longer typically used as first line treatments. Similarly, no data have been published concerning use of the newly available monoamine oxidase transdermal patch.

However, hepatitis C virus infection may be a risk factor for drug induced long QT syndrome, which is associated with an increased risk of a life-threatening cardiac arrhythmia known as torsades de pointes. An observational study found that hepatitis C infection was more common in patients with drug induced long QT syndrome (n = 62) than patients with normal electrocardiograms (n = 143) (42 versus 10 percent) [39]. Information about SSRIs and QT interval prolongation is discussed separately, as is the acquired long QT syndrome. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Cardiac' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

In additions, antidepressants can rarely injure the liver. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Side effects'.)

Advanced chronic liver disease can alter the pharmacokinetics of antidepressants; suggestions for using antidepressants in this population are included in the table (table 4).

FATIGUE — Fatigue is the most common neuropsychiatric side effect associated with IFN-alfa [40]. As a result, it is especially disconcerting that SSRIs (the most commonly used antidepressants) are not optimal treatment choices for fatigue. Several lines of evidence suggest that serotonergic treatment strategies are generally not as effective for somatic symptoms as they are for the emotional symptoms of depression [40-42].

Of most direct relevance to patients undergoing antiviral therapy, paroxetine was significantly more effective than placebo in reducing depressed mood, anxiety and cognitive complaints but not more effective than placebo in reducing fatigue, sleep complaints and appetite loss in patients receiving high dose IFN-alfa monotherapy for malignant melanoma [40]. Thus many patients with full-blown IFN-alfa-induced depression may feel better emotionally (ie, less sad, more hopeful, less irritable) following initiation of a selective serotonin reuptake inhibitor but may well be left with inadequately treated fatigue. Conversely, patients who present with IFN-alfa-induced fatigue without other prominent depressive symptoms may derive no benefit at all from selective serotonin reuptake inhibitors, while being subjected to the additional side effect burden (ie, loss of libido, GI complaints, disrupted sleep) associated with these agents.

Before considering pharmacologic interventions, the clinician should suggest behavioral strategies that improve fatigue and help patients adjust their activities to its presence. Treatment of fatigue is difficult. Unfortunately, reduction of the dose of IFN or RBV does not reliably improve fatigue. We suggest patients conserve energy by taking frequent rest periods, napping, if possible, and planning physical tasks and household tasks to be spread out over the course of the day. A gradual exercise-tolerance program, involving light exercise such as a daily walk, can be useful if initiated at the beginning of therapy, to condition patients to a higher level of activity and improve physical functioning, to better cope with fatigue.

Adequate fluid balance is also critical in dealing with fatigue. IFN can affect the hypothalamic temperature center, resulting in an increase in core body temperature, which leads to low-grade fevers and fatigue. Adequate hydration with caffeine-free fluids can counterbalance this effect and lead to improvement in energy levels. A good rule of thumb is to divide the patient's weight by two, which equals the daily recommended intake of fluids in fluid ounces (eg, 160 lb woman = 80 fl oz/d).

At present, the best documented treatment for fatigue associated with antiviral therapy is growth factors used to maintain adequate hemoglobin levels [43,44]. Due to a lack of adequate controlled trials, further recommendations for agents to treat IFN-alfa/ribavirin-induced fatigue must be considered provisional, because they are based on data from other disease-states. Having said this, significant data suggest that agents that modulate catecholamine signaling in the central nervous system reliably reduce fatigue and increase wakefulness.

Psychostimulants (especially methylphenidate and dextro-amphetamine) reduce fatigue in healthy controls and in patients with a number of medical illnesses [45-47]. Our clinical experience suggests that many patients with IFN-alfa/ribavirin-induced fatigue improve significantly with the addition of one of these agents to their regimen (either as an add-on to an antidepressant in patients with a full panoply of depressive symptoms, or as a single agent in fatigued patients without other depressive symptoms). However, psychostimulants are associated with abuse liability, which can make their use problematic in many patients with substance abuse issues.

Potential alternatives include:

The nonstimulant wake promoter modafinil (Provigil), which has received significant interest for the treatment of fatigue (although current data are mixed).

Ondansetron, a serotonin 5-HT3 receptor antagonist improved fatigue in hepatitis C virus patients (who were not on IFN) in a placebo-controlled trial [48]. Its role in treatment-emergent fatigue is unclear, particularly since it can be associated with constipation.

The activating antidepressant bupropion.

Dopamine agonists (ie, ropinirole and pramipexole), while occasionally causing fatigue, also show promise for the treatment of fatigue in other conditions and might be of potential benefit in subjects receiving IFN-alfa/ribavirin [49]. Consistent with this, amantadine, an antiviral agent with dopaminergic properties, was useful in the treatment of IFN-alfa/ribavirin-induced depressive symptoms when compared to placebo [50].

INSOMNIA, PAIN, ANOREXIA, AND IRRITABILITY — As with fatigue, other single neuropsychiatric symptoms are frequently the tip of a larger iceberg of emotional and physical suffering. Thus many patients who focus their complaints on fatigue, pain, or insomnia will be found, upon closer questioning, to be suffering from a diagnosable depressive condition [51]. In the context of IFN-alfa/ribavirin therapy, patients who really do only have one or two somatic symptoms are nonetheless at greatly increased risk for full major depression as the treatment progresses [52]. As a result, it makes clinical sense to fully evaluate and treat all symptomatic complaints to the fullest extent possible, both to improve health-related quality of life during antiviral therapy and also to attempt to prevent a worsening with continued treatment.

Insomnia — Optimal management strategies for insomnia may require both behavioral and pharmacologic options. Thus, insomnia should be addressed through instruction in good sleep hygiene, as well as through factors specific to treatment. For example, consuming large quantities of water may aid with fatigue, but this strategy can become counterproductive if patients drink so much fluid in the evening that they suffer sleep disruption from need to urinate.

Many of the available sleeping agents have been used in patients on IFN-alfa/ribavirin, although none have been adequately studied for this indication.

Frequently prescribed agents include the nonbenzodiazepine hypnotics zolpidem and zopiclone, which appear to have less addictive potential than the traditional benzodiazepines.

Trazodone, a sleep promoting antidepressant, is safe, frequently effective across a wide dose range (ie, 25 to 150 mg) and is especially useful for patients with abuse potential who require long-term treatment. Other agents that do not have primary indications for insomnia but that are widely used to aid sleep include the antidepressant mirtazapine (typically at doses between 7.5 mg and 60 mg) and the atypical antipsychotic agent quetiapine (typically at doses between 25 and 100 mg).

Over the counter sleeping preparations typically contain diphenhydramine, an agent with anticholinergic effects that have the potential to add to the side effect burden in some patients on IFN-alfa/ribavirin and are thus generally not good choices.

Whether the novel melatonin modulating sleep agent ramelteon will be of benefit during therapy has yet to be determined.

Aches and pains — Bodily aches and pains are common in patients on IFN-alfa/ribavirin. While not typically considered "neuropsychiatric side effects," pain complaints are nonetheless extremely common in the context of depression and are a risk factor for the development of mood disorders [42,51]. Furthermore, certain pain syndromes (especially neuropathic pain) respond to antidepressants with norepinephrine activity, even in patients who are not depressed.

The SNRI duloxetine has been best studied but data also support the use of venlafaxine and older tricyclic antidepressants [53-63]. As noted above, the FDA has issued a precaution regarding use of duloxetine in patients with chronic liver disease and thus it is probably not a first-line choice at this time.

Bupropion and mirtazapine may also be effective for pain, although there are limited data [64-67]. On a more fundamental level, techniques that help patients manage pain without resorting to addictive medications (ie, opiates) are probably protective against the development of depression during treatment. For example, many patients experience a significant increase in pain and malaise in the day or two following their weekly injection. The judicious use of nonsteroidal anti-inflammatory agents to suppress this weekly experience would be expected to decrease emotional and physical changes (ie, cytokine production) that promote the development of depression. The safety of pain medications in patients with advanced liver disease is described separately. (See "Management of pain in patients with advanced chronic liver disease or cirrhosis".)

Anorexia — A variety of nutritional supplements are available as a first-line strategy in helping anorexic patients consume adequate calories. In patients who fail these interventions, the use of weight promoting psychotropic agents can occasionally be helpful. Such agents include the antidepressant mirtazapine and the atypical antipsychotic agent olanzapine. However, the benefits of this type of strategy need to be weighed against potential dangers, including the association of olanzapine with insulin resistance and the rare development of agranulocytosis patients treated with mirtazapine.

Irritability — Widespread clinical experience and observational studies suggest that many, and perhaps most, patients who develop irritability during IFN-alfa/ribavirin therapy benefit from the initiation of a serotonergic antidepressant (ie, a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor) [10,13]. This should not be surprising given a large body of evidence attesting to the value of these agents in patients that are irritable for other reasons (ie, presence of a personality disorder or organic injury). In an open trial, benzodiazepines were also found to be effective for IFN-alfa/ribavirin-induced irritability [10].

MANIA — Patients on IFN-alfa occasionally develop frank mania, with diminished sleep, euphoric mood and increased energy, speech production, and risk-taking behavior. How many of these subjects had undiagnosed bipolar disorder prior to therapy is unknown, although mania does appear to occur de novo during treatment. More commonly seen are patients who develop extreme irritability, often with increased aggression, but who also complain of fatigue and lowered mood while on antiviral therapy [68]. How these presentations should be classified (ie, depression with irritability versus dysphoric mania) is a topic of some debate that would be of less urgency were it not for the very different treatment strategies required by manic versus depressed conditions.

Antidepressants do not typically help manic symptoms, and, in fact, have been known for years to be capable of inducing manic episodes [69]. On the other hand, several classes of medications (often lumped together as "mood stabilizers") are remarkably effective in curtailing mania. Such agents include lithium, valproic acid, carbamazepine and both typical (eg, haloperidol), as well as atypical antipsychotic drugs such as olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Thus, how any given patient on the continuum between mild irritability and frank mania is classified will directly indicate which type of treatment should be instituted.

Suggestions for differentiating dysphoric mania from depression are given in a table (table 5). However, it must be emphasized that no clear empiric data are available to guide the clinician who must choose between an antidepressant and a mood stabilizer in any given patient on IFN-alfa/ribavirin with irritability. Sometimes family members can prove invaluable in this regard, given that manic patients frequently lack insight into the seriousness of their condition. Whenever an irritable patient's self-report diverges significantly from the reports of others, one must worry that a manic phenomenon is underway, especially if the patient's behavior has changed dramatically after starting antiviral therapy.

Consensus has not been achieved on how patients who develop mania while on treatment should be treated. Treatment decisions are probably best guided by drawing upon the research and clinical experience. Psychiatrists recognize full-blown manic episodes as clinical emergencies that are usually best handled by admission to an inpatient unit. If this is not possible, it is of utmost importance to provide the safest environment possible for the patient and to institute treatment promptly.

Antidepressant medications should be discontinued immediately and sleep should be induced. If a psychiatrist cannot see the patient within 24 hours, the patients should be started on some type of anti-manic therapy while awaiting more definitive psychiatric care. Atypical antipsychotics, while not without risks and side effects, are probably the easiest "stop-gap" measure and often produce dramatic results within a relatively short period of time (ie, days rather than weeks). Commonly used atypical antipsychotics include olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole.

Lithium or valproic acid/carbamazepine require specific blood tests and close therapeutic monitoring early in treatment, and for these reasons, they may not be good choices for those unfamiliar with their use. Benzodiazepines are frequently of great value as adjunctive agents, both to aid in behavioral control and to extend the sleep period. Given the severity of mania, it is also of central importance to carefully weigh the benefits of ongoing antiviral therapy against the very real risks associated with mania. In most cases of mania, IFN is best stopped. Whether it should ever be restarted once the patient has been stabilized is an issue probably best decided on a case by case basis.

HOW LONG SHOULD TREATMENT LAST — Antidepressants begin to diminish IFN-induced depression and irritability within two weeks of initiation. However, antidepressants can take six weeks or more to have a full effect. Anti-manic agents tend to work more rapidly; therefore the clinician should expect to see improvement in mania within a week of initiating an atypical antipsychotic. When using psychostimulants for fatigue or various agents for insomnia, the clinician should expect to see an effect immediately. If such an effect is not observed, an alternate strategy should be used.

If a patient on IFN responds favorably to a pharmacological intervention, the intervention should be continued throughout the course of IFN, and should be maintained afterward for one to four months [1]. Following a course of IFN, we suggest keeping patients on antidepressants at least until they have returned to their baseline level of emotional and behavioral functioning. Because antidepressants are associated with withdrawal syndromes, especially when discontinued abruptly, all antidepressants should be tapered off over a period of weeks when possible. No data exist to guide the clinician on when to discontinue psychostimulants or anti-manic agents following cessation of IFN—such decisions rely exclusively on clinical judgment.

SUICIDAL IDEATION — Treatment with IFN-alfa has been associated with both attempted and completed suicides. The essence of treatment for suicidal ideation is to keep the patient alive long enough for the symptoms and/or situations driving the desire to die to be adequately addressed and resolved. When the risk for self-harm is high, safety is usually best maintained by admission to an inpatient psychiatric unit. When this is impossible, patients with suicidal ideation require careful monitoring and the best available oversight by family members or other loved ones.

Anxiety and agitation are two of the most important short-term predictors of suicide attempts and completions in depressed patients. Thus they are especially ominous in patients receiving IFN-alfa who develop suicidal ideation. For this reason they should be aggressively treated if present. Depression, mania, and active substance abuse are all associated with increased suicide risk; however, all patients on IFN-alfa/ribavirin should probably be queried for the presence of suicidal ideation as part of their medical evaluation. At the least, suicidal ideation should be carefully evaluated in all patients who present with other symptoms of a mood and/or anxiety disturbance. The development of serious suicidal ideation (defined as significant thoughts of killing one's self, with a concrete plan and the means to carry out the plan) should prompt the discontinuation of IFN and an immediate psychiatric referral to evaluate the need for hospitalization.

This subject is often best broached by asking an initial question concerning whether life still feels worthwhile. If answered in the negative, the clinician should follow up by directly asking if the patient has had a wish to die. If answered in the affirmative, the clinician should ask whether the patient has considered harming him/herself. If this is answered in the affirmative, the clinician should ask if the patient has a plan and the means to carry out this plan. If the patient acknowledges this, an immediate intervention should be made, which will usually take the form of assuring that the patient is escorted safely to an emergency room for further evaluation.

IFN-alfa in patients with psychiatric illness — Patients with serious preexisting psychiatric illnesses such as schizophrenia, bipolar disorder, severe depression, and recent or current substance abuse pose a special challenge. While often excluded from treatment in the past, with proper management many patients with significant psychopathology can be successfully shepherded through a full course of antiviral therapy, and should therefore not be automatically excluded from treatment [34,35].

However, patients should be as psychiatrically stable as possible prior to beginning therapy, and often this may require more aggressive management than is currently in place. It is especially important for mood states to be within the normal range. Given the complexities involved, it is clearly preferable for treating clinicians to co-manage these patients with mental health professionals experienced in the psychiatric risks and benefits of IFN-alfa/ribavirin.

SUMMARY AND RECOMMENDATIONS

Patients are likely to best cope with interferon-alfa (IFN-alfa) plus ribavirin in the context of an active, caring, and competent treatment environment that provides pretreatment education and assessment and careful monitoring during therapy. (See 'Psychosocial context of treatment' above.)

For patients who are about to start IFN-alfa, are at risk for suffering the side effect of depression, and do not have contraindications to antidepressants, we suggest prescribing antidepressants in conjunction with IFN-alfa, rather than not starting antidepressants (table 2 and algorithm 1) (Grade 2A). However, watchful waiting is a reasonable alternative. When we administer antidepressants, we typically use selective serotonin reuptake inhibitors, but serotonin-norepinephrine reuptake inhibitors and atypical antidepressants are appropriate alternatives. (See 'When to treat for interferon psychiatric side effects' above.)

All patients with psychiatric disorders should be in active effective treatment before beginning treatment, and all attempts should be made to "tune-up" patients as much as possible. This often requires ongoing collaboration with a psychiatrist or other mental health professional who is overseeing a given patient's psychopharmacological regimen (algorithm 1). (See 'Psychosocial context of treatment' above and 'Depression' above.)

In patients who are depressed or are at risk for depression, we suggest pharmacologic intervention using the approached discussed above (Grade 2B). Selective serotonin reuptake inhibitors have been best studied, but other options may be equally effective and possibly preferable in patients in whom certain characteristics predominate but who do appear to have depression. (See 'Insomnia, pain, anorexia, and irritability' above and 'Depression' above.)

Selective serotonin reuptake inhibitors may be of limited benefit in patients with fatigue, but without other significant depressive symptoms. Patients should be counseled on the behavioral modifications described above. In those who do not respond, we suggest treatment with psychostimulants such as modafinil or bupropion (Grade 2C). The antidepressant mirtazapine promotes sleep and weight gain and may also be a useful alternative. (See 'Fatigue' above.)

Similarly, several agents can be considered in patients with predominant symptoms of pain, insomnia, anorexia or irritability.

In patients whose predominant symptom is insomnia, we provide advice on good sleep hygiene. In nonresponding patients, we suggest a nonbenzodiazepine hypnotic (such as zolpidem or zopiclone) (Grade 2C). As an alternative, we suggest trazodone, a sleep promoting antidepressant, which is safe, frequently effective across a wide dose range (ie, 25 to 150 mg) and is especially useful for patients with abuse potential who require long-term treatment (Grade 2C). (See 'Insomnia' above.)

In patients whose predominant symptoms are aches and pains, we suggest a combined serotonin-norepinephrine reuptake inhibitor (SNRI) (Grade 2C). Combined serotonin-norepinephrine reuptake inhibitors available in the United States include venlafaxine, desvenlafaxine, and duloxetine. However, the Food and Drug Administration has issued a precaution about the use of duloxetine in patients with chronic liver disease and thus it is probably not a good choice. (See 'Aches and pains' above.)

Antidepressants with both norepinephrine and serotonin activity (eg, venlafaxine) may be more effective than selective serotonin reuptake inhibitors in the treatment of pain and may be agents of choice for patients who present with significant pain complaints.

In patients who develop irritability, we suggest either a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (Grade 2C). (See 'Irritability' above.)

A small percentage of patients receiving antiviral therapy develop mania, which should be considered a clinical emergency. In such cases, antidepressants should be stopped and an immediate psychiatric referral arranged. Agents effective for manic symptoms include antipsychotics and mood stabilizers. (See 'Mania' above.)

Suicide is a real possibility for patients who develop neuropsychiatric side effects during therapy. Risk for this should be assessed at every evaluation. Patients who develop suicidal ideation require immediate psychiatric evaluation. (See 'Suicidal ideation' above.)

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Topic 4857 Version 28.0

References