Pharmacologic Intervention
        Overview
        Interferon-related depression
        Antidepressant medication selection
        Selective serotonin reuptake inhibitors
        Discontinuation of antidepressants
        Side effects
        Drug-drug interactions
        Atypical antidepressants
        Benzodiazepines
        Psychostimulants
        Monoamine oxidase inhibitors
        St. John's wort
        Antidepressant effects
Psychotherapy
        Overview
        Empirical studies of the efficacy of psychotherapy

Whether to initiate therapy for depression depends on the probability that the patient will recover spontaneously in the next 2 to 4 weeks, the degree of functional impairment, and the severity and duration of the depressive symptoms.[1] Studies have shown that treatment of major depression is optimized by a combination of pharmacotherapy and psychotherapy. Thus, even if a primary care physician or oncologist undertakes the treatment of depressive symptoms pharmacologically, a referral for psychotherapy or supportive counseling should be considered.

Individuals should be referred for a psychiatric consultation for the following reasons:

• A primary care physician or oncologist does not feel competent treating the patient for depression because of specific clinical features in the presentation (i.e., if prominent suicidal tendencies are present).



• The depressive symptoms treated by the primary physician are resistant to pharmacologic interventions after 2 to 4 weeks of intervention.



• The depressive symptoms are worsening rather than improving.



• Initiating treatment with antidepressant drugs, titrating drug doses, or continuing treatment is interrupted or made problematic by adverse effects attributable to the medication.



• The depressive symptoms are interfering with the patient's ability to be cooperative with medical treatment.[2-4]

There is a paucity of randomized, placebo-controlled trials assessing the risks and benefits of antidepressants in patients with cancer and depression or depressive symptoms. Furthermore, these studies are limited by methodological challenges and a lack of broad representation of children, adolescents, older adults, and minority groups.[5] In certain cases of depression in patients with cancer, antidepressant therapy may be indicated. A survey of prescribing patterns in outpatient oncology settings over a 2-year period found that antidepressants were prescribed for about 14% of patients.[6] In a systematic review of newer pharmacotherapies for depression in adults, the response rate for treatment of depression with antidepressants was found to be approximately 54%.[7] The efficacy of the newer pharmacotherapies is similar to that of older antidepressants for general medical patients, including older adults and those with coexisting medical or psychiatric illness.[7] The dropout rates due to adverse effects are approximately 11% for newer antidepressants and 16% for older antidepressants.[7] Because of the relative paucity of data regarding antidepressant use in oncology settings, there is considerable variability in practice patterns related to prescribing antidepressants in cancer patients. Although studies generally indicate that about 25% of all cancer patients are depressed, one study found that only 16% of cancer patients were receiving antidepressant medication.[8]

Antidepressant Studies

• In adults, a double-blind placebo-controlled trial comparing fluoxetine with desipramine in treating depressive symptoms in 40 women with cancer found both medications to be effective and well tolerated. There were greater improvements on several quality-of-life measures in patients who received fluoxetine.[9]



• One study compared paroxetine with amitriptyline in the management of depression in women with breast cancer. Both treatments were equally effective. Paroxetine was associated with significantly fewer anticholinergic adverse effects than amitriptyline.[10]



• In a randomized controlled trial comparing fluoxetine with a placebo, patients receiving fluoxetine were found to have improved quality of life and decreased depressive symptoms.[11] Using a symptom-based approach (similar to the management of other cancer-related symptoms such as pain or nausea), this study assessed for depression by use of a 2-item screening procedure focused on presence of anhedonia (little interest or pleasure in doing things) and depressed or hopeless mood. Most of the sample consisted of patients with mild-to-moderate levels of depressive symptoms regardless of whether they met the diagnostic criteria for depression. Generalization was enhanced by inclusion of a sample of mixed cancer types (e.g., breast, thoracic, genitourinary, gastrointestinal) from a predominantly community cancer care setting, an equal male/female ratio, and a relatively large sample size (n = 163). A subgroup of patients identified as having higher levels of depressive symptoms was most likely to benefit from the treatment.

Most antidepressant prescribing is directed at the treatment of an existing depressive disorder or significant depressive symptoms. One study, however, supports the use of antidepressants to prevent depression in patients receiving high-dose interferon for adjuvant therapy of malignant melanoma.[12] The rationale for this approach is that treatment with high-dose interferon is associated with a particularly high rate of depression in this patient population, and proinflammatory cytokines implicated in the biological changes that result in depression may be directly reduced by antidepressants. In this double-blind study of patients receiving high-dose interferon, 2 of 18 patients in the paroxetine group developed depression during the first 12 weeks of therapy, compared with 9 of 20 patients in the placebo group (relative risk [RR] = 0.24; 95% confidence interval [CI], 0.08–0.93). Moreover, there were significantly fewer treatment discontinuations in the paroxetine group (5% vs. 35%, RR = 0.14; 95% CI, 0.05–0.85). Further study is required to confirm these findings and to determine whether prophylactic use of antidepressants has benefit in other treatment settings.

The choice of antidepressant depends on a patient's medical history and concomitant medical problems, the symptoms referable to depression, previous responses to antidepressant medications, and the side effects associated with the agents available.

The types of medications used to treat depression in patients with cancer include the SSRIs, tricyclic antidepressants (TCAs), and analeptic or CNS stimulant agents (i.e., amphetamines). The following table outlines the commonly used antidepressants and highlights starting dosages used in cancer patients. The Side Effects/Comments column identifies drug-specific side effects that may be clinically advantageous or problematic depending on the clinical situation when selecting antidepressant medications and monitoring patients receiving these drugs. Generally, there is a long latency period (3–6 weeks) from initiation of antidepressant medications until the onset of a therapeutic response. In many cases, antidepressant treatment begins at low doses followed by a period of gradual dose titration to achieve an optimum individualized response. Initial low doses may help to avoid initial side effects, but dose escalation may be required in order to see therapeutic effects. For some agents, there is a therapeutic window during which plasma concentrations correlate with a patient's antidepressant response (e.g., nortriptyline). For patients receiving these agents, serial drug concentration monitoring guides therapy and facilitates providing an adequate therapeutic trial, because plasma concentrations less than and greater than the defined therapeutic ranges are associated with treatment failure, suboptimal responses, and in the case of high drug concentrations, unnecessary toxicity.

When selecting an antidepressant drug, it is worthwhile to consider that side effects may have a clinical advantage. For example, some TCAs, such as amitriptyline, and atypical antidepressants, such as mirtazapine and trazodone, produce sedation and may be useful for agitated patients and for those who have difficulty getting to sleep. Consequently, treatment is often initiated as a single daily dose administered at bedtime. Although most patients will develop tolerance to antidepressants' sedative effects with continued treatment, the need for soporific agents may diminish with improvement in depressive symptoms.

When selecting antidepressants, either singly or in combination, consider the following:

• Target specific distressing symptoms.



• Evaluate coexistent medical problems that may be exacerbated by particular antidepressants.



• Minimize side effects and avoid worsening of current health status.



• Determine the patient's ability to swallow solid dosage forms; he or she may be able to take an antidepressant in liquid form (e.g., amitriptyline, nortriptyline, doxepin, fluoxetine). Alternatively, some antidepressants are available as parenteral dosage forms (e.g., amitriptyline and imipramine injection).



• Evaluate the patient's medication profile for potential interactions with antidepressant drugs.

Significant concern about the potential for suicide as a side effect of selective serotonin reuptake inhibitors (SSRIs) has led the U.S. Food and Drug Administration (FDA) to issue a caution about their use that includes the importance of careful monitoring of potential risks.[14] Before this FDA Health Advisory was issued, clinical experience and the results of small clinical trials suggested that antidepressants can be safely administered to adult cancer patients, although there are no controlled clinical trials to support this position. When SSRIs are prescribed for adult cancer patients, a careful follow-up plan should be implemented by individuals with expertise, and consultation referrals should be made for patients who do not respond as anticipated or who present other concerns.[15] The risk/benefit ratio for use of SSRIs may not be as favorable for children and adolescents. Several multicenter, double-blind, randomized, placebo-controlled clinical trials using SSRIs with children and adolescents with major depressive disorder but not cancer found modest improvements for fluoxetine,[16,17] paroxetine,[18] and sertraline.[19] Balancing these improvements were reports of serious adverse events that included worsening of psychiatric symptoms, increased suicidal ideation and gestures, increased conduct problems or hostility with paroxetine,[18] and suicide and suicide attempts with sertraline.[19] None of these clinical trials have included or focused on children and adolescents being treated for cancer. Risk/benefit concerns have reached the level of international regulatory concern. The Medicines and Healthcare Products Regulatory Agency of Great Britain has recommended that most of the drugs in the SSRI category not be used with children and adolescents,[20] and the FDA raised similar concerns in a Talk Paper and subsequently issued a "black box" warning.[21] The British Committee on Safety of Medicines considered only one of the SSRIs (fluoxetine) to have a favorable balance of risks and benefits, but it is only considered beneficial in approximately one in ten patients.[22] Consistent with this finding, age-stratified analyses of the child and adolescent studies found that for children younger than 12 years with major depression, only fluoxetine showed benefit over placebo.[23] As noted, none of the children or adolescents in these studies had cancer, so there are no reports available that address whether there are additional increased risks of adverse events associated with the use of SSRIs following exposure to different chemotherapeutic agents and/or central nervous system (CNS) radiation treatment. Frontline, alternative, effective, behavioral, and pharmacologic treatments for depression should be used for children and adolescents being treated for cancer. However, if the risks of depression are significant and SSRIs are considered, consultation from a child psychiatrist or neurologist is essential, and close monitoring of potential adverse events is crucial. No warning has been issued for adult use of SSRIs.

The optimal duration of antidepressant therapy for patients treated for depressive symptoms (without a depressive disorder) is unknown. Patients with a depressive disorder who achieve a beneficial response to antidepressant pharmacotherapy should continue treatment for a minimum of 4 to 6 months after depression resolves. When patients are discontinuing antidepressant medications, TCA doses should be tapered by approximately 25% per week to avoid cholinergic rebound (e.g., hypersalivation, diarrhea). In patients who experience intolerable adverse effects, however, doses may be tapered quickly. With the exception of fluoxetine, gradual tapering is advised when decreasing doses or discontinuing treatment for all SSRIs. Other antidepressants with short half-lives, such as venlafaxine, also should be tapered gradually. Withdrawal symptoms, both somatic and psychological, frequently emerge after abrupt discontinuation, during intermittent noncompliance, and sometimes during dose reduction; though these symptoms are generally mild, short-lived, and self-limiting, they can be distressing and may lead to missed workdays and decreased productivity. Mild symptoms can often be treated by reassuring a patient that they are usually transient. For more severe symptoms, it may be necessary to reinstate the dosage of the original antidepressant and slow the rate of taper. Symptoms of discontinuation may be mistaken for physical illness or relapse into depression and misdiagnosis may lead to unnecessary, costly tests and treatment. Thus, health care professionals need to be educated about the potential adverse effects of SSRI discontinuation.[24]

TCAs can produce abnormal myocardial conduction; thus, a cardiac history and a recent EKG should be obtained in patients with a history of cardiac problems. Many tricyclic antidepressants have a sedating effect; therefore, treatment typically is started at low doses at bedtime. The main exception is desipramine, which some patients find mildly stimulating and can be administered in the morning to reduce insomnia, if it develops. Daily doses are increased slowly every few days or at weekly intervals until symptoms improve. Many patients become tolerant to the drugs' sedative effects, and total daily doses may be divided and given during patients' waking cycles.

TCAs are still regarded as first-line agents for severe, major depression; however, SSRI use is increasing for that indication because of the effectiveness of SSRIs and the low risk of clinically significant side effects that are associated with TCAs, such as cardiac arrhythmias, hypotension, and anticholinergic effects. In addition, TCAs are highly toxic on overdose. Side effects commonly associated with the SSRIs include nausea, vomiting, diarrhea, somnolence, insomnia, headache, confusion, dizziness, asthenia, and sexual dysfunction. Drug-specific adverse effects associated with fluoxetine include gastric distress, brief periods of anxiety or agitation, and anorgasmia in females. Treatment with sertraline is sometimes complicated by dyspepsia, tremor, and ejaculatory delay in men.

The pharmacokinetic profiles of SSRIs permit them to be given once a day, thus improving patient compliance.[25] Sertraline and paroxetine have a half-life of approximately 20 hours; thus, steady-state systemic concentrations can be achieved within 1 week after starting treatment and altering dosage or administration schedules. In comparison, repeated dosing appears to inhibit fluoxetine metabolism; consequently, both fluoxetine and its active metabolite, norfluoxetine, may be present in the body for weeks after discontinuing treatment.

Clinicians who prescribe and monitor patients receiving antidepressants should also become familiar with their potential for interactions with other medications.[26] The SSRIs venlafaxine, nefazodone, and mirtazapine are metabolized by cytochrome P450 enzymes; their pharmacokinetics may be altered, or they may affect the clearance of drugs metabolized by the same enzymes. Marked differences exist, however, between the SSRIs and SSRI metabolites with regard to their effects on specific cytochrome P450 enzymes.[13] For example, both fluoxetine and norfluoxetine inhibit CYP3A4 isoenzyme; however, the metabolite is more potent than fluoxetine and in view of its longer half-life the potential for interactions may persist for weeks after fluoxetine is discontinued.[27] Understanding the similarities and differences in their pharmacology can aid clinicians in using these agents optimally and avoiding clinically important pharmacokinetic drug-drug interactions. In addition, since all SSRIs are highly protein-bound to albumin (± alpha-1 acid glycoprotein), clinicians must consider their potential for interactions with other highly protein-bound medications. Sertraline and paroxetine may be preferred in patients with renal or hepatic dysfunction since they are metabolized and excreted as inactive compounds.[28]

• Bupropion

  Bupropion is a unique alternative to tricyclics and SSRIs for treating persons with depression and cancer, especially when depression is accompanied by fatigue. Pharmacologically, bupropion is a weak inhibitor of monoamine reuptake and demonstrates a slight preference for dopamine transport inhibition; however, it may be metabolically converted to active substances with amphetamine-like activity that affect both dopamine and norepinephrine reuptake. Bupropion generally does not cause sexual dysfunction; therefore, it may be useful in treating patients who wish to remain sexually active and those who have experienced sexual dysfunction with other antidepressants. Bupropion treatment is initiated with doses of 75 mg once daily, preferably in the early part of the day. Patients may initially require a moderate- to long-acting sedative/hypnotic drug at bedtime for the insomnia, agitation, and motor restlessness sometimes associated with bupropion. Risk of seizure with bupropion may be as much as 4 times greater than is associated with other antidepressants. Single doses should not exceed 150 mg, a dose increase should not be greater than 100 mg of bupropion per day, and dose increases should be gradual—at least 3 days after a previous increase in dose. Because the risk of seizure markedly increases in patients receiving bupropion at doses between 450 mg and 650 mg, the total daily dose should not exceed 450 mg. Bupropion is contraindicated in patients with malignant diseases involving the brain and with a history of cranial trauma or seizure disorder [29] and in persons with a history of bulimia.[30]




• Venlafaxine

  Venlafaxine affects both norepinephrine and serotonin reuptake and enhances serotonin neurotransmission.[31] Venlafaxine does not produce the same uncomfortable antimuscarinic and antiadrenergic side effects as the TCAs; however, it does produce side effects similar to the SSRIs, particularly nausea, headache, somnolence, and dry mouth. In some patients, venlafaxine may cause sustained increases in blood pressure; blood pressure should therefore be evaluated before treatment is started, monitored after treatment is initiated, and monitored after doses are increased. Venlafaxine is given twice a day, with food.




• Trazodone and nefazodone

  The primary actions of the atypical antidepressants trazodone and nefazodone are not well established. Although they both antagonize serotonin reuptake, they are many times weaker in this respect compared with SSRIs. Trazodone is active, and both agents are metabolized to compounds that have agonistic activity at some serotonin receptors (5-HT₁). Both agents may have additional active metabolites that contribute to their clinical activity.[31] Nefazodone is reported to be useful in patients with agitated depression and may be better tolerated than the SSRIs. Nefazodone can complicate some patients' management because it is a potent inhibitor of hepatic cytochrome P450 3A4 isoenzymes. Its use is, therefore, relatively contraindicated in patients who are receiving methadone and absolutely contraindicated in those receiving terfenadine or astemizole.




• Mirtazapine

  There is growing clinical experience with mirtazapine in persons with cancer. Pharmacologically, mirtazapine is a noradrenergic and specific serotonergic antidepressant. It competitively antagonizes presynaptic alpha-adrenergic receptors (alpha2) and serotonin receptors (5-HT₂ and 5-HT₃), the net result of which enhances norepinephrine release and noradrenergic neurotransmission.[31,32] Sedation is the predominating side effect at subtherapeutic low doses (<15 mg/day), and anecdotal evidence suggests that sedation decreases at higher doses. Its side-effect profile also includes increased appetite, which may cause weight gain, dizziness, dry mouth, and constipation.[33] Although it is a structural analog of mianserin (an antidepressant that is marketed in Europe), mirtazapine has rarely been implicated in producing severe blood dyscrasias, including agranulocytosis, as has mianserin.[34] Little is known about mirtazapine interactions with other drugs, but it is thought to have a lesser risk of clinically significant drug interactions than SSRIs.[35] The initial dose for mirtazapine is 15 mg per day given at bedtime. Doses may be increased at intervals not less than 1 to 2 weeks, up to a maximum daily dose of 45 mg.

Benzodiazepines can be used to effectively treat the anxiety that may be associated with depression. In patients receiving antidepressant medications and benzodiazepines concomitantly, the latter drugs may be discontinued after patients' depressive symptoms begin to abate; however, both agents can be continued safely if needed. Benzodiazepines should never be stopped abruptly because withdrawal symptoms with possible seizures may occur. The dose of benzodiazepines should be tapered slowly at a rate of approximately 25% every 3 to 4 days.

Clinical experience suggests that analeptic agents (e.g., methylphenidate and dextroamphetamine) are useful at low doses for patients whose symptoms include depressed mood, apathy, decreased energy, poor concentration, and weakness.[36] They are particularly useful for patients with advanced cancer who have a limited life expectancy (weeks to a few months). Compared with traditional antidepressants such as the TCAs and SSRIs that take 3 to 4 weeks to take effect, the psychostimulants often demonstrate antidepressant effects within a few days of starting treatment. They promote a sense of well-being, decreased fatigue, and increased appetite. Analeptic agents can be helpful in countering the sedating effects of opioids, and in comparison with antidepressants, they are rapidly effective. Adverse effects associated with analeptic agents include insomnia, euphoria, and mood lability. High doses and long-term use may produce anorexia, nightmares, insomnia, euphoria, or paranoia.

Methylphenidate and dextroamphetamine are administered in divided doses early in a patient's waking cycle to avoid sleep disturbances, e.g., insomnia and nighttime arousal. Like benzodiazepines, these medications are adjuncts to antidepressant medications; they may be started concomitant with an antidepressant and discontinued when depressive symptoms abate.[37,38]

The use of monoamine oxidase inhibitors (MAOIs) in the cancer population has been limited because the nutritional requirements of a tyramine-free diet are generally more difficult to accomplish in patients receiving antineoplastic treatments. MAOIs are contraindicated in patients receiving opioids, sympathomimetics, and procarbazine because of the potential for developing hypertensive crisis.

MAOIs may cause adverse reactions when taken with other medications and certain foods. MAOIs impair the metabolism of morphine and other opioids as well as barbiturates and may lead to exaggerated ventilatory depression. Meperidine HCl (Demerol), an opioid, has been associated with hypertension, hyperpyrexia, skeletal muscle rigidity, seizures, and coma when used with MAOIs.[44] Exaggerated effects of antihistamines, anticholinergics, and tricyclic antidepressants may be secondary to impaired metabolism by MAOIs. In addition, the hypoglycemic effects of insulin and oral sulfonylureas may be potentiated by MAOIs.

MAOIs may also interact with specific anesthetic drugs used during surgery.[45] Cancer patients in particular may frequently undergo surgical procedures and should alert their anesthesiologist of all medications. Postoperative pain should not be treated with meperidine HCl. MAOIs should neither be taken with procarbazine, a chemotherapeutic agent used in the treatment of lymphomas and brain tumors, nor used with other antidepressants.

The U.S. Food and Drug Administration (FDA) has recently approved a transdermal antidepressant that may have particular value in the treatment of the depressed cancer patient who is unable to swallow or take medications by mouth. The antidepressant selegiline (sold under the trade name EMSAM) is an irreversible MAOI. To date, the drug has not been evaluated for the treatment of depression in cancer patients.

Many of the usual dietary restrictions (low-tyramine diet) and drug-drug interactions (the product should not be used with meperidine, propoxyphone, or methadone) are germane to selegiline (see table below). However, according to the package insert, the 20-mg skin patch (which delivers 6 mg of selegiline in a 24-hour period) can be used without the dietary restrictions found on all MAOIs marketed to date. This recommendation is supported by clinical trials and other evidence submitted to the FDA. The two higher doses (a 30-mg patch that delivers 9 mg in 24 hours and a 40-mg patch that delivers 12 mg in 24 hours) carry the usual dietary warning. This drug has not been evaluated in cancer patients for safety and efficacy.

Selegiline is a nonselective MAOI, inhibiting not only the MAO-B enzyme in the central nervous system but also MAO-A elsewhere in the body. In the digestive tract, MAO-A normally metabolizes tyramine, a dietary amine that is found in high concentrations in foods such as aged cheese and red wine. The breakdown of tyramine in the gut prevents significant amounts of it from being absorbed and circulated throughout the body. Tyramine is a potent pressor—leading to constriction of blood vessels—which ultimately results in increased blood pressure. Large amounts of tyramine can lead to hypertensive crises, resulting in stroke, heart attack, and even death. Because the medication is absorbed from the skin patch and bypasses the gut wall, it is thought that transdermal selegiline will have a significantly reduced effect on MAO-A in the digestive tract. In addition, at lower doses, selegiline is thought to inhibit MAO-B preferentially, while at higher doses both A and B isoenzymes are affected. With significantly reduced inhibition of digestive tract MAO-A, dietary restrictions are not considered necessary for the lower dose. In considering starting this drug, consult with a pharmacist about multiple classes of drug-drug interactions. This drug has not been evaluated in people with cancer.[47]

Foods that contain large amounts of tyramine, such as cheese, chicken liver, chocolate, beer, and wine, may provoke hypertension (initially manifesting as headache) and cardiac dysrhythmias.

There has been much interest in the use of St. John's wort (SJW, Hypericum perforatum) as an herbal antidepressant. Its use has become widely advertised as an over-the-counter supplement for mood enhancement.

In the United States, dietary supplements are regulated as foods, not drugs. Premarket approval by the FDA is not required unless specific disease prevention or treatment claims are made, which is often not the case with SJW. Because a review for manufacturing consistency is not required for dietary supplements and no specific standards for dose or purity exist, there may be considerable variation from lot to lot for all products marketed as dietary supplements, including SJW.

Promotional statements about SJW may address mood enhancement and positive outlook. It may be found as a stand-alone supplement or in combination with other herbs, vitamin and mineral supplements, or food products such as teas. The FDA issued a warning highlighting the results from a study conducted by the National Institutes of Health that showed a significant drug interaction between SJW and indinavir, a protease inhibitor used to treat HIV infection. In this study, concomitant administration of SJW and indinavir substantially decreased indinavir plasma concentrations, potentially due to induction of the cytochrome P450 metabolic pathway.[48]

While its specific mechanisms of action are unclear, there are 3 presumed active compounds in the herb. One of these compounds is a mild MAOI (see above precautions). Historically, prescription MAOIs have been used to treat depression as well as Parkinson disease, narcolepsy, and occasionally hypertension, but they are rarely used today. The side effects of SJW include dry mouth, dizziness, gastrointestinal (GI) distress, fatigue, and confusion.

A randomized double-blind placebo-controlled trial involving 200 adult outpatients with major depressive disorder compared the safety and efficacy of SJW with placebo. This study was designed to address the numerous methodological flaws in the existing literature [49] that served as the basis for the meta-analysis that had concluded that SJW is significantly superior to placebo.[50] This study represents the first report of a large-scale randomized placebo-controlled trial of SJW in the United States. This study does not support significant antidepressant or antianxiety effects of SJW. Specifically, compared with placebo, there were no significant differences in response rates in the overall sample of outpatients with major depression. On the basis of these trial data indicating lack of efficacy in depressed patients in primary care settings, as well as the lack of properly designed positive trials in cancer patients, SJW should not be recommended for major depression in cancer patients.

The following tables highlight tips that may be useful in determining what medication is best to use for a particular patient. The tables focus on the effects these medications may have beyond their antidepressant effects that may decrease or increase patient distress, such as fatigue, insomnia, and nausea and vomiting.