Suicide risk of antidepressant medication
Antidepressant medication selection
Selective serotonin reuptake inhibitors
Discontinuation of antidepressants
Monoamine oxidase inhibitors
St. John's wort
Empirical studies of the efficacy of psychotherapy
Current Clinical Trials
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. Studies have shown that treatment of severe 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. 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. 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%. 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. The dropout rates due to adverse effects are approximately 11% for newer antidepressants and 16% for older antidepressants. 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.
- 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.[Level of evidence: I]
- 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.[Level of evidence: I]
- 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.[Level of evidence: I] 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.
Over the past few years, significant concerns have been raised about the risk of suicidal thinking and behavior with the use of antidepressants in children, adolescents, and young adults. Since 2003, U.S. and European regulators have issued several public health warnings on this topic. The first such advisory issued by the U.S. Food and Drug Administration (FDA) warned about a possible association between antidepressants and suicidal thinking and behavior in children and adolescents. In December 2003, the Medicines and Healthcare Products Regulatory Agency of the United Kingdom issued a letter to doctors advising against the use of antidepressants in anyone younger than 18 years. In October 2004, the FDA mandated pharmaceutical companies to add a “black box” warning to the labeling of all antidepressants suggesting increased risk of suicidality in pediatric patients who were taking antidepressants. The FDA revised this boxed warning in May 2007 to include young adults younger than 25 years. The new, carefully worded warning emphasizes that the risk of suicidality is associated with both antidepressants and depression. In addition to raising concerns about increased suicidality in children, adolescents, and young adults, the warning acknowledges a significant protective effect of antidepressants in adults aged 65 and older.
The meta-analysis that led to the initial boxed warning in pediatric patients concluded that the antidepressants are associated with a twofold increase in suicidal ideation and behavior compared to the placebo in children and adolescents. A major meta-analysis published in the Journal of the American Medical Association reanalyzed the data from the child and adolescent studies (including seven studies not included in the initial meta-analysis), using a random-effects model.[Level of evidence: I] While this reanalysis found an overall increased risk of suicidal ideation/suicidal behavior consistent with the initial meta-analysis, the pooled risk differences were found to be smaller and statistically insignificant.
Concerns have been raised that the unintended consequence of the warnings will be overly restricted use of antidepressants among those who benefit the most and, hence, an increase in suicidality that the warning seeks to prevent. A study examining U.S. and Dutch data suggests a drop in selective serotonin reuptake inhibitor (SSRI) prescriptions for children and adolescents since the boxed warning was issued and a simultaneous increase in suicide rates in this patient population.
In summary, the risk/benefit equation favors appropriate use of antidepressants with careful monitoring for suicidality. It is important to note that none of the studies that led to the boxed warning included or focused on patients being treated for cancer. Clinical experience and results of small clinical trials suggest that antidepressants can be safely administered to adult cancer patients, although there are no large controlled clinical trials to support this position. When antidepressants are prescribed for patients with cancer, a careful monitoring plan should be implemented by individuals with expertise, and consultation referral should be made for patients who do not respond as anticipated or who present other concerns.Interferon-related depression
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.[Level of evidence: I] 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.Antidepressant medication selection
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). Table 2 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.Table 2. Antidepressant Medications for Ambulatory Adult Patients
|Drug Class/Generic Name (Proprietary Name)/Dosagesa||Side Effects/Comments|
|TCAs||Can cause cardiac arrhythmias.|
|EKG at baseline to evaluate for preexisting cardiac conduction abnormalities. Therapeutic drug concentration ranges in plasma have been identified for all agents, but dosage adjustments should be based on a patient's clinical response and not solely on plasma concentrations.b|
|In responding patients, decrease daily dosages to the lowest effective amount needed to sustain a response.c Can cause sexual dysfunction.|
|May be associated with weight gain.d|
|amitriptyline (Elavil)||Marked sedation, dizziness, headache, weight gain, anticholinergic effects,e orthostatic BP changes (postural hypotension); may produce sexual dysfunction. Therapeutic plasma concentrations (parent drug + active metabolite) = 110–250 ng/mL.|
|initial: 10–25 mg as a single daily dose, preferably at bedtime|
|maintenance: 150–300 mg/d|
|clomipramine (Anafranil)||Anticholinergic effects, dizziness, drowsiness, headache, weight gain, orthostatic hypotension.|
|initial: 25 mg/d and gradually increase to 100 mg/d the first 2 weeks; may be given at bedtime|
|maintenance: 100–250 mg/d maximum|
|desipramine (Norpramin)||Mild sedation, increased appetite, nausea, minimal anticholinergic effects,e orthostatic BP changes. Therapeutic plasma concentrations = 125–300 ng/mL.|
|initial: 25–50 mg/d as a single daily dose, preferably at bedtime|
|maintenance: 100–300 mg/d as a single daily dose; In elderly patients, daily doses >150 mg are not recommended|
|doxepin (Sinequan)||Moderate to heavy sedation, dizziness, headache, weight gain, moderate anticholinergic effects,e postural hypotension. Optimal antidepressant effect is characteristically delayed by 2–3 weeks, but onset of antianxiety effect is comparatively rapid. Therapeutic plasma concentrations (parent drug + active metabolite) = 100–200 ng/mL.|
|initial: 10–25 mg/d as a single daily dose, preferably at bedtime|
|maintenance: 75–300 mg/d as a single daily dose, preferably at bedtime|
|imipramine (Tofranil)||Moderate to heavy sedation, dizziness, headache, weight gain, moderate anticholinergic effects,e moderate to marked orthostatic BP changes; may produce sexual dysfunction (both genders). Therapeutic plasma concentrations (parent drug + active metabolite) = 200–350 ng/mL.|
|initial: 25–50 mg/d as a single daily dose, preferably at bedtime|
|maintenance: 75–200 mg/d as a single daily dose, preferably at bedtime|
|nortriptyline (Pamelor, Aventyl)||Mild to moderate sedation, constipation, nausea, increased appetite, mild to moderate anticholinergic effects.e Is the TCA least likely to produce postural hypotension. Therapeutic plasma concentrations = 50–150 ng/mL.|
|initial: 10–25 mg, 3–4 times daily|
|maintenance: 30–50 mg, 3 times daily, daily doses >150 mg are not recommended|
|SSRIs||Have few anticholinergic and cardiovascular adverse effects. Life-threatening and fatal reactions have occurred in patients who receive within 2 weeks of using MAOIs. Sexual dysfunction has been reported to be associated with use. There is limited experience with long-term use.|
|citalopram (Celexa)||Ejaculation disorder and other sexual dysfunctions, insomnia, dry mouth, nausea, somnolence. In vitro studies indicated that CYP3A4 and CYP2C19 are the primary enzymes involved in citalopram metabolism. Is a relatively weak inhibitor of CYP2D6.|
|initial: 10 mg/d|
|maintenance: 10–40 mg/d|
|fluoxetine (Prozac)||Anxiety, nervousness, insomnia, anorexia, mild bradycardia, sinoatrial node slowing, weight loss, solar photosensitivity, hyponatremia, sexual dysfunction; may alter glycemic control in diabetic patients. Substantially inhibits CYP2D6 and may inhibit the clearance of other drugs metabolized by cytochrome P450 CYP2D6 isozymes. Probably inhibits CYP2C9/10, moderately inhibits CYP2C19, and mildly inhibits CYP3A4. Fluoxetine metabolism is impaired in elderly patients.|
|initial: 10–20 mg/d|
|maintenance: 20–80 mg/d|
|escitalopram (Lexapro)||Nausea, vomiting, diarrhea, constipation, upset stomach, loss of appetite, dizziness, drowsiness, trouble sleeping, back pain, dry mouth.|
|initial: 10 mg/d|
|maintenance: 10–20 mg/d|
|fluvoxamine (Luvox)||Nausea, sexual dysfunction, headache, nervousness, insomnia, drowsiness.|
|initial: 50 mg at bedtime, adjust in 50 mg increments at 4- to 7-day intervals|
|maintenance: 100–300 mg/d|
|paroxetine (Paxil)||Anxiety, nervousness, insomnia, mild weight loss, headache, solar photosensitivity, hyponatremia, sexual dysfunction. Substantially inhibits and may interact with other drugs metabolized by cytochrome P450 CYP2D6 isozyme. Paroxetine metabolism is impaired in elderly patients.|
|initial: 10–20 mg/d|
|maintenance: 20–50 mg/d|
|sertraline (Zoloft)||Anxiety, nervousness, insomnia, mild weight loss, headache, solar photosensitivity, hyponatremia, sexual dysfunction. Produces mild inhibition of and may interact with drugs metabolized by cytochrome P450 CYP2D6 isozymes with little, if any, effect on CYP1A2, CYP2C9/10, CYP2C19, or CYP3A3/4.|
|initial: 25–50 mg/d|
|maintenance: 50–200 mg/d|
|tranylcypromine (Parnate)||Orthostatic hypotension, drowsiness, hyperexcitability, headache. Low-tyramine diet required.|
|initial: 10 mg twice daily, increase by 10-mg increments at 1- to 3-week intervals|
|maintenance: 10–40 mg/d|
|phenelzine (Nardil)||Orthostatic hypotension, drowsiness, hyperexcitability, headache. Low-tyramine diet required.|
|initial: 15 mg 3 times a day|
|maintenance: 15–90 mg/d|
|selegiline (EMSAM)||Application site reaction, orthostatic hypotension, diarrhea, headache, insomnia, dry mouth. Any dosages higher than 6 mg/24 h require low-tyramine diet.|
|initial: 6-mg patch/24 h (20-mg patch topically every 24 h)|
|maintenance: 6-mg patch/24 h (20-mg patch topically every 24 h). May increase at increments of 3 mg/24 h at 2-week intervals up to 12 mg/24 h.|
|ATYPICAL ANTIDEPRESSANTS||In general, serum drug concentrations do not correlate with antidepressant response.|
|bupropion (Wellbutrin, also approved for the treatment of smoking cessation as Zyban)||Initially activating dose-related seizure-inducing potential; contraindicated in patients with CNS involvement, a history of seizure, and concomitant conditions predisposing to seizure and in patients taking other drugs that lower seizure threshold. Mild to moderate sedation, mild to moderate anticholinergic effects,e mild orthostatic BP changes, agitation, insomnia, headache, confusion, dizziness, seizures, weight loss.|
|initial: 75 mg/d|
|maintenance: 200–450 mg/d not to exceed 150 mg/dose|
|trazodone (Desyrel)||Mild to moderate sedation; negligible anticholinergic effects; mild to moderate orthostatic BP changes, particularly in elderly patients; dizziness; headache; confusion; muscle tremors; may produce priapism. Taking with food can decrease gastrointestinal upset. Therapeutic plasma concentrations = 800–1,600 ng/mL.|
|initial: 50 mg/d|
|maintenance: 150–600 mg/d|
|mirtazapine (Remeron)||A tetracyclic antidepressant. Elimination is decreased in elderly persons. Somnolence, dizziness, increased appetite and weight gain, constipation, hypertension, edema, confusion, increased nonfasting triglycerides and cholesterol, significantly increased hepatic ALT, orthostatic hypotension. When used concomitantly with drugs that reduce seizure threshold (e.g., phenothiazines), may increase risk of seizure.|
|initial: 7.5–15 mg/d|
|maintenance: 15–45 mg/d|
|venlafaxine (Effexor)||Dose-related sustained hypertension, headache, dizziness, insomnia, nausea, constipation, abnormal ejaculation. Life-threatening and fatal reactions have occurred in patients who receive within 2 weeks of using MAOIs.|
|initial: 75 mg/d|
|maintenance: 150–375 mg/d|
|duloxetine (Cymbalta)||Nausea, dry mouth, constipation, decreased appetite, fatigue, sleepiness, increased sweating, decreased sexual drive or ability, urinary hesitation.|
|initial: 30 mg/d|
|maintenance: 30–60 mg/d|
|PSYCHOSTIMULANTS||Restlessness, agitation, insomnia, nightmares, psychosis, anorexia; may exacerbate preexisting cardiac disease. Should be administered early in a patient's daily waking cycle. Sometimes used adjuvantly to antagonize opioid analgesics' sedative effects.|
|dextroamphetamine (Dexedrine)||Drug tolerance, abuse, and dependence liability. Arrhythmia, nervousness, restlessness, insomnia. Contraindicated in patients with advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, and glaucoma.|
|initial: 2.5–5 mg/d|
|maintenance: 10–30 mg/d|
|methylphenidate (Ritalin, Methylin)||Drug tolerance, abuse, and dependence liability. Hypertension, tachycardia, nervousness, insomnia, anorexia, drowsiness, dizziness. May decrease convulsive threshold in patients with history of seizure disorders.|
|initial: 2.5–10 mg/d|
|maintenance: 20–60 mg/d|
|dexmethylphenidate (Focalin)||Dry mouth, tremor or muscle spasms, nervousness, trouble sleeping, headache, drowsiness, nausea, insomnia, increased sweating, dizziness, lightheadedness, changes in sexual function.|
|initial: 10 mg/d|
|maintenance: 10–20 mg/d|
|ALT = alanine aminotransferase; BP = blood pressure; EKG = electrocardiogram; MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants.|
|aConsult complete prescribing information for appropriate administration schedules.|
|bTCAs prolong cardiac conduction through His-Purkinje system similar to Type IA antiarrhythmic agents (e.g., quinidine). They are specifically contraindicated in patients with bundle-branch disease and second- or third-degree heart block. Their effects on conduction correlate with dosage and serum concentrations and for those agents with positive chronotropic and adrenergic-stimulating properties, TCAs can cause reentry arrhythmias. Persons at greatest risk are those with preexisting cardiac conduction defects and those who have taken an overdose.|
|cPlasma concentrations are most useful for guiding treatment in elderly patients who are (1) experiencing signs and symptoms of toxicity, (2) unresponsive to treatment, (3) suspected of being noncompliant with planned treatment, or (4) receiving other medications that may interact or otherwise alter antidepressant medication pharmacokinetics.|
|dTCAs and other antidepressants may cause sexual dysfunction characterized as decreased libido, penile erectile dysfunction, and decreased sensation during orgasm and ejaculation. Management consists of waiting for spontaneous resolution with continued therapy, decreasing the antidepressant dose, selecting an alternative antidepressant, or concomitant treatment with medications that treat the dysfunction (e.g., bethanechol for antidepressants with prominent anticholinergic effects).|
|eCommon antimuscarinic or anticholinergic effects include dry mouth, blurred vision, constipation, and urinary retention. Although patients may eventually develop tolerance to these effects with repeated medication use, symptoms may not completely resolve until the drug is discontinued.|
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.
The postulated mechanism of action of SSRIs involves the blockade of serotonin neuronal reuptake, leading to desensitization of serotonergic feedback receptors. All currently available SSRIs are equally efficacious; they differ primarily in their safety, tolerability, half-lives, and drug-drug interactions. While some side effects are more common with some SSRIs than with others, side effects and tolerability may differ significantly in individual patients. SSRIs have become the first-line treatment for depressive disorders, owing to their better tolerability side effect profile, especially in comparison with the TCAs. As discussed earlier, antidepressant studies conducted in patients with cancer are done mostly with SSRIs or TCAs. None of the clinical trials have included or focused on children and adolescents being treated for cancer.[19-22][Level of evidence: I] Overall, the evidence on the efficacy of SSRIs for treating cancer-related depression remains limited, and more studies are needed to address the efficacy, safety, tolerability, and drug-drug interaction issues in the context of cancer and cancer treatments. 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. 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.[Level of evidence: I] 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.Discontinuation of antidepressants
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.Side effects
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.[Level of evidence: II] 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.Drug-drug interactions
Clinicians who prescribe and monitor patients receiving antidepressants should also become familiar with their potential for interactions with other medications. 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. 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. 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.Atypical antidepressants
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 a history of cranial trauma or seizure disorder, and in persons with a history of bulimia.[Level of evidence: II]
Venlafaxine affects both norepinephrine and serotonin reuptake and enhances serotonin neurotransmission. Venlafaxine does not produce the same uncomfortable antimuscarinic and antiadrenergic side effects as the TCAs; however, it does produce side effects similar to those produced by 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.
The primary actions of the atypical antidepressant trazodone is not well established. Although it antagonizes serotonin reuptake, it is many times weaker in this respect compared with SSRIs. Trazodone is active and is metabolized to compounds that have agonistic activity at some serotonin receptors (5-HT1). It may have additional active metabolites that contribute to its clinical activity.
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 (alpha-2) and serotonin receptors (5-HT2 and 5-HT3), the net result of which enhances norepinephrine release and noradrenergic neurotransmission.;[Level of evidence: I] Sedation is the predominating side effect at subtherapeutic low doses (<15 mg/d), 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. 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. 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. 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.Psychostimulants
Clinical experience (see Table 3) 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.[Level of evidence: II] 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]Table 3. Clinical Trials of Psychostimulants in Cancer Patients
|Meyers et al. 1998 ||Brain tumor; N = 30||methylphenidate (Ritalin)||↑ mood, ↑ cognition, ↑ function|
|Olin and Masand 1996 ||Mixed cancer; N = 59; chart review||dextroamphetamine (Dexedrine); methylphenidate (Ritalin)||↓ depression, ↑ appetite|
|Bruera et al. 1992 ||Cancer pain vs. opioid infusion; N = 20||methylphenidate (Ritalin); placebo||↑ cognition, ↓ sedation|
|Fernandez et al. 1987 ||Mixed cancer; rapid onset; N = 30||methylphenidate (Ritalin; up to 80 mg)||↓ depression|
|Bruera et al. 1986 ||Pain; double-blind cross-over study; N = 24||mazindol (Mazanor)||↓ pain, ↓ appetite, no effect on mood|
|Joshi et al. 1982 ||Terminally ill||amphetamine||↑ comfort|
Monoamine oxidase inhibitors
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. 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. 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 FDA 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. 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 4 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.Table 4. Tyramine-Containing Foodsa
|Class of Food and Beverage||Tyramine-Rich Foods and Beverages To Avoid||Acceptable Foods Containing Little or No Tyramine|
|Meat, poultry, and fish||Air-dried, aged, and fermented meats, sausages, and salamis (including cacciatore, hard salami, and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in color or odor or that have become moldy); spoiled or improperly stored animal livers||Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage, and cooked sliced ham)|
|Vegetables||Broad bean pods (fava bean pods)||All other vegetables|
|Dairy||Aged cheeses||Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt|
|Beverages||All varieties of tap beer, and beers that have not been pasteurized so as to allow for ongoing fermentation||As with other antidepressants, concomitant use of alcohol with selegiline is not recommended. (Bottled and canned beers and wines contain little or no tyramine.)|
|Miscellaneous||Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu); OTC supplements containing tyramine||Brewer’s yeast, baker’s yeast, soy milk, commercial chain-restaurant pizzas prepared with cheeses low in tyramine|
|OTC = over-the-counter.|
|aAdapted from the EMSAM Medication Guide. The foods and beverages listed above should be avoided beginning on the first day of treatment with selegiline 9 mg/24 h or 12 mg/24 h and should continue to be avoided for 2 weeks after a dose reduction to 6 mg/24 h or following the discontinuation of selegiline 9 mg/24 h or 12 mg/24 h.|
Selegiline is a nonselective MAOI, inhibiting not only the monoamine oxidase B (MAO-B) enzyme in the central nervous system but also monoamine oxidase A (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.
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.St. John's wort
There continue to be high levels of enthusiasm for the use of herbs and dietary supplements for controlling symptoms and improving health-related quality of life and well-being. One popular herbal agent that has been used to treat depression is St. John's wort, a plant with Greek origins. The major active constituents in St. John's wort are hypothesized to be melatonin, hypericin, hyperforin, and adhyperforin, although hypericin may not reach sufficient concentrations in humans to have biologic activity. Hypericin is thought to be a monoamine oxidase inhibitor, while hyperforin and adhyperforin are believed to inhibit the reuptake of serotonin, dopamine, and norepinephrine.[48-51] These mechanisms of action provide the rationale for evaluating St. John's wort for depression management.
During the last 25 years, many trials have compared St. John’s wort to placebo, to antidepressants, and sometimes to both placebo and antidepressants. A wide range of results have emerged, from finding no differences between arms, to finding St. John's wort improving outcomes over placebo for moderate depression, to finding St. John's wort preferable to placebo in general, to finding St. John's wort equal to antidepressants in alleviating depressive symptoms.;[53,54][Level of evidence: I] Older studies comparing St. John's wort to antidepressant therapy tended to use low doses of antidepressants and did not titrate up by response to the usual doses used for managing depression. The best overview of the research in this area is provided in a meta-analysis of randomized controlled trials. Conclusions from this meta-analysis, which includes 37 trials, are that St. John's wort does not have a clinically important effect on major depressive disorder and that for milder depression, it may have some effect (but it is not large).
Side effects reported in studies of St. John's wort are minimal. One study that compared St. John's wort to sertraline and placebo found that the side effects of St. John's wort that were significantly different from those of placebo included anorgasm, frequent urination, and swelling.[Level of evidence: I] A meta-analysis of randomized controlled trials found that fewer patients withdrew from trials because of adverse effects from St. John's wort, compared with antidepressants.
It is important that a physician knows what drugs a patient is already using before that patient begins taking St. John's wort, which decreases the effectiveness of other concomitantly administered drugs. There are two important cautions when the use of St. John's wort for depression is being considered:
- As an herb, St. John's wort is regulated by the FDA as a food/dietary supplement. Although the FDA issued a final rule establishing regulations to require manufacturers of dietary supplements to prove good manufacturing processes and to correctly label their ingredients, the standardization of products such as St. John's wort with respect to the desired amount of potentially active ingredients is not carried out. Therefore, if hyperforin is the desired ingredient, the amount of hyperforin in any formulation of St. John's wort could differ substantially among brands.
- St. John's wort has been found to be metabolized within the cytochrome P450 system and has effects inhibiting as well as inducing various metabolic pathways. The pathways affected by St. John's wort are CYP3A4, CYP2C9, and CYP2D6. In one study in humans, effects on systemic concentrations of drugs via the CYP3A4 pathway were evident in as few as 14 days. Clinically, this means that the concomitant use of St. John's wort with other drugs could cause lower concentrations of drugs that are needed to have therapeutic effects. With respect to cancer and its treatment, St. John's wort has been shown to decrease concentrations of irinotecan in patients receiving treatment  and, in vitro, is suspected of reducing concentrations of docetaxel. Additionally, St. John's wort has been found to affect concentrations of cyclosporin A and tacrolimus, both important for transplant engraftment, as well as concentrations of indinavir for the treatment of HIV.
The bottom line regarding the use of St. John's wort for the management of depression is that despite a more tolerable side effect profile, there is a lack of evidence demonstrating an advantage to using this herbal agent over approved antidepressant therapy. The data do not support a strong effect on major depressive disorder or even on mild to moderate depression. This fact, combined with concerns about drug interactions and lack of standardization, makes St. John's wort an unattractive alternative for depression management.Antidepressant effects
Table 5 and Table 6 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.Table 5. Physical Symptom- and Distress-Driven Approach to Choosing an Antidepressanta in Adult Cancer Patients
|Opioid side effects||+||+|
|Loss of appetite (weight loss)||+||+|
|SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; + = use of this medication could relieve the symptom; – = use of this medication could worsen the symptom.|
|aIn general, doses should start low and increase slowly. This list does not indicate absolute indications or contraindications for particular medications. A current Physicians' Desk Reference or another reliable drug information resource and experience should guide clinical decision making.|
|bAlthough all SSRIs have the potential paradoxical side effect of hypersomnia, fluoxetine is particularly activating. Bupropion is also somewhat activating.|
|cSedating antidepressants are useful for insomnia, either alone or in addition to another antidepressant. Trazodone and mirtazapine are often used as sleep aids in combination with another antidepressant.|
|dSome antidepressants are useful in treating neuropathic pain. The most studied of these are the TCAs, particularly amitriptyline.|
|eSedating antidepressants are most useful for anxious/agitated patients. These include the TCAs, trazodone, mirtazapine, and nefazodone.|
Table 6. Factors to Consider in Choosing an Antidepressant For Adult Cancer Patients
|Comorbid Medical Conditions||SSRI||TCA||Psychostimulants||Other|
|SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; + = use of this medication could relieve the symptom; – = use of this medication may be a less appropriate choice.|
|aIn general, TCAs and psychostimulants can cause and exacerbate cardiac arrhythmia. SSRIs, bupropion, venlafaxine, and nefazodone are generally less likely to cause cardiac problems. EKGs should be obtained before starting TCA medication, and a cardiologist should be consulted if there is concern for cardiac compromise.|
|bThe shorter-acting SSRIs (sertraline and paroxetine) are less problematic than fluoxetine in patients with hepatic dysfunction. There is less potential for adverse drug interactions and fewer problems related to drug accumulation due to a shorter half-life. Sertraline and nefazodone reportedly have less effect on hepatic P450 enzyme activity.|
|cClinicians should consider whether antidepressant doses and administration schedules require modification for their patients with renal or hepatic insufficiency.|
|dThe TCAs are contraindicated in closed-angle glaucoma.|
It should be noted that electroconvulsive therapy (ECT) is a useful and safe therapy when other interventions have not succeeded in relieving the depressive syndrome that may represent a life-threatening complication of treatable cancer.[60,61] Experience is limited, however, in using ECT in patients receiving mirtazapine and trazodone, and there are no clinical studies establishing the use of ECT in patients receiving SSRIs. Prolonged seizures have occurred rarely in patients receiving fluoxetine.Psychotherapy
Traditionally, depressive symptomatology was managed with insight-oriented psychotherapy, which is quite useful for some people with cancer. For many other people, these symptoms are best managed with some combination of crisis intervention, brief supportive psychotherapy, and cognitive-behavioral techniques.
Psychotherapy for depression has been offered in a variety of forms. Most interventions have been time limited (ranging between 4 and 30 hours), have been offered in both individual and small-group formats, and have included a structured educational component about cancer or a specific relaxation component.
Cognitive-behavioral psychotherapy has been one of the most prominent types of therapies studied in recent investigations. Cognitive-behavioral interventions focus on altering specific coping strategies aimed at improving overall adjustment and typically focus on specific thoughts and their relationship to emotions and behaviors. Understanding and altering one’s thoughts can change emotional reactions and accompanying behaviors. For example, frequent, intrusive, uncontrollable thoughts about loss, life changes, or death can cause poor concentration and precipitate feelings of sadness, guilt, and worthlessness. In turn, these feelings can result in increased sleep, withdrawal, and isolation. A cognitive-behavioral intervention focuses on the intrusive thoughts, often challenging their accuracy or rationality and noting specific patterns of cognitive distortions. Simultaneously, patients develop specific cognitive coping strategies that are designed to alter emotional reactions and accompanying behaviors. The end result is improved coping, enhanced adjustment, and better overall quality of life.
Other goals of psychotherapy include enhancing coping skills, directly reducing distress, improving problem-solving skills, mobilizing support, reshaping negative or self-defeating thoughts, and developing a close personal bond with a knowledgeable, empathic health care provider.[Level of evidence: II];[64-66][Level of evidence: I] Consultation with a cleric or a member of a pastoral care department may also help some individuals.
Specific goals of these therapies include the following:
- Assist people with cancer and their families by answering questions about the illness and its treatment, clarifying information, correcting misunderstandings, giving reassurance, and normalizing responses to the illness and its effect on their families. Explore the present situation with the patient and how it relates to his or her previous experiences with cancer.
- Assist with problem solving, bolster the patient’s usual adaptive defenses, and help the patient and family develop further supportive and adaptive coping mechanisms. Identify maladaptive coping mechanisms and assist the family in developing alternative coping strategies. Explore areas of related stressors (e.g., family role and lifestyle changes), and encourage family members to support and share concerns with each other.
- When the focus of treatment changes from cure to palliation, reinforce strongly that, though curative treatment has ended, the team will aggressively treat symptoms as part of the palliation plan; the patient and family will not be abandoned; and staff members will work very hard to maintain comfort, control pain, and maintain the dignity of the patient and his or her family members.
Cancer support groups can be useful adjunctive therapies in the treatment of cancer patients.[68,69][Level of evidence: II] Recent support group interventions have demonstrated significant effects on mood disturbance, use of positive coping strategies, improvement in quality of life, and positive immune responses.[70,71][Level of evidence: I] Support groups can be found through The Wellness Community, the American Cancer Society, and many other community resources, including the social work departments of medical centers or hospitals.Empirical studies of the efficacy of psychotherapy
Psychotherapy as a treatment for depression in the general adult mental health population has been extensively researched and found to be effective. Recent reviews have also concluded that psychotherapy is an effective intervention for cancer patients experiencing depression.[Level of evidence: II] In studies designed to prevent the occurrence of depression (i.e., patients not selected because of their depressive symptoms), intervention effects are positive, though small to moderate effect sizes have been reported (effect sizes range from 0.19 to 0.54). However, in those studies in which patients were intentionally selected because they exhibited depressive symptoms, intervention effects were strong (effect size, 0.94). An effect size of 0.94 indicates that the average patient in the treatment group was advantaged, compared with approximately 82% of patients in the control group.
One well-designed randomized clinical trial of a cognitive-behavioral intervention for depressed cancer patients investigated the effect of training in problem solving on symptoms of depression.[Level of evidence: I] The intervention consisted of 10 1.5-hour weekly individual psychotherapy sessions focused on training to become an effective problem solver. Problem-solving tasks were emphasized, including skills in (a) better defining and formulating the nature of problems, (b) generating a wide range of alternative solutions, (c) systematically evaluating consequences of a solution while deciding on an optimal one, and (d) evaluating outcome after solution implementation. Between-session homework with tasks relevant to each step was assigned, and patients were provided with a written manual and encouraged to refer to it as problems arose. One hundred thirty-two adult cancer patients were randomly assigned to the problem-solving treatment or a wait-list control. Overall results showed both improved problem-solving abilities and clinically significant decreases in symptoms of depression.Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about depression that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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