Antidepressants in Patients With Advanced Cancer: When They’re Warranted and How to Choose Therapy

Oncology (Williston Park). 33(2):62-8.

Ebtesam Ahmed, PharmD, MS

Table 1. Risk Factors for Depression

Table 2. Characteristics of the Available Agents to Treat Depression

Citalopram

Nortriptyline

Venlafaxine

Cancer patients with depression experience more physical symptoms, pain, and fatigue; have a poorer quality of life; and are more likely to encounter negative thoughts compared with cancer patients who are not depressed. Accurate assessment and treatment of depression can have a positive impact on improving a patient’s quality of life. Pharmacotherapy for depression in patients with advanced cancer should be guided by a focus on symptom reduction, irrespective of whether the patient meets the diagnostic criteria for major depression. For effective treatment of a depressive illness, antidepressant medication and cognitive behavioral therapy need to be initiated sooner rather than later to reduce symptom burden and improve quality of life.

Click here to read an expert perspective from Mirat Shah, MD, Kerry O’Connor, MD, and Thomas J. Smith, MD, FACP.

Introduction

Depression is the most common psychological condition in patients with cancer. To improve the rate of recovery among such individuals, it is important that clinicians learn to recognize and treat the symptoms associated with this condition. Several practice guidelines recommend screening every patient with cancer for depression. In terms of treatment, both psychotherapy and pharmacotherapy have been shown to be effective in treating depression in this population. When pharmacotherapy is warranted, selection of treatment agent(s) should be made based on the patient’s medical history, cancer type, and disease severity. Increased awareness about the risk of depression along with knowledge of how to identify symptoms and initiate treatment are essential to improve the overall quality of life for patients with cancer.

Prevalence

The reported prevalence of depression in patients with cancer varies from 3% to 38%.[1] Depressive symptoms in this population range from feelings of sadness to a clinical diagnosis of major depressive disorder (MDD). The rate of depression is highest in those closest to the end of life and in patients with certain types of cancer, including pancreatic cancer, lung cancer, gastric cancer, and oropharyngeal cancer.[2] MDD is present in 16% of individuals with cancer, while minor depression and dysthymia occur in about 22% of patients. This wide variability can be explained by the lack of consensus regarding the appropriate diagnostic criteria to utilize in the setting of advanced illness, as well as by the differences in various assessment methods.[3]

Burden of Depression

Psychological distress is a major cause of concern among patients with advanced cancer.[4] Depressive syndromes are highly correlated with a reduced quality of life, increased difficulty managing the course of disease, decreased adherence to treatment, and earlier admission to inpatient or hospice care.[5] A meta-analysis revealed that minor or major depression increases the rate of mortality by up to 39%; in addition, patients displaying even a few depressive symptoms may be at a 25% increased risk of mortality.[6] Depression weakens the patient’s ability to experience pleasure, sense, and connection; it also intensifies pain and other symptoms and causes suffering and worry in friends and family members.

Screening and Diagnosis

Depression is underdiagnosed in patients with cancer due to the overlap in symptoms caused by these conditions, such as fatigue, insomnia, and anorexia.[1] The National Comprehensive Cancer Network (NCCN) provides the Guidelines for Distress Management, which are intended for any psychosocial problems found in patients with cancer. These guidelines recommend that every cancer patient be screened for depression during his or her initial visit to the oncologist. A screening tool called the “Distress Thermometer,” also available from the NCCN, can aid in this process. The tool asks patients to rank their level of stress during the past week on a scale of 0–10. A score of 4 or higher indicates that the patient should be referred to mental health services.[7]

Clinicians often rely more on the psychological or cognitive symptoms of depression (ie, worthlessness, hopelessness, excessive guilt, and suicidal ideation) than the physical/somatic signs (ie, weight loss, sleep disturbance) when making a diagnosis of MDD in patients with advanced disease. To effectively treat patients’ depression, it is also important that clinicians be able to recognize the risk factors that can lead to depression (see Table 1 for a complete list).[8-10]

In addition to recognizing risk factors for depression, it is important that clinicians be able to monitor patients for an appropriate reaction to advanced disease and death. If any depressive syndrome is suspected, physicians should utilize appropriate screening tools to aid in the diagnosis. The Patient Health Questionnaire-2 (PHQ-2), a two-item depression screener, can be utilized among patients who screened positive for depression in order to diagnose the condition.[11] Self-report tools, such as the 21-item Beck Depression Inventory (BDI) or the visual analog scale, may be helpful if a direct face-to-face evaluation is not feasible.[12] However, it should be noted that, compared with a brief interview addressing the commonly accepted disease criteria, the efficacy of these tools as a diagnostic aid is inferior.

Guidelines and self-report tools for depression

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) is one of the most common tools used to diagnose depression, particularly among non–terminally ill patients.[14] The DSM-5 outlines somatic complaints associated with the condition, such as changes in weight or appetite, sleep disturbance, fatigue or loss of energy, and difficulty thinking or concentrating. MDD is often not recognized in patients with cancer because the somatic symptoms of depression-including changes in appetite, energy, and/or sleep-may be attributed to normal cancer-related changes or to cancer treatment side effects. In addition, these somatic symptoms may overlap with the changes seen in patients with cancer who are not depressed.[14] This is why, in addition to the self-reported tools discussed previously, it is very important that physicians assess patients for signs of depression. This can be done by conducting an interview with the patient. Self-report tools may not provide accurate enough evidence on their own to diagnose depression. Clinicians must also ascertain that the patient’s symptoms are causing functional impairment.

Treatment

In cancer patients, the treatment of depression should be individualized to address the patient’s depressive symptoms, as well as the disease-related and psychosocial factors contributing to the development of depression. Typically, antidepressant medication is most effective for severe depression, whereas psychotherapy is recommended for both mild and severe cases of depression.[15,16] Cognitive behavioral therapy (CBT) is the most commonly recommended psychotherapy; compared with other types of therapy, the most evidence from clinical trials involving patients with major depression is available for CBT.[17] The NCCN guidelines also recommend supportive psychotherapy.[7] Among patients recently diagnosed with cancer, CBT, relaxation strategies, and problem-solving approaches are recommended.

One specific type of supportive therapy, dignity therapy, has been shown to improve depressive symptoms in clinical trials.[18] Dignity therapy is an individualized type of psychotherapy that provides patients the opportunity to discuss their preferences, such as reflecting on what matters most to them or on how they would like to be remembered by their loved ones. Patients receive an edited transcript of the session to share with friends and family.[19] Lastly, the NCCN guidelines recommend that cancer patients complete family and couples therapy to lessen distress. Studies have shown that both of these types of therapy are associated with reduced distress and grief among families.[20]

Pharmacotherapy selection. Several classes of antidepressants are available to treat depression, including:

• Selective serotonin reuptake inhibitors (SSRIs)

• Tricyclic antidepressants (TCAs) and tetracyclic antidepressants

• Serotonin-norepinephrine reuptake inhibitors (SNRIs)

• Serotonin modulators (eg, trazodone)

• Atypical antidepressants (eg, mirtazapine)

When selecting an antidepressant, clinicians should consider the patient’s symptoms and concurrent medications. Characteristics of the available agents to treat depression are described in Table 2.

Choice of Pharmacotherapy

When it comes to selecting pharmacotherapy to treat depression in patients with cancer, no particular medication class has been proven to be superior in terms of efficacy. Thus, when choosing a medication to initiate treatment, physicians must consider a number of factors. First and foremost, an assessment of the patient’s symptoms should be completed, since certain medications may be more beneficial in treating specific ailments. For example, a patient with symptoms of both depression and insomnia may benefit from an antidepressant that has a more sedative effect. Clinicians should also inquire whether the patient has ever used antidepressant medications in the past and, if so, whether they were effective.

Other considerations when selecting pharmacotherapy for depression include potential drug-drug interactions and adverse side effects. Cost issues, as well as the patient’s comorbid symptoms-such as insomnia, neuropathic pain, or poor appetite-should be considered. Furthermore, due to inadequate studies among the cancer patient population, dosing of antidepressants must be highly individualized. Failure to adhere to antidepressant therapy leads to several high-risk outcomes,[21] particularly among those who are nonadherent during the first 6 weeks of therapy.[22] Individuals who adhere to antidepressant therapy early and continue to take their medication as prescribed are more likely to recover from depression and to avoid future relapse.

SSRIs

The preferred first-line therapy for depression is an SSRI, the most commonly prescribed class of antidepressants. The favorable efficacy and side effect profiles associated with SSRIs make these agents the most attractive for some patients with cancer who are diagnosed with depression. SSRIs are generally as effective as TCAs for the treatment of depression, and they have a wider margin of safety than TCAs in the event of an overdose.[23] Compared with TCAs, SSRIs are associated with fewer cardiac arrhythmias, hypotension, and anticholinergic effects.[24] In addition, SSRIs generally have reduced sedative and autonomic properties. SSRIs should be started at a low dose and then titrated to the minimum effective dose to reduce the potential for side effects, such as jitteriness, restlessness, anxiety, agitation, headache, sexual dysfunction, gastrointestinal symptoms (ie, diarrhea and nausea), and insomnia.[23]

Among the SSRIs, citalopram or escitalopram are considered to be first-line therapy because they are well tolerated and pose few drug-drug interactions. Furthermore, since these agents do not significantly inhibit cytochrome P450 (CYP450) 2D6 (CYP2D6), they can be used in patients taking tamoxifen.

In a study evaluating the use of escitalopram among cancer patients in palliative care, 18 patients who met the DSM-IV criteria for depressive disorder were treated with 10 mg for 2 weeks. Patients were evaluated using the Hospital Anxiety and Depression Scale (HADS) and the Mini-Mental Adjustment to Cancer Scale (Mini-MAC). At the endpoint, there was a significant reduction in anxiety, as measured by HADS, and in hopelessness-helplessness, as measured by Mini-MAC.[25]

Fluoxetine has limited clinical use in advanced illnesses due to its long half-life, since it takes 5 to 6 weeks to reach steady-state drug concentrations; in addition, its potential for significant drug-drug interactions is high because it inhibits hepatic drug–metabolizing enzymes, such as CYP450.[26,27] Paroxetine can be sedating and may lead to withdrawal phenomena with missed doses.[28] Sertraline has been shown to reduce fatigue, appetite, anhedonia, and suicidal thoughts in all types of depression in patients with cancer undergoing chemotherapy.[29] In older adults with advanced cancer, the initial SSRI dose should be reduced to approximately one-half that used in healthy patients.

TCAs

An older class of antidepressants, TCAs have demonstrated efficacy in depressed, medically ill patients.[30] TCAs are also proven adjuvant analgesics for neuropathic and chronic low back pain.[31] While TCAs have been used frequently in the cancer setting, they are not as well tolerated as other antidepressants. This is due to their anticholinergic properties, which may cause symptoms such as dry mouth, blurred vision, urinary retention, and constipation. Older adults are particularly susceptible to confusion and hallucinations. TCAs may also induce delirium and prolong the QTc interval, and they can be dangerous in the event of overdose.[32] Therefore, their use is limited, since they may be problematic for patients with cardiac conditions and those taking other medications with anticholinergic properties. Of note, nortriptyline and desipramine have reduced anticholinergic properties compared with other tricyclics.

SNRIs

SNRIs are another class of antidepressants that may be helpful for patients with cancer. Research has shown that SNRIs are beneficial in managing neuropathic pain, vasomotor instability, or anxiety-predominant depression.[33] Venlafaxine is one example of an SNRI that is well tolerated in cancer patients. It is not significantly active in the CYP450 system, and, compared with other antidepressants, it is somewhat less protein-bound.[34] Venlafaxine is considered to be the first-line therapy in the SNRI class for those receiving tamoxifen due to its lack of CYP2D6 inhibition, as well as its ability to reduce hot flashes in those receiving chemotherapy or experiencing menopause as a result of taking tamoxifen. However, it should be used with caution in those with hypertension, as high doses of this agent may elevate blood pressure.

Duloxetine is another SNRI that is approved to treat anxiety, diabetic neuropathy, and chronic musculoskeletal pain.[35] A prospective, 12-week, case-control study compared the use of duloxetine in patients with depression and cancer vs depression alone. Patients received an initial dose of duloxetine 30 mg, which was then titrated to 60 mg after 1 week and up to 120 mg after 1 month, based on response. Patients were assessed using HADS, the Clinical Global Impression Scale-Severity (CGI-S), and the Montgomery–Åsberg Depression Rating Scale (MADRS). In individuals with both cancer and depression, scores significantly improved on each of the depression scales at both 4 and 12 weeks.[36] Duloxetine is contraindicated in patients with heavy alcohol use or chronic liver disease. Milnacipran has been shown to be significantly effective in the treatment of depression and fibromyalgia.[37,38]

Other antidepressants

The antidepressant bupropion has been shown to decrease fatigue and improve depression symptoms in cancer patients. An open-label study examined
sustained-release bupropion for depression and fatigue in the cancer population. Patients took bupropion for 4 weeks after titrating to 300 mg or the maximum tolerable dose. Nine of the patients were identified as depressed at baseline, based on a Hamilton Depression Rating Scale (HAM-D) score of > 17. Both depressed and non-depressed patients had significantly lower HAM-D scores at the endpoint, with depressed patients showing a greater decrease in HAM-D scores compared with non-depressed patients.[39] Bupropion is contraindicated for cancer patients with central nervous system disorders due to its association with increased prevalence of seizures.[40]

While trazodone is an effective antidepressant, its use is limited because it causes significant sedation.[41] However, it may be helpful among patients with sleep disturbances, as well as for those who require an adjunct analgesic effect in addition to an antidepressant effect. Nefazodone, another antidepressant, is associated with liver failure and has been withdrawn in many countries; therefore, it should not be used in medically ill patients.[42]

Although mirtazapine has a sedative effect, it has been shown to be effective for improving pain symptoms, as well as depression and quality of life in patients with advanced cancer.[43] When used at low doses, mirtazapine has also been shown to improve appetite and insomnia, particularly among patients on the 15 mg/day dose, and to provide sedation when warranted.[44]

Monoamine oxidase inhibitors (MAOIs) are generally considered to be less desirable for treating depression in patients with advanced medical illnesses due to the substantial number of adverse interactions associated with these agents. MAOIs are generally reserved for patients who have shown a past preferential response to them for depression.[45]

Psychostimulants

Antidepressants may not have sufficient time to reach their full effect in patients with a prognosis of days or weeks. In these cases, psychostimulants may be beneficial. Compared with antidepressants, psychostimulants have a more rapid onset of action of within 24 to 48 hours. They have been shown to improve attention, concentration, and overall performance on neurologic testing in the medically ill.[46] In addition, they can improve mood, appetite, and sense of well-being. Although generally well-tolerated, psychostimulants may cause side effects such as agitation, nausea, anorexia, insomnia (particularly if administered within 6 to 8 hours of bedtime), anxiety, and tremor. Modafinil has fewer sympathomimetic effects than amphetamines and is often a good choice for older patients.[47] Psychostimulants should be avoided in patients with delirium and used with caution in those with heart disease. Although the data on psychostimulants are somewhat mixed, controlled trials have shown their benefit as a monotherapy or to augment the effects of another antidepressant.[47]

Ketamine

A number of case reports and one small placebo-controlled trial of intravenous ketamine have shown that ketamine can rapidly improve depressive symptoms in patients with refractory depression in the setting of a terminal illness, particularly in the setting of chronic pain.[48,49]

Conclusion

Depression is underdiagnosed and undertreated in chronically ill cancer patients. It is imperative that healthcare providers be proactive in screening for depression, as well as in educating patients about the available treatment options for depression. Each individual case of depression is different and must be treated according to the patient’s medical history, cancer prognosis, and severity of symptoms. When selecting therapy, physicians must evaluate the side effect profile of each agent to ensure it is appropriate for the patient. A specific patient interview should also be conducted in order to carefully confirm the diagnosis and to avoid confusing the symptoms of progressing cancer with those of major depression. Once pharmacotherapy is initiated, close monitoring for adverse effects and the potential need for dose titration is warranted.

Summary Recommendations

• For patients with neuropathic pain and depression, consider duloxetine or venlafaxine.

• If the patient has insomnia or anorexia, consider the use of mirtazapine.

• When polypharmacy is present, consider citalopram, escitalopram, or mirtazapine.

• Closely monitor patients initiated on an antidepressant for adverse effects and the potential need for dose titration.

• Refer to social work and/or spiritual support services if the depression appears to be escalating in relation to social or spiritual factors.

Financial Disclosure:Ms. Ahmed has no financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

PERSPECTIVE

Asking Matters Most: Depression in Advanced Cancer

Mirat Shah, MD, Kerry O’Connor, MD, and Thomas J. Smith, MD, FACP

Depression is common in patients with advanced cancer and leads to poor symptom control and decreased life expectancy, as highlighted in this article. Ms. Ahmed notes that depression is underdiagnosed in this group because some symptoms-loss of appetite, fatigue, and trouble sleeping-mimic the symptoms of advanced cancer. In our experience, there are additional factors that prevent diagnosis.

Oncology providers tend to think that depression is a normal reaction to advanced cancer, rather than something that can be treated. They may feel ill-equipped to manage depression once it is diagnosed, or that a different member of the care team is better-suited to the task. In addition, clinicians are pressed for time during clinic visits. Without a prompt, patients often don’t bring up these symptoms and instead try to cope on their own.

Asking the simple question “Are you depressed?” helps patients feel heard and valued, and has acceptable sensitivity and specificity for cancer patients.[1] After we asked this question of a 35-year-old woman with advanced uterine cancer at our clinic, she remarked, “Thank you for listening. No one ever listens. Listening helps.” Another man with metastatic colorectal cancer who was asked this same question remarked, “Thank you for being human.” These responses highlight that being present and actively listening to patients are therapeutic acts in and of themselves.

After asking the question, additional members of the care team can assist as needed, and, as noted in this article, therapy and medication may also help. But asking is the most important step. Although we sometimes may not be able to cure, by asking and listening, we can still heal.

FINANCIAL DISCLOSURE: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Reference

1. Chochinov HM, Wilson KG, Enns M, Lander S. “Are you depressed?” Screening for depression in the terminally ill. Am J Psychiatry. 1997;154:674-6.

Dr. Shah is an Oncology Fellow at Johns Hopkins Medicine, Baltimore, Maryland.

Dr. O'Connor is a Hospital and Palliative Medicine Fellow at Johns Hopkins Medicine, Baltimore, Maryland.

Dr. Smith is the Harry J. Duffey Family Professor of Palliative Medicine and a Professor of Oncology at Johns Hopkins Medicine, Baltimore, Maryland.

References:

1. Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004;57-71.

2. Boyd AD, Riba M. Depression and pancreatic cancer. J Natl Compr Canc Netw. 2007;5:113-6.

3. Akechi T, Okuyama T, Sugawara Y, et al. Major depression, adjustment disorders, and post-traumatic stress disorder in terminally ill cancer patients: associated and predictive factors. J Clin Oncol. 2004;22:1957-65.

4. Wilson KG, Chochinov HM, McPherson CJ, et al. Suffering with advanced cancer. J Clin Oncol. 2007;25:1691-7.

5. Wilson KG, Chochinov HM, Skirko MG, et al. Depression and anxiety disorders in palliative cancer care. J Pain Symptom Manage. 2007;33:118-29.

6. Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer. 2009;115:5349-61.

7. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Distress Management (Version 2.2018). https://www.nccn.org/professionals/physician_gls/pdf/distress.pdf. Accessed January 22, 2019.

8. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer. 2000;8:175-9.

9. Pelletier G, Verhoef MJ, Khatri N, Hagen N. Quality of life in brain tumor patients: the relative contributions of depression, fatigue, emotional distress, and existential issues. J Neurooncol. 2002;57:41-9.

10. Boston P, Bruce A, Schreiber R. Existential suffering in the palliative care setting: an integrated literature review. J Pain Symptom Manage. 2011;41:604-18.

11. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003;41:1284-92.

12. Lees N, Lloyd-Williams M. Assessing depression in palliative care patients using the visual analogue scale: a pilot study. Eur J Cancer Care (Engl). 1999;8:220-3.

13. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5). Arlington, VA: American Psychiatric Association; 2013.

14. Rivest J, Levenson J. Clinical features, assessment, and diagnosis of unipolar depressive disorders in patients with cancer. UpToDate. https://www.uptodate.com/contents/clinical-features-assessment-and-diagnosis-of-unipolar-depressive-disorders-in-patients-with-cancer. Updated April 20, 2018. Accessed January 22, 2019.

15. Li M, Fitzgerald P, and Rodin G. Evidence-based treatment of depression in patients with cancer. J Clin Oncol. 2012;30:1187-96.

16. Baltenberger EP, Schmitt G, and Thomas CJ. Treatment of depressive symptoms in patients with cancer. Mental Health Clinician. http://mhc.cpnp.org/doi/full/10.9740/mhc.n194575. Published May 2014. Accessed January 22, 2019.

17. Daniels S. Cognitive behavior therapy for patients with cancer. J Adv Pract Oncol. 2015;6:54-6.

18. Houmann LJ, Chochinov HM, Kristjanson LJ, et al. A prospective evaluation of dignity therapy in advanced cancer patients admitted to palliative care. Palliat Med. 2014;28:448-58.

19. Chochinov HM, Hack T, Hassard T, et al. Dignity therapy: a novel psychotherapeutic intervention for patients near the end of life. J Clin Oncol. 2005;23:5520-5.

20. Northouse LL, Katapodi MC, Song L, et al. Interventions with family caregivers of cancer patients: meta-analysis of randomized trials. CA Cancer J Clin. 2010;60:317-39.

21. Pompili M, Venturini P, Palermo M, et al. Mood disorders medications: predictors of nonadherence - review of the current literature. Expert Rev Neurother. 2013;13:809-25.

22. Valenstein M, Kim HM, Ganoczy D, et al. Higher-risk periods for suicide among VA patients receiving depression treatment: prioritizing suicide prevention efforts. J Affect Disord. 2009;112:50-8.

23. Kennedy GJ, Marcus P. Use of antidepressants in older patients with co-morbid medical conditions: guidance from studies of depression in somatic illness. Drugs Aging. 2005;22:273-87.

24. Qin B, Zhang Y, Zhou X, et al. Selective serotonin reuptake inhibitors versus tricyclic antidepressants in young patients: a meta-analysis of efficacy and acceptability. Clin Ther. 2014;36:1087-95.

25. Schillani G, Capozzo MA , Era D, et al. Pharmacogenetics of escitalopram and mental adaptation to cancer in palliative care: report of 18 cases. Tumori. 2011;97:358-61.

26. Fisch MJ, Loehrer PJ, Kristeller J, et al. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol. 2003;21:1937-43.

27. Ciraulo DA, Shader RI. Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics. J Clin Psychopharmacol. 1990;10:48-50.

28. Fava M. Prospective studies of adverse events related to antidepressant discontinuation. J Clin Psychiatry. 2006;67 Suppl 4:14-21.

29. Torta R, Siri I , Caldera P. Sertraline effectiveness and safety in depressed oncological patients. Support Care Cancer. 2008;16:83-91.

30. Arroll B, Macgillivray S, Ogston S, et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med. 2005;3:449-56.

31. Jackson KC 2nd, St Onge EL. Antidepressant pharmacotherapy: considerations for the pain clinician. Pain Pract. 2003;3:135-43.

32. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3:241-53.

33. Marks DM, Shah MJ, Patkar AA, et al. Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise. Curr Neuropharmacol. 2009;7:331-6.

34. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo and paroxetine in social anxiety disorder. Arch Gen Psychiatry. 2005;62:190-8.

35. Frampton JE, Plosker GL. Duloxetine: a review of its use in the treatment of major depressive disorder. CNS Drugs. 2007;21:581-609.

36. Torta R, Leombruni P, Borio R, Castelli L. Duloxetine for the treatment of mood disorder in cancer patients: a 12-week case-control clinical trial. Hum Psychopharmacol. 2011;26:291-9.

37. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol, 2005;32:1975-85.

38. Rouillon F, Warner B, Pezous N, Bisserbe JC. Milnacipran efficacy in the prevention of recurrent depression: a 12-month placebo-controlled study. Milnacipran recurrence prevention study group. Int Clin Psychopharmacol. 2000;15:133-40.

39. Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology. 2006;15:259-67.

40. Rissmiller DJ, Campo TJ. Extended-release bupropion induced grand mal seizures. J Am Osteopath Assoc. 2007;107:441-2.

41. Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psych. 2005;66:469-76.

42. Stewart DE. Hepatic adverse reactions associated with nefazodone. Can J Psychiatry. 2002;47:375-7.

43. Theobald DE, Kirsh KL, Holtsclaw E, et al. An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms. J Pain Symptom Manage. 2002;23:442-7.

44. Ersoy MA, Noyan AM, Elbi H. An open-label long-term naturalistic study of mirtazapine treatment for depression in cancer patients. Clin Drug Investig. 2008;28:113-20.

45. Thase ME. MAOIs and depression treatment guidelines. J Clin Psychiatry. 2012;73:e24.

46. Rozans M, Dreisbach A, Lertora JJ, Kahn MJ. Palliative uses of methylphenidate in patients with cancer: a review. J Clin Oncol. 2002;20:335-9.

47. Centeno C, Sanz A, Cuervo MA, et al. Multicentre, double-blind, randomised placebo-controlled clinical trial on the efficacy of methylphenidate on depressive symptoms in advanced cancer patients. BMJ Support Palliat Care. 2012;2:328-33.

48. Yang C, Zhou ZQ, Yang JJ. Be prudent of ketamine in treating resistant depression in patients with cancer. J Palliat Med. 2011;14:537.

49. Iglewicz A, Morrison K, Nelesen RA, et al. Ketamine for the treatment of depression in patients receiving hospice care: a retrospective medical record review of thirty-one cases. Psychosomatics. 2015;56:329-37.

50. Hirsch M, Birnbaum RJ. Side effects of antidepressant medications. https://www.uptodate.com/contents/selective-serotonin-reuptake-inhibitors-pharmacology-administration-and-side-effects. Published December 2018. Updated January 31, 2018. Accessed January 29, 2019.

51. Kando JC, Wells BG, Hayes PE. Depressive disorders. In: DiPiro JT, Talbert RL, Yee GC, et al, editors. Pharmacotherapy: a pathophysiologic approach. 6th ed. New York: The McGraw-Hill Companies, Inc; 2005.

52. Perry PJ, Alexander B, Liskow BI, DeVane CL. Psychotropic Drug Handbook. 8th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2007.

53. Qaseem A, Snow V, Denberg TD, et al. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:725-33.

54. Drugs @ FDA database. Zoloft® (sertraline) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019839s070,020990s032lbl.pdf. Accessed January 28, 2019.

55. Drugs @ FDA database. Parnate® (tranylcypromine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/012342s063lbl.pdf. Accessed January 28, 2019.

56. Drugs @ FDA database. Pristiq® (desvenlafaxine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021992s033s036lbl.pdf. Accessed January 28, 2019.

57. NIH U.S. National Library of Medicine, DailyMed. Prozac® (fluoxetine) prescribing information. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c88f33ed-6dfb-4c5e-bc01-d8e36dd97299. Accessed January 28, 2019.

58. Drugs @ FDA database. Cymbalta® (duloxetine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021427s036lbl.pdf. Accessed January 28, 2019.

59. NIH U.S. National Library of Medicine, DailyMed. Amitriptyline prescribing information. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=acd53964-52dc-4534-b20f-14a7561b8a6c. Accessed January 28, 2019.

60. NIH U.S. National Library of Medicine, DailyMed. Celexa® (citalopram) prescribing information. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4259d9b1-de34-43a4-85a8-41dd214e9177. Accessed January 28, 2019.

61. Drugs @ FDA database. Norpramin® (desipramine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/014399s065lbl.pdf. Accessed January 28, 2019.

62. NIH U.S. National Library of Medicine, DailyMed. Tofranil® (imipramine) prescribing information. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1827a5aa-733a-49d9-89d9-48ea0367b230. Accessed January 28, 2019.

63. Drugs @ FDA database. Lexapro® (escitalopram) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021323s033,021365s024lbl.pdf. Accessed January 28, 2019.

64. Drugs @ FDA database. Paxil® (paroxetine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020031s058s066,020710s022s030lbl.pdf. Accessed January 28, 2019.

65. Drugs @ FDA database. Effexor XR® (venlafaxine extended-release) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020699s090lbl.pdf. Accessed January 28, 2019.

66. Drugs @ FDA database. Wellbutrin® (bupropion) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018644s045,020358s052lbl.pdf. Accessed January 28, 2019.

67. Drugs @ FDA database. Remeron® (mirtazapine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020415s023s024.pdf. Accessed January 28, 2019.