Fast Fact #309 – Adults with serious illness have a higher incidence of major depressive disorders than healthy adults, with an estimated incidence of 15% (1). In this Fast Fact, we will provide a clinical framework for selecting pharmacologic agents for seriously ill patients with depression.  See Fast Fact #7, Fast Fact 43, and Fast Fact #146 for assistance in diagnosing and screening for depression in palliative care patients.

Determine prognosis    Most antidepressants take more than 4 weeks to become effective, so they should only be considered in patients expected to live at least that long (2). Use is also limited to patients who are able to swallow oral medications or place them in a feeding tube. For patients with a prognosis < 4 weeks, a psychostimulant such as methylphenidate or dextroamphetamine may act within 1-2 days and be safe in patients without significant cardiovascular disease or delirium. Although the data on psychostimulants are somewhat mixed, controlled trials have shown benefit as both a monotherapy and to augment the effects of another anti-depressant (3-5). See Fast Fact #61. Intravenous or intranasal use of ketamine can also be considered (see Fast Fact #384) in patients with a short prognosis, however it requires enrollment in a Risk Evaluation and Management Strategy program (6).

Consider co-morbid symptoms    When choosing an antidepressant, consider the patient’s other co-morbid symptoms such as insomnia, neuropathic pain, or poor appetite (7). Other considerations include the patient’s past responses to specific agents and possible drug interactions. Common classes of antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and others.

SSRIs    Also called “second generation antidepressants”, these are the most commonly prescribed antidepressants. SSRIs should be started at a low dose and then titrated to the minimum effective dose to minimize adverse effects such as QTc prolongation, sexual dysfunction, headaches, nausea and diarrhea. Fluoxetine is associated with emotional activation and may worsen anxiety. Paroxetine can be sedating and lead to withdrawal phenomena with missed doses. Because sertraline, citalopram, and escitalopram have lower side effect profiles and are neither activating nor sedating, they may be better choices for palliative care patients (8). The starting dose of sertraline is 25-50 mg/day with a usual effective dose of 50-200 mg/day; it is available in a concentrated liquid formulation for patients with dysphagia related issues. Both citalopram and escitalopram have been shown to have few drug interactions. The starting dose of citalopram is 20 mg/day with a maximum daily dose of 40 mg. The starting dose of escitalopram is 10 mg/day with a usual effective dose of 10-20 mg/day (9-11).

SNRIs inhibit serotonin and norepinephrine reuptake, two neurotransmitters important in endogenous pain pathways (12). This class may be helpful for neuropathic pain, vasomotor instability, and anxiety-predominant depression. Venlafaxine has shown effectiveness for the amelioration of hot flushes and the prevention of chemotherapy-induced polyneuropathy (CIPN); duloxetine has shown efficacy for the treatment of CIPN and may help with more generalized forms of musculoskeletal pain (13). SNRIs may prolong bleeding times and therefore may not be safe in patients with active bleeding or intracranial metastases. The starting dose for venlafaxine is 37.5 mg with a usual effective dose of 75-225 mg/day. It requires close monitoring for missed-dose withdrawal and hypertension. The starting dose for duloxetine is 30 mg with a usual effective dose of 60-120 mg/day. It has been associated with hepatic insufficiency and a worsening of acute-angle glaucoma.

TCAs are an older class of anti-depressants that can be cost-effective at lower doses.  They also are proven adjuvant analgesics for neuropathic and chronic back pain (see Fast Fact #480). Unfortunately, their anticholinergic properties can induce delirium, prolong the QTc interval, and be dangerous in overdose. Therefore, their use is limited to heart-healthy patients under the age of 65. Although the preponderance of supporting data for the analgesic effects is for amitriptyline (usual starting dose 10-25 mg/day; usual effective dose is 150 mg/day), nortriptyline is felt to be less sedating (usual starting dose 25 mg/day; effective dose is 50-100 mg/day).

Other medications   Mirtazapine has histaminergic side effects that can be helpful especially for patients with cancer who experience insomnia, poor appetite, and nausea (14). It has few drug interactions but can be associated with orthostatic hypotension.  Its usual starting dose is 7.5-15 mg/nightly; usual effective doses are 15-30 mg/day. Bupropion is thought to be less sedating and have a lower incidence of sexual side effects, but it may lower the seizure threshold. The usual starting dose for bupropion is 150 mg/day; the usual effective dose is 150-300 mg/day (15). Aripiprazole may augment the antidepressant effects of SSRIs and SNRIs as early as a week after initiation (16).

Summary recommendations: 

• For patients with prognoses of weeks, consider a psychostimulant like methylphenidate.
• Consider duloxetine when neuropathic pain is present.
• When polypharmacy is present, consider citalopram, escitalopram or mirtazapine.
• If the patient has insomnia, nausea, or anorexia, consider the use of mirtazapine.
• Closely monitor patients initiated on an antidepressant for adverse effects and dose titration.
• Refer to a mental health clinician for pre-existing major depression, the presence of comorbid psychiatric illness, suicidal ideation, refractory symptoms, or psychiatric polypharmacy.
• Refer to social work and/or spiritual support services if the depression appears to be escalating in relation to social or spiritual factors.

References:

1. Hotopf M, Chidgey J, Addington-Hall J, Ly KL. Depression in advanced disease:  a systematic review Part 1. Prevalence and case finding. Palliat Med. 2002 Mar;16(2):81-97.
2. Block SD. Assessing and managing depression in the terminally ill patient. Ann Intern Med. 2000;132(3):209-218.
3. Woods SW, Tesar GE, Murray GB, Cassem NH. Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry. 1986 Jan;47(1):12-5.
4. Olin J, Masand P. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics. 1996 Jan-Feb;37(1):57-62.
5. Lavretsky H, Reinlieb M, et al.  Citalopram, methylphenidate, or their combination in geriatric depression: a randomized, double-blind, placebo-controlled trial.  Am J Psychiatry 2015; 172:561-69.
6. Mathew SJ, Shah A, Lapidus K, et al. Ketamine for Treatment-Resistant Unipolar Depression: Current Evidence. CNS drugs. 2012;26(3):189-204.
7. Janberidze E, Hjermstad MJ, Brunelli C, Loge JH, Lie HC, Kaasa S, Knudsen AK;  EURO IMPACT. The use of antidepressants in patients with advanced cancer–results from an international multicentre study. Psychooncology. 2014 Oct;23(10):1096-102.
8. Lloyd Williams  M, Friedman T, Rudd N. A survey of antidepressant prescribing in the terminally ill. Palliat Med 1999;13:243–8.
9. Rayner L, Price A, Hotopf M, Higginson IJ. Expert opinion on detecting and treating depression in palliative care: A Delphi study. BMC Palliative Care. 2011;10:10.
10. Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and sertraline: are they all alike? International Clinical Psychopharmacology. 2014;29(4):185-196.
11. Preskorn SH. Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 1993;94:2S–12S.
12. Marks DM, Shah MJ, Patkar AA, Masand PS, Park G-Y, Pae C-U. Serotonin-Norepinephrine Reuptake Inhibitors for Pain Control: Premise and Promise.Current Neuropharmacology. 2009;7(4):331-336.
13. Piccolo J, Kolesar JM. Prevention and treatment of chemotherapy-induced peripheral neuropathy. Am J Health Syst Pharm. 2014 Jan 1;71(1):19-25.
14. 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.
15. Shopsin B. Bupropion: a new clinical profile in the psychobiology of depression. J Clin Psychiatry 1983;44:140–2.
16. Thase ME, Trivedi MH, et al. Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of 2 studies. Prim Care Companion J Clin Psychiatry 2008;10:440–447.  

Author Affiliations: Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston, MA.
Version History: First electronically published in January 2016; reviewed and updated by Dr. Kerry Case in September 2024
Conflicts of Interests: none reported