- Polypharmacy is the standard of care in many refractory medical disorders, and its use for depression is common and increasing.
- Even unvalidated combinations can be used rationally by means of on-off trials in a particular patient.
- Compliance should be monitored carefully before moving to polypharmacy.
- If a patient has partial response to a maximum approved dosage, consider increasing dosage before adding another medication.
Polypharmacy is used increasingly in the treatment of depression.1 Although it can be beneficial—and at times may even be unavoidable—it can also be overused, resulting in drug-drug interactions, accumulation of adverse effects, reduced treatment adherence, and unnecessary increases in the cost of health care.2 This article describes current trends in psychiatric polypharmacy in the treatment of depression along with ways to use polypharmacy to optimize treatment outcomes.
For the purposes of this article, polypharmacy will be defined as a situation in which 2 or more medications are being used to treat the same condition or in which 2 or more similar medications are being used to treat different conditions.3 An example of the first category would include adding bupropion to improve symptoms of depression in a patient who is already taking an SSRI. The second category can be illustrated, for example, by a patient who is taking an SSRI for depression while he or she is also taking bupropion for smoking cessation, or by a patient treated with an SSRI for depression in addition to a tricyclic agent to treat neuropathic pain.
Polypharmacy can be further divided into narrower categories: adjunctive treatment, combination therapy, and augmentation.4 In adjunctive treatment, a second agent is added to treat symptoms of the disorder rather than the disorder itself, such as using a benzodiazepine or low-dose trazodone to facilitate sleep while waiting for an antidepressant to begin working directly on the neurovegetative depressive symptoms. Combination therapy is the use of 2 medications at full dosages to treat a disorder, such as combining 2 antidepressants at full strength (as in the above example of an SSRI plus bupropion). In augmentation treatment, the second agent does not work alone but may potentiate the benefits of the first medication (eg, adding liothyronine [T3] to antidepressant treatment).
Polypharmacy is not unique to the treatment of depression and is an increasingly common practice in other areas of psychiatry, such as in the treatment of bipolar disorder5 and schizophrenia.6 In many refractory medical disorders, polypharmacy is the standard of care—for example, tuberculosis, diabetes mellitus, hypertension, and HIV infection.
Prevalence of Polypharmacy in Depression
Just how common is polypharmacy in the treatment of depression? Available literature suggests that the practice is common not only in the United States but internationally as well, although the overall prevalence is not known. Data are particularly sparse in the United States because of the absence of a national health care database, and the prevalence can only be extrapolated by looking at the practice patterns of particular clinicians or specific health care systems, such as the Veterans Administration. More accurate assessments can be made about the practices in Europe and Canada, where there are better data from more centralized health care systems.
Looking at available US data, polypharmacy in depression appears to be common, and it is increasing. For example, in 1 inpatient unit of the NIMH, polypharmacy in the treatment of refractory mood disorders (both unipolar and bipolar) showed a clearly increasing trend over 2 decades. From 1974 to 1979, the average patient was taking 1.5 medications at the time of discharge. Only 3% of patients were taking 3 or more medications during that period. From 1990 to 1995 this had increased—the average patient was taking 3 medications at the time of discharge. The total rate of patients with unipolar depression who received polypharmacy that included antidepressants was 24%.5
The best US data on the frequency of polypharmacy in depression is from a study of Veterans Affairs practices, in which prescription records were reviewed in all patients who received a diagnosis of depression in a single year. Of the 220,502 patients in whom depression was diagnosed, 22% received some type of antidepressant polypharmacy. The most common second agent was an additional antidepressant in 11% of cases; a second-generation antipsychotic was added in 7% of cases. Only 0.5% received lithium as the augmenting agent. Bupropion was the most commonly combined antidepressant, used in 38% of combinations, followed by mirtazapine in 19%. Not surprising, patients with severe depression and comorbidities were more likely to be receiving polypharmacy.7
A study that followed up with 1347 patients discharged from a Spanish inpatient unit from 2001 to 2004 found that 93% of the patients from all diagnostic categories were receiving psychiatric polypharmacy at discharge; 11% were receiving 5 drugs, and 5% were receiving 6 or more psychiatric drugs.8
Canadian data from 1994 to 2001 show that the percentage of patients in whom depression was diagnosed remained stable, but the percentage of patients who received an antidepressant increased from 14% to 30%. In the same period, patients receiving polypharmacy with more than 1 antidepressant increased from approximately 3.4% to 8.8%.1
Rationale for Polypharmacy
The 2 most common situations in which polypharmacy is used are for managing adverse effects and supplementing inadequate response to monotherapy; however, there are many other reasons why polypharmacy is used.
Polypharmacy may be on the rise because of the increased comfort clinicians feel with safety profiles and lack of drug-drug interactions among many of the newer agents, but it also may be caused by the increased expectations of clinicians and their patients. Remission, rather than response, has become increasingly recognized as the optimal treatment outcome. Most medication studies base drug benefit on response, defined as a 50% reduction of initial symptoms, whereas remission is considered full relief from depressive symptoms. Although only 30% to 40% of patients achieve full remission with initial monotherapy, remission remains the goal of pharmacotherapy9; patients present for treatment hoping to be rid of depressive symptoms and not just for relief from half of their symptoms.
There are several, largely hypothetical, reasons why polypharmacy may be effective. Using 2 or more medications may target different aspects of neurotransmission of the same monoamine, with 1 medication affecting monoamine receptors and the other affecting reuptake. Alternatively, a second agent may target a different neurotransmitter system; the most common paradigm of this is the potentially synergistic effect of increasing both synaptic serotonin and norepinephrine. There is also the possibility that 2 agents can have a synergistic mechanism that is irreducible to either drug when used alone. The true synergies of the various polypharmacy regimens remain largely theoretical, because there is still a lack of a definitive explanation for the mechanism of action of antidepressants. There are also cases in which polypharmacy appears to be effective, when what is really occurring is that 1 agent is effective while the other is doing nothing more than adding cost and adverse effects.4,10
When prescribing more than 1 medication, clinicians should aim to practice “rational” polypharmacy, which is defined as any practice that has been established by randomized controlled trials, such as lithium augmentation. However, as with much in the practice of psychiatry, you do not have to work with patients with treatment-refractory depression for long to reach the limits of evidence-based medicine. Polypharmacy can be considered rational even when unvalidated, by using on-off trials in a particular patient.3 Using polypharmacy to treat adverse effects (eg, sildenafil or bupropion to treat SSRI-induced sexual dysfunction) is also a rational approach, as is treating comorbidities with polypharmacy—a patient with attention-deficit/hyperactivity disorder and depression is unlikely to achieve full remission from both disorders with monotherapy.
1. Patten SB, Beck C. Major depression and mental health care utilization in Canada: 1994 to 2000. Can J Psychiatry. 2004;49:303-309.
2. Preskorn SH, Silkey B, Shah R, et al. Complexity of medication use in the Veterans Affairs healthcare system: part I: outpatient use in relation to age and number of prescribers. J Psychiatr Pract. 2005;11:5-15.
3. Kingsbury SJ, Yi D, Simpson GM. Psychopharmacology: rational and irrational polypharmacy. Psychiatr Serv. 2001;52:1033-1036.
4. Thase ME, Howland RH, Friedman ES. Treating antidepressant nonresponders with augmentation strategies: an overview. J Clin Psychiatry. 1998;59 (suppl 5):5-12.
5. Frye MA, Ketter TA, Leverich GS, et al. The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry. 2000; 61:9-15.
6. Glick ID, Pham D, Davis JM. Concomitant medications may not improve outcome of antipsychotic monotherapy for stabilized patients with nonacute schizophrenia. J Clin Psychiatry. 2006;67:1261-1265.
7. Valenstein M, McCarthy JF, Austin KL, et al. What happened to lithium? Antidepressant augmentation in clinical settings. Am J Psychiatry. 2006;163:1219-1225.
8. de las Cuevas C, Sanz E. Polypsychopharmacy: a frequent and debatable practice in psychiatric inpatients. J Clin Psychopharmacol. 2005;25:510-512.
9. Keller MB. Past, present, and future directions for defining optimal treatment outcome in depression: remission and beyond. JAMA. 2003;289:3152-3160.
10. Shelton RC. The use of antidepressants in novel combination therapies. J Clin Psychiatry. 2003;64 (suppl 2):14-18.
11. Adli M, Baethge C, Heinz A, et al. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci. 2005;255: 387-400.
12. de las Cuevas C, Sanz EJ, de la Fuente JA, Cueto M. Polypharmacy in psychiatric patients as an alternative to limited mental health resources [in Spanish]. Actas Esp Psiquiatr. 2005;33:81-86.
13. Redrobe JP, Bourin M, Colombel MC, Baker GB. Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity. Psychopharmacology. 1998;138:1-8.
14. Souery D, Mendlewicz J. Compliance and therapeutic issues in resistant depression. Int Clin Psychopharmacol. 1998;13(suppl 2):S13-S18.
15. Hanlon JT, Fillenbaum GG, Schmader KE, et al. Inappropriate drug use among community-dwelling elderly. Pharmacotherapy. 2000;20:575-582.
16. Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287:337-344.
17. Kupfer DJ, Frank E. Comorbidity in depression. Acta Psychiatr Scand Suppl. 2003;418:57-60.
18. Levenson JL, Hamer RM, Rossiter LF. Relation of psychopathology in general medical inpatients to use and cost of services. Am J Psychiatry. 1990;147: 1498-1503.
19. Rapaka RS. Nutraceuticals, herbals and related products. Life Sci. 2006;78:2025.
20. DeBattista C, Lembke A. Update on augmentation of antidepressant response in resistant depression. Curr Psychiatry Rep. 2005;7:435-440.
21. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659.
22. Nierenberg AA. Methodological problems in treatment resistant depression research. Psychopharmacol Bull. 1990;26:461-464.
23. Thase ME. The failure of evidence-based medicine to guide treatment of antidepressant nonresponders. J Clin Psychiatry. 2006;67:1833-1835.
24. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using mea-surement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006; 163:28-40.
25. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
26. Rush AJ, Trivedi MH, Wisniewski SR, et al. Buprpion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
27. Nelson JC. The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry. 2006; 163: 1864-1866.
28. Bauer M, Adli M, Baethge C, et al. Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms. Can J Psychiatry. 2003;48:440-448.
29. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519-1530.
30. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163: 1161-1172.
31. Sussman N, Joffe RT. Antidepressant augmentation: conclusions and recommendations. J Clin Psychiatry. 1998;59:70-73.
32. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.