Polypharmacy to Optimize Depression Outcomes

Psychiatric TimesPsychiatric Times Vol 25 No 9
Volume 25
Issue 9

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.


  • 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%.1Rationale 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.

Irrational Polypharmacy

Irrational polypharmacy may be harder to define, although it takes many recognizable forms. Irrational polypharmacy frequently occurs when a treatment focuses exclusively on the potential instability of the patient to the exclusion of the known risks of polypharmacy (eg, a second drug is added and is beneficial, but no attempt is made to lower the dose of or discontinue the first drug).

Similarly, in what might be called a “stuck cross-titration,” a clinician may add an antidepressant while lowering the current medication dosage with the intent to discontinue. Midway through the cross-titration, when the patient is taking the new drug but has not yet stopped the old drug, the patient reports remission of symptoms. At this point, the titration stops and no further attempt is made to reduce the first medication.

In a case in which an adjunctive medication is added (eg, benzodiazepine to treat panic attacks) while waiting for an SSRI to alleviate depressive symptoms, irrational polypharmacy would occur if the benzodiazepine were continued indefinitely without attempting to reduce the dosage. Diagnostic uncertainty can result in polypharmacy as well, such as in a patient who complains of anxiety and receives a benzodiazepine, when further questioning might reveal that the anxiety is caused by worsened auditory hallucinations, in which case, the proper course would be to adjust antipsychotic medications.3 Overadherence to the Physicians’ Desk Reference and other standard texts containing maximum recommended dosages can also result in irrational polypharmacy.

Although there are few studies to support the practice,11 many psychiatrists have experience with patients who report relief from depression only at dosages above those approved by the FDA. If a patient has experienced partial benefit without adverse effects from the maximum approved dosage of an SSRI, increasing the dosage should be considered before adding a second medication.3

Pressures of cost and time can lead to irrational polypharmacy as well. This may be particularly true in inpatient units, where there are increasing pressures to discharge patients as quickly as possible, leading clinicians to attempt to use polypharmacy to achieve a more rapid response. The use of polypharmacy as a substitute for time in treatment is not supported by available data.12Inadequate attention to receptor pharmacology can also lead to irrational polypharmacy, such as adding low-dose venlafaxine to an SSRI, the primary effect of which is overlapping serotonergic reuptake inhibition.13When to Avoid Polypharmacy

When a patient does not respond to more traditional treatments, a clinician should “Run the Axes,” that is, review the patient’s Axes I through IV issues (Table). Compliance should also be examined carefully before moving to polypharmacy, because up to 20% of treatment resistance can be attributed to poor treatment compliance.14

There are numerous reasons to avoid polypharmacy. Polypharmacy increases the risk of adverse effects, patient noncompliance, and medication errors, and it adds unnecessary costs.15,16 Even when clinicians try to remain aware of these risks, many polypharmacy regimens can be too complex to predict all possible drug-drug interactions.

Patients with major depression are high users of medical health care services and are more likely to receive medications to treat medical conditions in addition to their psychiatric medications,17,18 which further increases polypharmacy risks. Furthermore, clinicians should be aware of the over-the-counter medications, herbal remedies, and the burgeoning market of food supplements sold as health remedies (“nutraceuticals”) that patients may be using.19

What to ask when a patient does not respond to treatment

Because a minority of patients achieve remission with initial monotherapy, there is a great need for studies that help guide treatment of refractory depression so that unnecessary polypharmacy can be avoided or at least treatment can be based on solid evidence. Although there are numerous augmentation strategies in use, including combining antidepressants and augmenting with lithium, triiodothyronine (T3), dopamine agonists, dopamine antagonists, corticosteroids, and anticonvulsants, most of these have been poorly studied until recently.20The Challenge in Studying Polypharmacy

The dearth of literature on the use of polypharmacy in depression is primarily a result of the difficulties of studying refractory depression. It is difficult to establish that patients entering a study meet a clear standard for refractory depression. It is challenging for researchers to verify the dosage, length of treatment, and circumstances of prior medication trials. A treatment trial that depends on retrospective treatment failures would be likely to enroll many patients with refractory depression along with many patients who have not previously received adequate treatment, introducing a confounding heterogeneity into the study cohort.

The best way to overcome these problems is with a prospective study.21 Generally, at least 200 patients must be enrolled to conduct an adequately powered study of a novel antidepressant.22 However, if researchers are looking for patients in whom prior drug treatment has failed, at least 1000 patients may be needed. A typical successful medication trial has a 40% to 60% response rate, 10% to 20% attrition rate, and 10% to 20% exclusion rate because of noncompliance, and 5% to 10% exclusion rate from previously unrecognized comorbidities. Therefore, if a trial begins with 1000 patients, only 200 patients may not respond to the first agent and would remain eligible to participate in the next step of the study.4 Such studies are lengthy and expensive, and few such trials have been conducted.

It has been noted that the pharmaceutical industry is reluctant to sponsor these trials because of the perception that a medication that is shown to treat refractory depression will be thought of primarily as a second- or third-line agent.23 It is also difficult to recruit patients with chronic depression into a trial that includes a placebo arm.4 The largest study to date to address the benefits of polypharmacy in the treatment of refractory depression is the now well-known NIMH-sponsored STAR*D study.


STAR*D confirmed prior evidence that only about one-third of patients achieve remission with an initial antidepressant.24 Patients who did not achieve remission after a trial of an initial antidepressant had about a 30% chance of achieving remission after switching to another agent. When a patient did not respond to an SSRI (in this case, citalopram), it was shown that the common practice of augmenting with bupropion, and the less common practice of augmenting with buspirone, were both equally effective (30% remission rates), although bupropion was somewhat better tolerated.25 Combination therapy was slightly more effective than switching to a different agent. Patients who switched agents were as likely to respond to another SSRI (sertraline) as they were to agents from other medication classes (bupropion or venlafaxine), with all 3 drugs achieving remission rates between 18% and 24%.26

In patients who did not respond to this second stage of treatment, each successive step was significantly less likely to bring them to remission. This lower rate of remission past the second step of treatment most likely indicates a more refractory underlying disorder; it may also be that after several different treatment steps, the “nonpharmacological” benefits (otherwise known as placebo) such as attention, reassurance, and education, are less likely to be beneficial.27

The augmentation strategy with the best evidence base is the addition of lithium, yet it is the least used.7,28 STAR*D compared lithium with T3 in patients in whom 2 prior levels of treatment had failed and confirmed that lithium can be a useful agent; it helped achieve remission in 16% of patients with refractory depression, although many found it difficult to tolerate. T3 augmentation fared a little better (23% remission rate). This difference was not statistically significant, although T3 was associated with fewer adverse effects.29 These results were similar to those for patients who were switched to either nortriptyline or mirtazapine; the remission rate for both was less than 20%.30

Although STAR*D data suggest that combining medications may be slightly more effective than switching, these differences were not robust. It remains to be answered if and when it is better to add or switch medications in a patient who has not achieved remission after an initial trial of monotherapy. It is not clear how many antidepressants should be tried before polypharmacy is considered or how long a drug combination should be continued. It is also unclear whether certain augmenting agents work dramatically when successful but have lower overall response rates than other agents.31



STAR*D showed that although it may be difficult, it is important to achieve full symptom remission in patients with depression; remission has been shown to have a lower rate of relapse than simple treatment response. In those patients for whom more treatment steps were required to achieve remission, relapse rates were higher.32

We should use the available evidence to guide treatment as much as possible, but for now, clinicians can expect to find many situations in which unvalidated trial and error will be a necessary part of the armamentarium. Although polypharmacy may help improve depression in many patients with treatment-refractory symptoms, it should be used with care, and both risks and expenses need to be considered.

Even with sequential monotherapies and polypharmacy, it may be that fewer than 50% of patients achieve a state of sustained remission.26 Each successive treatment failure reduces the likelihood of future success and an attitude of humility and compassion remains a useful element in the treatment of refractory depression.

Drugs Mentioned in This Article
Bupropion (Wellbutrin, Zyban)
Buspirone (BuSpar)
Citalopram (Celexa)
Liothyronine (Cytomel)
Lithium (Eskalith, Lithobid)
Mirtazapine (Remeron)
Nortriptyline (Aventyl, Pamelor)
Trazodone (Desyrel)
Sertraline (Zoloft)
Sildenafil (Viagra)
Venlafaxine (Effexor)




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