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.13

When 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

Table What to ask when a patient does not respond to treatment
Axis I
Is the initial diagnosis correct?
Might there be occult substance abuse impairing treatment response?
Axis II
Is there a personality disorder, such as borderline personality disorder, in which a chronic feeling of emptiness has been conflated with major depression?
Axis III
Is there a complicating medical condition?
Axis IV
Does the patient have an acute and ongoing life stressor, such as unemployment or recent divorce, that might limit the benefit that can be expected from pharmacology alone?


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.20

The 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.

Pages: 1  2  3