A Precautionary Tale in Psychiatry

BIOLOGICAL VARIANCE PRODUCED BY MULTIPLE MEDICATION USE
There are approximately 3500 different chemical entities as prescription drugs on the US market.¹⁶ Given that number, 520 quadrillion different combinations of up to 5 drugs could theoretically be prescribed to a patient. Why use 5 drugs in this example? According to a recent report by the US Department of Health and Human Services, 7% of Americans aged 18 years or older had taken 5 or more prescription drugs in the week before the survey.¹⁷ The same report found that 20% of all Americans aged 65 years or older had taken 5 or more prescription drugs in the week before the survey.

Since the turn of the millennium, an average of 17 new drugs has entered the US market every year. That translates into a new drug becoming available for prescription every 3 weeks. That, in turn, means that every 3 weeks a treating physician can encounter a patient receiving a medication that had previously not been available. Depending on the pharmacodynamics and pharmacokinetics of the new drug, it may also mean a source of new biological variance among patients.

Mathematically, the first new drug marketed in 2007 can be used in approximately 150 trillion different 5-drug combinations (ie, the new drug plus up to 4 other drugs already on the market when it enters the market). Needless to say, the safety and tolerability of all of those potential combinations were not tested before the new drug was approved. That is the reason why the careful and well-trained prescriber is the major safeguard against clinically relevant DDIs. That is also a major reason why some of the adverse effects of new medications come to light only after they have been marketed. The reason is that those adverse effects only occur because of the presence of another drug (ie, DDIs such as the fatal arrhythmias that occurred when terfenadine(Drug information on terfenadine) was used in combination with ketoconazole(Drug information on ketoconazole)).

PREVALENCE OF MMU
Multiple pharmacoepidemiological studies have documented that MMU is widespread and growing in the United States and Europe.^18-26 As previously mentioned, a random survey of Americans by the US Department of Health and Human Services¹⁷ found that 7% of Americans 18 years or older took 5 or more prescription drugs in the week before the survey. Not surprisingly, those numbers increase when the individuals surveyed are patients.

For example, a recent pharmacoepidemiological study revealed that the average outpatient in the Veterans Administration Health System (VAHS) took 4 or 5 drugs depending on his age and whether he was taking antidepressants.^19,20 Even more impressive was the observation that up to 96% of these patients (depending on age and whether they were taking an antidepressant) were on unique regimens (ie, no other patient in the sample of a 1000 or more patients was taking the same specific combination of medications). As already discussed, drugs are a source of clinically important biological variance among patients. This VAHS study thus showed that an enormous number of these patients are biologically unique from every other patient when viewed solely in terms of what medications they are taking.

There are at least 5 reasons why patients are taking more than 1 medication (Table 1). Of all of these reasons, perhaps the most compelling is that the patient has more than 1 illness. Even in this situation, the treating physician must consider whether the various medications being taken—even though aimed at different conditions—might interact to adversely affect the patient.

Further increasing the complexity of the situation, the patient who has different medical conditions is likely to have more than 1 physician from different specialities treating him or her. That poses a potential communication problem among those different prescribers because their individual prescribing actions may have a combined effect in the patient that is different from what they might have otherwise anticipated.

This issue was underscored by the aforementioned VAHS study in which the percentage of patients taking 8 or more medications doubled for every prescriber that a patient was seeing up to 4 prescribers, at which point 80% of such patients were taking 8 or more medications.¹⁹