Psychiatric Polypharmacy: The Good, the Bad, and the Ugly

A great deal of data exists about the dangers of polypharmacy. Persons with psychiatric disorders experience increased risk for adverse drug interactions because of the great frequency with which multiple medications are used.¹ Using multiple antipsychotics concomitantly has been associated with increased mortality in patients with schizophrenia.² Reports of adverse psychiatric polypharmacy effects are abundant, including increased duration of hospital stay.³

In this article we define polypharmacy as the use of 2 or more medications of the same chemical class or with the same or similar pharmacological actions to treat the same condition or separate conditions. For example, prescribing thyroid medication to augment antidepressant response would be polypharmacy, while using thyroid medication to treat hypothyroidism, with concomitant antidepressant therapy for depression would not be considered polypharmacy (Table 1).

Although the use of multiple medications to treat different conditions is beyond the scope of this paper, it should be realized that there is a potential for problems any time multiple medications are used. As an example, cases of carbamazepine toxicity have been reported when this mood stabilizer is used in combination with protease inhibitors for HIV because of the well-known CYP3A4 inhibition of this antiretro- viral class.⁴

A medication that treats the adverse effects of another agent would not be considered polypharmacy by this definition. For instance, using anticholinergic agents to treat extrapyramidal side effects of first-generation antipsychotics or the use of amiloride to treat lithium-induced polyuria may be empirically based. However, the need for 2 medications might be avoided with the use of second-generation antipsychotics in the first example or valproic acid in the second example.

The term polypharmacy does not in itself suggest whether its use is warranted. Ideally, only one medication would be used to optimally treat a symptom or disorder. However, even a cursory review of the literature suggests that many, if not most, patients show suboptimal response to any one given agent. New medications more specifically target disease state symptoms and have improved side-effect profiles, making combination treatment strategies more attractive and possibly less daunting. The legitimate increase in pressures to help improve patient status has changed the standard for successful treatment in psychiatry; the bar has been raised.

Perhaps the best example of this phenomenon is in the treatment of depression. Response is no longer considered an acceptable goal-remission is now the clear end point for therapy. Multiple lines of evidence show that patients who only respond have a poorer quality of life and are more likely to relapse.^5,6

There are certainly some well-researched uses of medication combinations. Even casual reflection shows that the number of possible medication combinations to treat any psychiatric condition is enormous. Surveys have found that the use of 4 or 5 medications simultaneously is not uncommon in the treatment of bipolar disorder⁷ or other psychiatric conditions.^8,9 Given the overwhelming number of possible combinations, it is unlikely that more than a few of these will be researched.

Although double-blind, placebo-controlled trials are considered the standard, relatively few such studies of polypharmacy exist. Therefore, clinicians must venture beyond this evidentiary base. Less firm evidence may be gathered from clinical series and expert opinions, which may not be completely current nor deal with the specific clinical dilemma being faced. Therefore, alternative ways of approaching this problem are needed (Table 2).

The good
Two polypharmacy strategies may be considered good. The first involves using a combination of 2 medications based on research showing that the combination is more effective than the use of either one alone. Since such studies are in short supply, the second strategy, rational polypharmacy, would be to extrapolate the combined pharmacodynamics of concomitant medications from existing research results, expert opinions, or hypotheses.

Perhaps the largest group of research studies supporting polypharmacy exists for manic episodes in bipolar disorder. The combination use of either lithium or valproate with the second-generation antipsychotics olanzapine, quetiapine, or risperidone has proved to be effective in the treatment of manic episodes.^10-12 Therefore, since research supports using 3 of the second-generation antipsychotics in combination with mood stabilizers for mania, it would seem reasonable to generalize these findings as applicable to the other 2 second-generation antipsychotics, aripiprazole and ziprasidone. Moreover, they too are approved for the treatment of manic episodes in bipolar disorder, so combining them with a mood stabilizer would be rational polypharmacy.

Various algorithms exist reflecting both research and clinical experience from authorities and panels of experts. These guidelines frequently suggest rational approaches to the concomitant use of more than 2 drugs. Post and colleagues¹³ report on the complexity and sophistication necessary for such combinations, particularly in the treatment of bipolar disorder.

Knowledge about the biology of a disorder and the pharmacodynamic properties of medications can be foundations on which rational polypharmacy regimens can be built. For example, the addition of bupropion, which possesses norepinephrine and dopamine reuptake inhibition, to an SSRI would appear rational in the treatment of depression, despite the lack of firm double-blind, placebo-controlled evidence that this combination is effective.

It should be realized that regardless of the rationale or quality of the research, the combination chosen might not be effective for a given patient. Therefore, it is incumbent upon the clinician to carefully monitor the effects of such combinations. Although the use of detailed research scales would be ideal, time constraints in most practices mitigate against this. However, the use of selected items from such scales or the use of a clinical global impression scale would be helpful in avoiding long-term use of additional medications that provide little or no benefit.

Schizophrenia is one area where such monitoring is necessary because polypharmacy research is either lacking or contradictory. For example, although there are case studies suggesting that the addition of risperidone may augment response to clozapine, the only double-blind studies of this combination report contradictory results.^14-16

Since some positive results exist, using risperidone and clozapine together may be beneficial, but the combination requires monitoring for symptom improvement to ensure the adequacy of such treatment. We have often been consulted about cases of schizophrenia in which patients are taking several antipsychotics simultaneously and the clinician is seeking to add another. When asked whether they had considered a trial of clozapine alone for the patient, the answer is invariably no.

The bad
For the purposes of this article, bad polypharmacy will refer to the combination of 2 or more medications without attention to pharmacodynamic properties. Inattention to pharmacokinetic properties will be discussed in the next section.

Several reasons for bad polypharmacy have been described.¹⁷ One example is clinicians' fear of "rocking the boat," so they refrain from discontinuing any current medications that are partially effective. An additional medication is then added to the existing regimen in an attempt to achieve full therapeutic effects. In these cases, the additional medication may be sufficient as monotherapy, which would make a medication switch more appropriate than a combination approach.

Another cause of bad polypharmacy deserves mention: following fads. For example, we have frequently seen the addition of low-dose quetiapine for sleep to suboptimal doses of antipsychotics or mood stabilizers. Although clearly more expensive, it is unclear whether the use of low-dose quetiapine provides any greater benefit than a pure antihistamine agent. Another recent example we observed was the addition of gabapentin to a large variety of medications in the hope of augmenting response in schizophrenia, bipolar disorder, depression, and other conditions despite an absence of sound evidence for its efficacy.

We have unfortunately observed plentiful inattention to the combined pharmacodynamic properties of medications. An example is the use of 2 SSRIs, both at suboptimal doses. Another is the addition of a serotonin- norepinephrine reuptake inhibitor (SNRI), such as venlafaxine, to an SSRI when the serotonin reuptake inhibition of the SNRI alone may be sufficient.

Another recently observed example was the combined use of an anticholinergic agent with donepezil. Obviously, the cholinergic antagonist should cancel out any benefits of a cholinesterase inhibitor. This, again, shows inattention to the combined pharmacodynamic effects.

The ugly
In contrast to polypharmacy that is mostly wasteful or ineffective, as described in the previous section, the "ugly" refers to polypharmacy that may be harmful. Two major errors may lead to harm: inattention to pharmacokinetic interactions and inattention to side-effect profiles of medication combinations.

Much has been learned in recent years about the cytochrome P-450 (CYP450) system as well as medications that may induce or inhibit specific isoenzymes. We have repeatedly observed patients taking a number of medications receive an additional medication with potent CYP450 induction or inhibition properties, which potentially leads to adverse effects or decreased effectiveness of the original medications. Conversely, we have observed detrimental effects following the removal of a medication that was inducing or inhibiting concomitant medications. As simple examples, although the potent CYP450 inhibition of paroxetine and fluoxetine are well known, less attention is typically paid to the metabolism of medications used with them.

Similarly, inattention to the use of multiple medications with similar side-effect profiles may lead to greater problems than the use of either alone. For instance, many psychiatric medications may lead to weight gain. Nevertheless, several such medications are often freely combined without considering alternatives that are more weight-neutral.

Conclusions
As more therapeutic agents are introduced with varying pharmacological profiles, it becomes increasingly important for practitioners to be familiar with existing research, the mechanisms of action of medications, and metabolic pathways in order to use rational polypharmacy. Various interventions have been described that lessen irrational polypharmacy, including peer review processes, continuing education on rational polypharmacy approaches, and clinical pharmacy involvement in patient care.^18,19

If future trends in psychiatric disease management follow along their current route, polypharmacy will continue to be necessary in order to obtain optimal therapeutic goals. With this in mind, it becomes imperative for providers to remain judicious when using polypharmacy strategies in the treatment of psychiatric disorders.

Disclosures:

Dr Kingsbury is chief of outpatient mental health at the VA Southern Nevada Healthcare System in Las Vegas and clinical professor of psychiatry in the department of Psychiatry and Behavioral Science at the University of Nevada. Dr Lotito is a clinical pharmacy specialist in psychiatry and director of the PGY1 pharmacy residency program at the VA Southern Nevada Healthcare System in Las Vegas. She is also assistant professor of pharmacy practice at the University of Southern Nevada College of Pharmacy. Dr Kingsbury reports that he is on the speakers' bureau for AstraZeneca, Bristol-Myers Squibb, Forest, Janssen, and Pfizer. Dr Lotito reports that she has no conflicts of interest concerning the subject matter of this article.

References:

1. Preskorn SH, Silkey B, Shah R, et al. Complexity of medication use in the Veterans Affairs healthcare system, part 1: outpatient use in relation to age and number of prescribers. J Psychiatr Pract. 2005;11:5-15.
2. Joukamaa M, Heliovaara M, Knekt P, et al. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry. 2006;188:122-127.3. Parks ED, Josef N. A retrospective study of determinants of length of stay in a geropsychiatric state hospital. Psychiatr Q. 1997;68:91-99.
4. Bates DE, Herman RJ. Carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir. Ann Pharmacother. 2006;40:1190-1195.
5. Karp JF, Buysse DJ, Houck PR, et al. Relationship of variability in residual symptoms with recurrence of major depressive disorder during maintenance treatment. Am J Psychiatry. 2004;161:1877-1884.
6. Pintor L, Torres X, Navarro V, et al. Is the type of remission after a major depressive episode an important risk factor to relapse in a 4-year follow up? J Affect Disord. 2004;82:291-296.
7. Frye MA, Ketter TA, Leverich GS, et al. The increasing use of polypharmacy for refractory mood disorders: 22 years of study. J Clin Psychiatry. 2000;61:9-15.
8. Silkey B, Preskorn SH, Golbeck A, et al. Complexity of medication use in the Veterans Affairs healthcare system, part 2: antidepressant use among younger and older outpatients. J Psychiatr Pract. 2005;11:16-26.
9. West JC, Wilk JE, Olfson M, et al. Patterns and quality of treatment for patients with schizophrenia in routine psychiatric practice. Psychiatr Serv. 2005;56:283-291.
10. Yatham LN, Paulsson B, Mullen J, Vagero AM. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol. 2004;24:599-606.
11. Sachs G, Grossman F, Okamoto A, et al. Risperidone plus mood stabilizer versus placebo plus mood stabilizer for acute mania of bipolar disorder: a double-blind comparison of efficacy and safety. Am J Psychiatry. 2002;159:1146-1154.
12. Tohen M, Chengappa KN, Suppes T, et al, Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 2002;59:62-69.
13. Post RM, Speer AM, Leverich GS. Complex combination therapy: the evolution toward rational polypharmacy in lithium-resistant bipolar illness. In: Akiskal HS, Tohen M, eds. Bipolar Psychopharmacotherapy Caring for the Patient. Chichester, UK: John Wiley & Sons Ltd; 2006:135-167.
14. Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006;354:472-482.
15. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005;162:130-136.
16. Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry. 2005;66:63-72.
17. Kingsbury SJ, Yi D, Simpson GM. Rational and irrational polypharmacy. Psychiatr Serv. 2001;52:1033-1035.
18. Patrick V, Schleifer SJ, Nurenberg JR, Gill KJ. Best practices: an initiative to curtail the use of antipsychotic polypharmacy in a state psychiatric hospital. Psychiatr Serv. 2006;57:21-23.
19. Wu JY, Leung WY, Chang S, et al. Effectiveness of telephone counseling by a pharmacist in reducing mortality in patients receiving polypharmacy: randomized controlled trial. BMJ. 2006;333:522-527.