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.
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.
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.
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.
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.