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).
Examples of good, bad, and ugly
|Lithium or valproate + risperidone, olanzapine, or quetiapine for bipolar mania
Clozapine + risperidone for treatment-resistant schizophrenia*
Lithium or valproate + ziprasidone or aripiprazole for bipolar mania
SSRI + mirtazepine for posttraumatic stress disorder
Clozapine + haloperidol for treatment-resistant schizophrenia
|SSRI + venlafaxine for depression
Aripiprazole (at suboptimal dosing) for mania + quetiapine (low-dose) for sleep
Lithium (at suboptimal dosing) + gabapentin for mood stabilization
Citalopram + paroxetine (both at suboptimal doses) for depression
Donepezil for dementia + oxybutynin for incontinence
|Fluoxetine + amitriptyline for depression
Valproic acid for mood stabilization + antiretroviral for HIV infection
Olanzapine for psychosis + low-dose mirtazapine for sleep + valproic acid for seizures
SSRI for depression + tramadol for pain
*Cannot be strongly recommended as good polypharmacy because it needs careful monitoring.
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.
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.
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.
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