Combination Treatments: Your Individual Mileage May Vary
Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-term Outcomes of a Single-Blind Randomized Study
Rush AJ, Trivedi MH, Stewart JW, et al
Am J Psychiatry. 2011;168:689-701
Effectiveness of Switching From Antipsychotic Polypharmacy to Monotherapy
Essock SM, Schooler NR, Stroup TS, et al; The Schizophrenia Trials Network
Am J Psychiatry. 2011;168:702-708
Gabapentin Combined With Naltrexone for the Treatment of Alcohol Dependence
Anton RF, Myrick H, Wright TM, et al
Am J Psychiatry. 2011;168:709-717
Summary of Studies
Three articles were published in the July 2011 issue of the American Journal of Psychiatry that reported on the potential utility of combinations of psychotropic medications, a practice commonly encountered in real-world clinical settings. In the first study, 2 antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment. The study enrolled 665 outpatients with at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Patients were randomized to receive escitalopram plus placebo, sustained-release bupropion plus escitalopram, or extended-release venlafaxine plus mirtazapine. Patients, but not study personnel, were blinded to the identity of the second agent being administered (placebo, escitalopram, or mirtazapine). Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 37.7%-38.9% and the response rates were 51.6%-52.4%. At 7 months, remission rates (41.8%-46.6%), response rates (57.4%-59.4%), and most secondary outcomes were not significantly different. The authors concluded that neither medication combination outperformed monotherapy and that the combination of extended-release venlafaxine plus mirtazapine may have a greater risk for adverse events.
The second study enrolled 127 adult outpatients with schizophrenia taking 2 antipsychotics who were then randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing 1 antipsychotic. Treatment was open-label with blinded clinical raters. The trial lasted 6 months, with a 6-month naturalistic follow-up. Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy but the 2 groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. Two thirds of participants were successfully switched. The suggestion is that it is reasonable to encourage trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy and that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.
The third study enrolled 150 alcohol-dependent individuals in a double-blinded trial and evaluated whether the combination of naltrexone and gabapentin was better than naltrexone alone and/or placebo alone during the early drinking cessation phase (first 6 weeks) and, if so, whether this effect persisted. During the first 6 weeks, the naltrexone-gabapentin group had a longer interval to heavy drinking than the naltrexone-alone group, which had an interval similar to that of the placebo group; had fewer heavy drinking days than the naltrexone-alone group, which in turn had more than the placebo group; and had fewer drinks per drinking day than the naltrexone-alone group and the placebo group. However, these differences faded over the remaining weeks of the study after gabapentin was discontinued. This trial was thus supportive of a combination approach.
The US Food and Drug Administration has approved the marketing of certain combinations of psychotropic medications (for example, combinations of some second-generation antipsychotics with lithium or valproate for bipolar disorder, or the combination of some second-generation antipsychotics with antidepressants for major depressive disorder). In reality many more combinations of an assortment of agents are routinely clinically prescribed.
There is often initial excitement when the first small clinical trials support the idea of certain combination approaches being helpful, consistent with "practice-based evidence." This enthusiasm is usually dampened when larger trials fail to show a benefit. However, there is a tremendous degree of heterogeneity among our patients in terms of treatment response. Moreover our diagnostic scheme is based on phenomenology and does not account for the different pathophysiologic processes that likely are occurring. What these studies offer is some reshuffling of the treatment options that we should offer first but do not necessarily eliminate any of them.
Of importance is that these studies were done with outpatients. Severity of illness may lead to more heroic measures (ie, combinations). Of note, routine switching from antipsychotic combination treatment to monotherapy in a chronically hospitalized person with schizophrenia may be a considerable challenge, even over the span of weeks or months, as directly observed in my experiences in a state hospital environment.
In the end we can return to the notion that the practice of evidence-based medicine is not just about the evidence but also incorporates relevant clinical experience and the individual patient's preferences and values into the clinical decision-making process. And, as they say, "Your individual mileage may vary."