Antidepressants: How much is too much?

According to the recently published Combining Medications to Enhance Depression Outcomes (CO-MED) study, using two antidepressants in a patient with major depressive disorder (MDD) provides no better results than using only one antidepressant. These findings, however, starkly contrast the findings of previous studies which have proved just the opposite.

The large-scale trial funded by the National Institutes of Mental Health showed that when treatment in patients with MDD commenced, a single antidepressant yielded the same remission rate as two antidepressants. They also found that therapy with two drugs has the potential to inflict more side effects on a patient than a single drug.

"We found no clinical advantage over escitalopram-placebo from either combination of antidepressant medications in terms of either remission or response rates at either twelve weeks or seven months," reported the team of investigators led by John A. Rush, University of First Duke-National University of Singapore Graduate Medical School.

The study was performed in order to determine whether higher remission rates could be achieved with a combination of two antidepressants used together as initial treatment. In placebo-controlled, antidepressant monotherapy—or using only one drug—usually produces remission rates of 30% to 35%.

CO-MED was a single-blind, prospective, multicenter, randomized study involving 665 participants who suffered from at least moderately severe non-psychotic chronic or recurrent MDD.

The participants were randomly assigned in a 1:1:1 ratio to one of the three following treatment groups:

• Escitalopram (up to 20 mg/d) plus placebo group
• Sustained-release bupropion (up to 400 mg/d) plus escitalopram (up to 20 mg/d) group
• Extended-release venlafaxine (up to 300 mg/d) plus mirtazapine (up to 45 mg/d) group

The primary objective of this study was symptom remission, which was based on the last two scores on the sixteen-item Quick Inventory of Depressive Symptomatology Self-Report. During the first twelve weeks, at least one of the ratings had to be less than six and the other had to be less than eight in order for a patient to achieve this outcome.

Secondary objectives were side effect burden, adverse events, quality of life, quality of functionality, and attrition.

The researchers found that neither of the combined drug groups outperformed the monotherapy group in the first twelve weeks, nor in the remaining seven months of the study.

At the end of the first twelve weeks, remission and response rates, as well as the majority of the secondary objectives, did not differ among the three treatment groups. The remission rates were about 39% for the escitalopram-placebo and bupropion-escitalopram groups, and about 38% for the venlafaxine-mirtazapine group. The overall response rates for the three study groups were about 52%.

"The remission rates approximated those expected on the basis of monotherapy studies of chronic depression," the researchers wrote.

In comparison with the monotherapy group, the combination group receiving both venlafaxine and mirtazapine was connected to an increased side effect burden and with a worsening of side effects.

At the end of the remaining seven months after the initial twelve weeks, there were still no between-group differences in remission rates (42% to 47%), response rates (57% to 59%), and most secondary objectives, including quality of life and work and social adjustment.

Side effects at seven months, however, were still greater with the venlafaxine-mirtazapine combination than with escitalopram-placebo. Over the entire course of the study, the attrition rates did not differ among treatment groups.

Some experts are saying that there is a problem with these findings, however.

The CO-MED results are greatly different from the findings of two smaller studies — one published in 2009, the other in 2010 —that showed a benefit of starting with combination antidepressant therapy.

The lead investigator on these two earlier trials, Pierre Blier, MD, PhD, from the University of Ottawa Institute of Mental Health Research, in Ontario, Canada, reported that there are problems with the CO-MED study and readers should use caution in interpreting the results.

In these two previous studies, Blier's researchers discovered that patients suffering from depression benefitted from an initial combination of mirtazapine plus paroxetine, fluoxetine, or bupropion; such treatments yielded remission rates roughly twice those of patients who received fluoxetine or paroxetine alone initially.

The CO-MED findings "complete an all too familiar sequence in which the encouraging results of small studies prompt a much larger and carefully designed effort, one that then ends with surprisingly negative conclusions," wrote William Coryell, MD, of the University of Iowa in Iowa City, in a commentary.

Coryell stated that the possible reasons for the negative CO-MED results and earlier positive findings could be the variance between patient groups.

Blier, however, believes the results of the CO-MED study conflict the results of his studies because of "uneven/inadequate doses.” Blier stated in a reply submitted to the American Journal of Psychiatry that the dose of escitalopram in the CO-MED study was near the maximal dose in the monotherapy group and significantly lower in the escitalopram-bupropion group.

"Whether the escitalopram-bupropion combination is indeed superior to monotherapy will be determined by the results of an ongoing double-blind National Institute of Mental Health-funded study in 240 patients studied at Columbia University and the University of Ottawa," Blier noted.

Blier also stated that another limitation of CO-MED is the fact that it was a single-blind, not double-blind study.

"The fact that the physicians were not blind to treatment may have made them reluctant to achieve and maintain adequate doses fearing tolerability and compliance issues," Blier wrote further.

"In my practice, if I have a patient with moderate to severe depression, I will present them with the option of taking two antidepressants; that sounds aggressive, but actually it is not. Treating with two medications is common practice," continued Blier.

In a commentary published with the CO-MED study, Carol A. Tamminga, MD, professor and chairman of psychiatry at the University of Texas Southwestern Medical Center at Dallas, addressed the question of whether polypharmacy is good treatment with "there seems not to be an easy or a universal answer.”

Tamminga continued to state that "there is no doubt that we need new treatment targets and there is considerable basic neuroscience research, which is generating data and testing hypotheses about depression biology.”

"We all look forward to the time when cutting-edge depression biology will generate treatments for patients," she concluded.

The study was published in the July issue of the American Journal of Psychiatry.