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Treatment Choices Complicated By Repeated Failures

Proving that the third time isn't always the charm, STAR*D's level 3 results show that successive antidepressant monotherapy may not be ideal.

To some, the results from the third phase of the National Institute of Mental Health's (NIMH) STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial may prove to be disappointing when considered in isolation.

On the whole, however, clinicians as well as patients may view results of all three phases of the large effectiveness trial as not only instructive, but also encouraging.

Results from STAR*D's level 3 were reported in the July American Journal of Psychiatry by Maurizio Fava, M.D., a professor of psychiatry at Harvard Medical School and associate chief of psychiatry for clinical research at Massachusetts General Hospital, along with the other members of the STAR*D study team.

The trial was designed to answer real-world questions faced by clinicians and their patients regarding subsequent treatment choices following an antidepressant medication's failure to promote remission.

"What we now see is that if you have failed two consecutive antidepressant treatment trials," Fava told Psychiatric News, "switching to another antidepressant may not be as efficacious as initially thought." That conclusion, he added, "goes against the traditional thought that successive monotherapy trials of one antidepressant after another would be the best approach to take with resistant depression."

When a patient does not respond to a particular agent, Fava continued, "clinicians typically just try a drug from a different class. If that doesn't work, they just keep switching and switching until they find something that works."

Now, however, based on the level 3 results from STAR*D, that switching strategy "may not be the best approach after all."

Multilevel Approach Used

In level 1 of the protocol, more than 3,000 patients began treatment with citalopram (Celexa) at doses up to 60 mg a day. Of those patients, 27.5 percent met criteria for remission by the end of 14 weeks (with remission defined as a score of less than or equal to 7 on the Hamilton Depression Rating Scale) (Psychiatric News, January 20).

Level 2 of STAR*D included patients from level 1 who did not achieve remission on citalopram or who could not tolerate the drug's side effects. Level 2 participants were presented with two paths in which they could continue in the study: through either a switch protocol or an augmentation protocol.

Patients were asked to accept or decline the following possibilities: to switch from citalopram to sustained-release bupropion, sertraline, or extended-release venlafaxine or to continue taking citalopram and augment it with either bupropion, buspirone, or cognitive-behavioral therapy.

Then, based on their choice, each participant was randomly assigned to one of their "acceptable" protocols—a process termed "equipoise randomization."

In level 2, remission rates ranged from 18 percent to 25 percent for those who switched to a different medication, and were around 30 percent for those who continued citalopram and augmented with either bupropion or buspirone (Psychiatric News, April 21).

Level 3 included patients who did not remit during level 2 treatment or were unable to tolerate the regimen to which they were assigned. Again, patients were allowed to accept or decline randomization into a switch strategy or an augmentation strategy. On the basis of those preferences, participants were again randomly assigned using equipoise randomization.

In level 3, 113 patients were randomly assigned to switch from their level 2 medication to mirtazapine (Remeron) at doses up to 60 mg a day for up to 14 weeks of treatment. In addition, 121 patients from level 2 were randomly assigned to switch to nortriptyline (Pamelor) at doses up to 200 mg a day.

(The results reported here are from this level 3 switch protocol. A future report will describe level 3 results with the augmentation protocol.)

Remission Rates Disappointing

Of patients who switched from their level 2 antidepressant to mirtazapine, 14 of 113 (12.3 percent) achieved remission by the end of 14 weeks. Of those who switched to nortriptyline, 24 out of 121 (19.8 percent) met criteria for remission. Although there was a numerical difference in rates of remission between the two groups, the difference was not statistically significant.

The researchers also found no statistically significant difference in the response rates to mirtazapine and nortriptyline. Neither time to remission nor time to response differed between the two medication groups. For those who did achieve remission on mirtazapine, the mean time to remission was 5.7 weeks compared with 6.3 weeks for those on nortriptyline.

Overall, no significant differences were found in tolerability/adverse events between the two antidepressants.

Completion rates for level 3 also did not significantly differ between the mirtazapine (33.3 percent) and nortriptyline (30.6 percent) groups. Of note, four trial participants were hospitalized for suicidal ideation or attempts, all of whom were receiving mirtazapine.

In their report, Fava and his colleagues said that "there is no clear advantage in switching to either one of these two treatments for outpatients who have not responded to multiple treatment trials." They also concluded that "the use of successive monotherapies results in only modest remission rates, even when the antidepressants have pharmacological profiles that clearly differ from those of previous agents," as was the case in the three levels of STAR*D.

"I think the issue here," Fava told Psychiatric News, "is that combining agents, as in adding or augmenting strategies, should be considered as an alternative."

The overall message, he continued, is that after a first failed antidepressant trial, whatever strategy you try next—switching or augmentation—appears to work. After two [consecutive] failed antidepressant trials, what you try next may, in some ways, have greater impact."

Fava maintains that more research is needed to define more clearly the best options for particular subclasses of patients. Pending reports from the STAR*D Study Team may help address these issues.

In an accompanying editorial, Matthew Menza, M.D., an associate professor of psychiatry and director of the Affective Disorders Program at the Robert Wood Johnson Medical School, calls STAR*D "a laudable endeavor." The study's results will continue to be published, he added, "and beyond this first wave, we will continue to see results that may affect our practice."

He cautioned, however, that "clinical trials tell us how groups of patients do on average. For an individual patient, a particular treatment may or may not work. These trials do not tell us which patient will respond to which treatment; they merely suggest what treatment is most likely to be helpful."

As for the relatively small and nonsignificant difference between mirtazapine and nortriptyline in level 3, Menza wrote, "We are left wondering whether the difference was mere chance or if we really should be using tricyclic antidepressants, such as nortriptyline, more than we currently do."

"A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report" is posted at <http://ajp.psychiatryonline.org/> under the July issue.

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