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National Institutes of Health

Science Update
July 1, 2006

Switching to a Third Antidepressant Medication May Prove Helpful to Some with Treatment-Resistant Depression

The next wave of results from the nation's largest real-world study of treatment-resistant depression shows that patients had a moderate chance of becoming symptom-free when they switched to a third antidepressant medication, following two previously unsuccessful medication attempts. These results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, funded by NIMH, were published in the American Journal of Psychiatry on July 1, 2006.

During Levels 1 and 2 of the STAR*D trial, which started with 2,876 participants, about half of all patients became symptom-free. Of the other half, about one in five became symptom-free when they went on to Level 3 and switched medications again.

"STAR*D continues to provide valuable real-world information about treating depression," said NIMH Director Thomas R. Insel, M.D. "Not only are the results enlightening, but they are telling us that more research is needed to help people with this debilitating illness, especially those who have tried several treatments and the treatments have failed."

As in Level 2, patients in Level 3 were given the choice of either switching medications or adding another medication to their existing medication; 234 patients chose to switch medications in Level 3. The results for those who chose to add to their existing medication will be available later in 2006.

The patients were randomly assigned to take either mirtazapine (Remeron), an "atypical" antidepressant, or nortriptyline (Aventyl or Pamelor), a tricyclic antidepressant, for up to 14 weeks. Both work differently in the brain than the selective serotonin reuptake inhibitors (SSRIs) and other medication used in Levels 1 and 2 of the STAR*D trial.

Overall, the two medications were about equally effective with 10 to 20 percent of patients becoming symptom-free. The type and severity of side effects were similar for both medications. In addition, neither medication resulted in a faster improvement rate than the other, suggesting that no clear advantage exists for either medication.

"Patients who do not respond to two consecutive antidepressant trials should not give up. Many of them will get better if they keep trying different treatment regimens or combinations, although the benefits from a third trial of an antidepressant alone appear to be rather modest," said lead author Maurizio Fava, MD, of the Massachusetts General Hospital in Boston.

STAR*D was conducted in real-world, primary and specialty care settings, which allows the researchers to generalize their findings more broadly than typical clinical trials that are conducted in tightly controlled settings. It is especially relevant to clinical situations in which doctors must change and tailor medications to address the specific medical requirements of each individual patient. Similar to the treatment of other chronic illnesses such as heart disease and diabetes, STAR*D shows that successful treatment of depression can involve prescribing different antidepressant medications, from either the same or from a different pharmacologic class, if the first one or two medications do not work.

Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert J, McGrath PJ, Thase ME, Warden D, Biggs M, Luther JF, Niederehe G, Ritz L, Trivedi MH. A comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report. American Journal of Psychiatry. 2006 July;163(7):1161-72.