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Subsequent Treatment Strategies for Persistent Depression Yield Modest Results

Science Update

Patients with treatment-resistant depression had a modest chance of becoming symptom-free when they tried different treatment strategies after two or three failed treatments, according to results from the nation's largest real-world study of depression. These results from Levels 3 and 4 of the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study were reported in the American Journal of Psychiatry on September 1, 2006.

In Level 3 of the study, participants who had not become symptom-free after receiving treatments in Levels 1 and 2 had the option of either switching to another medication, or taking another medication in addition to their existing medication. The modest results for the 235 participants in the Level 3 "switch" group were reported in the July 1, 2006, issue of the American Journal of Psychiatry.

Of the 142 participants in the Level 3 "add-on" group, each was randomly prescribed either lithium — a mood stabilizer commonly used to treat bipolar disorder — or triiodothyronine (T3)— a medication commonly used to treat thyroid conditions— to add to the medication they were already taking. These medications were chosen because they have been shown to boost the effectiveness of antidepressant medications.

After being on one of these new combinations for an average of nine weeks, about 20 percent of participants became symptom-free. Those taking T3 complained of fewer troublesome side effects than those taking lithium. In addition, only 10 percent of people taking the T3 discontinued treatment, while 23 percent of those taking lithium discontinued.

"The rates of remission at Level 3 were modest. But these results do provide some insight to clinicians who may be considering adding lithium or T3 to a patient's existing treatment regimen," said lead author Andrew Nierenberg, M.D., of Massachusetts General Hospital. "Although neither of these approaches was more effective than the other, there may be a slight advantage to T3, with its lower side effect burden, over lithium, especially within the context of two previously unsuccessful treatment attempts."

In Level 4, 109 participants who had not become symptom-free in any of the previous levels were taken off all other medications and switched to one of two treatments. The first was a combination of venlafaxine-XR (Effexor-XR) and mirtazapine (Remeron), both of which had been used in previous STAR*D levels but not together. The second treatment was tranylcypromine, a monoamine oxidase inhibitor (MAOI). MAOIs, an older class of antidepressants, can dangerously interact with a substance called tyramine, which is found in certain foods or medications. Therefore, patients taking an MAOI must adhere to certain dietary restrictions.

After an average of nine weeks, about 10 percent of participants became symptom-free. Those taking the venlafaxine-XR/mirtazapine combination had fewer side effects, stayed on the medications longer, and had lower drop-out rates. Although the results do not definitively identify a treatment regimen that would be most beneficial to patients who had not benefited from prior treatment regimens, they do suggest that the venlafaxine-XR/mirtazapine combination has some advantages.

"The Level 4 findings suggest that the venlafaxine-XR/mirtazapine treatment may be a better choice than the MAOI, given the MAOI's many dietary and medicinal restrictions associated with it," said lead author Patrick McGrath, M.D., of the New York State Psychiatric Institute. "But Level 4's very modest remission rates also bring home the point that better treatments are needed for people with the most difficult-to-treat depression," he concluded.

The multi-step, 41-site STAR*D study began with 2,876 participants. Those who did not become symptom-free during Levels 1 and 2 went on to subsequent treatment levels. Those results were described earlier.

STAR*D was conducted in real-world, primary and specialty care settings, allowing the researchers to generalize their findings more broadly than typical clinical trials that are conducted in tightly controlled settings. The results are especially relevant to doctors and clinicians who must go through a trial and error process to find the right medication or combination of medications for individual patients.

The two studies are:

Nierenberg AA, Fava M, Trivedi MH, Wisniewski ST, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D Report . American Journal of Psychiatry. 2006. 163:9.

McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ. .Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D Report . American Journal of Psychiatry. 2006; 163:9.