Depression :: Drug Trial Shows Some Gains Against Major Depression

But the benefits were relatively small, indicating need for newer medications. Two different drug regimens for difficult-to-treat major depression — one a combination of two newer drugs and the other a single, older drug — were comparable in putting people with depression in remission.

But the combination treatment showed a greater reduction in depressive symptoms, although not full recovery.

“The positive message is that one should not give up,” said Dr. Richard M. Steinbook, a professor of psychiatry at the University of Miami Miller School of Medicine. “People who have failed three different forms of treatment still have hope.”

While the findings do give guidance on how to treat people with stubborn depression, it also should give impetus to the search for new drugs, the researchers said.

“These were the hard cases, so getting even 10 percent of them well was pretty good,” said study author Dr. Patrick J. McGrath, co-director of the Depression Evaluation Service at New York State Psychiatric Institute and Columbia University Medical Center in New York City. “The bad news is that those rates are pretty low, so we do need better treatments.”

The study is the latest in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial, the largest effectiveness study ever done on depression. It examines the benefits of antidepressants in “real-world” settings. The trial was funded by the National Institute of Mental Health.

Researchers designed the overall trial to look at major depression that had not responded to multiple treatments and to look at remission, meaning full recovery, as opposed to “response,” which is partial relief of symptoms.

People who did not experience remission in Levels 1, 2 and 3 of STAR*D were eligible to participate in Level 4, the subject of the latest paper.

Of the 4,041 participants who initially enrolled in STAR*D, 109 entered Level 4. This appears to be the first study to look at patients who had not benefited in three prior medication trials.

Participants were randomly selected to receive either tranylcypromine (Parnate) alone or venlafaxine (Effexor) plus mirtazapine (Remeron). Parnate is an older monoamine oxidase inhibitor while Effexor and Remeron are newer medications.

“The idea is to try to get at the underlying problem by as many possible mechanisms as you can,” McGrath said, of the drug combination chosen. “It’s similar to the way you might treat cancer with a multi-drug regimen.”

Parnate is used infrequently these days but has been effective in people who have not responded to other therapies.

People in the Parnate arm of the trial had remission rates of 6.9 percent and those in the combination arm, 13.8 percent, considered to be roughly comparable results. “That looks like the combination was twice as effective but, in fact, those differences were not statistically significant,” McGrath said.

But participants in the combination arm did have a statistically significant reduction in depression symptoms, as opposed to full remission — 25 percent versus 6 percent.

“The degree of improvement of symptoms gives a little edge to the combination over the single agent,” McGrath said. He warned, however, that this could have been a chance finding.

Another cautionary note: Parnate was given at the highest recommended dose, but this was still below the dose at which it is often effective. The drug might show better results at higher doses and when administered by experts. Not all the doctors in this trial were familiar and comfortable with the drug, which can have severe side effects if administered incorrectly.

The comparison was not an entirely fair one, Steinbook said. Monoamine oxidase inhibitors require a huge amount of preparation to go on, and patients are supposed to wear a bracelet or carry a wallet card warning of possible interactions.

Also, Steinbook said, data such as this loses the nuances of the type of patient who might respond better to this type of drug.

All in all, the glass could be half full or half empty, McGrath said. On the one hand, some people who had not responded to three other vigorous treatments had some or full relief from one of these regimens. On the other hand, the rates were still pretty low.

“Before this study started, experts would have predicted that by giving antidepressants systematically, almost everybody will get better. That turned out not to be true,” McGrath said. “Is it worthwhile to develop newer and better treatments? I think the answer is yes, and that hadn’t been so clear.”

Funding for new drugs has been lacking, McGrath explained, and these findings might give a jump start to the field.

The study findings were published in the September issue of the American Journal of Psychiatry.

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