Combination olanzapine-fluoxetine significantly improves symptoms of treatment-resistant depression compared with either drug alone

Combination olanzapine-fluoxetine significantly improves symptoms of treatment-resistant depression compared with either drug alone, according to a presentation at the annual meeting of the American Psychiatric Association.

The results come from a pooled analysis of two recent parallel, randomized, double-blind two-month studies. Clinical assessment was based on the Montgomery-Asberg Depression Rating Scale (MADRS).

"Treatment-resistant depression is one of the greatest clinical challenges that psychiatrists face today, which is compounded by the fact that there is no FDA-approved medication for this illness," said Michael E. Thase, MD, professor of psychiatry at the University of Pittsburgh Medical Center and the Western Psychiatric Institute and Clinic. "This is a rigorously designed study conducted in treatment-resistant depression patients who have not responded to two previous, adequately dosed antidepressants.”

Treatment-resistant depression is defined by failure to sustain or achieve remission despite adequate antidepressant therapy. Adequate antidepressant therapy is defined as receiving an appropriate medication, at the proper dosage, for a suitable length of time. Conservative estimates indicate that between 10 percent and 20 percent of patients with major depressive disorder continue experiencing symptoms despite multiple treatments.

In the two identically designed studies, a total of1,313 patients between 18 and 65 years of age who met DSM-IV criteria for recurrent major depressive disorder without psychotic features were enrolled into an eight-week, open-label fluoxetine lead-in period.

Patients could only be enrolled if they did not respond to an antidepressant except fluoxetine after at least six weeks of therapy at an adequate dosage during the current major depression episode.

Of the 1313 patients, 605 patients did not respond to fluoxetine: They were randomized over an eight-week study period to olanzapine 6, 12, or 18 mg daily plus fluoxetine 50 mg daily, to olanzapine alone, or to fluoxetine alone (50 mg daily).

Mean modal doses (mg/day) for the double-blind studies were 8.6 and 48.8 for combination medication (olanzapine and fluoxetine, respectively), 8.7 for olanzapine alone, and 49.5 for fluoxetine alone.

Of the 605 randomized patients, 441 patients (72.9 percent) completed the studies. A pooled analysis of both double-blind studies was conducted at the end of the eight-week trial period. Upward dose titrations were required at two-week intervals if no tolerability or safety issues were identified.

The primary efficacy measure was improvement from baseline to endpoint on the MADRS. In the first study, while all three treatment arms demonstrated improvements from baseline, there was no statistically significant difference in improvement among the three treatment arms (combination, -10.8; fluoxetine -9.4; olanzapine -10.1).

In the second study, patients taking combination medication had a significant difference compared with both single agents (average scores of -14.6 on the MADRS compared to fluoxetine -9.0, and olanzapine, -7.7).

Forty-four percent of combination patients responded to therapy compared with 30 percent of fluoxetine patients and 17 percent of olanzapine patients. In addition, pooled results showed significantly greater improvement for combination (-12.6) versus fluoxetine (-9.2) and olanzapine (-8.9) alone.


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