麻豆传媒

Keeping patients with psychotic depression on both sertraline (Zoloft) and olanzapine (Zyprexa) after remission led to fewer relapses than when the antipsychotic drug was stopped, a randomized trial found.

Among 126 patients treated with sertraline and olanzapine who met remission criteria and then remained symptom-free for 8 weeks, those who continued the drug combination for an additional 36 weeks had far fewer relapses than did those who remained on sertraline but had placebo substituted for olanzapine (20.3% vs 54.8%), reported Alastair Flint, MB, of Toronto General Hospital in Canada, and colleagues.

That translated to a hazard ratio of 0.25 (95% CI 0.13-0.48, P<0.001) for relapse with the extended combination therapy, according to their report in .

But patients remaining on olanzapine gained an average of 6 pounds during the treatment extension, on top of the mean 12 pounds gained during the earlier trial phases. Patients on sertraline and placebo lost a mean 3 pounds during the extension.

"With placebo, the majority of relapses occurred within the first 12 weeks after randomization, whereas relapses among the sertraline-olanzapine group were distributed throughout the 36-week trial," Flint and colleagues wrote. "Relapses resulted in a high frequency of psychiatric hospitalization, highlighting the severity and cost of this disorder and the importance in preventing relapse."

Compared to individuals with general major depressive disorder, patients with psychotic depression are less likely to respond to placebo or hospitalization alone, and tend to have a higher burden of symptoms, wrote William Coryell, MD, of the University of Iowa in Iowa City, in an .

This trial makes it clear that combined sertraline and olanzapine is "highly effective" for this population, Coryell noted, since nearly all differences in relapse rates between groups occurred within the first 2 months of the trial and the authors found a number needed to treat of 2.8.

What is less clear is whether this combined therapy should be prescribed indefinitely, he added; successfully enrolling enough patients to test this question is near impossible.

"It seems likely then that judicious discontinuation of antipsychotic agents followed by close vigilance over the subsequent several months is likely to be an effective strategy," Coryell wrote. "For those patients who tolerate antipsychotic medications well, longer periods taking combined treatment may be preferable."

Coryell also highlighted "a number of caveats" to this recommendation. First, this trial enrolled patients with delusions but not patients who only had hallucinations, which may have captured some patients with other personality disorders. Young patients with new-onset psychosis may also later go on to meet criteria for schizophrenia; Coryell advised clinicians to "be alert" to such symptoms in the absence of major depression.

The so-called enrolled adult patients (18-85) meeting criteria for major depressive disorder with at least one associated delusion at four medical centers in the U.S. and Canada. Patients with other psychotic disorders, bipolar disorder, or physiological illness such as type 1 diabetes or neurological disease were excluded.

Patients initially received open-label sertraline at 150-200 mg/day and olanzapine at 15-20 mg/day and then, after achieving remission status for 2 weeks or near-remission status for 12 weeks -- as defined by (HDRS) criteria -- they entered an 8-week open-label stabilization phase. Those maintaining remission or near-remission criteria after the stabilization phase and who had scores of at least 24 were then enrolled in the randomized, double-blind, 36-week extension trial.

Sixty-two patients were assigned to sertraline and placebo and 64 continued the sertraline-olanzapine combination. They were assessed weekly for the first 8 weeks and then once per month afterwards.

Relapse was defined as a major depressive or manic episode, HDRS scores of 18 or more, , suicidality, or psychiatric hospitalization.

Mean patient age was about 55 and most participants were white (84% in the active and 79% in the control group). Roughly three-quarters of patients had histories of two or more depressive episodes with the first major depressive episode occurring at a median age of about 36.

Risk for relapse was significantly different between groups after controlling for age, remission versus near-remission status, and study site, Flint and his team reported.

Some biomarkers of adverse metabolic effects -- including weight, waist circumference, and total cholesterol -- were higher in the combination group. But LDL and HDL cholesterol, triglyceride, and hemoglobin A1c levels did not differ significantly between groups.

In both arms, 12 participants experienced serious adverse events, all but one from hospitalization. Also, markedly more patients in the sertraline-olanzapine group experienced at least one fall than in the placebo group (31.3% vs 17.7%). Other common side effects to antipsychotic medications were similar between the olanzapine and placebo groups, Flint and colleagues said.

The trial's findings may not be generalizable to other antipsychotic medications; the authors noted olanzapine was used because it is the only form with established efficacy for this population. Tapering olanzapine more slowly might have led to fewer relapses in the control group, the authors acknowledged, and the study shed little light on the "optimal duration" of post-remission olanzapine treatment. Also, half of the patients in the placebo group were observed for 20 weeks or less during the randomized phase, perhaps underestimating some outcomes.

Finally, Flint and his team did not collect data on biomarkers of relapse, which could help identify those patients most likely to benefit from continued antipsychotic therapy versus its withdrawal.

Comment