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Combination Treatment for Psychotic Depression Holds Promise

Science Update

A combination of an atypical antipsychotic medication and an antidepressant known as a selective serotonin reuptake inhibitor (SSRI) may be more effective in treating psychotic depression than an atypical antipsychotic alone, according to results from an NIMH-funded clinical study.


Psychotic depression is characterized by major depression accompanied by symptoms such as hallucinations, delusions, and breaks with reality. A person with psychotic depression may be unwilling or unable to care for him or herself and often is admitted to the hospital. Typically, psychotic depression is treated with electroconvulsive therapy (ECT), known to be effective but not always acceptable to patients and their families. It is less commonly treated with an antipsychotic or an antipsychotic plus an antidepressant.

Results of the Study

In a 12-week trial, all 259 participants were required to have psychotic depression with at least one delusion or irrational belief, although not all had hallucinations. Participants were randomly assigned to one of two treatments—the atypical antipsychotic olanzapine (Zyprexa) plus the SSRI sertraline (Zoloft) (combination therapy), or to olanzapine plus a placebo, or inactive, pill (monotherapy). Barnett S. Meyers, M.D., of Cornell University, and colleagues compared rates of remission and side effects among the participants. They also compared the responses of the 117 patients younger than 60 with the responses of the 142 patients older than 60 to determine if the two age groups responded differently.

The researchers conducted assessments at the beginning of the trial, weekly for the first six weeks, and then every other week until week 12. They found that 42 percent of those on combination therapy remitted compared to 24 percent of those on the monotherapy, with no significant differences in remission rates between age groups. Combination therapy's superiority became most evident between weeks eight and 12 of the trial.

Overall, the two age groups experienced comparable side effects. Both groups experienced significant increases in cholesterol and triglyceride levels, and both gained weight. However, the younger age group gained twice as much on average—about 14 pounds—compared to the older group, which gained an average of 7 pounds. This finding is consistent with other reports that have found older adults tend to gain less weight with atypical antipsychotics, specifically olanzapine, the researchers said. However, older participants also tended to be on lower doses of the antipsychotic than the younger adults, which may partially explain the disparity in weight gain, according to the researchers.

Unexpectedly, older participants had no more difficulty tolerating the medications than younger participants, nor were they any more likely to experience falls, sedation or have greater movement disorder symptoms than younger participants.

Overall, about 45 percent of participants dropped out of the study, although the drop-out rate was lower in the combination treatment group (37 percent) compared to the monotherapy group (53 percent).


Because the drop-out rate was relatively high and no follow-up data on those who discontinued were collected, the authors caution against applying the study's results to clinical practice prematurely. Still, the authors suggest that combination therapy holds promise as an alternative therapy to ECT. "Psychotic depression is difficult to treat," said NIMH Director Thomas R. Insel, M.D. "This study provides insight into one approach to treatment that may be a valid alternative for many patients who cannot or will not undergo ECT."

What's Next

Longer-term studies are needed to evaluate side effects. "Future research must weigh the benefits of continuing atypical antipsychotic medication beyond 12 weeks against the risks of associated metabolic side effects," lead author Meyers concluded.


Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley-Miklus C, Papademetriou E, Leon AC, Heo M for the STOP-PD study group. A double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression—The Study of Pharmacotherapy of Psychotic Depression (STOP-PD). Archives of General Psychiatry. 2009;66(3):838-847.