The National Institute of Mental Health (NIMH) has embarked on a multicenter, multiyear study of the treatment of people with major depressive disorder with psychotic features. The study will compare the safety and efficacy of a second-generation antipsychotic alone with those for a combination of the antipsychotic plus an antidepressant. For those who partially remit on either regimen, a follow-up phase is included in which patients' original medication regimen may be augmented with lithium.

Unlike most NIMH-sponsored trials, the Acute Pharmacotherapy of Psychotic Depression trial doesn't have a catchy acronym, seemingly required of such clinical studies these days. Even so, the acronym-deprived study got under way last year, enrolling patients at four large academic medical centers (see box below). With just over 200 patients enrolled over the last 16 months, the study is two-thirds of the way to its goal of 315 patients. Under the five-year, multimillion-dollar grant, researchers hope to reach that enrollment goal by the end of 2004 and are aiming for final data analysis to be completed by the end of 2007.

Barnett Meyers, M.D., a professor of psychiatry at Cornell University's Weill Medical College in New York City, is the NIMH grantee and principal investigator and serves as chair of the NIMH Psychotic Depression Collaborative Study Group.

At an APA annual meeting session in New York City last month, Meyers and his colleagues discussed the study's development and its protocols, and detailed some early demographic data on patients enrolled during the first 16 months of the study. The study has two primary goals: to determine whether combination treatment is more efficacious than an antipsychotic alone for treating both depressive and psychotic symptoms, and to determine whether psychotic depression presents and responds differently in older patients compared with young adults.

Patients eligible to enter the study must have been diagnosed with major depressive disorder and have an identifiable delusion that can be confirmed by at least two clinicians.

The APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder notes that combined antipsychotic and antidepressant medication or electroconvulsive therapy (ECT) should be used for patients with psychotic depression. The NIMH study will determine which medication therapy is most effective.

"We already know that this is an especially difficult patient population to treat," noted Meyers. "As a result, we've very carefully evaluated assessment methods, and we've discussed the fact that we will be faced with a population at high risk for negative outcomes—including suicidal ideation and attempts. We are going to have to tolerate those risks and closely monitor and manage them."

Meyers noted that "keeping these people alive is a real issue. But to exclude patients who suffer from psychotic depression and are suicidal would mean you are not studying a real-world population."

Patients with bipolar depression, obsessive-compulsive disorder, and body dysmorphic disorder are excluded from the study. Patients also must not have an acute substance abuse disorder or used illicit drugs within the three months prior to entering the study. Patients with chronic comorbid medical disorders are allowed to enter the study, as long as they are not acutely ill or unstable.

The study will involve an acute treatment phase, lasting 12 weeks, aimed at stabilizing patients on either olanzapine (Zyprexa) plus matched placebo, or olanzapine plus sertraline (Zoloft).

Because of the general severity of the disorder and the inherent consequences of inadequate treatment, patients judged by study investigators as nonresponders to their blindly assigned treatment will be pulled out of the study and may receive other treatments, including additional or other medications or ECT.

Patients who achieve partial remission after the first 12 weeks of the study can continue in a second 12-week phase. During the continuation phase, those who partially remit on olanzapine alone will continue on olanzapine with the addition of sertraline. Those who partially remit on the initial combination of both drugs will have lithium added to their regimen. For those who fully remit during the first 12 weeks, they may continue for the second 12 weeks with the same medication.

While only the first phase of the study is designed to be randomized, both phases will be conducted under double blind with matching placebo. Medication assignments will be monitored by independent researchers so that neither the patients nor the clinicians rating patients' progress know what regimen each patient is receiving.

Meyers noted the study has presented some unique challenges in addition to the real aspect of facing potential suicide risk during treatment. The investigators are also working out monitoring schedules for metabolic changes that have been associated with olanzapine therapy. In addition, the team is assessing how to compare the phenomenology of psychotic depression in young adult patients with that of the elderly. They are keenly aware, Meyers added, of the potential overlap with schizoaffective disorder.

But the biggest challenge of all has been simply finding eligible subjects to enroll. Now 16 months into the 42-month study protocol, they have about 216 patients. The University of Toronto's Flint presented demographics on the first 77 patients enrolled, noting that they are indeed a severely ill group of patients. In the first 77, 39 younger adults were enrolled, along with 38 over the age of 60. The group as a whole averages 56 years old; 65 percent are women, and 65 percent were referred from inpatient services. The average 17-item Hamilton Depression Rating Scale score of the subjects is 31.5, and the average Brief Psychiatric Rating Scale score is 58. However, the group does not have any cognitive dysfunction, Flint noted, with an average Mini-Mental Status Exam score of 27.3.

Retention of subjects in the study over time is also a problem that concerns the researchers, Flint said. Between recruitment and signing of consent, delays can occur, especially if surrogate consent must be obtained due to questions about the subjects' own competency, yet it is unethical to delay treating the patient's illness. After consent has been obtained, it takes about four days to get a subject randomized and into study therapy.

Once treatment has begun, Flint added, the team had initially expected about one-third of all patients to drop out of the study within the first 12-week phase. So far, however, they have seen a dropout rate closer to 56 percent. Most patients, Flint said, have dropped out because of a lack of efficacy, and side effects have been a significant issue in older patients, but not in younger adult ones.

Barry Lebowitz, Ph.D., chief of the NIMH Aging Branch, noted that the difficulties inherent in the psychotic depression study are indicative of the institute's shifting focus toward studying real-world patients.

"We can now do studies that people actually care about and that have results that actually make a significant clinical difference," Lebowitz said. "But we know that when you deal with unselected patients in real settings, you are going to get real outcomes: unintended overdoses, comorbid fatalities, suicides, accidents. You have to develop proactive strategies to reduce these risks, but you know that you will not be successful all the time."

This is a remarkable study, Lebowitz emphasized, focusing on a very severe illness that has not been studied before.

"Clinicians' opinions are very fixed in this area, which unfortunately is what tends to happen when you have an absence of evidence. Here, we have an absolutely remarkable opportunity to change that."

More information on the trial can be accessed online at<www.clinicaltrials.gov/ct/show/NCT00056472?order=1>.▪