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
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
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>.▪