New Treatment Means New Hope

This article originally appeared in Pathways, a magazine published for physicians and the community by UMass Memorial Medical Center.

Delusions. Feelings of guilt and worthlessness. Paranoia. Psychomotor impairment. Suicidal preoccupation. These are some of the symptoms of psychotic depression (PD), a mental illness that is surprisingly more common than generally realized, affecting an estimated 16 to 54 percent of patients suffering from depression. Despite its prevalence, however, PD remains under-recognized, under-diagnosed and under-treated.

"Psychotic depression is difficult to treat and even harder to study," said Anthony Rothschild, MD, director of the Center for Psychopharmacologic Research and Treatment at UMass Memorial Medical Center. "It is an ‘orphan illness' in that there are no FDA-approved medications for treating it. And not many researchers in the world have made it an area of interest."  This may explain, in part, why the National Institutes of Mental Health (NIMH) has not funded a pharmacological study of PD in 20 years.

Until now.

Due in no small measure to the persistence of Dr. Rothschild and a handful of colleagues - all longstanding and renowned experts in PD - the NIMH awarded an unprecedented $1.5 million grant for a collaborative, four-site double-blind study that could define the standard of care for psychotic depression. This long-awaited clinical trial will compare two promising medication treatments for PD: the antipsychotic olanzapine (trade name Zyprexa®) alone and in combination with the antidepressant sertraline (trade name Zoloft®). The trial will further compare the response rates and side effects between older and younger PD patients. In addition to UMass Memorial and UMass Medical School, the other sites involved in the study are Cornell University in New York, the University of Pittsburgh and the University of Toronto.

Why has PD been ignored for so long? "It has always been difficult to treat," explained Dr. Rothschild. "Other forms of depression are highly responsive to medications and psychotherapeutic intervention. But psychotherapy does not work well with PD, and antidepressants do not address psychotic symptoms. There simply has been a tendency to focus on the forms of depression that are more easily treated; that is where the progress in drug research and development has been made.

"PD can be treated," Dr. Rothschild said, noting that electroconvulsive therapy (ECT) is often successful. "But ECT is not for everyone, and it is not as readily accessible as medications. This is why it is so important for us to explore treatment with medications."

Dr. Rothschild points out that diagnosing PD also presents a significant challenge, even to specialists. "Psychosis is not always apparent," he said. "With schizophrenia or bipolar disorder, it is frequently clear that the person is out of touch with reality. But this is not the case with PD; the delusions are not wildly bizarre. For example, a patient may believe he is dying of cancer, but unless you know that he does not have cancer, the delusion is seemingly plausible. Add to the situation a patient who is somewhat paranoid, depressed and withdrawn, and not forthcoming about symptoms, and you can easily miss the psychotic dimension of it."

Part of the issue is that PD remains a subclassification of major depression in the Diagnostic and Statistical Manual of Mental Disorders (DSM). In 1992, Dr. Rothschild and Stanford University Professor Alan Schatzberg, MD, published a paper in the American Journal of Psychiatry arguing that PD should have its own diagnostic category in the DSM. "We believed that there was enough scientific evidence to do so," Dr. Rothschild said. "And we also hoped that if the PD profile were raised, it would help clinicians to be more aware of the diagnosis, and the pharmaceutical industry would be more interested in researching and developing medications to treat it. Now, 13 years later, there is even more evidence to support our recommendation, and I am confident that when DSM-V comes out - still six years away - PD will have its own diagnostic category.

"Psychotic depression is a very serious illness," he emphasized, underscoring the need for increased awareness and treatment of the disorder. "The suicide rate among people with PD is very high." Dr. Rothschild noted that PD can occur as part of postpartum depression, and was a likely culprit in the high-profile case in which a Texas mother killed her children.

The prevalence of PD among the elderly also is cause for vigilance. Depression in this patient population is often missed. Many of the symptoms of depression can be mistaken for what many people think of as a natural response to aging; it also can present as pseudo-dementia. I would urge the primary care and geriatric community to be alert to the possibility of depression, and PD in particular, in elderly patients.

"We are still enrolling patients in the NIMH study and encourage the medical community to refer patients they think may be appropriate to participate," noted Dr. Rothschild. "Suspicion should be raised if any severely depressed patient also has agitation and psychomotor retardation. PD patients also exhibit guilt and paranoia. Listen for cues such as ‘My thoughts aren't quite right.' And in older people, we see somatic complaints such as changes in sleep patterns and appetite, fatigue, and muscular aches and pains.

"We provide a free consultation to determine if the patient is a candidate for the study," he added. "We also give a thorough diagnostic and physical evaluation to all participants." Subjects must be at least 18 years old; health insurance is not required.

The study protocol calls for subjects to take olanzapine either alone or in combination with sertraline for an initial 12-week acute phase. Those who respond completely, with cessation of both depression and delusions, are asked to continue their medication for another 12-week stabilization phase. For those who respond only partially, another medication is added in the second 12 weeks: sertraline for those on olanzapine alone, and lithium for those already on olanzapine with sertraline.

This study represents a significant step forward in the diagnosis and treatment of PD. The last time the NIMH funded a major PD study was in the 1980s. In the meantime, new classes of antidepressant and antipsychotic drugs have been introduced, but there has been no systematic effort to determine what constitutes state-of-the-art treatment for psychotic depression. Until now.