Through the Times With Alan F. Schatzberg, M.D.

August 1, 2005

A discussion about new depression treatments with the chairperson of Stanford University’s department of psychiatry, Alan Schatzberg, M.D.

Psychiatric Times

August 2005

Vol. XXII

Issue 9

For 30 years, Alan F. Schatzberg, M.D., chairperson of the department of psychiatry and behavioral sciences at the Stanford University School of Medicine, has sought to identify and provide effective treatments for patients with major depression. His efforts have ranged from co-founding one of the first comprehensive treatment programs for affective disorders to investigating the efficacy of the abortifacient mifepristone (RU-486) as a potential lifesaver for patients suffering from psychotic major depression.

Schatzberg received his M.D. from New York University in 1968. Fortuitously, it was a time when psychiatry was burgeoning as a field and starting to incorporate biological and pharmacological approaches, he told Psychiatric Times.

"I just was fascinated by a field that could combine psychodynamic and psychosocial perspectives with pharmacological perspectives," Schatzberg said. "Also, the brain as an organ is incredibly complex and rich in terms of the kinds of functions it controls and the complexity of people's suffering."

Schatzberg was a psychiatry resident at the Massachusetts Mental Health Center from 1969 to 1972, becoming chief resident at the Southard Clinic in 1971. He also was a clinical fellow in psychiatry at Harvard Medical School. For him, Massachusetts Mental Health Center "was one of the great places to train in the late 1960s and early '70s."

"The department was mainly psychodynamic in orientation, but it had some excellent pharmacological teaching and some terrific faculty who were doing research, as well as training. It became clear that the biological perspective was gaining momentum and was allowing for the study of behavior and the mind and the brain in ways that we didn't have before," he said. "Certain disorders seemed to be quite biologic."

"This observation that certain disorders, particularly endogenous or melancholic depression, might be heavily biologic, didn't start with me," Schatzberg added. He pointed to Sigmund Freud's book Mourning and Melancholia, in which Freud acknowledged that some forms of depression were clearly biological in nature and not really due to a variety of unconscious conflicts.

Toward the end of his residency, Schatzberg became interested in the biology and treatment of depressive disorders. After serving in the U.S. Air Force, he joined the staff at McLean Hospital and the faculty of Harvard Medical School in 1974. Joseph Schildkraut, M.D., whom Schatzberg had known at Massachusetts Mental Health Center, served as his mentor.

"With Joe being at Mass Mental Health Center and my being at McLean and my working with Jonathan Cole, [M.D.,] who is one of the great founders of psychopharmacology and was another mentor to me, we started one of the first affective disease programs in the United States in 1970s," he said. "That program included an ambulatory [and] consultative service and clinic, as well as an inpatient unit and also research and training."

The Affective Disorders Program became a vehicle for Schatzberg to conduct research in mood disorders, particularly depression. Because of his 30-year vantage point in the field, PT asked Schatzberg whether he thought the incidence and prevalence of depression were increasing.

"I think the numbers are going up," he responded, citing two factors that may increase the rates of depression.

"First of all, as people live longer and have medical conditions, a lot of these conditions have comorbid depression, even in the absence of previous depression ... You also have the issue of substance abuse, which has high rates of comorbid depression," he explained.

An expert in psychopharmacology and past president of the American College of Neuropsychopharmacology, Schatzberg has authored more than 450 publications and abstracts, including the third edition of the American Psychiatric Publishing's Textbook of Psychopharmacology with co-author Charles Nemeroff, M.D., Ph.D., and the fifth edition of the Manual of Clinical Psychopharmacology with co-authors Jonathan Cole, M.D., and Charles DeBattista, D.M.H., M.D.

He was asked about the U.S. Food and Drug Administration's direction to pharmaceutical manufacturers to add a black box warning that describes the increased risk of suicidality in children and adolescents given antidepressant medications. Emphasizing he is not a child psychiatrist, Schatzberg said, "A certain amount of prudence ought to be used when prescribing antidepressants to kids." Some of the problems linked with the administration of antidepressants to children, he explained, may be related to emerging hypomanias, manias or mixed states that are not recognized.

"If the kid needs the antidepressant bad enough--has a significant depression--then it makes sense to treat the child and to be careful," he said.

If physicians totally avoid the use of antidepressants for children, there is a risk of undertreating large numbers of people, he added.

Promising Treatments

Asked to delineate promising new treatments for depression nearing approval, Schatzberg said, "Unfortunately, there is less out there right now than one would hope."

He cited two approaches that have FDA approvable letters. One is vagus nerve stimulation being developed by Cyberonics, Inc., which the FDA earlier this year deemed approvable as an adjunctive long-term treatment of chronic or recurrent depression for adults 18 years and older. The second is the selegiline transdermal patch being developed by Somerset Pharmaceuticals, Inc., which the FDA deemed approvable in February 2004 as an acute and maintenance treatment for depression.

Vagus nerve stimulation treatment involves stimulating the left vagus nerve in the neck with a series of minuscule electrical pulses traveling through a small surgically implanted wire attached to a pulse generator in the chest.

Selegiline is a monoamine oxidase (MAO)-B inhibitor, primarily used orally as an adjunct to L-dopa and carbidopa in the treatment of Parkinson's disease. The doses required for treating depression to achieve both MAO-A and MAO-B inhibition must be much higher than those used in Parkinson's disease, and dietary interactions can occur.

When you give selegiline transdermally, Schatzberg explained, you avoid the gut, so many of the dietary problems are eliminated. Additionally, the drug has more MAO-A activity in the brain. While the transdermal delivery of the drug is safer, Schatzberg warned that it does not eliminate the need to avoid combining selegiline with such drugs as selective serotonin reuptake inhibitors.

Two other promising approaches mentioned by Schatzberg include repetitive transcranial magnetic stimulation (rTMS) being developed by Neuronetics for treating refractory depression and mifepristone, a glucocorticoid antagonist, being developed by Corcept Therapeutics, Inc., for treating psychotic major depression.

Repetitive transcranial magnetic stimulation involves the use of a noninvasive device to generate pulses of magnetic energy that stimulate neurons in the brain. Currently, it is being studied for the treatment of major depressive disorder in a 10-week, randomized, sham-controlled, multicenter trial in outpatients recruited in both academic and private research centers (see <www.clinicaltrials.gov>).

"Mifepristone is an interesting approach," Schatzberg said. For patients with psychotic depression, it appears to offer some relief from their delusions and hallucinations.

Psychotic major depression affects some 3 million people in the United States annually; currently, there are no FDA-approved treatments. People with psychotic major depression are about 70 times more likely to commit suicide than the general population and often require lengthy and expensive hospital stays, according to Corcept Therapeutics (Kurland, 2005). The company has initiated three Phase III clinical trials designed to evaluate the safety and efficacy of mifepristone for treating psychotic features of psychotic major depression. The medication has been granted FDA fast-track status for this indication. Beyond its possible use in psychotic major depression, Schatzberg said the drug is being evaluated for its use in bipolar depression and Alzheimer's disease.

Clinician, Educator, Author

Beyond his research work, Schatzberg has spent much of his career involved in clinical care and psychiatric education. In 1988, he served as clinical director of the Massachusetts Mental Health Center and professor of psychiatry at Harvard Medical School. In 1991, he moved to Stanford University to become the Kenneth T. Norris Jr. Professor and chairperson of the department of psychiatry and behavioral sciences. From 1993 to 1995, he directed the psychiatry residency training program and in 1993, the graduating residents honored him with the Best Teaching Award. That same year, Psychiatric Times' founder John Schwartz, M.D., asked Schatzberg to join the publication's editorial board. The two had gone to the same medical school. "He was one or two years behind me at NYU Medical School, so we knew each other for many years," Schatzberg said.

Schatzberg also is a member of the editorial board for the Archives of General Psychiatry, American Journal of Psychiatry and European Neuropsychopharmacology, among many others. Additionally, he is co-editor-in-chief of the Journal of Psychiatric Research and an associate editor for American Psychiatric Publishing, Inc. This year, Schatzberg won the Distinguished Service in Psychiatry Award presented by the American College of Psychiatrists.

Since assuming the role as department chair, Schatzberg has seen the department become extremely active, with a multiplicity of research projects. Schatzberg said, "We have a number of outstanding investigators doing very nice work that ties to major psychiatric illnesses."

Reference

Kurland F (2005), Corcept therapeutics initiates third phase III trial of Corlux. Available at: www.corcept.com/pressrel_05-04-2005.htm. Accessed May 11.