Ross J. Baldessarini, MD: Celebrating a Pioneer

Ross J. Baldessarini, MD, originally thought he wanted to be an industrial organic chemist, not a doctor.

The prospect of medical school didn’t thrill the Williams College chemistry major. He found it to be more like a trade school than an academic endeavor, not to mention it being “cutthroat and nasty.” But after a company he worked for one summer laid off 80% of its scientists following a corporate acquisition, he decided to rethink his future.

That decision took him to the Johns Hopkins University School of Medicine and a physiology course taught by neuroscientist Vernon B. Mountcastle, which led to a career that has included groundbreaking work in psychopharmacology (psychiatric medications) and looking at the molecules and chemistry of bipolar disorder.

Mountcastle asked the Western Massachusetts native to work in his neurophysiology lab after what he felt was an impressive delivery of an in-class lecture. That led to the National Institutes of Health (NIH), an internship at the former Boston City Hospital, a stint with the Public Health Service, and then back to Johns Hopkins for clinical training in psychiatry.

So, when Seymour S. Kety, a mentor at NIH and Johns Hopkins, was looking for someone to help him establish the Laboratories for Psychiatric Research (LPR) at Massachusetts General Hospital in 1969, Baldessarini signed on. He took on the director’s role following Kety’s retirement—and the LPR’s move to McLean Hospital in 1977.

“I was in the right place for all the wrong reasons,” he said recently from his office in the Mailman Research Center on McLean’s Belmont campus, a structure he helped to design after the lab was lured from Boston.

In addition to his research tasks, he took on the challenge of teaching psychopharmacology, which at that time was so fledging a specialty there were no textbooks. After relying on a colleague’s very scholarly text, he took it upon himself to write one of his own—on a regular subway ride from Newton.

“I scribbled and scribbled on yellow legal pads for a year, and at the end of it, a textbook popped out,” he said. Following the commute, the bulk of his day was spent in the lab, working to figure out the rules by which nerve terminals took up, stored, and released neurotransmitters, important to understanding the clinical effect of psychotropic drugs on psychiatric diseases.

Bipolar disorder is characterized by unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks. Although first described in AD 150 by the Greco-Roman physician Aretaeus, bipolar disorder didn’t make its way into the Diagnostic and Statistical Manual of Mental Disorders until the third edition in 1980.

Yet, said Baldessarini, bipolar disorder “is about as a close to a disease as we have in psychiatry. It has the genetics, it has very stereotyped clinical presentations, it has unique treatments that don’t work in other conditions.”

While studying the pharmacology of neurotransmitters in bipolar disorder, he and his lab zeroed in on the biochemical causes of a widely recognized phenomenon—a high risk of relapse after stopping psychotropic medication.

Case reports showed disease could return within weeks, rather than a more common one-year cycle. The findings were extended to the impact of stopping antipsychotic drugs such as sedatives and antidepressants. The studies determined the optimal time to wean a patient off psychotropic drugs with minimal impact was two weeks.

Since closing the lab a decade ago after turning 70, Baldessarini has taken a more clinical approach to his research, looking for clues that may foretell how a patient’s illness may progress. For example, someone whose first episode involves depression is likely to experience that as the “predominate polarity,” as opposed to someone whose first incident is mania.

He has also focused on “mixed features,” in which a person can be both manic and depressed at the same time. This pattern was first recognized by Aretaeus, but not really studied until taken up by German psychiatrists Emil Kraepelin and Wilhelm Weygandt in the late 1890s.

Today, mixed features are recognized in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM- 5), and Baldessarini is looking at data that shows clinical outcomes, including higher suicide rates, are worse in mixed feature cases than in more traditional cases. That has led to new treatments that use “soothing agents,” like anticonvulsants and antipsychotic drugs, rather than antidepressants.

“We are at the beginning of a new era of subtyping of mood disorders for prognostic purposes, for better clinical care, to try to prevent suicide, and finally work out how to treat these people better,” he said.

The current work reflects the constant progression of his career, to finding pathways to better understand diseases to be better able to treat them. Not bad for someone who didn’t want to be a doctor.