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In Memoriam: George K. Aghajanian, MD

July 07, 2023

The Department of Psychiatry sadly shares the news of the death of George K. Aghajanian, MD, at the age of 91 on July 4, 2023. At the time of his death, Dr. Aghajanian was the Foundations Fund Professor Emeritus of Psychiatry. George was one of the founding pioneers of modern psychiatric neuroscience and one of the most important leaders and mentors in the history of our department.

George’s early life was shaped by the Armenian Holocaust, which took the lives of many of his relatives. His family fled to the United States, where his father established a business that involved international trade. As a result, George was born in Beirut, Lebanon, although his family soon returned to the United States.

At Yale Medical School, George set the stage for the rest of his career. He worked closely with Dr. Daniel X. Freedman on the psychopharmacology of psychedelic drugs, publishing his first paper in Science on this topic in 1958. After completing Psychiatry Residency at Yale and two years of service in the Army Medical Corps, he returned to Yale as an assistant professor in 1965.

George and his collaborators generated foundational insights into the biogenic amine signaling and psychopharmacology. This process was greatly facilitated by the donation of an electron microscope to support his research, by a friend and residency classmate. Particularly in collaboration with Dr. Floyd Bloom (later editor of Science), he characterized the subcellular localization of monoamines and the effects of pharmacologic agents on their disposition. This work led to pioneering physiological studies. George and his collaborators, including Drs. Benjamin Bunney, Robert Roth, and Michael Sheard were the first to record the activity of brain serotonin neurons (1968), norepinephrine (locus coeruleus) neurons (1971), and dopamine neurons (1973). Later, George’s laboratory would be the first to “patch clamp” brain monoamine neurons.

By combining analyses of cell biology, biochemistry, electrophysiology, pharmacology, and behavior, George created one of the most impactful laboratories of his era. In so doing, he provided the foundation for countless translational neuroscience advances for Yale psychiatry, fueling its emergence as one of the world leaders in this area of research. Below we highlight just a few key contributions in which George played a critical role:

The first psychopharmacologic treatment in psychiatry discovered through mechanistic translational neuroscience. In 1978, George showed that noradrenergic neurons tolerant to morphine exhibited withdrawal-related hyperactivity suppressed by the alpha-2 adrenergic agonist, clonidine. This led Drs. Mark Gold, Redmond, and Herbert Kleber conducting trials showing that clonidine was the first non-opiate to treat the human opiate withdrawal syndrome. In 2018, a drug related to clonidine, lofexidine, would receive FDA approval for this indication.

Insights into the rapid antidepressant effects of ketamine. In 1970, George began producing fundamental insights into the mechanisms through which monoamine antidepressants affected brain circuits. This elegant work provided the foundation for many novel clinical trials on the Clinical Neuroscience Research Unit conducted by Drs. Heninger, Charney, Price, Delgado, Berman, and others. Forty years later, George collaborated with the late Dr. Ronald Duman on a study that profoundly changed our understanding of antidepressant effects on brain function. The antidepressant effects of ketamine had been identified at Yale in the late 1990s. However, a decade later, we still had little insight into how it produced these rapid effects. Using multiphoton imaging, George showed that stress-related reductions in dendritic spines in rodents could be reversed 24 hours after a single dose of ketamine. The robustness and rapidity of the ability of ketamine to restore brain structural connectivity was not anticipated and it had a profound effect on neuroscience and on quieting skepticism related to ketamine efficacy. Remarkably, although published at age 78, this has become George’s most highly cited paper. It serves as a reminder of the scientific vitality that he maintained up to the end of his career.

Psychedelics redux. Psychiatry has rediscovered psychedelics and there are many large-scale efforts devoted to optimizing their use in the treatment of psychiatric disorders. George studied these drugs in the very early days of this research. He identified the first neural signature of psychedelic drugs on brain activity. In 1979, he identified a second effect of psychedelics on brain function, activation of the facial motor nucleus by 5-methoxy-DMT. This was the first neural signature of a psychedelic acting at the serotonin-2A receptor, i.e., their primary brain target. He and his collaborators, such as Drs. Gerard Marek, Evelyn Lambe, and Michael Rogawski illuminated many more aspects of the actions of psychedelic drugs, such as how they activate cortical networks – a key step in their putative therapeutic effects. While many of George’s trainees have remained in academia, several of them, such as Drs. Marek, Kurt Rasmussen, and Jeffrey Sprouse are pursuing the development of psychedelic therapeutics in the biotechnology/pharmaceutical industry.

George was incredibly humble. Nonetheless, he received many of the highest accolades of his field. He was a member of the National Academy of Medicine. The ACNP awarded him the Daniel Efron Prize for his research and the Julius Axelrod Prize for his mentorship. George received the Scheele Medal of the Swedish Academy of Pharmacy, the Hillarp Award from the International Amine Group, and the Hoffheimer Prize from the American Psychiatric Association. The Brain and Behavior Research Foundation awarded him the Lieber Prize for Schizophrenia Research, the highest award in this area. And, of course, the Heffter Research Institute which focuses on psychedelics, gave him their Basic Research Award.

George had an enormous impact on the department that went beyond his research. He was brilliant, exacting, rigorous, generous, and ethical. He held himself and everyone around him to the highest standards. He was one of two spiritual leaders, with George Heninger, of neuroscience research in psychiatry for at least four decades. We celebrated their leadership in 2014. George led a very healthy and balanced life. He was devoted to his family and he was a passionate golfer. He approached golf with the same dedication, rigor, and precision that he approached electrophysiology.

George's life was enriched by the love and support of his family. He is survived by his wife of 64 years, Anne; his four children, Michael, Andrew, Carol, and Laura; daughters-in-law Melinda and Lynn; and his son-in-law Rand David. George embraced his role as a grandfather. He leaves behind eight grandchildren, Jeremy, William, Ben, Madeline, Jonah, Audra, Ella, and Aliza, who brought him joy and filled his life with love and laughter. In addition to his immediate family, he is survived by his nephew Alan Kurkjian and his cousin Robert Abdalian. He provided wisdom to each of them, imparted valuable life lessons and leaves behind memories that will be treasured for generations to come.

Like all who worked with him, we (co-authors) miss George and we are deeply grateful to him for his mentorship. We learned so much from him; not just what he knew but how he pursued science. When meeting with him, he would often open a drawer, pick out a well-marked paper, and refer to an obscure but revealing sentence in the discussion. We were inspired by his passion for science. George welcomed us into his world and maintained his focus on identifying mechanism. This focus on mechanism became deeply engrained in us and perhaps even his family. At his 90th birthday party, his eight grandchildren got together and proclaimed, “it’s all about the mechanism.”

George’s family will be holding a memorial service at the Guilford Funeral Home on July 15, 2023. We plan to have a departmental celebration of his career in the upcoming year.

Prepared by:
John H. Krystal, MD
Marina Picciotto, PhD
Eric J. Nestler, MD, PhD

Submitted by Christopher Gardner on July 07, 2023