Dr. Alan Schatzberg is a renowned American psychiatrist, currently serving as the Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences at Stanford University and Director of the Stanford Mood Disorders Center. He is widely recognized for his groundbreaking research into the biology and treatment of depressive disorders.

Dr. Schatzberg reflects on early efforts in the 1980s to biologically subtype depression using markers like MHPG and cortisol. Promising findings—such as low catecholamine output predicting response to noradrenergic agents—highlighted potential, but the field has yet to produce clinically useful biomarkers. This underscores the complexity of psychiatric disorders, which are multifactorial and heterogeneous, making personalized medicine in psychiatry a persistent challenge. Even after four decades, biological psychiatry remains largely dependent on trial-and-error treatment, emphasizing the need for innovative diagnostics.

A pivotal insight discussed is the discovery that naltrexone, an opioid antagonist, blocks ketamine’s rapid antidepressant effects. This challenges the assumption that ketamine’s efficacy stems solely from NMDA receptor antagonism. The involvement of the opioid system raises concerns about addiction liability and suggests that the antidepressant “aha moment” may be partly opioid-mediated, intertwining biological and psychological processes like hope and expectation.

Dr. Schatzberg proposes that placebo responses may be mediated by endogenous opioid release, reframing them as biological phenomena rather than mere psychological artifacts. This reconceptualization has major implications for clinical trial design and understanding patient outcomes, especially with agents like ketamine and psychedelics, where expectation bias can significantly influence results.

The conversation raises safety concerns about the off-label, unsupervised use of ketamine, particularly oral formulations compounded for home use. Historical cases from China and Australia show how easy access can lead to abuse and addiction. Similarly, low-dose buprenorphine shows promise for suicidal ideation, but requires careful monitoring to avoid dependence and withdrawal. These insights highlight the need for regulatory oversight, controlled dosing protocols, and patient registries to ensure safe and effective use.

Dr. Schatzberg revisits his work with mifepristone (RU-486), a glucocorticoid receptor antagonist that showed efficacy in treating hypercortisolic psychotic depression. Though early development hurdles limited approval, ongoing research suggests potential in managing refractory diabetes linked to hypercortisolism. This illustrates how revisiting older findings can open new therapeutic avenues, especially at the intersection of endocrinology and psychiatry.

Dr. Schatzberg’s mentorship of leaders like Dr. Mark George and Dr. Nolan Williams has helped advance treatments such as TMS and neuroimaging biomarkers. His presidencies of the ACNP, Society of Biological Psychiatry, and APA reflect a rare breadth of leadership, shaping research priorities and clinical standards. His commitment to updating foundational textbooks ensures continued education for future generations.

The discussion also explores the methodological hurdles in psychedelic clinical trials, particularly the difficulty of blinding due to the drugs’ distinctive effects. Drs. Schatzberg and Gold propose combining ketamine with naltrexone to create more effective placebos that block antidepressant effects without causing dissociation—an approach that could improve trial rigor and reliability.