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Prof. Jerrold F. Rosenbaum

 

Jerrold F. Rosenbaum  Controversias Psiquiatria Barcelona
Talk Is a better antidepressant the answer?: the future of antidepressant pharmacotherapy beyond the monoamines
Date Friday, April 21st, 2017
Time 15:00 - 15:45

 
BIOGRAPHY

A graduate of Yale College, Yale University School of Medicine and Psychiatric Residency at the Massachusetts General Hospital, Dr. Rosenbaum chairs the Department of Psychiatry at Massachusetts General Hospital, Harvard Medical School, comprising over 600 clinicians and researchers, and 150 trainees, ranked by U.S. News and World Report as the #1 Department of Psychiatry in the United States in 2016 and for 18 of the last 21 years, with 50 specialty clinical and research programs and over 50 million dollars of annual research spending. At MGH, the US's largest hospital based research institution, with over 800 million dollars of annual research funding, he served as Chair of the Executive Committee on Research. He specializes in mood and anxiety disorders. The 2007 recipient of the C. Charles Burlingame Award for lifetime achievement in psychiatric research and education, he is the 2016 recipient of the Dean's Leadership Award for the Advancement of Women Faculty for Harvard Medical School. He served as President and the Chairman of the Board of the Anxiety and Depression Association of America (ADAA) and is Chair of the Scientific Council and on the Board of the American Foundation for Suicide Prevention. He also serves on the Board of Trustees of the Massachusetts General Hospital and on the Board of Trustees of the Partners Healthcare System. He is co-founder of PsyBrain, an early phase discovery company of novel drugs and diagnostics for psychiatric and related disorders. Dr. Rosenbaum has authored more than 400 original articles and reviews and has published 20 books. In addition to treatment resistant depression, a focus has been longitudinal studies of children at risk for anxiety disorders and depression, which examine behavioral differences, risk factors, longitudinal outcomes, treatment, genetics, and brain structure and function of children of parents with mood and anxiety disorders.

 
ABSTRACT

Systematic longitudinal assessment of the efficacy of currently available antidepressants indicate that these agents are only modestly efficacious with respect to short-term and sustained remission of depressive symptoms. Reflecting on the current antidepressant pharmacopoeia, relying heavily on agents whose initial mechanism of action involves the perturbation of homeostatic functioning of monoaminergic systems, experienced clinicians typically assert, despite evidence to the contrary, that with enough time and trials, most depressed patients meaningfully improve. The art of practice often focuses on what is termed "treatment resistant depression" although it would be more apt to say the treatments fail the patients than that the patients are resistant. The array of strategies including alternative treatments, psychotherapies, novel agents, devices, exercise and nutritional substances already suggest that there are other paths to relieving depression than simply influencing the transmission of monoamines such as serotonin, norepinephrine and dopamine.

The challenge ahead is not merely one of choosing plausible targets for drug development, of which there are many, but rather the challenge inherent in forcing a heterogeneous population of patients with diverse etiology, distinct phenotypes, and evidently disparate biologies into a single diagnosis, major depressive disorder (MDD) for study. That complexity, when married with a broken or at times corrupt clinical trial industry, renders the ability to define sub-groups who respond to specific agents and agents that might have usefulness for a sub-group barely remotely possible. It may be time to revert back to small sample or even intense studies of individuals and "N of 1" trials for early stage discovery. The potential in this regard of intense focus on individuals combining genetics and imaging holds promise. Once we have valid approaches to define sub-groups, we may find that some of our previously failed novel treatments (e.g. neurokinins) that dropped by the wayside, may, like the early fate of the cancer drug Iressa, rebound to be of use in sub-populations of what we now lump together as MDD.

There are many pathways to consider in exploring next generation treatments: novel targets, networks and pathways, and as always intense efforts to repurpose potentially effective medications with other current indications and "reverse engineering" to discover mechanisms.

Among promising potential approaches for future pharmacological therapeutics are continued focus on agents that alter brain plasticity or induce neurogenesis, treatments that decrease inflammation or target microglia, or the array of strategies to enhance bioenergetics and mitochondrial energy metabolism. Direct influences to circuits and networks with devices that use magnetic fields, ultrasound, or light in addition to closed loop implantables hold further promise for the future of antidepressant treatment.

 
REFERENCES

[web] Hyde CL, et al. (2016). Identification of 15 genetic loci associated with risk of major depression in individuals of European descent, Nature Genetics 48 1031–1036, 2016

[web] Ionescu DF, Rosenbaum JF, et al. (2015). Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015 Jun;17(2):111-26.

[web] Smoller JW, et al. (2014). The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function. Biol Psychiatry. 2014 Dec 1;76)11):902-10.

Gelenberg AJ, et al. (2008). The history and current state of antidepressant clinical trial design: a call to action for proof-of-concept studies. J Clin Psychiatry 2008;Dec;69(10):1513-28.

[web] Perlis RH, et al. (2008). Phenotype Genotype Project on Addiction and Mood Disorders. Association of a polymorphism near CREB1 with differential aversion processing in the insula of healthy participants. Arch Gen Psychiatry 2008;Aug;65(8):882-92.

[PDF] Smoller JW, et al. (2008). Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch Gen Psychiatry 2008;65(3):298-308.

Fava M, et al. (2003). Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatric Clin N Am 2003;26(2):457-494.