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Friday, 24.03.2017

Comment (Andrew Winokur)

Dr. Shorter has provided a fascinating historical journey through the origins of work in the field of “endocrine psychiatry”, as well as providing some candid observations on the current lack of stature that the field holds in contemporary psychiatric research.  As an individual who entered the field in the mid-1970’s and became substantively engaged in research in the area of psychoneuroendocrinology, this commentator was strongly influenced and inspired by many investigators who had already provided substantial contributions to the field.  Names that come readily to mind as leading psychoneuroendocrine researchers of that era include Carroll, Mason, McEwen, Rose, Rubin, Sachar, Stokes, Weitzman and Wurtman, among many others.  While I had thought that I had a decent knowledge of the background to work in this field, Dr. Shorter’s historical overview provided me with an introduction to the contributions of true pioneers, such as Maxime Laignel Lavastine, who he describes as the true founder of scientific  neuroendocrinology, and many others  Thus, Dr. Shorter’s exceptional scholarship with regard to the history of this area provided a wonderful education for this reader.

Dr. Shorter shares some opinions about the fall in stature of the field of endocrine psychiatry.   To cite two examples from his piece: “Today, to the extent that ‘psychiatric endocrinology’ exists, it is placed well on the back burner of the field”, and “Unfortunately, the opposite happened: endocrine approaches went downhill, essentially vanishing from psychiatry by the 1990’s”.   There are valid reasons to emphasize disappointment in how the field has evolved, and the apparent lack of tangible payoffs in terms of new diagnostic applications or therapeutic interventions based on developments in endocrine psychiatric research.  It should also be noted that Dr. Shorter does conclude his essay with a section entitled “Sprigs of Hope”.  Nevertheless, to this commentator, there are more reasons to emphasize the positive contributions of the field of psychoneuroendocrinology over the past 50 plus years, as well as to see a basis for anticipating further contributions to basic science and to improved care of psychiatric patients in the years to come growing out of further research developments in this area.

The aspect of endocrine psychiatry or psychoneuroendocrinology that I would like to highlight relates to  advances in understanding of interrelationships between endocrine function and CNS activity that have implications for behavior, for providing insights to the pathophysiological mechanisms of psychiatric disorders and for the development of novel therapeutic interventions.  In the early part of the 20th Century, the anterior pituitary gland was viewed as the “Master Gland” that orchestrated and coordinated the functioning of the entire endocrine system (Krieger, 1980).  Gradually, evidence became available indicating that the hypothalamus played an important role in the regulation of endocrine function, but it took an intensive 25 year research effort on the part of Guillemin’s group  In  Houston and Schally’s group in New Orleans to accomplish the initial isolation and characterization of a group of peptide compounds referred to as the hypothalamic releasing hormones, monumental work that led to these two investigators being awarded the Nobel Prize in 1977 (Guilimen, 1980). This paradigm shifting work established the existence of compounds that were synthesized in typical CNS neurons, but were released into a vascular system (the portal vessel) to pass, in the manner of other hormones, to distant sites where they acted on receptors on anterior pituitary cells to stimulate, or in some cases, inhibit the release of anterior pituitary hormones.  Distinctions between what was a hormone and what was a neurotransmitter/neuromodulator started to become obscure.  Many additional examples of the extraordinary degree of integration across neurotransmitter and hormonal function were rapidly identified.  In work by Pfaff, McEwen and others, peripheral hormones such as gonadal steroids and glucocorticoids were demonstrated to have receptors located in the CNS, including in the hypothalamus and in other brain regions such as the hippocampus.  Thus, the brain was identified as a site of action for peripheral hormones, and effects of various hormones on CNS neurotransmitter activity were identified (McEwen, 1980).  Peptides initially identified as hypothalamic releasing hormones were soon demonstrated to be present in many regions of brain and spinal cord, as well as in peripheral structures in some cases (Krieger et al., 1983).  “Dale’s Principle” of one neuron-one neurotransmitter had to be revised with the demonstration of the co-localization of monoamine and neuropeptide substances (Burnstock, 2004).  Moreover, studies demonstrated that a monoamine neurotransmitter might be released at a lower level of neuronal activity in some cases, while a co-localized peptide compound might be released from the same neuron at a more rapid rate of neuronal firing (Bradley et al., 2002).  The hypothalamic releasing hormones were demonstrated to be under regulatory  control by various monoamine neurotransmitters, providing some of the rationale for the use of “the hypothalamus as a window into the brain” as an approach to gain inferential evidence in support of the monoamine theories of mood disorders (Sachar et al/. 1976).  The explosion of work on  peptides in the CNS extended far beyond the hypothalamic releasing hormones to also include dozens of other peptide compounds that were shown to be present in brain tissue and to be associated with a wide array of neurophysiological and behavioral effects.  Included among these neuropeptide compounds were the endogenous opiates, the “gut and brain” peptides and the recently identified orexins, which were originally identified just over a decade ago, and have already been demonstrated to be implicated in the pathophysiology of narcolepsy as well as to represent a promising target for therapeutic intervention (Reisine, 1993, Sakurai, 2007).  Finally, significant advances in the field of psychoneuroimmunology include a direct linkage to neuroendocrine mechanisms, and work in this area has been proposed to be of potential relevance to the pathophysiology and treatment of mood disorders (Miller et al., 2009).

The list provided in this brief commentary represents only a partial accounting of scientific advances that have emerged from research spanning at least 5 decades that provides new insights to the interrelationships between the endocrine system, brain function, behavior and psychiatric disorders.  I believe that this impressive foundation of basic science knowledge offers significant potential to contribute to important new insights about pathophysiological alterations related to a variety of psychiatric disorders as well as to open new avenues for novel therapeutic interventions.


Bradley, E, Law, A, Bell, D, Johnson, CD, Effects of varying impulse number on cotransmitter contributions to sympathetic vasoconstriction in rat tail artery. Am J Physiol Heart Circ Physiol 2003, 284:H2007-H2014

Burnstock, G, Cotransmission, Curr Opin Pharmacol 2004, 4:47-52

Guillemin, R, Hypothalamic hormones: Releasing and inhibiting factors.  In: Krieger, DT and Hughes, JC (eds.), Neuroendocrinology, HP Publishing Co., Inc, NY, 1980, pp. 23-32

Krieger,DT,  The hypothalamus and neuroendocrinology.  In: Krieger, DT. and Hughes, JC (eds.) Neuroendocrinology, HP Publishing Co., Inc. NY, 1980, pp. 3-12.

Krieger, DT, Brownstein, MJ, Martin, JD, (eds) Brain Peptides, John Wiley & Son, NY, 1983

McEwen, BS, The brain as a target of endocrine hormones, In: Krieger, DT and Hughes, JC (eds), Neuroendocrinology, HP Publishing Co, Inc, NY 1980, pp 33-43

Miller  AH, Maletic, V, Raison, CL, Inflammation and it discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009, 65: 732-741

Reisine, TD, Syaptic transmission: Peptides, In: Frazer, A, Molinoff, PB, Winokur, A (eds), Biological Bases of Brain Function and Disease, Raven Press, NY, 1993, pp 127-141

Sachar, EJ, Gruen, PH, Altman, N, Halpern, FS, Frantz, AG, Use of neuroendocrine techniques in psychophyarmacological research. In: Sachar, EJ (ed), Hormones, Behavior and Psychopathology. Raven Press, NY, 1976, pp 161-176

Sakurai, T, The neural cirtcuit of orexin (hypocretin): maintaining sleep and wakefulness. Nature Rev/Neuroscience 2007, 8:171-181

Andrew Winokur
August 29, 2013.