About the Author

Ronald S. Smith Ronald Stephen Smith was the author of numerous biomedical papers on the immune→brain connection, cytokines, depression, schizophrenia, psychosocial disease and headache. He was Professor of Chemistry and Nutrition at Gavilan College for many years and was also a Research Chemist at Shell Development's Biological Sciences Research Center. For the last two decades of his life, he researched the biomedical literature on immunology, neuroscience, nutrition and cardiovascular disease while lecturing nationwide in continuing education seminars for health care professionals.


Professor Smith spent 1996 and 1997 writing this book on Cytokines and Depression but died unexpectedly of an aortic aneurism in June 1997 with 9 of 11 chapters written. This website was created by his son, Brent Smith, in order to share the book and its insights with the world. The material has been left alone with almost no editing. If you have questions, comments, suggestions, or find errors in the text, please feel free to contact Brent at smithbr@gmail.com. He also enjoys hearing from people who've found these ideas helpful. The contents of this website are also available as a Kindle e-Book on Amazon.com.

What others are saying about Ronald Smith's work

"In the early 1990's a significant breakthrough was made when several research groups recognized that sickness behaviours were remarkably similar to the symptoms of depression...The first to propose explicitly that depression was driven by PI molecules was Ronald Smith in a seminal paper published in 1991."

F.R. Walker et al. Stress Nutrition and Physical Activity in Inflammatory Diseases. Chapter 15: Stress and Inflammation: An Emerging Story. p266.

"The link to depression was made in Smith’s ‘macrophage theory of depression’ in which he noted the similarities between sickness behavior and depression, and proposed specifically that IL-1 secreted by macrophages was responsible for the depression. This exciting series of proposals caught the imagination of many researchers, and has achieved folklore status."

Adrian J. Dunna, Artur H. Swiergiel, Renaud de Beaurepaire. Cytokines as mediators of depression: What can we learn from animal studies? Neuroscience & Biobehavioral Reviews 29:891-909, 2005.

"The etiology of depression is still controversial, and several theories have emerged to explain it. Taking into account the communication between the immune and central nervous systems, Smith, in the early 1990s, proposed a role for cytokines in depression. The 'cytokine theory of depression', that has been widely studied in the last two decades, proposes that enhanced production of proinflammatory cytokines is associated with the pathogenesis of depression. Indeed, several studies show a significant increase in the production of proinflammatory cytokines among depressed patients." "The 'cytokine theory of depression' has also been supported by a large set of results in animals models."

Susana Roque et al. Interleukin-10: A Key Cytokine in Depression? Cardiovascular Psychiatry and Neurology Volume 2009 (2009), Article ID 187894, 5 pages.

"The macrophage theory of depression was formulated by Smith in 1991. This hypothesis proposes that excessive secretion of macrophage cytokines such as interleukin (IL) -I, tumour necrosis factor-a (TNF-a), and interferon-a (IFN-a) are a cause of some cases of major depression. To date, there are several lines of evidence that arise from both clinical and experimental studies to support this hypothesis."

Thomas J. Connor, Brian E. Leonard. Depression, Stress, and Immunological Activation: The Role of Cytokines in Depressive Disorders. Life Sciences, Vol. 62, No. 7, pp. 583-606. 1998.

Scientific Publications of Ronald S. Smith
The Effects of Psychological Stress on Humans: Increased Production of Pro-Inflammatory Cytokines and Th1-like Response In Stress-Induced Anxiety
Michael Maes, Cai Song, Aihua Lin, Raf De Jongh, An Van Gastel, Gunter Kenis, Eugene Bosmans, Ingrid De Meester, Ina Benoy, Hugo Neels, Paul Demedts, Aleksandar Janca, Simon Scharpe, Ronald S. Smith
Cytokine, Volume 10, Issue 4, April 1998, Pages 313-318.
In Vivo Immunomodulatory Effects of Clozapine in Schizophrenia
Michael Maes, Eugene Bosmans, Gunter Kenis, Raf De Jong, Ronald S. Smith, Herbert Y. Meltzer
Schizophrenia Research, Volume 26, Issues 2-3, 29 Aug 1997, Pages 221-225.
The Effects of Psychological Stress on the Immune System in Humans
M. Maes, C. Song, A. Lin, L. Gabriels, R. De Jongh, A. Van Gastel, D. Kenis, E. Bosmans, I. De Meester, I. Benoyt, H. Neels, A. Janca, S. Scharpe, R. S. Smith
Biological Psychiatry, Volume 42, Issue 1, Supplement 1, 1 July 1997, Page 5S.
Fatty Acid Composition in Major Depression: Decreased ω3 fractions in cholesteryl esters and increased C20:4ω6/C20:5ω3 ratio in cholesteryl esters and phospholipids
Michael Maes, Ronald Smith, Armand Christophe, Paul Cosyns, Roger Desnyder, Herbert Meltzer
Journal of Affective Disorders, Volume 38, Issue 1, 26 Apr 1996, Pages 35-46.
The Monocyte-T-Lymphocyte Hypothesis of Major Depression
Michael Maes, Ronald Smith, Simon Scharpe
Psychoneuroendocrinology , Volume 20, Issue 2, 1995, Pages 111-116.
Interleukin-2 and Interleukin-6 in Schizophrenia and Mania: Effects of Neuroleptics and Mood Stabilizers
Michael Maes, Eugene Bosmans, Joseph Calabrese, Ronald Smith, Herbert Y. Meltzer
Journal of Psychiatric Research, Volume 29, Issue 2, March-April 1995, Pages 141-152.
The Macrophage-T-Lymphocyte Theory of Schizophrenia: Additional Evidence
Ronald S. Smith, Michael Maes
Medical Hypotheses, Volume 45, Issue 2, August 1995, Pages 135-141.
The Cytokine Hypotheses of Depression, Schizophrenia and Psychosomatic Disorders
Ronald S. Smith
Invited Speaker, 20th European Conference on Psychosomatic Research, August 24-27th, 1994, Gent, Belgium.
Is the increasing omega-6/omega-3 fatty acid ratio a causal factor in the epidemic of depression and violence in Western countries?
Ronald S. Smith
1st International Congress of the International Society for the Study of Fatty Acids and Lipids, Lugano, Switzerland, June 30-July 3, 1993.
A Comprehensive Macrophage-T-lymphocyte Theory of Schizophrenia
Ronald S. Smith
Medical Hypotheses, Volume 39, Issue 3, November 1992, Pages 248-257.
The Cytokine Theory of Headache
Ronald S. Smith
Medical Hypotheses, Volume 39, Issue 2, October 1992, Pages 168-174.
The Monocyte-Macrophage Theory of Depression
Ronald S. Smith
Depression Briefing 3:235-238, 1992.
The GI T-Lymphocyte Theory of Schizophrenia: Some new observations
Ronald S. Smith
Medical Hypotheses, Volume 37, Issue 1, January 1992, Pages 27-30.
Is Fish Oil Protective Against AIDS?
Ronald S. Smith
Journal of Orthomolecular Medicine 6:64-66, 1991.
The Macrophage Theory of Depression
Ronald S. Smith
Medical Hypotheses, Volume 35, Issue 4, August 1991, Pages 298-306.
Errata in Volume 36, Issue 2, October 1991, Page 178
Is Schizophrenia Caused by Excessive Production of Interleukin-2 and Interleukin-2 Receptors by Gastrointestinal Lymphocytes?
Ronald S. Smith
Medical Hypotheses, Volume 34, Issue 3, March 1991, Pages 225-229.
The Immune System is a Key Factor in the Etiology of Psychosocial Disease
Ronald S. Smith
Medical Hypotheses, Volume 34, Issue 1, January 1991, Pages 49-57.
Nutrition, Hypertension, and Cardiovascular Disease
Ronald S. Smith
The Lyncean Press 2nd Ed., 1989.
Thermal Decomposition of Tertiary Alkyl Peroxides. Substituent Effects in Peroxide Bond Homolysis and β Scission of Alkoxy Radicals
W. H. Richardson, M. B. Yelvington, A. H. Andrist, E. W. Ertley, R. S. Smith, T. D. Johnson
The Journal of Organic Chemistry 1973 38 (25), 4219-4225.
Polar and Steric Substituent Constants for an Alkylperoxy Group and Related Ether Groups
W. H. Richardson, R. S. Smith, G. Snyder, B. Anderson, G. L. Kranz
The Journal of Organic Chemistry 1972 37 (24), 3915-3919.
The Base-Catalyzed Fragmentation of a Peroxide, 2-t-Butylperoxy-2-methylpropanoic Acid
William H. Richardson, Ronald S. Smith
Journal of the American Chemical Society, 1969 91 (13), 3610-3616.
A Comparison of Peroxide and Ether Groups as Proton Acceptors in Intramolecular Hydrogen Bonding of Alcohols
William H. Richardson, Ronald S. Smith
The Journal of Organic Chemistry 1968 33 (10), 3882-3885.
A Peroxide Fragmentation Reaction
William H. Richardson, Ronald S. Smith
Journal of the American Chemical Society 1967 89 (9), 2230-2231.
A Peroxide Fragmentation Reaction and Related Studies
Ronald S. Smith
Masters Thesis. San Diego State University, 1967.