DEPRESSION AND ANXIETY 30:285–287 (2013)

The Cutting Edge

PSYCHONEUROIMMUNOENDOCRINOLOGY: THE
BIOLOGICAL BASIS OF MIND–BODY PHYSIOLOGY AND
PATHOPHYSIOLOGY
Charles B. Nemeroff, M.D., Ph.D. is the Leonard M. Miller Professor and Chairman of
the Department of Psychiatry and Behavioral Sciences and Director of the Center on Aging
at the University of Miami Miller School of Medicine in Miami, Florida. He received his
M.D. and Ph.D. (Neurobiology) degrees from the University of North Carolina (UNC)
School of Medicine in Chapel Hill, North Carolina. After psychiatry residency training
at UNC and Duke University, he held faculty positions at Duke University and Emory
University before relocating to the University of Miami in 2009. He has served as President
of the American College of Psychiatrists (ACP) and the American College of Neuropsy-
chopharmacology and sits on the Scientific Advisory Board and Board of Directors of the
American Foundation for Suicide Prevention and the Anxiety and Depression Association
of America. He has received a number of research and education awards including the
Kempf Award in Psychobiology, the Samuel Hibbs Award, Research Mentoring Award,
Judson Marmor Award and the Vestermark Award from the American Psychiatric Associ-
ation (APA), and the Mood Disorders Award, Bowis Award, and Dean Award from the ACP. He was elected to the
Institute of Medicine of the National Academy of Sciences in 2002. His research has focused on the pathophysiology
of mood and anxiety disorders with a focus on the role of child abuse and neglect as a major risk factor. He has also
focused on the role of mood disorders as a risk factor for major medical disorders including heart disease, diabetes,
and cancer. He has served on the Mental Health Advisory Council of NIMH and the Biomedical Research Council
for NASA. He is the co-editor in chief of the Textbook of Psychopharmacology, published by the APA, now in its 4th
edition. His research is currently supported by grants from the NIH.

“What we feel and think and are is to a great extent
determined by the state of our ductless glands and
viscera.” —Aldous Huxley
This neologism I created for the title of this essay,
psychoneuroimmunoendocrinology, encompasses the
major disciplines that we now know serve as the ma-
jor communication systems in mammalian organisms—
the endocrine, nervous, and immune systems. Together
with input from psychological processes, these complex
networks communicate with each other monitoring and
regulating a variety of internal physiological functions,
as well as vigilantly guarding against internal and exter-
nal threats. Although now considered virtually elemen-
tary by even beginning medical and graduate students,
the notion that crosstalk between these systems occurs
on a regular basis and contributes to disease vulnera-
bility was not largely accepted by leaders in our field
even as recently as a few decades ago. The manuscripts
that comprise this special issue of Depression and Anxiety,
based on two symposia (The Interface Between Anxi-
ety and Medical Disorders, and Integrating Mind–Body
Connections) that were presented at the 2012 Annual
Meeting of the Anxiety and Depression Association of
America (ADAA), represent examples of some of the
cutting-edge research in this now burgeoning area. As
requested by the Editor-in-Chief, I have attempted to
combine the content of these reports with some of my
own small contributions to this discipline to highlight
the important role this field plays in the development of
what is now called “personalized medicine.”
I will briefly focus on three of my research areas: the
effects of depression on both risk for cardiovascular dis-
ease (CVD) and its untoward effects on disease outcome,
the effects of depression on cancer progression, and fi-
nally the effects of child abuse and neglect on risk for
medical and psychiatric disorders in adulthood. Each of
these research programs is emblematic of the interac-
tion of behavioral factors with the nervous, endocrine,
and immune systems. Space constraints preclude a com-
prehensive discussion of these complex multidisciplinary
research areas and references are provided for the more
interested readers. None of this work of mine could have
possibly been launched without three major factors—the
∗ Correspondence to: Charles B. Nemeroff, Leonard M. Miller
Professor and Chairman, Department of Psychiatry and Behav-
ioral Sciences, Director, Center on Aging, University of Miami
Leonard M. Miller School of Medicine, Miami, FL 33136. E-mail:
cnemeroff@med.miami.edu
DOI 10.1002/da.22110
Published online in Wiley Online Library (wileyonlinelibrary.com).


C 2013 Wiley Periodicals, Inc.
286 Nemeroff
phenomenal mentoring provided by my Ph.D. mentor
and then lifelong friend, Arthur J. Prange, Jr., M.D.,
Professor of Psychiatry at the University of North Car-
olina; a remarkable cadre of industrious and bright doc-
toral students, fellows, junior and senior colleagues, too
numerous to list here; and NIH and foundation funding
for the research.
Depression has conclusively been demonstrated to
increase risk for, and to predict poor outcome of, CVD.
Factors that have been demonstrated to contribute to
these observations include (1) platelet clotting cascade
dysfunction leading to an increased likelihood of throm-
bus formation; (2) increased inflammation as assessed
by increased inflammatory cytokines and C-reactive
protein (CRP); (3) reduced heart rate variability, a
measure of central nervous system (CNS) control of
cardiac function; (4) increased hypothalamic-pituitary-
adrenal (HPA) axis activity; (5)decreased circulating
endothelial precursor cells; (6) reduced physical ac-
tivity and increased substance/tobacco/alcohol abuse.
These and other cognate findings have been recently
summarized.[1]
There are now much data to suggest that depres-
sion worsens the course of breast cancer and perhaps
other cancers; likewise, depression treatment may help
improve cancer outcomes. Many of the biological find-
ings in depression noted above in the discussion of heart
disease have also been posited to mediate the untoward
effects of depression on cancer progression and this field
has been reviewed.[2]
For the past 25 years, I have focused much of my re-
search efforts on elucidating the biological mechanisms
by which child abuse and neglect increase risk for mood
and anxiety disorders, and a variety of other medical
disorders including CVD, obesity, and diabetes, as well.
This rapidly expanding database has been reviewed
recently.[3] Early-life trauma acts upon the developing
CNS to produce structural alterations (hippocampus
and cortical regions) associated with specific psychiatric
symptoms (deficits in executive function, memory, and
emotional and sensory processing), altered functional
brain imaging responses to provocative emotional stim-
uli, as well as persistent alterations in a variety of brain
neurotransmitter systems including the corticotropin-
releasing factor (CRF), serotonin, and dopamine
circuits.[4–7] Long-term effects of child maltreatment
on immune mechanisms have been documented. One
series of exciting findings has been the identification
of specific genetic polymorphisms that mediate the
depressogenic (e.g., CRF R1 , Brain derived neurotropic
factor (BDNF), and 5HT3 ) and anxiogenic (FKBP5 and
PAC1) effects of early-life stress on psychiatric disease
vulnerability, and more recently epigenetic mechanisms
have been shown to play a seminal role in this process
by our group and others.[8–12]
In this special issue of Depression and Anxiety, three of
the reports focus on the emerging role of inflammation
as one of the critical mediators at the interface of stress
and depression on their effect on vulnerability to a
Depression and Anxiety
variety of serious medical disorders including heart
disease, diabetes, and other disorders of aging. One
of the pioneers in this field, Janice Kiecolt-Glaser, is
represented by the report by her group summarizing
this rapidly expanding field.[13] They emphasize the
bidirectional nature of the depression–inflammation
relationship: Depression has repeatedly been associated
with increased markers of inflammation, especially
inflammatory cytokines and inflammation, in both
preclinical laboratory animal and clinical studies, is
depressogenic. They also remind us that there are con-
siderable data to suggest that, in many ways, depression
can be considered a biological stress response run amok.
Andrew Miller et al.[14] described their elegant system-
atic mechanistic studies that have sought to determine
the CNS substrates upon which inflammation acts to
produce its anxiogenic and depressogenic effects. This
group has pioneered studies demonstrating that cytokine
signaling pathways, including p38 mitogen-activated
protein (MAP) kinase exert effects on glutamate,
dopamine, and serotonin-containing neural circuits
that mediate, in part, the CNS effects of inflammation.
The shunting of tryptophan toward the kynurenine
pathways contributes to serotonin depletion, as well as
effects on other neurotransmitter systems. They also
describe two additional lynchpins of the inflammatory
hypothesis of depression, namely the well-documented
increase in depression in patients who were admin-
istered interferon-α for the treatment of malignant
melanoma and hepatitis C,[15] which produces a robust
inflammatory response, and the findings that certain
drugs that inhibit the inflammatory response possess
antidepressant properties. The data here are admittedly
scant, but their recent pilot study with the TNFα an-
tagonist infliximab revealed clear antidepressant effects
in depressed patients with elevated CRP levels.[16]
Finally, as regards inflammation is the contribution
by O’Donovan et al.[17] who confirmed the findings of
our group and others of elevated IL-6 levels in major
depression and provided novel data on elevations in IL-
10 levels, as well. Moreover and most importantly, de-
pressed patients with high suicidal ideation had signifi-
cantly higher IL-6 and CRP levels, a finding independent
of a number of demographic and clinical factors includ-
ing depression severity. It would have been of interest
to obtain early life trauma data on this sample in view of
our work and that of Pariente and colleagues[18] on the
sustained inflammatory response to such untoward life
events.
The remaining four manuscripts comprising this
issue are all thematically linked to the mind–body
relationship. Paulus[19] provides a thoughtful and
thought-provoking discussion of a long neglected
area—the brain’s control of the inner workings of the
body, interoception, and how emotional states impact
this process. He focused on the poorly understood and
fascinating interplay between breathing and anxiety.
His review of the physiology of respiration and its
alterations in anxiety states is comprehensive and very
 The Cutting Edge: Mind–Body Physiology and Pathophysiology
informative to clinicians in helping to understand how
their patients interpret interoceptive signals relative to
normal controls. The therapeutic implications of this
work, including the effects of mindfulness-based stress
reduction and other psychotherapies is very promising.
Mavrides and I[20] reviewed the treatment of depres-
sion in patients with CVD. In spite of considerable work
in this much needed area, all we can conclude is that
selective serotonin reuptake inhibitors (SSRIs) are safe
in the treatment of depression in patients with cardiac
disease, and effective in some, but not all, studies. There
is a clear need for well-powered, large-scale, random-
ized clinical trials of antidepressants, and psychotherapy
to not only establish efficacy, but to also determine pre-
dictors of response. Finally, and most importantly, it is
important to determine whether optimal treatment of
depression is associated with a reduction in markers of
cardiac disease risk such as CRP and calcium imaging
scores.
Sareen et al.[21] highlighted the somewhat paltry lit-
erature on predictors of psychiatric vulnerability after
physical injury, a much ignored area. Although both pre-
morbid psychiatric history and injury severity are well-
established risk factors, little is known in this area that
is injury specific, for example, burns versus automobile
accidents.
Finally, there is a summary of David Spiegel’s keynote
address on hypnosis, a veritable tour de force, including
a remarkable summary of the neurobiology of hypno-
sis and hypnotizability[22] . The dorsal anterior cingu-
late cortex (DACC) and dorsolateral prefrontal cortex
(DLPFC) are integral to hypnosis because of their role in
selective attention. The discussion of the use of the fun-
damentals of hypnosis in the treatment of posttraumatic
stress disorder (PTSD) in controlling access to traumatic
memories is particularly illuminating. The use of hyp-
nosis in helping patients cope with medical, surgical, and
dental procedures is similarly relevant to psychiatric and
psychological practice at the mind–body interface.
There is little doubt that the advances described in
these reports, taken together, represent an incremental
advance in our understanding of what was once termed
the mind–body dichotomy. Stay tuned as the science un-
ravels even more of this most complex area in the years
to come.
“Good for the body is the work of the body, and good
for the soul is the work of the soul, and good for either
is the work of the other.”—Henry David Thoreau
The author is supported by NIH MH-094759 and
DA-031201.
REFERENCES
1. Nemeroff CB, Goldschmidt-Clermont PJ. Heartache and heart-
break: the link between depression and cardiovascular disease. Nat
Rev Cardiol 2012;9:526–539.
2. Giese-Davis J, Collie K, Rancourt KM, Neri E, Kraemer HC,
Spiegel D. Decrease in depression symptoms is associated with
287
longer survival in patients with metastatic breast cancer: a sec-
ondary analysis. J Clin Oncol 2011;29:413–420.
3. Heim C, Shugart M, Craighead WE, Nemeroff CB. Neurobio-
logical and psychiatric consequences of child abuse and neglect.
Dev Psychobiol 2010;52:671–690.
4. Heim CM, Mayberg HS, Mletzko T, Nemeroff CB, Pruess-
ner JC. Decreased cortical representation of genital somatosen-
sory field after childhood sexual abuse. Am J Psychiatry 2013 (in
press).
5. Cisler JM, James GA, Tripathi S, et al. Differential functional
connectivity within an emotion regulation neural network among
individuals resilient and susceptible to the depressogenic effects of
early life stress. Psychol Med 2013;43:507–518.
6. Gould F, Clarke J, Heim C, Harvey PD, Majer M, Nemeroff CB.
The effects of child abuse and neglect on cognitive functioning in
adulthood. J Psychiatr Res 2012;46:500–506.
7. Plotsky PM, Thrivikraman KV, Nemeroff CB, Caldji C, Sharma
S, Meaney MJ. Long-term consequences of neonatal rearing on
central corticotropin releasing factor systems in adult male rat
offspring. Neuropsychopharmacol 2005;30:2192–2204.
8. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 poly-
morphisms and childhood abuse with risk of posttraumatic stress
disorder symptoms in adults. JAMA 2008;299:1291–1305.
9. Bradley RG, Binder EB, Epstein MP, et al. Influence of child abuse
on adult depression. moderation by the corticotropin-releasing
hormone receptor gene. Arch Gen Psychiatry 2008;65:190–200.
10. Gatt JM, Nemeroff CB, Dobson-Stone C, et al. Interactions be-
tween BDNF Val66Met polymorphism and early life stress predict
brain and arousal pathways to syndromal depression and anxiety.
Mol Psychiatry 2009;14:681–695.
11. Caldji C, Hellstrom IC, Zhang TY, Diorio J, Meaney MJ. En-
vironmental regulation of the neural epigenome 2011;585:2049–
2058.
12. Klengel T, Mehta D, Anacker C, et al. Allele-specific FKBP5
DNA demethylation mediates gene–childhood trauma interac-
tions. Nat Neurosci 2012;1:33–41.
13. Jaremka L, Lindgren M, Kiecolt-Glaser J. Synergistic rela-
tionships among stress, depression, and distressing relation-
ships: insights from psychoneuroimmunology. Depress Anxiety
2013;30:288–296.
14. Miller A, Haroon E, Raison C, Felger J. Cytokine targets in the
brain: impact on neurotransmitters and neurocircuits. Depress and
Anxiety 2013;30:297–306.
15. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for
the prevention of depression induced by high dose interferon-alfa.
N Engl J Med 2001;344:961–966.
16. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized
controlled trial of the tumor necrosis factor antagonist infliximab
for treatment-resistant depression: the role of baseline inflamma-
tory biomarkers. JAMA Psychiatry 2013;70:31–41.
17. O’Donovan A, Rush G, Hoatam G, et al. Suicidal ideation is asso-
ciated with elevated inflammation in patients with major depres-
sive disorder. Depress Anxiety 2013;30:307–314.
18. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi
A. Elevated inflammation levels in depressed adults with a history
of childhood maltreatment. Arch Gen Psychiatry 2008;65:409–
415.
19. Paulus M. The breathing conundrum—interoceptive sensitivity
and anxiety. Depress Anxiety 2013;30:315–320.
20. Mavrides N, Nemeroff CB. Treatment of depression in cardio-
vascular disease. Depress Anxiety 2013;30:328–341.
21. Sareen J, Erickson J, Medved M, et al. Risk factors for post-injury
mental health problems. Depress Anxiety 2013;30:321–327.
22. Spiegel D. Tranceformations: hypnosis in brain and body. Depress
Anxiety 2013;30:342–352.
Depression and Anxiety