Psychology, Health & Medicine

ISSN: 1354-8506 (Print) 1465-3966 (Online) Journal homepage: http://www.tandfonline.com/loi/cphm20

A systematic review of psychoneuroimmunology-

based interventions

Lucam J. Moraes, Márcia B. Miranda, Liliany F. Loures, Alessandra G. Mainieri

& Cláudia Helena C. Mármora

To cite this article: Lucam J. Moraes, Márcia B. Miranda, Liliany F. Loures, Alessandra G. Mainieri
& Cláudia Helena C. Mármora (2017): A systematic review of psychoneuroimmunology-based
interventions, Psychology, Health & Medicine, DOI: 10.1080/13548506.2017.1417607

To link to this article: https://doi.org/10.1080/13548506.2017.1417607

Published online: 20 Dec 2017.

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 Psychology, Health & Medicine, 2017
https://doi.org/10.1080/13548506.2017.1417607

A systematic review of psychoneuroimmunology-based

interventions
Lucam J. Moraesa,d, Márcia B. Mirandaa,d, Liliany F. Louresb,d, Alessandra G. Mainieric,d
and Cláudia Helena C. Mármoraa,b,d
a
Department of Psychology, Federal University of Juiz de Fora, Juiz de Fora, Brazil; bSchool of Physiotherapy,
Federal University of Juiz de Fora, Juiz de Fora, Brazil; cDepartment of Clinical Medicine, Research Center in
Spirituality and Health, School of Medicine, Federal University of Juiz de Fora, Juiz de Fora, Brazil; dStudies and
Downloaded by [University of New England] at 15:22 22 December 2017

Research Group in Neuroscience, Federal University of Juiz de Fora, Juiz de Fora, Brazil

ABSTRACT ARTICLE HISTORY

Psychoneuroimmunology-based interventions are used to attenuated Received 20 February 2017
disease progression and/or side effects of pharmacological treatment. Accepted 24 November 2017
This systematic review evaluates the different therapeutic and/or KEYWORDS
clinical psychoneuroimmunology-based interventions associated Psychoneuroimmunology;
to both psychological, neuroendocrine and immunological health promotion;
variables. The review was conducted for all English, Portuguese complementary therapies
and Spanish language articles published between 2005 and 2015.
Independent investigators analyzed 42 studies concerning human
psychoneuroimmunology-based interventions. Decreased levels of
cortisol, epinephrine and norepinephrine (stress-related hormones)
were associated to interventions like yoga, meditation, tai chi,
acupuncture, mindfulness, religious/spiritual practices, cognitive
behavior therapy, coping and physical exercises. Moreover, those
interventions were also associated to reductions in inflammatory
processes and levels of pro-inflammatory cytokines in cancer, HIV,
depression, anxiety, wound healing, sleep disorder, cardiovascular
diseases and fibromyalgia. Despite the associations between PNI
variables and clinical/therapeutic interventions, only one study
evidenced significant effects on a disease progression.

Introduction
Psychoneuroimmunological studies started in the 1960s. Psycho-neuroendocrine-immune
pathways were pointed first by Treadwell and Rasmussen (1961) demonstrating the role
of cortisol (released by the hypothalamic-pituitary-adrenal axis) associated to stress and
immunosuppression during anaphylaxis allergic reaction. Later Solomon and Moos (1965)
found associations between arthritis rheumatoid and emotions. Anti and pro-inflammatory
effects of sympathetic nervous system were also observed associated to norepinephrine
(sympathetic nerve fibers) and adrenal-epinephrine releasing (Besedovsky, Rey, Sorkin,
Da Prada, & Keller, 1979; Galant & Remo, 1975; Hadden, 1971) as well as behaviorally

CONTACT Lucam J. Moraes ljmpsico@gmail.com

© 2017 Informa UK Limited, trading as Taylor & Francis Group
 2  L. J. MORAES ET AL.

conditioned immunosuppression (Ader & Cohen, 1975), innervation of lymphoid organs

(Felten & Felten, 1987), and immune-neuroendocrine networking (Besedovsky & Del Rey,
2000; Besedovsky & Rey, 2007). In the last decade a neuroinflammatory pathway was found
in patients affected by viral or bacterial infections who experienced drastic negative subjec-
tive changes that has been called sickness behavior (Dantzer, O’Connor, Freund, Johnson, &
Kelley, 2008). Felling of feverish, nausea, tiredness, fragmented periods of sleep, depressive
mood, irritability, mild cognitive difficulties in attention and memory are the principal
characteristics of sickness behavior that is known to be associated with pro-inflamma-
tory cytokines circulating such as interleukin-1α and β (IL-α and IL-β), tumor necrosis
factor (TNF-α) and interleukin-6 (Audet et al., 2014; Dantzer et al., 2008; Ader, 2007,
2001; Dantzer, 2001; Dantzer & Kelley, 2007). Moreover, different studies point out associ-
ations between psychoneuroimmunological variables and cancer (Lissoni, Giusy, Lissoni,
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& Rovelli, 2017), depression and schizophrenia (Muller, 2017), anxiety (Ray, Gulati, & Rai,
2017), autoimmune diseases (Honeyman, 2016), and HIV/AIDS (Ironson et al., 2014).
Despite the current amount of psychoneuroimmunology studies, little is known about the
differential impacts of different kinds of psychoneuroimmunology-based interventions on
disease progression. Thus the aim of the study was to summarize the different therapeutic
and/or clinical psychoneuroimmunology-based interventions associated to both psycho-
logical, neuroendocrine and immunological variables and its effects on disease progression.

Method
Databases (PubMed/Medline, SCOPUS and Web of Science) were searched for relevant
studies published between 2005 and 2015. The term ‘psychoneuroimmunology’ was binary
combined (AND) with the following words: job, burnout, HIV, cancer, wound and healing,
herpes, lupus, autoimmune disease, sleep, stress, pain, physical activity, psychotherapy,
psychoanalysis, behavioral therapy, complementary medicine, depression, anxiety, schizo-
phrenia, post traumatic stress, spirituality, religion, psychosocial factors, cytomegalovirus,
natural killer cell, positive emotions, mindfulness, coping, cognitive therapy, cytokines,
cardiovascular disease, interventions, cytokines, sickness behavior, mood, depression, schiz-
ophrenia, sleep, cardiovascular disease, cardiovascular disease and stress, psychoneuroim-
munology-based. After, combinations of 3 terms were employed adding the words cortisol,
epinephrine and norepinephrine to original binary combinations.
Title and abstract of the articles were screened for relevance and the eleged ones should
meet 2 criteria: (1) language (Portuguese, Spanish and/or English); (2) psychoneuroimmu-
nological (PNI) outcome measures (instruments and/or strategies to measure psycholog-
ical, neuroendocrine and immunological mechanisms). Studies that did not measure PNI
outcome, general reviews, animal studies and those that the full text could not be accessed
were excluded. The Endnote software (Thompson Reuters, X7.4) was used to organize the
data-set and to exclude duplicates.
Last the studies were analyzed according to their quality and scores were given as fol-
low: introduction [adequate review of the literature concerning the aim and objectives of
the study (3 points)], method [clear and precise description of the design, sample, data
acquisition and data analyses procedures (13 points)], results [clear and precise description
of the outcomes (3 points)] and discussion [discussion and interpretation of the results
 PSYCHOLOGY, HEALTH & MEDICINE  3

concerning the aim and objective of the study and limitations of the study (7 points)]. A
cutoff of 21points was defined to assure the quality of the included studies in final data-set
(Figure 1).

Results
3483 studies were identified in all databases; 1409 were duplicates and 2074 records were
screened based on the abstracts. Studies that did not address the psychoneuroimmunolog-
ical variables (1724) or full-text were inaccessible (7) were excluded. A total of 343 full-text
studies were assessed for eligibility; 44 studies did not achieve 21 points in the qualitative
analysis and were excluded. Two hundred ninety-nine full-text studies were reviewed. Of
these, 42 studies covered psychoneuroimmunology-interventions based (Figure 1).
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After, the 42 studies were analyzed according to PNI variables, type of intervention,
clinical groups, methodological design and its effects on disease progression (Table 1).
Concerning the PNI variables presented in the studies, cortisol (40.5%) and catecholamine
(16.7%) were mostly measure as neurological variables. On the other hand, different psy-
chological variables were measured, such as depression (54.7%), anxiety (31%), fatigue,
sleep disturbances, quality of life and stress (16.7%), other were mood (14.3%), pain and
social support (4.8%). Finally, IL-6 (57.2%) and TNF-α (47.6%) were the most present
immunological variables, other interleukins (11.9% to 23.8% each) were: IL-1, IL-4, IL-8,
IL-10 and IL-12, and IFN-gamma and NK cells (23.8%).
The studies were analyzed according to the type of intervention (Table 2) and clinical
population (Table 3). Eleven of them presented more than one intervention.
Seven different types of methodological designs were identified: randomized controlled
trial (38.1%, n = 16), randomized trial (26.2%, n = 11) and others (non-randomized con-
trolled trial, follow up, prospective, simple interrupted, pilot and longitudinal; 35.7%,
n = 15). Most randomized controlled trial analyzed were interventions (mindfulness,

Figure 1. Flow of information through the different phases of systematic review.

 Downloaded by [University of New England] at 15:22 22 December 2017

Table 1. Summary of studies.

Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Van Middendorp, Rheumatoid arthritis Oral emotional disclo- Randomized clinical Cortisol and nor- Psychological IL-6,IFN-γ, IL-10 No effect on psychological well-be-
Geenen, Sorbi, (n = 68) sure sessions or time trial epinephrine well-being: de- ing and clinical outcome was
van Doornen, management control pressed mood found. Decreased cortisol and
and Bijlsma condition (4 weeks) and cheerful IFN-gamma level after emotional
(2009) mood disclosure
Bower et al. Younger women Mindful awareness Randomized con- Inflammation-re- Perceived stress, IL-6, CRP, and the Improvements in perceived stress,
 L. J. MORAES ET AL.

(2015) with breast cancer practices or wait-list trolled trial lated transcrip- depressive soluble TNF fatigue, subjective sleep distur-
(n = 71) condition controlled tion factors: anti symptoms, receptor type bance. Reductions in pro-in-
(6 weeks) and pro-inflam- fatigue, sleep II (a marker of flammatory gene expression. No
matory cytokine quality TNF activity) effects for CRP, IL-6, or sTNF-RII
production
Shelley and Pak- Coronary artery by- Psychological prepara- Single-blind rand- Cortisol Pain, depression, TNF-α The effects have been small and
enham (2007) pass graft patients tion or standard care omized clinical trial anxiety, and varied. No significance
(n = 80) for Surgery (30 min) stress
Cohen et al. Prostate cancer Stress management Randomized clinical Neuroinflammato- Mood NKCC, IL-1β, SM group had higher level of NKCC,
(2011) (n = 159) (SM), supportive trial ry processes IL-12p70, IFN-γ, IL-1β, IL-12p70 and TNF-α. Lowest
attention (SA) and IL-6, IL-8, IL-10 level of mood disturbance before
standard care (SC) and TNF-α surgery in the SM group
(two sessions)
Black, O’Reilly, Older adults with Mindful awareness Randomized clinical Neuroinflammato- Sleep disturbanc- Inflammatory Improvement in sleep quality,
Olmstead, sleep disturbance practices or sleep trial ry processes es, Depression, signaling via depression and fatigue
Breen, and (n = 49) hygiene education Anxiety, Stress activated factor
Irwin (2015) (6 weeks) and Fatigue nuclear factor
(NF-κBin)
Black et al. (2013) Dementia caregivers Kirtan Kriya Meditation Randomized con- Neuroinflammato- Depression and Expression of The KKM group showed lower
(n = 49) or Relaxing Music trolled clinical trial ry processes quality of life NF-κB and in- levels of depressive symptoms
listening (8 weeks) terferon-relat- and greater improvement in
ed transcripts mental health compared with the
factors RM group. Reduced expression
of genes bearing NF-κB-re-
sponse elements and increased
expression of genes bearing IRF1
response elements

(Continued)
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Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Bottaccioli et al. Healthy adults who PsychoNeuroEndo- Non-randomized Cortisol Psychological dis- Immunological Reduction in all psychological
(2014) attended PNEIMED crinoImmunolo- controlled study tress (anxiety, processes scores and cortisol level
courses (n = 40) gy-based meditation depression, so-
(30 h) matization, and
inadequacy)
Bower et al. Breast cancer (n = 31) Iyengar yoga interven- Randomized con- Cortisol Fatigue NF-κB signaling, Yoga group showed reduced
(2014) tion or Health Edu- trolled trial glucocorticoid activity of NF-κB and CREB family
cation (HE) control receptor, CREB transcription factors, increased
(12 weeks) transcription, activity of glucocorticoid recep-
TNF receptor tor. Levels of sTNF-RII remained
type II (sT- stable in the yoga group and
NF-RII), TNF-α increased in the HE group. No
activity, IL-1 changes in CRP, IL-6 or cortisol
receptor antag-
onist (IL-1ra),
CRP and IL-6
Campo et al. Senior female cancer Tai Chi Chih (TCC) or Randomized con- Cortisol Psychosocial IL-12, IL-6, TNF-α, TCC group had reduced cortisol
(2015) survivors (n = 63) Health Education trolled trial processes IL-10 and IL-4 level. No effect of immunological
control (12 weeks) variables
Kohut et al. Older adults (n = 87) Cardiovascular Randomized trial Neuroinflammato- Depression, per- CRP, IL-6, TNF-α Reductions in CRP, IL-6 and IL-18 in
(2006) (CARDIO) group or ry processes ceived stress, and IL-18 CARDIO group. TNF-α declined
strength/ flexibility/ optimism, in both groups. The psychoso-
balance (FLEX) group sense of coher- cial variables improved in both
(10 months) ence and social groups
support
Liu et al. (2015) Depressive disorder Medicine group or ac- Randomized con- Neuroinflammato- Depressive symp- Serum 5-Hydrox- The acupuncture-medicine group
(n = 126) upuncture-medicine trolled clinical trial ry processes toms (MADRS), ytryptamine had lower MADRS and SERS
group (6 weeks) adverse effects (5-HT), IL-1β, scores. 5-HT, IL-4 and IL-10 were
of antidepres- IL-6, IL-4, and higher in the acupuncture-medi-
sants (SERS) IL-10 cine group. IL-6 were lower in the
acupuncture-medicine group
Moreira et al. Major depressive Narrative cognitive Randomized clinical Neuroinflammato- Depressive IL-6 and TNF-α Depressive symptoms, IL-6 and
(2015) disorder (n = 97) therapy (NCT) and trial ry processes symptoms TNF-α were lower in CBT group
cognitive behav-
PSYCHOLOGY, HEALTH & MEDICINE 

ioral therapy (CBT)

(7 weeks)
5

(Continued)
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Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Rogers et al. Breast cancer (n = 46) Exercise intervention Randomized Con- Neuroinflammato- Fatigue, depres- IL-6, IL-8, IL-10 Fatigue and anxiety showed a
(2014) (3 months) trolled Trial ry processes sion, anxiety, and TNF-α decline in the intervention group
and sleep
dysfunctions
Saxton et al. Breast cancer (n = 85) Exercise and hy- Randomized Con- Cortisol Depressive symp- Lymphocyte, Depressive symptoms were
(2014) pocaloric healthy trolled Trial toms, perceived NK cells, IL-6, reduced and increased morning
 L. J. MORAES ET AL.

eating intervention stress TNF-α, leuko- salivary cortisol in the interven-

(6 months) cyte count. tion group
Starkweather Older adults (n = 10) Exercise group Prospective nonrand- Cortisol Stress, mood, and IL-6 The exercise group reported sig-
(2007) (10 weeks) omized compari- quality of life nificant improvements in stress,
son group mood, and several quality of life
indices; decrease in serum IL-6.
There was a positive correlation
between levels of IL-6 and corti-
sol, perceived stress and cortisol
Brunoni et al. Unipolar depressive Transcranial direct cur- Double-blind, place- Neuroinflammato- Depressive IL-2, IL-4, IL-6, All cytokines, except TNF-α, de-
(2014) disorder (n = 73) rent stimulation or bo-controlled trial ry processes symptoms IL-10, IL-17a, creased over time for all groups
sertraline treatment IFN-γ, and irrespectively of the treatment
(6 weeks) TNF-α condition. No significant corre-
lations between cytokine levels
with depression
Munitz-Shenkar Children and adoles- Hematopoietic stem Longitudinal follow Neuroinflammato- Depression and IL-1β, IL-2 and The time of engraftment depres-
et al. (2007) cents (malignancies cell transplantation up and correlation- ry processes anxiety IL-6 sion and anxiety were relatively
or hematological al study high and resolved subsequently.
disease) (n = 23) In contrast, serum cytokines (IL-
1β and IL-6) increased significant-
ly only after the engraftment
Rethorst et al. Major depressive Exercise dose groups randomized trial Neuroinflammato- Depressive IFN-γ, IL-1β, IL-6, Higher baseline levels of TNF-α
(2013) disorder (n = 73) (12 weeks) ry processes symptons and TNF-α were associated with greater de-
crease in depression symptoms.
A positive correlation between
change in IL-1β and change in
depression symptom scores was
observed
(Continued)
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Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Wenzel et al. Cervical cancer Psychosocial telephone Randomized clinical Cortisol Anxiety, de- IL-4, IL-5, IL-6, IL- PTC had improved depression.
(2015) (n = 204) counseling (PTC) trial pression and 10 and IL-13 Participants with decreasing IL-4,
(9 weeks) quality of life IL-5, IL-10, and IL-13 had signif-
icantly greater improvement in
QOL than those with increasing
cytokine levels
Yasui et al. (2009) Midlife women with Administration of Randomized trial Estradiol and FSH Anxiety and mild IL-1β, IL-2, IL-4, IL- IL-6 concentrations were decreased
psychological kamshoyosan or par- depression as 5, IL-6, IL-7, IL-8, by both treatments with paroxe-
symptoms such as oxetine (6 months) menopausal IL-10, TNF-α, tine and kamishoyosan in women
anxiety and mild symptoms IFN-γ, MIP- 1β with psychological symptoms,
depression (n = 76) (macrophage but other serum cytokines and
inflammato- chemokines concentrations did
ry protein) not change significantly
and MCP-1
(monocyte
chemotactic
protein)
Rogers et al. Postmenopausal Exercise aerobic inter- Pilot randomized Neuroinflammato- Sleep disturbanc- IL-6, IL-8, IL-10 The intervention group demon-
(2015) breast cancer survi- vention (3 months) controlled trial ry processes es, depression, and TNF-α strated a significant increase in
vors (n = 46) anxiety and sleep duration when compared
fatigue with control group
Bote, Garcia, Patients (women) Single bout of moder- Non-randomized, Cortisol, noradren- Stress IL-1 β, TNF-α, IL-6, In patients with fibromyalgia the
Hinchado, and with fibromyalgia ate cycling (45 min) controlled trial aline (NA) and IL-10 and IL-18 exercise induced a decrease in
Ortega (2013) (n = 8) heat shock pro- the systemic concentration of
tein 72 (eHsp72) IL-8, cortisol, NA, and eHsp72
McCain et al. Individuals with HIV Cognitive–behavioral Randomized clinical Cortisol and dehy- Social support, CD4+, CD8+, All treatment groups had aug-
(2008) infection (n = 387) relaxation training: trial droepi-andoster- subjective and CD57+ T mented lymphocyte proliferative
Tai chi training and one (DHEA) impact of lymphocytes; function and it is associated with
spiritual growth living with NCK cytotox- enhancement in immune system
(10 weeks) HIV, quality of icity; IFN-γ, functional status
life, spiritual TNF-α, IL-2, IL-4,
well-being IL-6, and IL-10;
lymphocyte
proliferation
PSYCHOLOGY, HEALTH & MEDICINE 

(Continued)
7
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Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Li et al. (2008) Healthy female Forest bathing trip Cross-sectional study Adrenaline, Mood state NK cells The forest bathing trip significantly
nurses (n = 13) (walking to relaxa- noradrenaline, increased NK cells activity, and
tion and recreation estradiol and the numbers of NK. There were
by breathing in progesterone significantly decreased T cells and
volatile substances) the concentrations of adrenaline
(3 days) and noradrenaline
 L. J. MORAES ET AL.

Matsunaga, Healthy male volun- Positive emotions were Cross-sectional study Dopamine, norep- Positive emotions NK cells activity The activity of peripheral circulat-
Isowa, et al. teers (n = 12) manipulated by the inephrine, and ing NK cells and the peripheral
(2008) viewing of a film epinephrine dopamine level were elevated
featuring attractive while participants experienced
persons, using PET positive emotions. These values
scan (2 h) were positively correlated
Matsunaga, Healthy male and Positive emotions were Cross-sectional study Norepinephrine Positive emotions NK cells and T Skin conductance level and the
Yamauchi, female volunteers manipulated by the and epinephrine and Mood state cells proportion of NK cells in periph-
Nogimori, (n = 12) viewing of a film eral blood increased significantly,
Konagaya, and featuring favorite and these physiological changes
Ohira (2008) persons (2 h) were positively correlated
Arranz, Siboni, Female patients suf- Acupuncture protocol Cross-sectional study Cortisol Anxiety IL-2 and TNF-α Levels of IL-2, which were de-
& De la Fuente fering high levels of treatment (30 min) creased in women with anxiety,
(2006) anxiety (n = 27) increase following acupuncture,
and the levels of TNF-α and
cortisol, which were increased
in these patients, decrease after
the session
Nunes et al. Women with breast Relaxation and visuali- Randomized con- Cortisol and gua- Stress, anxiety T-cells prolifer- RVT was effective to reduce stress,
(2007) cancer (n = 34) zation therapy (RVT) trolled trial nine-cytosine and depression ation anxiety, and depression scores.
program (24 days) content (GC) Cortisol levels as well as prolif-
eration remained unchanged
following RVT

(Continued)
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Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Robins et al. Women with early Tai chi training or Randomized con- Endorphins and Perceived stress, IL-1β, IL-2, IL-4, Significant elevations in IFN-γ
(2013) stage breast cancer spiritual growth trolled trial enkephalins Depressive IL-5, IL-6, IL-7, were noted for both intervention
(n = 109) groups (10 weeks) symptons, IL-8, IL-10, groups possibly reflecting better
Functional IL-12, IL-13, recovery of proinflammatory
well-being, IL-17, granu- cytokine production
Physical locyte colony
well-being stimulating
and Emotional factor (G-CSF),
wellbeing granulocyte-
mac-
rophage-(GM-)
CSF, IFN-γ,
MCP-1, MIP-1β,
and TNF-α
Ergun et al. (2013) Female breast cancer Exercise programs Prospective rand- Neuroinflammato- Fatigue, De- IL-6; IL-8; TNF-α; Statistically significant decreases
patients (n = 60) (Supervised exercise omized controlled ry processes pression and epithelial were found in IL-8 and neutrophil
group, home exercise study Quality of life neutrophil acti- activating protein-78 levels in the
group and education vating protein home exercise group. The educa-
group) (12 weeks) 78, vascular tion group showed a statistically
endothelial significant increase in monocyte
growth factor, chemoattractant protein-1 level
growth related
oncogene al-
pha, regulated
upon activa-
tion, T cells,
angiogenin,
platelet derived
growth factor,
thrombopoe-
tin, oncostatin
M, MCP-1, MCP-
2, and MCP-3
PSYCHOLOGY, HEALTH & MEDICINE 

(Continued)
9
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10

Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Chen et al. (2008) Peritoneal dialyses Cognitive-behavioral Pilot randomized Hemoglobin, al- Sleep quality IL-6; IL-8; IL-1β IL-1β level decreased in the inter-
patients (n = 24) therapy (4 weeks) controlled trial bumin, calcium, and TNF-α vention group, but increased in
phosphorus, the control group
urea nitrogen,
and creatinine
Carlson, Speca, Breast and prostate Mindfulness-based Longitudinal follow Cortisol Mood, stress and T-cells, NK cells, Decreased levels of cortisol, pro-in-
 L. J. MORAES ET AL.

Faris, and Patel cancer outpatients stress reduction up quality of life NKT cells, IFN-γ, flammatory cytokines (Th1),
(2007) (n = 59) (12 months) TNF, IL-4, IL-10 blood pressure, and psycholog-
ical stress, and increased quality
of life
Kiecolt-Glaser et Breast cancer Hatha yoga classes or Randomized Con- Neuroinflammato- Fatigue and IL-6, TNF-α, IL-1β After 3 months of intervention
al. (2014) (n = 200) a wait-list control trolled Trial ry processes depression experimental group reduced
(3 months) fatigue, IL-6, TNF-α, and increased
vitality
Witek-Janusek et Breast cancer (n = 75) Mindfulness based Non-randomized Cortisol Quality of life IL-2, IL-6, IL-10, Reduced cortisol, IL-4, IL-6, and in-
al. (2008) stress reduction Controlled Trial IL-4, IFN-γ, NK creased quality of life and coping
program (8 weeks) cells, lympho-
cytes
Barker, Knisely, Healthcare profes- Therapy dog (20 min) Pilot study Cortisol, epineph- Stress Lymphocytes A 5 min intervention of therapy
McCain, and sionals (n = 20) rine, norepi- dog might be effective in reduce
Best (2005) nephrine cortisol and psychological stress
in healthcare professionals
Manzaneque et Healthy participants Qigong (Chinese psy- Randomized con- Neuroinflammato- Anxiety, depres- TNF-α and IFN-γ Qigong might be effective in
al. (2009) (n = 39) chosomatic exercise) trolled trial ry processes sion Psycholog- increase psychological well-being
(1 month) ical well-being and sleep duration. No significant
and quality of alterations in cytokines levels
sleep were found
(Continued)
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Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Fang et al. (2009) Heterogeneous Mindfulness-based Non-randomized Neuroinflammato- Anxiety, de- NK Cells and CRP Reductions in anxiety and distress
patient population stress reduction controlled trial ry processes pression and were associated with reductions
(n = 24) (8 weeks) somatization in CRP. Improvement in mental
and quality well-being was associated with
of life increased NK cytolytic activity
from pre- to post-MBSR, whereas
patients who reported no im-
provement in mental well-being
showed no change in NK cytolyt-
ic activity
Bormann, HIV-infected adults Spiritual mantram Randomized trial Cortisol Stress, anxiety Lymphocytes Faith levels increased among man-
Aschbacher, (n = 71) intervention (5 week) and depression tram participants from pre- to
Wetherell, post intervention. Greater faith at
Roesch, & Red- pre intervention was significantly
wine (2009) associated with lower average
cortisol at post intervention in
the mantram group but not in
the controls. The associations
between faith at post interven-
tion and cortisol levels at 5-week
follow-up were significant among
both groups but weaker than
the pre- to post intervention
association identified in the man-
tram group
Lewandowski, Chronic noncancer Guided imagery inter- Simple interrupted Cortisol Faith Lymphocytes Guided imagery intervention was
Jacobson, Palm- pain (n = 25) vention (12 weeks) time-series design CD4 effective in anxiety reduction. No
ieri, Alexander, significant associations between
and Zeller HPA, hyperalgesia and immuno-
(2011); logical markers were found.
Pullen et al. Patients with chronic Yoga treatment or Randomized con- Cortisol Pain and stress Lymphocytes and Yoga treatment reduced IL-6, CRP.
(2008) heart failure standard medical trolled trial IL-Iβ Quality of life did not present
(n = 19) therapy (2 weeks) significant difference between
PSYCHOLOGY, HEALTH & MEDICINE 

experimental and control groups

(Continued)
11
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12

Table 1. (Continued).
Neuroendocrine Psychosocial Immunological
Author and year Study sample Intervention (time) Design variables variables variables Significant results
Kiecolt-Glaser et Healthy women Hatha yoga’s potential Controlled trial Neuroinflammato- Quality of life IL-6; CRP; Yoga practice improved positive
al. (2010) (novice and expert stress-reduction ry processes Extracellular affect and psychological stress
yoga practitioners) (2 weeks) superoxide reduction. The experts group
(n = 50) dismutase (EC- showed lower levels of IL-6 and
SOD) CRP, and greater ability to reduce
stress
 L. J. MORAES ET AL.

Lai, Liao, Huang, Healthcare workers Soothing music Randomized con- Neuroinflammato- Stress IL-6, TNF-α, IL-10 Stimulating music group showed
Chen, and Peng (n = 60) (3 weeks) trolled trial ry processes higher blood pressure compared
(2013) to sedative music group, but no
difference was found between
sedative and relaxing music
groups
 PSYCHOLOGY, HEALTH & MEDICINE  13

Table 2. Types of interventions.

Interventions N = 53 %
Psychological 13 24.5
Psychotherapy and counseling 13 24.5
Physical 17 31.9
Physical exercises 10 18.9
 Yoga 4 7.4
 Tai chi 3 5.6
Psychosocial 19 36.0
Meditation 2 3.8
Mindfulness 5 9.5
Relaxation 5 9.5
 Acupuncture 2 3.8
Religious/spiritual practices 3 5.6
 Guided imagery 2 3.8
Psychotropic drugs 4 7.6
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Pharmacotherapy 2 3.8
Medical procedure 2 3.8

Table 3. Percentage of studies with clinical and healthy populations.

Pathologies N %
Cancer 13 30.3
Depression and anxiety 6 14.2
Healthy people 10 23.8
Others (postmenopausal women, fibromyalgia, hematological and cardiovascular diseases) 5 11.9
Chronic diseases 2 4.8
Stress 2 4.8
HIV 2 4.8
Sleep disorders 2 4.8

Table 4. Description of randomized controlled trial.

Clinical group Intervention Assessment
Cancer Mindfulness Intra/inter subjects
Yoga X Health education Intra/inter subjects
Tai Chi X Health education Inter subjects
Exercise (3 studies) Intra/inter subjects
Relaxation X Guided imagery Intra/inter subjects
Tai Chi X Spiritual growth Inter subjects
Yoga Intra/inter subjects
Stress Meditation X Relaxing music Inter subjects
Music Intra/inter subjects
Depressive disorder Pharmacotherapy X Acupuncture Intra/inter subjects
Postmenopausal Exercise Intra/inter subjects
Sleep disturbance Psychotherapy Intra/inter subjects
Health people Exercise Inter subjects
Chronic disease Yoga Intra/inter subjects

relaxation, guided imagery, tai chi, spiritual growth, yoga, exercise) in cancer (n = 9), and
interventions (meditation, relaxing and music) in stress (n = 2) (Table 4).
Concerning the intervention effects on disease progression (randomized controlled
trial), only one cancer study (Ergun, Eyigor, Karaca, Kisim, & Uslu, 2013) assessed the
disease progression linked to angiogenesis and apoptosis (6.2%, n = 1), others assessed
through inflammatory markers (18.8%, n = 3) and impairment of PNI function and clinical
 14  L. J. MORAES ET AL.

Table 5. Percentage of randomized controlled trial with effect on disease progression.

Variable N %
Inflammation markers 3 18.8
Impairment of PNI function 1 6.2
Angiogenesis and apoptosis 1 6.2
Clinical parameters 1 6.2
No assessed 10 62.6

parameters (6.2%, n = 1). The other studies (62.5%, n = 10) did not mention any form of
assessment (Table 5).

Discussion
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Previous literature evidenced bidirectional interactions between psychological aspects, neu-

roendocrine mechanisms and immune changes (Ader, 2001, 2007). Similarly the reviewed
studies have evidenced associations between psychological, neuroendocrine, and/or immu-
nological variables, as well as possible interventions impacts on psychoneuroimmunological
variables. However, little was found about intervention effects on diseases progressions.
Only one study evidenced an intervention impact on disease progression (Ergun et al.,
2013), which pointed changes in angiogenesis and apoptosis levels after twelve weeks phys-
ical exercise intervention among breast cancer women. However, PNI-based interventions
impacts were significantly on the reduction of stress, depression, fatigue, sleep disorder,
and quality of life improvement. Moreover, non-conventional interventions such as yoga,
tai chi, acupuncture, spiritual practices, and meditation, have showed significant associa-
tions with neuro and immunological variables changes such as cortisol, epinephrine and
norepinephrine reductions, IL-6 and TNF-α decreasing, natural killer and leukocytes cells
improvement. These interventions showed to be an important complement to medical and
pharmacological treatments.
Further, an important consideration in evaluating PNI-based interventions is the prob-
lem of causality. The cross-sectional nature of most of these studies prevents the evaluation
of potential cause and effect relationships between psychoneuroimmunological variables,
diseases progressions and interventions effects. Reviewed evidence pointed possible asso-
ciations between variables but none cause-effect relationships. Therefore, randomized
clinical studies might promote the evaluation of potential cause and effect relationships
between PNI-based clinical/therapeutic interventions and diseases progressions, and be
able to answer questions as, are these interventions able to affect psychoneuroimmunolog-
ical variables? And, in which extension could it stop or even reduce a disease progression
such as tumor progressions, HIV/AIDS infection or an autoimmune disease development?
Or, in which size were psychoneuroimmunology variables associated with these effects?
So, the few number of randomized clinical PNI-based studies mays difficulty to verify the
causal directions of variables effects. Furthermore, an additional limitation is a potential
of publication bias, since studies with some psycho-neuroendocrine-immune association
are more likely to be published.
Overall, most reviewed studies may suggest that clinical and/or therapeutic PNI-based
interventions might be effective in changing psychological, neuroendocrine and immuno-
logical variables and contributing for a greater stability of pathological conditions, most
 PSYCHOLOGY, HEALTH & MEDICINE  15

of studies evidenced significant effects of psychosocial or physical exercises clinical and/

or therapeutic interventions that could be complementary to some pharmacological treat-
ments. Future randomized clinical trials are necessary to investigate possible interventions
impacts on diseases progressions, as well possible causal directions between the variables
of the studies.

Disclosure statement
No potential conflict of interest was reported by the authors.

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