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Original Investigation
June 3, 2020

Psychosocial Interventions and Immune System Function: A Systematic Review and Meta-analysis of Randomized Clinical Trials

Author Affiliations
  • 1Center for Mind and Brain, University of California, Davis
  • 2Department of Psychology, San Diego State University, San Diego, California
  • 3Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles
JAMA Psychiatry. 2020;77(10):1031-1043. doi:10.1001/jamapsychiatry.2020.0431
Key Points

Question  How consistently are psychosocial interventions associated with changes in immune system function, and which immunologic, demographic, or clinical factors moderate these associations?

Findings  In this systematic review and meta-analysis of 56 unique randomized clinical trials and 4060 participants, psychosocial interventions were associated with positive changes in immunity over time, including improvements in beneficial immune system function and decreases in harmful immune function that persisted for at least 6 months following treatment for participants randomly assigned to a psychosocial intervention vs a control group. These associations were most reliable for cognitive behavior therapy and multiple or combined interventions and for studies that assessed proinflammatory cytokines or markers.

Meaning  These findings suggest that psychosocial interventions may enhance immune system function and may thus represent a viable strategy for improving immune-related health.

Abstract

Importance  Recent estimates suggest that more than 50% of all deaths worldwide are currently attributable to inflammation-related diseases. Psychosocial interventions may represent a potentially useful strategy for addressing this global public health problem, but which types of interventions reliably improve immune system function, under what conditions, and for whom are unknown.

Objective  To address this issue, we conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) in which we estimated associations between 8 different psychosocial interventions and 7 markers of immune system function, and examined 9 potential moderating factors.

Data Sources  PubMed, Scopus, PsycInfo, and ClinicalTrials.gov databases were systematically searched from February 1, 2017, to December 31, 2018, for all relevant RCTs published through December 31, 2018.

Study Selection  Eligible RCTs included a psychosocial intervention, immune outcome, and preintervention and postintervention immunologic assessments. Studies were independently examined by 2 investigators. Of 4621 studies identified, 62 were eligible and 56 included.

Data Extraction and Synthesis  Data were extracted and analyzed from January 1, 2019, to July 29, 2019. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed. Data were extracted by 2 investigators who were blind to study hypotheses and analyses, and were then analyzed using robust variance estimation. Analysis included 8 psychosocial interventions (behavior therapy, cognitive therapy, cognitive behavior therapy [CBT], CBT plus additive treatment or mode of delivery that augmented the CBT, bereavement or supportive therapy, multiple or combined interventions, other psychotherapy, and psychoeducation), 7 immune outcomes (proinflammatory cytokine or marker levels, anti-inflammatory cytokine levels, antibody levels, immune cell counts, natural killer cell activity, viral load, and other immune outcomes), and 9 moderating factors (intervention type, intervention format, intervention length, immune marker type, basal vs stimulated markers, immune marker measurement timing, disease state or reason for treatment, age, and sex).

Main Outcomes and Measures  The primary a priori outcomes were pretest-posttest-control (ppc) group effect sizes (ppc g) for the 7 immunologic outcomes investigated.

Results  Across 56 RCTs and 4060 participants, psychosocial interventions were associated with enhanced immune system function (ppc g = 0.30, 95% CI, 0.21-0.40; t50.9 = 6.22; P < .001). Overall, being randomly assigned to a psychosocial intervention condition vs a control condition was associated with a 14.7% (95% CI, 5.7%-23.8%) improvement in beneficial immune system function and an 18.0% (95% CI, 7.2%-28.8%) decrease in harmful immune system function over time. These associations persisted for at least 6 months following treatment and were robust across age, sex, and intervention duration. These associations were most reliable for CBT (ppc g = 0.33, 95% CI, 0.19-0.47; t27.2 = 4.82; P < .001) and multiple or combined interventions (ppc g = 0.52, 95% CI, 0.17-0.88; t5.7 = 3.63; P = .01), and for studies that assessed proinflammatory cytokines or markers (ppc g = 0.33, 95% CI, 0.19-0.48; t25.6 = 4.70; P < .001).

Conclusions and Relevance  These findings suggest that psychosocial interventions are reliably associated with enhanced immune system function and may therefore represent a viable strategy for improving immune-related health.

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    3 Comments for this article
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    Systematic review of psychosocial interventions and immune system function: inclusion of a retracted study
    Anthony Pelosi, FRCP FRCPsych | Priory Hospital Glasgow
    Shields et al are to be congratulated for their careful systematic review of the effects of psychosocial interventions on functioning of the immune system.[1] They have been very brave in their enthusiastic discussion of the implications of the results and I am sure this will lead to vigorous and productive debate. I personally think that they have been unwise to combine within one meta-analysis studies of such widely disparate conditions – from stress through to cancer. But that is not why I am writing this comment. I thought I should promptly let the authors, editors and readers know that there is a flaw in this study. They have included a randomised trial by Ronald Grossarth-Maticek and the late Hans Eysenck that examined immunologic changes when patients with metastatic breast cancer received psychodynamic psychotherapy, or behavioural therapy, or their own type of therapy that they called novational behaviour therapy, or no psychotherapeutic input.[2] This article was retracted in February of this year following an enquiry by King’s College London and further investigation by the editors and publishers of Psychological Reports.[3, 4] So far 14 articles from these scientists’ research programme have been retracted. It is likely that more than 80 publications by Eysenck or by Eysenck and Grossarth-Maticek will have to be removed from the literature.[5]

    It looks from Shields and colleagues’ forest plot that inclusion of the Grossarth-Maticek and Eysenck research has not distorted the overall results. However, I fear they will have to re-do the meta-analysis and rewrite their mentions of psychosocial interventions in people with cancer.

    I hope that the research of Eysenck and Grossarth-Maticek will not be allowed to undermine the important work of Shields and his colleagues and all the other serious scientists who are grappling with the complicated and difficult field of psychoneuroimmunology.

    1. Shields GS, Spahr CM, Slavich GM. Psychosocial Interventions and Immune System Function. JAMA Psychiatry. 2020.
    2. Grossarth-Maticek R, Eysenck HJ. Length of Survival and Lymphocyte Percentage in Women with Mammary Cancer as a Function of Psychotherapy. Psychological Reports. 1989;65(1):315-321.
    3. King's College London. King’s College London enquiry into publications authored by Professor Hans Eysenck with Professor Ronald Grossarth-Maticek May 2019.
    4. Retraction notice. Psychological Reports. 2020:003329412090199
    5. Marks DF, Buchanan RD. King’s College London’s enquiry into Hans J Eysenck’s ‘Unsafe’ publications must be properly completed. Journal of Health Psychology. 2020;25(1):3-6.
    CONFLICT OF INTEREST: None Reported
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    Moving CBT into Chronic Disease Care
    Victor Kolade, MD MS | The Guthrie Clinic
    The meta-analysis by Shields et al. (1) is a welcome announcement of the potential of cognitive behavior therapy (CBT) and other psychosocial interventions to reduce the incidence of postoperative infections and the intensity of autoimmune disorders, among others. The effectiveness data appear compelling enough for insurers to stop limiting CBT to the treatment of mental health disorders, as has been done in several states (2). And perhaps the cost comparisons provided will motivate payers everywhere to cover CBT for medical indications such as those validated by this research, rather than citing insufficient evidence as a reason not to (3).
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    1. Shields GS, Spahr CM, Slavich GM. Psychosocial Interventions and Immune System Function: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Psychiatry. Published online June 03, 2020. doi:10.1001/jamapsychiatry.2020.0431
    2. Bonakdar R, Palanker D, Sweeney MM. Analysis of State Insurance Coverage for Nonpharmacologic Treatment of Low Back Pain as Recommended by the American College of Physicians Guidelines. Glob Adv Health Med. 2019;8:2164956119855629. Published 2019 Jul 29. doi:10.1177/2164956119855629
    3. Heyward J, Jones CM, Compton WM, et al. Coverage of Nonpharmacologic Treatments for Low Back Pain Among US Public and Private Insurers. JAMA Netw Open. 2018;1(6):e183044. doi:10.1001/jamanetworkopen.2018.3044
    CONFLICT OF INTEREST: None Reported
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    Results Excluding the Now-Retracted Grossarth-Maticek & Eysenck Study
    George Slavich, PhD | University of California, Los Angeles
    We thank Dr. Pelosi for his kind remarks regarding this article. As noted, this meta-analysis included a study by Grossarth-Maticek & Eysenck that was retracted in February 2020, approximately one year after this literature review was completed and one month after our article was accepted and sent for publication. At the request of the JAMA Psychiatry editorial team, we reanalyzed the dataset and report our findings below.

    To remind readers, the Grossarth-Maticek & Eysenck study examined “50 patients suffering from terminal mammary cancer and visceral metastases [who] received chemotherapy, and in addition half of them received psychotherapy, while half
    did not.” With the now-retracted Grossarth-Maticek & Eysenck study removed, the overall association between psychosocial interventions and changes in immune system function was essentially the same and still significant (ppc g = 0.30, 95% CI, 0.20-0.39; t49.9 = 6.05; P < .001). Similarly, psychosocial interventions were still associated with a significant 14.5% improvement in beneficial immune system function (95% CI, 5.5%-23.6%) and a significant 18.0% decrease in harmful immune system function (95% CI, 7.2%-28.8%) over time. We previously reported that “psychosocial interventions were associated with enhanced immune system function (ppc g = 0.30, 95% CI, 0.21-0.40; t50.9 = 6.22; P < .001)” and that “overall, being randomly assigned to a psychosocial intervention condition vs a control condition was associated with a 14.7% (95% CI, 5.7%-23.8%) improvement in beneficial immune system function and an 18.0% (95% CI, 7.2%-28.8%) decrease in harmful immune system function over time”. Therefore, excluding this study and its 50 participants had no effect on the main findings.

    In reexamining all of the moderating factors previously investigated, only one difference emerged. Namely, the difference between psychosocial interventions that included at least one group session vs those that did not, which was previously marginally significant (F1,55 = 3.70; P = .06), became significant (F1,54 = 4.85; P = .03), such that interventions with a group component (ppc g = 0.38, 95% CI, 0.23-0.53) were more consistently associated with changes in immune system function than those without a group component (ppc g = 0.18, 95% CI, 0.06-0.30). No other moderators that were previously nonsignificant became significant or vice versa. In terms of the cancer findings, we previously reported that psychosocial interventions were not significantly associated with changes in immune system function in participants seeking treatment for cancer (ppc g = 0.31, 95% CI, -0.05-0.68; t5.5 = 2.16; P = .08), and this finding remained the same with the Grossarth-Maticek & Eysenck study removed (ppc g = 0.24, 95% CI, -0.12-0.66; t4.5 = 1.76; P = .145). Because their study did not use CBT, none of the CBT-specific analyses were altered as a result of excluding the study.

    In closing, we wholeheartedly denounce all forms of scientific misconduct and are sorry that the Grossarth-Maticek & Eysenck study was not retracted prior to our analysis. However, our reanalysis of the data confirms the previously reported findings and suggests that psychosocial interventions with a group component may have some added benefit that may be worthy of further investigation. Given the importance of this topic, we hope more high-quality RCTs will be conducted to improve the quality and size of this literature and to examine the relevance of these findings for clinical outcomes, a follow-up topic this meta-analysis was not designed to investigate.
    CONFLICT OF INTEREST: None Reported
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