Asian Journal of Psychiatry 86 (2023) 103636

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Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

Effects of a six-month yoga intervention on the immune-inflammatory

pathway in antipsychotic-stabilized schizophrenia patients: A randomized
controlled trial
Thrinath Mullapudi a, 1, Monojit Debnath a, 1, Ramajayam Govindaraj b, Praveen Raj c,
Moinak Banerjee d, Shivarama Varambally c, e, *, 2
a
Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
b
Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
c
Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
d
Human Molecular Genetics Lab, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India
e
Department of Integrative Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Schizophrenia is a complex neuropsychiatric disorder for which several etiopathological theories
Schizophrenia have been proposed, one of the prominent ones being immune dysfunction. Recent studies on yoga as an add-on
Cytokines therapy have shown improvement in negative symptoms, cognition, and quality of life in schizophrenia patients.
Inflammation
However, the biological mechanism/s of action of yoga in schizophrenia are not clear. The current study was
Pharmacotherapy
Yoga therapy
aimed at exploring the effects of long-term (6 months) add-on yoga therapy on the immune inflammatory
Immunomodulation pathway in schizophrenia patients.
Methods: Sixty schizophrenia patients were randomized to add-on yoga therapy (YT=30) and treatment-as-usual
(TAU=30) groups of which 21 patients in YT and 20 in TAU group completed the study. Blood samples and
clinical assessments were obtained at baseline and at the end of 6 months. The plasma levels of nine cytokines
(IL-2, IL-4, IL-5, IL-10, IL-12(p70), IL-13, GM-CSF, IFN-γ, and TNF-α) were quantified using multiplex suspension
array. The clinical assessments included SAPS, SANS, BPRS, PSS, CGI, SOFS and WHOQUOL-BREF.
Results: Patients in the yoga group showed significant reductions in plasma TNF-α (Z = 2.99, p = 0.003) and IL-5
levels (Z = 2.20, p = 0.03) and greater clinical improvements in SAPS, SANS, PSS, and SOFS scores as compared
to TAU group. Further, plasma TNF-α levels exhibited a positive correlation with negative symptoms (rs =0.45, p
= 0.02) and socio-occupational functioning (rs =0.61, p = 0.002) in the YT group.
Conclusions: The findings of the study suggest that improvements in schizophrenia psychopathology with yoga
interventions are associated with immuno-modulatory effects.

1. Introduction etiological hypotheses, abnormal immune functioning has been impli­

cated as one of the widely recognized etiological constructs of schizo­
Schizophrenia is an etiologically heterogenous, and phenotypically phrenia, both by clinical and pre-clinical studies (Subbanna et al., 2018;
complex neuropsychiatric disorder, which significantly disrupts normal Talukdar et al., 2020). Altered levels of inflammatory cytokines in the
functions of several somatic and psychological domains of an individual. peripheral blood and post-mortem brain tissues and their impact on the
Multiple environmental risk and vulnerability factors have been thought core clinical features of schizophrenia have been demonstrated by
to confer the risk of schizophrenia through gene-environment in­ several studies (Goldsmith et al., 2016; Van Kesteren et al., 2017;
teractions (Wahbeh and Avramopoulos, 2021). Among the several Dawidowski et al., 2021). More importantly, there is an emerging

* Correspondence to: Department of Psychiatry and, Department of Integrative Medicine, NIMHANS, Hosur Road, Bangalore 560029, India.
E-mail addresses: [email protected] (T. Mullapudi), [email protected] (M. Debnath), [email protected] (R. Govindaraj), [email protected]
(P. Raj), [email protected] (M. Banerjee), [email protected] (S. Varambally).
1
Contributed equally.
2
Department of Psychiatry and, Department of Integrative Medicine, NIMHANS, Hosu Road, Bangalore – 560029. India

https://doi.org/10.1016/j.ajp.2023.103636
Received 13 February 2023; Received in revised form 20 May 2023; Accepted 21 May 2023
Available online 24 May 2023
1876-2018/© 2023 Elsevier B.V. All rights reserved.
T. Mullapudi et al. Asian Journal of Psychiatry 86 (2023) 103636

evidence for immuno-inflammatory pathway alterations leading to effects of yoga therapy, the current study for the first time aims to
neuroprogressive changes in schizophrenia (Talukdar et al., 2021). explore the impact of long-term (6 months) add-on yoga therapy on
The multifactorial basis of schizophrenia has substantially contrib­ immuno-inflammatory pathway in patients with schizophrenia.
uted to the complex nature of schizophrenia phenome and symptoma­
tome (Maes et al., 2020b). This in turn has drastically affected the 2. Study participants and methods
diagnosis, treatment and prognosis of schizophrenia. Currently, phar­
macotherapy, albeit with certain limitations, is the main stay treatment 2.1. Study participants
for the management of schizophrenia (Patel et al., 2014; Lieberman
et al., 2005). Significant lacunae remain in the treatment of negative A total of 597 individuals diagnosed with schizophrenia were
symptoms (Remington et al., 2016) and cognitive deficits (Baldez et al., screened from the out-patient and in-patient services of the Department
2021) in schizophrenia, although antipsychotics are quite effective in of Psychiatry, National Institute of Mental Health and Neurosciences
the treatment of positive symptoms. Further, several problems like (NIMHANS), Bangalore and the District Mental Health Services, Ram­
refractoriness to medication and frequent relapses still persist despite anagara, Karnataka, India as part of a Randomized Controlled Trial
the use of best second-generation antipsychotics (Tandon et al., 2010) funded by the DBT-Wellcome Trust India Alliance evaluating the effects
and these drugs also have troublesome adverse effects, both neurological of a validated yoga module on symptoms and neuroplasticity markers in
(Stroup and Gray, 2018) and metabolic (Pillinger et al., 2020). Till date, patients with schizophrenia (Varambally et al., 2019). The diagnosis of
no effective remedies exist to alleviate these disabling symptoms and schizophrenia was based on DSM-V (American Psychiatric Association,
adverse effects which lead to significantly increased mortality and 2013) criteria and Mini-International Neuropsychiatric Interview Plus
morbidity in patients. Further, a relapsing and remitting course has been (M.I.N.I.) (Sheehan et al., 1998) and confirmed independently by a
observed in majority of these patients (Rubio et al., 2020). qualified psychiatrist. The inclusion criteria for selecting schizophrenia
During the past few years, several attempts have been made to patients were 18–45 years of age, both sexes, right handedness, stable
evaluate the efficacy of various non-pharmacological/alternative ther­ dosage of antipsychotic medications (risperidone or clozapine) for six
apies for the management of major psychiatric disorders including weeks, and clinical global impression rating score of ≥ 3, and willing to
schizophrenia (Asher et al., 2017; Helgason and Sarris, 2013). Notably, sign informed consent. The exclusion criteria were recent history of
yoga-based interventions have shown encouraging results as a comple­ high-grade fever/infection within the past 6 weeks, treatment with
mentary treatment approach in schizophrenia and other major psychi­ medications known to affect immune system or co-existing diseases that
atric disorders (Cabral et al., 2011). A specific yoga module as an add-on can potentially influence immune function, risk of harm to self or others,
therapy was shown to have beneficial effects on negative symptoms (Rao need for electroconvulsive therapy, already practicing/recent practice
et al., 2021; Duraiswamy et al., 2007), social cognition, cognitive of yoga/ meditation, comorbid substance dependence in the past 6
function (Govindaraj et al., 2021; Verma et al., 2018) and quality of life months or substance abuse in the past 1 month as per DSM-V (except
(Ikai-Tani et al., 2020). Some biological and social cognitive markers nicotine), significant neurological disorder including seizure disorder or
have been shown to correlate with the improvements in psychopathol­ recent head injury, family history of any neurological disorders and
ogy, facial emotion recognition and increase in plasma oxytocin levels pregnancy or postpartum (<6 weeks after delivery).
(Jayaram et al., 2013). A recent study has also suggested usefulness of The demographic and clinical information were collected using
yoga therapy in managing antipsychotic-induced side effects in patients structured scales and proforma. Psychopathology was assessed using the
with schizophrenia (Verma et al., 2018). However, there is a lack of Scale for Assessment of Positive Symptoms (SAPS) (Andreasen, 1984),
information on the effects of yoga therapy on the immune-inflammatory Scale for Assessment of Negative Symptoms (SANS) (Andreasen, 1989),
pathways in patients with schizophrenia. and Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962).
Metabolic syndrome (MetS) is present in around 32% of patients Social and occupational performance was rated on the Social Occupa­
with schizophrenia and is a major contributor for the increased mor­ tional Functioning Scale (SOFS) (Saraswat et al., 2006) and Quality of
tality and morbidity (Mitchell et al., 2013). Evidence suggests that life on the World Health Organization’s quality of life assessment
pro-inflammatory pathways are important in the development of (WHOQUOL-BREF) (Skevington et al., 2004). Perceived stress was rated
metabolic diseases like obesity, insulin resistance, type 2 diabetes using the Cohen Perceived Stress Scale (Cohen et al., 1983). All the
(Hotamisligil, 2010). Increasing studies indicate significant association clinical assessments were made at baseline and at the completion of six
of peripheral immune dysfunction with metabolic abnormalities in months. This study was approved by the Institutional Ethics Committee
schizophrenia. Patients with MetS have markedly higher total WBC of NIMHANS [No. NIMH/DO/ETHICS SUB-COMMITTEE (BS & NS)
counts, and C-reactive protein (CRP)/high sensitive CRP (hsCRP) levels 10TH MEETING/2019] and registered in Clinical trial registry India (No.
than patients without the MetS, and further abnormal immune compo­ CTRI/2019/12/022264).
nents were a significant predictor of MetS in schizophrenia (Miller et al.,
2013; Liemburg et al., 2018; Lee et al., 2019). Growing evidences 2.2. Study intervention
indicate dysfunctional inflammatory processes are associated with
increased incidence of MetS in patients with schizophrenia, which adds A single blinded, prospective randomized controled trial was carried
significantly to the risk profile and is associated with a marked reduction out for a duration of 6 months in schizophrenia patients (Fig. 1). Briefly,
in lifespan in these patients compared to the general population the patients fulfilling the inclusion and exclusion criteria, and willing to
(Mitchell et al., 2013). consent were randomly assigned to either the yoga therapy (YT) group
Notably, immuno-modulatory effects of yoga therapy have been re­ or Treatment-as-usual (TAU) group by using computer-generated
ported in other chronic conditions in recent times (Djalilova et al., 2019; random numbers and allocation concealment. The patients in the yoga
Estevao, 2022; Shah et al., 2022). Robust support towards this notion group were trained in a validated yoga module for schizophrenia
came from a large-scale molecular study on meditation practice showing (Govindaraj et al., 2016) (Table 1). The yoga module involves breathing
enhanced immune function without activating inflammatory responses and preparatory loosening exercises followed by asanas and pranayama;
(Chandran et al., 2021). In a recent study from our group, yoga therapy all practises were instructed to be performed with breathing awareness.
was shown to reduce the plasma levels of complement proteins like C1q, The module was taught by a certified yoga instructor for one month (20
Factor H and properdin, implying immune-dampening effects of yoga sessions over one month period) at the Department of Integrative
therapy in major depressive disorder (Subbanna et al., 2021). Given the medicine, NIMHANS. Further, patients in the yoga group were asked to
predominant role of immune dysregulation in schizophrenia pathobi­ continue the yoga practice at home for at least 3 days a week for the
ology and importance of immune markers in indexing the beneficial remaining five months.

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T. Mullapudi et al. Asian Journal of Psychiatry 86 (2023) 103636

Fig. 1. . The CONSORT (Consolidated Standards of Reporting Trials) flow diagram showing each stage of the trial.

Patients’ level of competence and performance in each of the yoga patient and the patients were told not to reveal their group to the
session were assessed with yoga performance assessment (YPA) and treating clinician.
patients were asked to maintain a record of number of days practiced per
week in a diary at home with the help of a caregiver. Also, YPA was
assessed at the end of each month from second to sixth months to check 2.3. Collection of blood samples
the consistency in performing the yoga sessions. All the patients
continued their antipsychotic medications as per the advice of the Approximately, 6 ml of peripheral blood was drawn from cubital
treating psychiatrist till the end of the study and patients requiring vein in Ethylenediaminetetraacetic acid (EDTA) coated vacutainer at
medication change for clinical reasons were dropped from the study. around 8–9 am, after overnight fasting at base line and after the trial
The treating clinician was blinded to the intervention received by the period (6 months). All the clinical assessments were also done at the
baseline as well as after the trial period. After 30 min, the blood samples

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T. Mullapudi et al. Asian Journal of Psychiatry 86 (2023) 103636

Table 1 cytokine data were not normally distributed. Hence, baseline data were
Shows the details of the yoga module used in the current study. analysed by Independent sample T test, gender by Chi-Square test (χ2),
Serial Yoga practice Duration (in and pre- and post-differences by non-parametric Wilcoxon signed rank
No. min.) test. Correlational analyses were performed using Spearman’s correla­
I. Preparatory loosening exercises with Surya namaskar tion test. Statistical tests are reported as significant when p-value is
1) Jogging (forward, backward, sideward) 2 < 0.05.
2) Forward & backward bending 1
3) Twisting 1
3. Results
4) Surya namaskar (Sun salutation) (8 rounds - 4 10
rounds slow & 4 rounds fast)
II. Slow movements with breathing awareness The participants of both the YT and TAU groups had comparable
1) Hand stretch breathing (90◦ , 135◦ , 180◦ ) 2 demographic parameters and clinical scores at baseline (Table 2).
2) Tiger breathing (9 rounds) 1
3) Shashankasana breathing 1
4) Dandasana 30 s 3.1. Impact of yoga therapy on schizophrenia psychopathology
III. Asanas
1) Sitting
Wilcoxon Signed Rank test was performed to assess the change in
1
a) Vakrasana (Half spinal twist)
clinical scores such as SAPS, SANS, SOFS, BPRS, CGI, PSS and WHOQOL-
1 BREF after the trial period in both the yoga therapy and treatment as
b) Ustrasana (Camel pose) usual groups. In the yoga therapy group, there were significant re­
2) Prone position asanas ductions in the SAPS, SANS, BPRS, CGI, PSS, SOFS and WHOQOL-BREF
1
scores, while in the treatment as usual group, significant reduction was
a) Bhujangasana (Cobra pose)
1 observed only in the SANS, BPRS, CGI, and WHOQOL-BREF scores
b) Shalabasana (Locust pose)s (Table 3).
1
c) Dhanurasana (Bow pose)
3) Supine position asanas 3.2. Impact of yoga therapy on the inflammatory cytokines in
3 schizophrenia patients
a) Sarvangasana/ Vipareetakarani (Inverted psychic
attitude)
Amongst the studied cytokines, the plasma levels of only four cyto­
1
b) Matsyasana (Fish pose) kines, such as IL-5, IL-12(p70), GM-CSF and TNF-α were at detectable
IV. Pranayama concentrations in all patients of both groups. Therefore, only these four
1) Bhastrika 2 cytokines were considered for further analysis. Significant differences
2) Nadisodhana (Alternate nostril breathing) (9 2 were observed for the plasma levels of TNF-α, IL-5 and GM-CSF between
rounds)
V. Relaxation & AUM Chanting
baseline and after the trial period in schizophrenia patients undergoing
1) Nadhanusandhana (A, U, M & AUM chanting- 9 8 yoga therapy, while the level of only GM-CSF was found to differ
rounds each)
Table 2
Demographic details and comparison of clinical characteristics of schizophrenia
were centrifuged at 3500 rpm for 10 min to separate the plasma sam­
patients at baseline between yoga therapy group and Treatment-as-usual group.
ples. The plasma samples were aliquoted and stored immediately at
Variable YT (n = 21) TAU (n = 20) t/χ2 p value
minus 80 ◦ C till analysis.
Mean ± SD Mean ± SD value

Age (years) 31.33 ± 7.34 34.95 ± 5.28 1.80 0.08

2.4. Measurement of the plasma levels of the cytokines Sex (M: F) 14: 7 13: 7 0.01 0.91
Duration of illness 7.29 ± 4.71 8.53 ± 5.08 0.81 0.42
The plasma levels of 9 cytokines (IL-2, IL-4, IL-5, IL-10, IL-12(p70), (years)
Age of onset (years) 25.10 ± 7.37 27.55 ± 7.93 1.03 0.31
IL-13, GM-CSF, IFN-γ, and TNF-α) were quantified in 21 schizophrenia
Socio-Economic Status 3.05 ± 1.07 3.25 ± 0.77 0.68 0.49
patients undergoing yoga therapy and 20 schizophrenia patients of SAPS 16.67 15.00 0.45 0.66
Treatment-as-usual group at baseline and at six months using Bio-Plex ± 10.39 ± 13.31
Pro Human Cytokine Th1/Th2 Assay (Cat. no. M5000005L3) in a Bio- SANS 40.90 44.50 ± 8.32 1.12 0.27
Plex 200 analyzer (Bio-Rad, Hercules, CA, USA). The sensitivity of the ± 11.91
BPRS 34.14 ± 4.81 35.95 ± 3.39 1.38 0.18
cytokines of this panel was high (pg/ml) and the limit of detection (LOD)
PSS 18.19 ± 4.55 18.85 ± 4.60 0.46 0.65
were as follows: IL-2 (1.78 – 7368 pg/ml), IL-4 (0.16 – 927 pg/ml), IL-5 CGI 4.04 ± 0.38 3.95 ± 0.51 0.69 0.49
(4.82 – 21,714 pg/ml), IL-10 (1.75–22,614 pg/ml), IL-12(p70) (1.22 – SOFS 25.684 27.70 ± 3.89 1.39 0.17
29,610 pg/ml), IL-13 (1.17 – 6231 pg/ml), GM-CSF (0.59 – 1975 pg/ ± 5.31
WHOQOL-BREF Total 74.91 72.37 ± 7.21 0.87 0.39
ml), IFN-γ(1.06 – 25,220 pg/ml), and TNF-α (2.8 – 12,834 pg/ml). All
± 10.96
the samples were assayed in duplicate. The standard curve of each TNFα 12.99 11.46 ± 2.34 1.14 0.26
cytokine was generated by using the standards provided in the kit by the ± 5.675
manufacturer. Bioplex Manager software 6.1 was used to analyse the IL-5 13.95 ± 8.22 10.94 ± 8.65 1.14 0.26
data according to the manufacturer’s instructions. IL-12(p70) 4.12 ± 2.96 3.69 ± 3.33 0.44 0.66
GM-CSF 3.39 ± 2.66 2.98 ± 2.13 0.54 0.59

t- Independent sample T Test, χ2 - Chi Square Test. Significance at p < 0.05,

2.5. Statistical analysis
SAPS – Scale for assessment of positive symptoms; SANS – Scale for assessment
of negative symptoms; SOFS – Social occupational functioning scale; BPRS- Brief
The statistical analyses were performed using SPSS software, psychiatry rating scale; CGI-Clinical global impression; PSS- Perceived stress
version-24 (IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: scale; WHOQOL BREF- WHO quality of life Brief version. IL-5 – Interleukin 5; IL-
IBM Corp). The potential outliers were excluded and data normality 12(p70) – Interleukin 12 (p70); GM-CSF- Granulocyte-macrophage colony-
check was performed by Shapiro Wilk test. All the baseline data were stimulating factor; TNFα - Tumor necrosis factor α. All cytokines are in pg/ml
normally distributed whereas some of the six months clinical and concentration.

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T. Mullapudi et al. Asian Journal of Psychiatry 86 (2023) 103636

Table 3
Differences in the psychopathology scores and plasma cytokine levels in the
yoga therapy and Treatment-as-usual groups between baseline and after the trial
period.
Baseline Follow-up Z p-value
Mean ± SD (6 M) score#
Mean ± SD

Yoga therapy group

(n ¼ 21)
SAPS 16.67 7.04 ± 7.12 3.68 < 0.001**
± 10.39
SANS 40.90 19.38 4.02 < 0.001**
± 11.91 ± 13.47
BPRS 34.14 27.81 3.23 0.001*
± 4.81 ± 3.17
PSS 18.19 14.00 2.36 0.02*
± 4.55 ± 4.93
CGI 4.04 2.19 ± 0.81 4.04 < 0.001**
± 0.38
SOFS 25.67 23.14 3.10 0.002*
± 5.31 ± 4.95
WHOQOL-BREF 74.92 81.29 3.23 0.001* Fig. 2. Correlation of change in plasma TNF-α levels with change in SANS score
± 10.97 ± 9.81 in yoga therapy group. Mean and 95% confidence interval are represented by a
TNFα (pg/ml) 12.99 9.89 ± 3.68 2.99 0.003* continuous line and dotted lines, respectively.
± 5.67
IL-5 (pg/ml) 13.95 12.10 2.20 0.03*
± 8.22 ± 8.22
IL-12(p70) (pg/ml) 4.12 3.85 ± 3.08 1.32 0.19
± 2.96
GM-CSF (pg/ml) 3.39 3.17 ± 2.60 2.39 0.02*
± 2.66
Treatment-as-usual
group (n ¼ 20)
SAPS 15.00 12.80 1.92 0.06
± 13.31 ± 14.22
SANS 44.50 36.40 3.59 < 0.001**
± 8.33 ± 10.28
BPRS 35.95 33.15 2.26 0.02*
± 3.39 ± 5.11
PSS 18.85 16.95 1.88 0.08
± 4.60 ± 5.28
CGI 3.95 3.45 ± 0.75 2.02 0.03*
± 0.51
SOFS 27.70 26.85 1.57 0.18
± 3.89 ± 5.54
WHOQOL-BREF 72.37 74.50 2.03 0.04*
± 7.22 ± 7.50
TNFα 11.46 11.15 1.68 0.09
± 2.34 ± 8.19
IL-5 10.94 10.08 0.25 0.80
± 8.65 ± 8.59 Fig. 3. Correlation of change in plasma TNF-α levels with the change in SOFS
IL-12(p70) 3.69 3.29 ± 3.04 1.07 0.29 scores in yoga therapy group. Mean and 95% confidence interval are repre­
± 3.33
sented by a continuous line and dotted lines, respectively.
GM-CSF 2.98 2.79 ± 2.05 2.22 0.03*
± 2.13
inflammatory markers such as TNF-α, IL-5 and GM-CSF in patients with
# Wilcoxon signed rank test. Significance at **p ≤ 0.001*p < 0.05. The sensi­
schizophrenia. Six months of yoga therapy significantly reduced the
tivity of the Th1/Th2
cytokines panel was high (pg/ml) and the limit of detection (LOD) for cytokines plasma levels of TNF-α, IL-5 and GM-CSF in patients with schizophrenia.
were as follows: IL-5 (4.82 – 21,714 pg/ml), IL-12(p70) (1.22 – 29,610 pg/ml), Schizophrenia patients receiving standard antipsychotic medication had
GM-CSF (0.59 – 1975 pg/ml), and TNF-α (2.8 – 12,834 pg/ml). significantly reduced plasma levels of only GM-CSF after the trial period.
It is noteworthy that six months yoga therapy also significantly reduced
significantly in the TAU group (Table 3). Reduction in plasma levels of psychopathology as measured by SAPS, SANS, BPRS, PSS, CGI, SOFS and
TNF-α showed a significant positive correlation with the changes in WHOQOL-BREF. More importantly, the reduction of the plasma levels of
SANS score (rs =0.45, p = 0.02) (Fig. 2) and SOFS score (rs =0.61, TNF-α was correlated with improvements in negative symptoms and
p = 0.002) (Fig. 3) among schizophrenia patients in the YT group. SOFS.
Diverging lines of evidence have reported a pivotal role of TNF-α in
4. Discussion schizophrenia immunopathogenesis. Association between blood TNF-α
levels (Luo et al., 2019; Goldsmith et al., 2016) as well as genetic vari­
The immune inflammatory pathway has emerged as a paradigmatic ations within TNF-α gene with schizophrenia risk (Suchanek-Raif et al.,
etiological model in a substantial subset of patients with schizophrenia 2018; Srinivas et al., 2016) have been reported by multiple studies.
(Bishop et al., 2022). Immune aberrations are also increasingly being Further, elevated TNF, sTNFR1 and sTNFR2 levels and a significantly
considered as relevant biosignatures in clinical practice. The current increased TNF/sTNFRs ratio, which serve as a surrogate marker of TNF
study for the first time reports novel observations on the significant bioactivity were reported in the blood of schizophrenia patients (Hoseth
impact of long-term (6 months) add-on yoga therapy on the crucial et al., 2017; Aukrust et al., 1999). Elevated plasma levels of TNF-α have

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T. Mullapudi et al. Asian Journal of Psychiatry 86 (2023) 103636

been reported to mediate increased psychopathology and neuro­ at baseline decreased remarkably (Z = 2.20, p = 0.03) after the add-on
cognitive impairments in schizophrenia (Maes et al., 2020a). Notably, yoga therapy. This suggests that yoga may ameliorate schizophrenia
TNF-a is increasingly being considered as a potential target of therapy. symptoms through its action on IL-5 as well as by modulating eosinophil
Chronic schizophrenia patients on long-term antipsychotic treatment function and allergic responses.
were shown to have significantly lower TNF-a levels compared to Besides TNF-α and IL-5, the plasma levels of GM-CSF were signifi­
healthy controls (Lv et al., 2015). A meta-analysis of cytokine alterations cantly downregulated after the trial period. However, reductions in its
in schizophrenia after treatment with antipsychotics found that TNF-a levels were observed in schizophrenia patients of both YT and TAU
levels are elevated in first episode drug naïve (FEDN) and acute groups. Current evidence suggests that GM-CSF acts as a signaling
relapse schizophrenia patients which tend to decrease (although not molecule between invading tissue lymphocytes and myeloid cells and
statistically significant) after 58 mean days of antipsychotic treatment thereby a major mediator of inflammation in body tissues (Ingelfinger
(Miller et al., 2011). Schizophrenia patients included in our study were et al., 2021). GM-CSF has been implicated in the pathogenesis of many
on a minimum of 6 weeks of stable antipsychotics, risperidone or clo­ autoimmune disorders. In the brain, GM-CSF is known to have a role in
zapine (second generation antipsychotics) and rarely on first generation the activation of microglia with subsequent impact on the neuronal
antipsychotics. A meta-analysis examining the antipsychotics’ (typical, survival, excitability, and synaptic transmission. In an in vivo study of
atypical and mixed) effects on blood cytokine levels in schizophrenia axonal spheroids and pigmented glia (ALSP), a subtype of frontal tem­
found that TNF-a levels are not significantly reduced post treatment poral dementia, the elevated expression of GM-CSF lead to microgliosis,
(Tourjman et al., 2013). This coincides with our finding on the unaltered demyelination and cognitive impairments which are reversed by
plasma levels of TNF-α in schizophrenia patients receiving only anti­ GM-CSF down regulation (Chitu et al., 2020). In an in vitro study, the
psychotic treatment. exposure of microglia cells to GM-CSF lead to microglia activation and
It is important to note that TNF-α has both immune and non-immune neuronal network dysfunction (Dikmen et al., 2020) which might
attributes. TNF-α is a key mediator of inflammatory signaling (Zelova contribute to cognitive impairment. The above evidence suggests
and Hosek, 2013). Besides this, TNF-α plays pivotal roles in maintaining important roles for GM-CSF in neuronal dysregulation as well as
normal function of brain, especially the regulation of synaptic plasticity, neuroinflammation.
including synaptic scaling, hippocampal neurogenesis, etc. (Pickering Pathological relevance of GM-CSF in psychosis has been described by
et al., 2005; Heir and Stellwagen, 2020). TNF-α is known to execute its multiple studies (Hercus et al., 2018; Frydecka et al., 2018; Noto et al.,
effector functions through activation of two different receptors, such as 2019). In a recent cross-sectional study, significantly elevated levels of
TNF-R1 and TNF-R2. In a recent study, TNF-R1 and TNF-R2 signaling GM-CSF were seen in multiple-episode schizophrenia patients compared
was shown to exert differential effects on adult hippocampal neuro­ to healthy controls (Frydecka et al., 2018). In the current study,
genesis and TNF-R1 was identified as the negative regulator of neuronal reduction in the plasma levels of GM-CSF is a notable finding, being
progenitor proliferation in both the normal and pathological brain (Iosif reported for the first time. This reduction may have been contributed to
et al., 2006). In an in vitro study, exposure of hippocampal pyramidal by antipsychotic medication and/ or yoga therapy. This improvement
neuronal cells to TNF-α led to the activation of TNF-R1, increased could possibly be linked to good medical care received by patients in this
excitatory (AMPA) synaptic strength and decreased inhibitory (GABA) study and better adherence to pharmacotherapy due to regular
synaptic strength, contributing to exacerbation of excitotoxic damage to follow-ups by project staff. This finding needs confirmation and further
neurons (Stellwagen et al., 2005). This implies a pivotal role of TNF-α in evaluation in future studies.
the regulation of neurotransmission in the human nervous system. A few earlier studies have demonstrated significant modulatory ef­
However, altered regulation of TNF-α signaling was shown to cause fects of adjunct yoga therapy on various core features of schizophrenia,
neuroinflammation and disrupt the normal functioning of the brain as particularly negative symptoms and quality of life (Bangalore and Var­
well as affect the behavior (Olmos and Llado, 2014). In an animal study, ambally, 2012; Govindaraj et al., 2020; Rao et al., 2021). The current
local increase of TNF-α in the hippocampal dentate gyrus was shown to study for the first time provides evidence towards immuno-modulatory
impair memory by triggering an astrocyte-neuron signaling cascade effects of adjunct long-term yoga therapy in patients with schizophrenia.
(Habbas et al., 2015). Given the pivotal role of TNF-α in
schizophrenia-related neurobiological aberrations and immunopatho­ 4.1. Strengths and limitations
genesis of schizophrenia, it seems to be a potential pathogenic immune
molecule. The modulatory effects of yoga therapy on the plasma levels of The main strengths of this study include i) standard methods of
TNF-α add important knowledge to the aetiopathology of schizophrenia diagnosis, randomization and rater-blinding, ii) use of a validated yoga
and suggest that yoga therapy might confer beneficial effects in module for schizophrenia patients, iii) evaluation of long-term i.e., 6
schizophrenia through TNF-α signaling pathway, predominantly by months yoga therapy and iv) analysis of a panel of nine immune mole­
modulating inflammatory and synaptic plasticity-related processes. cules. A small sample size is one of the major limitations of the study.
Another notable finding was the significant reduction of the plasma
levels of IL-5 in schizophrenia patients undergoing add-on yoga therapy 5. Conclusion
after the trial period. IL-5 is predominantly involved in the induction,
proliferation and differentiation of eosinophils (Bochner and Gleich, Our study, for the first time, shows preliminary evidence towards
2010) and also activates B cells for antibody production (Horikawa and immuno-modulatory effects of yoga therapy in patients with schizo­
Takatsu, 2006). Preclinical studies have shown that IL-5 deficiency leads phrenia stabilized on antipsychotics. These findings, if replicated, can
to reduced circulating eosinophils and fails to establish immune throw light on the contribution of the immuno-inflammatory pathway in
response against parasites (Tran et al., 2017). IL-5 plays a key role in the aetiopathology of schizophrenia and also provide further support for
inflammation and allergic responses (Greenfeder et al., 2001). Elevated yoga as a complementary intervention. These findings also have impli­
levels of IL-5 has been reported in asthma, hypereosinophilic syndrome cations for reducing the burden of difficult-to treat negative symptoms
and eosinophilic esophagitis (Roufosse, 2018). Contextually, adolescent and MetS which are associated with increased levels of inflammation in
asthma is shown to be associated with increased risk of schizophrenia patients suffering from this severe but enigmatic disorder.
(Pedersen et al., 2012; Khandaker et al., 2014). Studies on IL-5 in psy­
chiatric conditions, particularly schizophrenia, are limited. IL-5 levels Funding
were found to be significantly elevated in adult schizophrenia patients
(Yeh et al., 2019) as well as in first-episode pediatric psychosis patients This study was supported by the DBT-Wellcome Trust India Alliance
(Falcone et al., 2015). In our study, the elevated levels of IL-5 observed grant awarded to Dr. Shivarama Varambally (Grant Number IA/CPHI/

6
T. Mullapudi et al. Asian Journal of Psychiatry 86 (2023) 103636

15/1/502026). Govindaraj, R., Naik, S.S., Mehta, U.M., Sharma, M., Varambally, S., Gangadhar, B.N.,
2021. Yoga therapy for social cognition in schizophrenia: an experimental medicine-
based randomized controlled trial. Asian J. Psychiatr. 62.
Greenfeder, S., Umland, S.P., Cuss, F.M., Chapman, R.W., Egan, R.W., 2001. Th2
Declaration of Competing Interest cytokines and asthma The role of interleukin-5 in allergic eosinophilic disease.
Respir. Res. 2 (2), 71–79.
Habbas, S., Santello, M., Becker, D., Stubbe, H., Zappia, G., Liaudet, N., Klaus, F.R.,
The authors have no conflict of interest to declare. Kollias, G., Fontana, A., Pryce, C.R., Suter, T., Volterra, A., 2015. Neuroinflammatory
TNFalpha Impairs Memory via Astrocyte Signaling. Cell 163 (7), 1730–1741.
Acknowledgement Heir, R., Stellwagen, D., 2020. TNF-mediated homeostatic synaptic plasticity: from in
vitro to in vivo models. Front. Cell Neurosci. 14.
Helgason, C., Sarris, J., 2013. Mind-body medicine for schizophrenia and psychotic
We thank Mr. Kaushik K for conducting yoga therapy sessions for the disorders: a review of the evidence. Clin. Schizophr. Relat. Psychoses 7 (3), 138–148.
study participants. Hercus, T.R., Kan, W.L.T., Broughton, S.E., Tvorogov, D., Ramshaw, H.S., Sandow, J.J.,
Nero, T.L., Dhagat, U., Thompson, E.J., Shing, K., Mckenzie, D.R., Wilson, N.J.,
Owczarek, C.M., Vairo, G., Nash, A.D., Tergaonkar, V., Hughes, T., Ekert, P.G.,
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