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

Schizophrenia is an etiologically heterogenous, and phenotypically
complex neuropsychiatric disorder, which significantly disrupts normal
functions of several somatic and psychological domains of an individual.
Multiple environmental risk and vulnerability factors have been thought
to confer the risk of schizophrenia through gene-environment in­
teractions (Wahbeh and Avramopoulos, 2021). Among the several
cated as one of the widely recognized etiological constructs of schizo­
phrenia, both by clinical and pre-clinical studies (Subbanna et al., 2018;
Talukdar et al., 2020). Altered levels of inflammatory cytokines in the
peripheral blood and post-mortem brain tissues and their impact on the
core clinical features of schizophrenia have been demonstrated by
several studies (Goldsmith et al., 2016; Van Kesteren et al., 2017;
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: thrinath97@gmail.com (T. Mullapudi), monozeet@gmail.com (M. Debnath), ramji.zero@gmail.com (R. Govindaraj), pvr.ggs@gmail.com
(P. Raj), moinak@gmail.com (M. Banerjee), ssv.nimhans@gmail.com (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.
evidence for immuno-inflammatory pathway alterations leading to
neuroprogressive changes in schizophrenia (Talukdar et al., 2021).
The multifactorial basis of schizophrenia has substantially contrib­
uted to the complex nature of schizophrenia phenome and symptoma­
tome (Maes et al., 2020b). This in turn has drastically affected the
diagnosis, treatment and prognosis of schizophrenia. Currently, phar­
macotherapy, albeit with certain limitations, is the main stay treatment
for the management of schizophrenia (Patel et al., 2014; Lieberman
et al., 2005). Significant lacunae remain in the treatment of negative
symptoms (Remington et al., 2016) and cognitive deficits (Baldez et al.,
2021) in schizophrenia, although antipsychotics are quite effective in
the treatment of positive symptoms. Further, several problems like
refractoriness to medication and frequent relapses still persist despite
the use of best second-generation antipsychotics (Tandon et al., 2010)
and these drugs also have troublesome adverse effects, both neurological
(Stroup and Gray, 2018) and metabolic (Pillinger et al., 2020). Till date,
no effective remedies exist to alleviate these disabling symptoms and
adverse effects which lead to significantly increased mortality and
morbidity in patients. Further, a relapsing and remitting course has been
observed in majority of these patients (Rubio et al., 2020).
During the past few years, several attempts have been made to
evaluate the efficacy of various non-pharmacological/alternative ther­
apies for the management of major psychiatric disorders including
schizophrenia (Asher et al., 2017; Helgason and Sarris, 2013). Notably,
yoga-based interventions have shown encouraging results as a comple­
mentary treatment approach in schizophrenia and other major psychi­
atric disorders (Cabral et al., 2011). A specific yoga module as an add-on
therapy was shown to have beneficial effects on negative symptoms (Rao
et al., 2021; Duraiswamy et al., 2007), social cognition, cognitive
function (Govindaraj et al., 2021; Verma et al., 2018) and quality of life
(Ikai-Tani et al., 2020). Some biological and social cognitive markers
have been shown to correlate with the improvements in psychopathol­
ogy, facial emotion recognition and increase in plasma oxytocin levels
(Jayaram et al., 2013). A recent study has also suggested usefulness of
yoga therapy in managing antipsychotic-induced side effects in patients
with schizophrenia (Verma et al., 2018). However, there is a lack of
information on the effects of yoga therapy on the immune-inflammatory
pathways in patients with schizophrenia.
Metabolic syndrome (MetS) is present in around 32% of patients
with schizophrenia and is a major contributor for the increased mor­
tality and morbidity (Mitchell et al., 2013). Evidence suggests that
pro-inflammatory pathways are important in the development of
metabolic diseases like obesity, insulin resistance, type 2 diabetes
(Hotamisligil, 2010). Increasing studies indicate significant association
of peripheral immune dysfunction with metabolic abnormalities in
schizophrenia. Patients with MetS have markedly higher total WBC
counts, and C-reactive protein (CRP)/high sensitive CRP (hsCRP) levels
than patients without the MetS, and further abnormal immune compo­
nents were a significant predictor of MetS in schizophrenia (Miller et al.,
2013; Liemburg et al., 2018; Lee et al., 2019). Growing evidences
indicate dysfunctional inflammatory processes are associated with
increased incidence of MetS in patients with schizophrenia, which adds
significantly to the risk profile and is associated with a marked reduction
in lifespan in these patients compared to the general population
(Mitchell et al., 2013).
Notably, immuno-modulatory effects of yoga therapy have been re­
ported in other chronic conditions in recent times (Djalilova et al., 2019;
Estevao, 2022; Shah et al., 2022). Robust support towards this notion
came from a large-scale molecular study on meditation practice showing
enhanced immune function without activating inflammatory responses
(Chandran et al., 2021). In a recent study from our group, yoga therapy
was shown to reduce the plasma levels of complement proteins like C1q,
Factor H and properdin, implying immune-dampening effects of yoga
therapy in major depressive disorder (Subbanna et al., 2021). Given the
predominant role of immune dysregulation in schizophrenia pathobi­
ology and importance of immune markers in indexing the beneficial
2
Asian Journal of Psychiatry 86 (2023) 103636
effects of yoga therapy, the current study for the first time aims to
explore the impact of long-term (6 months) add-on yoga therapy on
immuno-inflammatory pathway in patients with schizophrenia.
2. Study participants and methods
2.1. Study participants
A total of 597 individuals diagnosed with schizophrenia were
screened from the out-patient and in-patient services of the Department
of Psychiatry, National Institute of Mental Health and Neurosciences
(NIMHANS), Bangalore and the District Mental Health Services, Ram­
anagara, Karnataka, India as part of a Randomized Controlled Trial
funded by the DBT-Wellcome Trust India Alliance evaluating the effects
of a validated yoga module on symptoms and neuroplasticity markers in
patients with schizophrenia (Varambally et al., 2019). The diagnosis of
schizophrenia was based on DSM-V (American Psychiatric Association,
2013) criteria and Mini-International Neuropsychiatric Interview Plus
(M.I.N.I.) (Sheehan et al., 1998) and confirmed independently by a
qualified psychiatrist. The inclusion criteria for selecting schizophrenia
patients were 18–45 years of age, both sexes, right handedness, stable
dosage of antipsychotic medications (risperidone or clozapine) for six
weeks, and clinical global impression rating score of ≥ 3, and willing to
sign informed consent. The exclusion criteria were recent history of
high-grade fever/infection within the past 6 weeks, treatment with
medications known to affect immune system or co-existing diseases that
can potentially influence immune function, risk of harm to self or others,
need for electroconvulsive therapy, already practicing/recent practice
of yoga/ meditation, comorbid substance dependence in the past 6
months or substance abuse in the past 1 month as per DSM-V (except
nicotine), significant neurological disorder including seizure disorder or
recent head injury, family history of any neurological disorders and
pregnancy or postpartum (<6 weeks after delivery).
The demographic and clinical information were collected using
structured scales and proforma. Psychopathology was assessed using the
Scale for Assessment of Positive Symptoms (SAPS) (Andreasen, 1984),
Scale for Assessment of Negative Symptoms (SANS) (Andreasen, 1989),
and Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962).
Social and occupational performance was rated on the Social Occupa­
tional Functioning Scale (SOFS) (Saraswat et al., 2006) and Quality of
life on the World Health Organization’s quality of life assessment
(WHOQUOL-BREF) (Skevington et al., 2004). Perceived stress was rated
using the Cohen Perceived Stress Scale (Cohen et al., 1983). All the
clinical assessments were made at baseline and at the completion of six
months. This study was approved by the Institutional Ethics Committee
of NIMHANS [No. NIMH/DO/ETHICS SUB-COMMITTEE (BS & NS)
10TH MEETING/2019] and registered in Clinical trial registry India (No.
CTRI/2019/12/022264).
2.2. Study intervention
A single blinded, prospective randomized controled trial was carried
out for a duration of 6 months in schizophrenia patients (Fig. 1). Briefly,
the patients fulfilling the inclusion and exclusion criteria, and willing to
consent were randomly assigned to either the yoga therapy (YT) group
or Treatment-as-usual (TAU) group by using computer-generated
random numbers and allocation concealment. The patients in the yoga
group were trained in a validated yoga module for schizophrenia
(Govindaraj et al., 2016) (Table 1). The yoga module involves breathing
and preparatory loosening exercises followed by asanas and pranayama;
all practises were instructed to be performed with breathing awareness.
The module was taught by a certified yoga instructor for one month (20
sessions over one month period) at the Department of Integrative
medicine, NIMHANS. Further, patients in the yoga group were asked to
continue the yoga practice at home for at least 3 days a week for the
remaining five months.
T. Mullapudi et al.
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
session were assessed with yoga performance assessment (YPA) and
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
the consistency in performing the yoga sessions. All the patients
continued their antipsychotic medications as per the advice of the
treating psychiatrist till the end of the study and patients requiring
medication change for clinical reasons were dropped from the study.
The treating clinician was blinded to the intervention received by the
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Asian Journal of Psychiatry 86 (2023) 103636
patient and the patients were told not to reveal their group to the
treating clinician.
2.3. Collection of blood samples
Approximately, 6 ml of peripheral blood was drawn from cubital
vein in Ethylenediaminetetraacetic acid (EDTA) coated vacutainer at
around 8–9 am, after overnight fasting at base line and after the trial
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
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
The statistical analyses were performed using SPSS software,
version-24 (IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY:
IBM Corp). The potential outliers were excluded and data normality
check was performed by Shapiro Wilk test. All the baseline data were
normally distributed whereas some of the six months clinical and
SAPS – Scale for assessment of positive symptoms; SANS – Scale for assessment
of negative symptoms; SOFS – Social occupational functioning scale; BPRS- Brief
psychiatry rating scale; CGI-Clinical global impression; PSS- Perceived stress
scale; WHOQOL BREF- WHO quality of life Brief version. IL-5 – Interleukin 5; IL-
12(p70) – Interleukin 12 (p70); GM-CSF- Granulocyte-macrophage colony-
stimulating factor; TNFα - Tumor necrosis factor α. All cytokines are in pg/ml
concentration.

4
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

5
T. Mullapudi et al.
been reported to mediate increased psychopathology and neuro­
cognitive impairments in schizophrenia (Maes et al., 2020a). Notably,
TNF-a is increasingly being considered as a potential target of therapy.
Chronic schizophrenia patients on long-term antipsychotic treatment
were shown to have significantly lower TNF-a levels compared to
healthy controls (Lv et al., 2015). A meta-analysis of cytokine alterations
in schizophrenia after treatment with antipsychotics found that TNF-a
levels are elevated in first episode drug naïve (FEDN) and acute
relapse schizophrenia patients which tend to decrease (although not
statistically significant) after 58 mean days of antipsychotic treatment
(Miller et al., 2011). Schizophrenia patients included in our study were
on a minimum of 6 weeks of stable antipsychotics, risperidone or clo­
zapine (second generation antipsychotics) and rarely on first generation
antipsychotics. A meta-analysis examining the antipsychotics’ (typical,
atypical and mixed) effects on blood cytokine levels in schizophrenia
found that TNF-a levels are not significantly reduced post treatment
(Tourjman et al., 2013). This coincides with our finding on the unaltered
plasma levels of TNF-α in schizophrenia patients receiving only anti­
psychotic treatment.
It is important to note that TNF-α has both immune and non-immune
attributes. TNF-α is a key mediator of inflammatory signaling (Zelova
and Hosek, 2013). Besides this, TNF-α plays pivotal roles in maintaining
normal function of brain, especially the regulation of synaptic plasticity,
including synaptic scaling, hippocampal neurogenesis, etc. (Pickering
et al., 2005; Heir and Stellwagen, 2020). TNF-α is known to execute its
effector functions through activation of two different receptors, such as
TNF-R1 and TNF-R2. In a recent study, TNF-R1 and TNF-R2 signaling
was shown to exert differential effects on adult hippocampal neuro­
genesis and TNF-R1 was identified as the negative regulator of neuronal
progenitor proliferation in both the normal and pathological brain (Iosif
et al., 2006). In an in vitro study, exposure of hippocampal pyramidal
neuronal cells to TNF-α led to the activation of TNF-R1, increased
excitatory (AMPA) synaptic strength and decreased inhibitory (GABA)
synaptic strength, contributing to exacerbation of excitotoxic damage to
neurons (Stellwagen et al., 2005). This implies a pivotal role of TNF-α in
the regulation of neurotransmission in the human nervous system.
However, altered regulation of TNF-α signaling was shown to cause
neuroinflammation and disrupt the normal functioning of the brain as
well as affect the behavior (Olmos and Llado, 2014). In an animal study,
local increase of TNF-α in the hippocampal dentate gyrus was shown to
impair memory by triggering an astrocyte-neuron signaling cascade
(Habbas et al., 2015). Given the pivotal role of TNF-α in
schizophrenia-related neurobiological aberrations and immunopatho­
genesis of schizophrenia, it seems to be a potential pathogenic immune
molecule. The modulatory effects of yoga therapy on the plasma levels of
TNF-α add important knowledge to the aetiopathology of schizophrenia
and suggest that yoga therapy might confer beneficial effects in
schizophrenia through TNF-α signaling pathway, predominantly by
modulating inflammatory and synaptic plasticity-related processes.
Another notable finding was the significant reduction of the plasma
levels of IL-5 in schizophrenia patients undergoing add-on yoga therapy
after the trial period. IL-5 is predominantly involved in the induction,
proliferation and differentiation of eosinophils (Bochner and Gleich,
2010) and also activates B cells for antibody production (Horikawa and
Takatsu, 2006). Preclinical studies have shown that IL-5 deficiency leads
to reduced circulating eosinophils and fails to establish immune
response against parasites (Tran et al., 2017). IL-5 plays a key role in
inflammation and allergic responses (Greenfeder et al., 2001). Elevated
levels of IL-5 has been reported in asthma, hypereosinophilic syndrome
and eosinophilic esophagitis (Roufosse, 2018). Contextually, adolescent
asthma is shown to be associated with increased risk of schizophrenia
(Pedersen et al., 2012; Khandaker et al., 2014). Studies on IL-5 in psy­
chiatric conditions, particularly schizophrenia, are limited. IL-5 levels
were found to be significantly elevated in adult schizophrenia patients
(Yeh et al., 2019) as well as in first-episode pediatric psychosis patients
(Falcone et al., 2015). In our study, the elevated levels of IL-5 observed
6
Asian Journal of Psychiatry 86 (2023) 103636
at baseline decreased remarkably (Z = 2.20, p = 0.03) after the add-on
yoga therapy. This suggests that yoga may ameliorate schizophrenia
symptoms through its action on IL-5 as well as by modulating eosinophil
function and allergic responses.
Besides TNF-α and IL-5, the plasma levels of GM-CSF were signifi­
cantly downregulated after the trial period. However, reductions in its
levels were observed in schizophrenia patients of both YT and TAU
groups. Current evidence suggests that GM-CSF acts as a signaling
molecule between invading tissue lymphocytes and myeloid cells and
thereby a major mediator of inflammation in body tissues (Ingelfinger
et al., 2021). GM-CSF has been implicated in the pathogenesis of many
autoimmune disorders. In the brain, GM-CSF is known to have a role in
the activation of microglia with subsequent impact on the neuronal
survival, excitability, and synaptic transmission. In an in vivo study of
axonal spheroids and pigmented glia (ALSP), a subtype of frontal tem­
poral dementia, the elevated expression of GM-CSF lead to microgliosis,
demyelination and cognitive impairments which are reversed by
GM-CSF down regulation (Chitu et al., 2020). In an in vitro study, the
exposure of microglia cells to GM-CSF lead to microglia activation and
neuronal network dysfunction (Dikmen et al., 2020) which might
contribute to cognitive impairment. The above evidence suggests
important roles for GM-CSF in neuronal dysregulation as well as
neuroinflammation.
Pathological relevance of GM-CSF in psychosis has been described by
multiple studies (Hercus et al., 2018; Frydecka et al., 2018; Noto et al.,
2019). In a recent cross-sectional study, significantly elevated levels of
GM-CSF were seen in multiple-episode schizophrenia patients compared
to healthy controls (Frydecka et al., 2018). In the current study,
reduction in the plasma levels of GM-CSF is a notable finding, being
reported for the first time. This reduction may have been contributed to
by antipsychotic medication and/ or yoga therapy. This improvement
could possibly be linked to good medical care received by patients in this
study and better adherence to pharmacotherapy due to regular
follow-ups by project staff. This finding needs confirmation and further
evaluation in future studies.
A few earlier studies have demonstrated significant modulatory ef­
fects of adjunct yoga therapy on various core features of schizophrenia,
particularly negative symptoms and quality of life (Bangalore and Var­
ambally, 2012; Govindaraj et al., 2020; Rao et al., 2021). The current
study for the first time provides evidence towards immuno-modulatory
effects of adjunct long-term yoga therapy in patients with schizophrenia.
4.1. Strengths and limitations
The main strengths of this study include i) standard methods of
diagnosis, randomization and rater-blinding, ii) use of a validated yoga
module for schizophrenia patients, iii) evaluation of long-term i.e., 6
months yoga therapy and iv) analysis of a panel of nine immune mole­
cules. A small sample size is one of the major limitations of the study.
5. Conclusion
Our study, for the first time, shows preliminary evidence towards
immuno-modulatory effects of yoga therapy in patients with schizo­
phrenia stabilized on antipsychotics. These findings, if replicated, can
throw light on the contribution of the immuno-inflammatory pathway in
the aetiopathology of schizophrenia and also provide further support for
yoga as a complementary intervention. These findings also have impli­
cations for reducing the burden of difficult-to treat negative symptoms
and MetS which are associated with increased levels of inflammation in
patients suffering from this severe but enigmatic disorder.
Funding
This study was supported by the DBT-Wellcome Trust India Alliance
grant awarded to Dr. Shivarama Varambally (Grant Number IA/CPHI/
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.
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