Thesis - DR Amanll

COMPARISON OF SERUM PROCALCITONIN, hs-CRP, IL-6,
AND IL-10 LEVELS AT BASELINE AND AFTER 4 WEEKS OF

OLANZAPINE TREATMENT IN PATIENTS WITH
SCHIZOPHERNIA
By
Dr. Amanullah Ghori
Under the Guidance of

Prof. (Dr.) Basudeb Das, MD
Director and Professor of Psychiatry
Central Institute of Psychiatry, Ranchi
&
Co-guidance of
Prof. Dr. K.K. Kshitiz, MD
Professor of Biochemistry
&
Dr. Aniruddha Mukherjee, MD
Associate Professor of Psychiatry
CENTRAL INSTITUTE OF PSYCHIATRY

RANCHI, JHARKHAND (INDIA)
DISSERTATION
SUBMITTED TO RANCHI UNIVERSITY
IN PARTIAL FULFILLMENT OF
DIPLOMA IN PSYCHOLOGICAL MEDICINE (DPM)
2019-2021
GOVERNMENT OF INDIA
RANCHI-834006, JHARKHAND, INDIA
Declaration
I, Dr. Amanullah ghori, do hereby declare that the present study titled a COMPARISON
OF SERUM PROCALCITONIN, hs-CRP, IL-6, AND IL-10 LEVELS AT BASELINE, AND AFTER 4 WEEKS
OF OLANZAPINE TREATMENT IN PATIENTS WITH SCHIZOPHERNIA” has been conducted by me
at the Central Institute of Psychiatry, Ranchi; under the guidance of Prof. (Dr.) Basudeb Das,
M.D., Director and Professor of Psychiatry and co-guidance Prof. (Dr.) K.K. Kshitiz, M.D.,
Professor of Biochemistry and Dr. Aniruddha Mukherjee, M.D., Associate Professor of
Psychiatry. This dissertation is submitted to the Ranchi University in partial fulfilment of the
requirements of the Diploma in Psychological Medicine.
I further declare that this is an original study and no part of it has been published or submitted
to any university previously before this date.
Place: Ranchi (Dr. Amanullah Ghori)
Dated:
GOVERNMENT OF INDIA
RANCHI-834006, JHARKHAND, INDIA
Certificate
This is to certify that Dr. Amanullah Ghori is a bonafide student of Central Institute
of Psychiatry, Ranchi; pursuing D.P.M. (Diploma in Psychological Medicine) of Ranchi
University for the academic session 2019-2021. He has carried out this study titled “COMPARISON
OF SERUM PROCALCITONIN, hs-CRP, IL-6, AND IL-10 LEVELS AT BASELINE AND AFTER 4 WEEKS
OF OLANZAPINE TREATMENT IN PATIENTS WITH SCHIZOPHERNIA” at this institute under our
supervision. This dissertation is hereby approved for submission to Ranchi University as partial fulfilment
of the requirements of Diploma in Psychological Medicine.
Dr.Aniruddha Mukherjee, MD Dr. K.K. Kshitiz, MD

Associate Professor of Psychiatry Professor of Biochemistry
Central Institute of Psychiatry, Ranchi Central Institute of Psychiatry, Ranchi
Prof. (Dr.) Basudeb Das, MD

Director and Professor of Psychiatry
Place: Ranchi
Dated:
ACKNOWLEDGEMENT
I would like to extend sincere gratitude to my esteemed guide and worthy supervisor
Prof. (Dr.) Basudeb Das, MD, Director and Professor of Psychiatry, for his invaluable
and exemplary guidance in giving this study its present form.
I am grateful to Dr. K.K. Kshitiz, MD, Professor, Department of Biochemistry for
the help rendered at every aspect of this journey.
I am inestimably obliged to my co-guide Dr. Aniruddha Mukherjee, MD,
Associate Professor, Department of Psychiatry, who guided and encouraged me through all
the steps of my work on this topic. His valuable time, insightful comments, and unwavering
support at every step helped me to make this work possible.
I pay my regards to Mr. Hariom Pachori, who helped me with the analysis of data
and understand the basics of statistics.
I would like to express my heartfelt gratitude to all laboratory staff members in
the Department of Biochemistry, Central Institute of Psychiatry, for helping me with
the laboratory measurements, promptly and efficiently.
I am thankful to all participants of this study, without whom this study would not
have been completed.
I would like to thank my Senior Residents and seniors, batchmates and juniors
especially, Dr. Anjana Gandhi, Mr. Aqueel Ahmed for their constant support, insights and
encouragement.
Finally, I would like to thank my parents, my brother and sister and my wife
Ms. Shaheen, who constantly showered their love and blessings on me and were there
through hurdles and stressful moments.
Dr. Amanullah Ghori

CONTENTS
CHAPTER PAGE NO.
INTRODUCTION 1
REVIEW OF LITERATURE 4
AIM, HYPOTHESIS AND OBJECTIVES 18
METHODOLOGY 19
RESULTS 25
DISCUSSION 34
SUMMARY AND CONCLUSION 44
LIMITATIONS 45
FUTURE DIRECTIONS 46
REFERENCES 47
APPENDICES 59
INTRODUCTION
Schizophrenia is a serious neuropsychiatric illness affecting around 1% of the global
population. It is characterized by positive symptoms including delusions, hallucinations,
disorganized speech and catatonic behavior; and negative symptoms such as avolition (lack of
motivation) and emotional withdrawal. Symptoms usually appear in adolescence or early
adulthood. In general, the outcome for female schizophrenia patients is better than that for male
schizophrenia patients. It is more common in men, and in terms of age of onset, men tend to be
younger by an average of about five years than women when they develop schizophrenia. In
terms of symptomatology, overall men with schizophrenia tend to have more negative
symptoms, whereas women exhibit more affective symptoms (Leung and Chue .2000). There
are also differences in prognosis; for example, women with schizophrenia tend to have better
outcomes for clinical course and occupational and social functioning compared to men.
Despite research over few decades pathophysiology of schizophrenia remains poorly

understood. There is a lack of understanding of the pathogenesis of schizophrenia4. Though
there are several proposed theories. The ‘’cytokine hypothesis’’ and ‘’two hit hypothesis’’ of
schizophrenia have suggested that inflammation is an important factor in schizophrenia.
Cytokine hypothesis suggestive of maternal infection, obstetric complications, neonatal
hypoxia and brain injury all recruit cytokines to mediate inflammatory processes. Abnormal
expression levels of specific cytokines such as epidermal growth factor, interleukins (ILs) and
neuregulin-1 are found both in the brain and peripheral blood of patients with schizophrenia.
Accordingly, cytokines have been proposed to transmit peripheral immune/ inflammatory
signals to immature brain tissue through the developing blood–brain barrier, perturbing
structural and phenotypic development of the brain. "Two-hit" hypothesis has gained
increasing attention. In this model, genetic or environmental factors disrupt early central
nervous system (CNS) development (Watanabe et al., 2006, Feigenson et al., 2013 ). These
early disruptions produce long-term vulnerability to a "second hit" that then leads to the onset
of schizophrenia symptoms. The cell-cell signaling pathways involved in non-axial induction,
morphogenesis, and differentiation in the brain, as well as in the limbs and face, could be targets
for a "first hit" during early development. These same pathways, redeployed for neuronal
maintenance rather than morphogenesis, may be targets for a "second hit" in the adolescent or
adult brain. Furthermore, dysregulation of cell-cell signaling by a "first hit" may prime the CNS
for a pathologic response to a "second hit" via the same signaling pathway. Thus, parallel
COMPARISON OF SERUM PROCALCITONIN, hs-CRP, IL-6, AND IL-10 LEVELS AT BASELINE AND AFTER 4 WEEKS OF
OLANZAPINE TREATMENT IN PATIENTS WITH SCHIZOPHERNIA 1
disruption of cell-cell signaling in both the developing and the mature CNS provides a plausible
way of integrating genetic, developmental, and environmental factors that contribute to
vulnerability and pathogenesis in schizophrenia.
As schizophrenia is associated with inflammation and dysregulation of various inflammatory
marker. Studies are exploring the effects and interactions of multiple inflammatory marker and
their contribution in psychiatric disorders. Procalcitonin is being studied in context of
schizophrenia and other psychiatric conditions. Procalcitonin is a 14 kDa acute phase protein
encoded by the Calc-I gene. In comparison to CRP, PCT has been suggested as a better marker
of inflammation due to its higher sensitivity and specificity in sepsis (Simon et al., 2004). There
is evidence suggesting that procalcitonin is an established marker of inflammation which has
not been well studied in context with schizophrenia. Patients suffering from schizophrenia have
been found to have elevated levels of procalcitonin compared to healthy individuals (Varun et
al., 2018). Previous study also reported that PCT was not a useful marker in patients with
chronic schizophrenia on antipsychotic medication (Campos et al., 2015).CRP is a non-specific
inflammation marker, which is elevated in several scenarios such as tissue injury and infection.
A study by Abdullah et al. (2019) suggests that there is a positive correlation between hs-CRP
levels and severity of positive symptoms of both first episode of psychosis and schizophrenia.
Although CRP has been investigated considerably in schizophrenia as an inflammatory marker,
Studies indicate its insufficiency as a good predictor of inflammation (Hartwig et al., 2017).
IL-6, a 26-Kda protein, can function as both a pro- and anti-inflammatory cytokine. IL-6 also
produced by both neurons and microglia’s, and acts as a neurotropic factor in the central
nervous system (CNS) (Ringheim et al.,1995).Various lines of evidence suggest a compelling
role for IL-6 in the underlying pathogenesis of schizophrenia. Shahrak et al. (2016) study
suggest that serum IL-6 levels were found significantly increased in the patients with
schizophrenia and gender-matched healthy controls. IL-6 appeared to be significantly lower
after 6 weeks of medical treatment compared with the baseline levels. IL-10 is an important
Th2-type cytokine, produced by activated macrophages, T regulatory, B regulatory, and Th2
lymphocytes, and inhibits expression of other pro-inflammatory cytokines such as IFN-γ, IL-
2, and TNF-α in Th1 cells. Hence, IL-10 contributes to dampen the immune and inflammatory
response, being a potential anti-inflammatory mediator. Which determines immune regulations
and the balance between inflammatory and anti-inflammatory responses (Potvin et al., 2008).
It is an anti-inflammatory marker which has been well studied in context of schizophrenia. A
study by Xiu et al. (2014) study revealed that patients exhibited a significant decrease in IL-10
levels. Serum IL-10 was inversely correlated with the PANSS negative symptom, as well as
with the PANSS cognitive factor sub scores in patients. Their results suggested that decreased
IL-10 may be implicated in the negative symptoms, and at the acute stage of schizophrenia
episode.
So far only one recent study has examined combination of serum procalcitonin and CRP levels
in schizophrenia using sandwich ELISA. It was suggested that neutralizing the inflammation
would be helpful in treatment of schizophrenia cases. Thus, we recommended a combination
of serum procalcitonin, hs-CRP, IL-6 and IL-10 levels as baseline, and after 4 weeks of
olanzapine treatment among schizophrenia patients. Identifying inflammation in subset of
patients may help design targeted therapies with a combination of anti-inflammatory drugs and
anti-psychotics.So in order to give a marker for treatment response, inflammatory status as well
as anti-inflammatory action of olanzapine in patients suffering from schizophrenia combination
of procalcitonin, hs-CRP, IL-6, and IL-10 levels should be measured.
REVIEW OF LITERATURE
Schizophrenia: -
Schizophrenia is among the most disabling and economically catastrophic medical disorders,
ranked by the World Health Organization as one of the top 10 illnesses contributing to the
global burden of disease. Schizophrenia is a complex mental disorder, with typical onset in late
adolescence or early adulthood. In addition to poor recovery outcomes, those living with
schizophrenia have a significantly reduced life expectancy. Characteristics of schizophrenia
typically include positive symptoms, such as hallucinations or delusions; disorganized speech;
negative symptoms, such as a flat affect or poverty of speech; and impairments in cognition,
including attention, memory, and executive functions. Although its phenomenology is
fascinating, its pathophysiology and etiology remain unclear, and people with the illness suffer
greatly (Tamminga et al., 2010). It is a clinical syndrome of variable, but profoundly disruptive,
psychopathology that involves cognition, emotion, perception, and other aspects of behavior.
The illness is commonly associated with impairments in social and occupational functioning.
Epidemiology:-
Epidemiology in schizophrenia has undergone a mini-revolution in the past decade. The view
that schizophrenia is a diverse illness that inexorably affects 1 in 100 persons regardless of
gender is giving way to a more nuanced perspective. Schizophrenia appears to have a 0.7%
prevalence rate that varies considerably across cultures (a five-fold difference). Men are at
greater risk than women to develop the disorder and tend to develop the disorder earlier (Saha
et al., 2005). The incidence of new cases of schizophrenia is 0.03% and may be declining.
Incidence also varies across cultures. Being born or residing in an urban setting is associated
with a greater risk for developing schizophrenia. Migrants, additionally, have an increased risk
of developing schizophrenia; this is especially true if the migrants have dark skin and migrate
to an area with a light-skin dominant group. African Americans are 3 times more likely to
develop schizophrenia than European Americans.
Schizophrenia is also associated with increased mortality. Individuals with group
schizophrenia die prematurely (Brown et al., 2002), Suicide is a major contributor to this
discrepancy, and it has been estimated that 5.6% of individuals diagnosed with schizophrenia
die by suicide, with the period of greatest risk coming during the early phase of the illness.
While individuals with schizophrenia are 13 times more likely to die by suicide than individuals
in the general population, Saha et al. (2007) have recently shown that individuals with
schizophrenia also have elevated mortality across a wide array of illness categories (Saha et
al., 2007).
High excess mortality is found across all age groups and this differential mortality gap between
those with and without schizophrenia may have increased in recent decades. Schizophrenia has
also been linked to higher rates of comorbid illnesses and most excess deaths are due to
underlying physical illnesses, especially chronic diseases such as coronary heart disease,
stroke, type II diabetes, respiratory diseases, and some cancers. Unnatural causes, including
suicide, account for less than 15% of excess deaths. Schizophrenia is a disorder with a relatively
low prevalence. A systematic review conducted by Saha et al. (2007) demonstrated a median
population period prevalence of 3.3 per 1000. Developing health services for schizophrenia
will require robust and informative epidemiological estimates, including estimates of the
number of people living with schizophrenia in a given population and how these have changed
over time estimates that are currently unavailable for schizophrenia. Recent innovations in
statistical modeling, as part of the global burden of disease (GBD) studies, have allowed for
the derivation of detailed and comparable epidemiological estimates for schizophrenia by age,
sex, geography, and year.
Quantification of the burden of disease attributable to schizophrenia was first undertaken in the
GBD Study carried out by the World Health Organization in 1990, with an update in
2004. Recent iterations of the GBD Study, conducted by the Institute for Health Metrics and
Evaluation at the University of Washington, have expanded the number of included disorders
and made significant methodological improvements.
The most recent iteration is GBD 2016 suggest core metric used to measure disease burden in
GBD is the disability-adjusted life year (DALY). One DALY is equivalent to 1 healthy year of
life lost to the disease. The DALY is calculated by summing the years of life lived with
disability (YLDs) and years of life lost (YLLs) to premature mortality for a given disease. This
inclusion of disability when measuring disease burden has been particularly influential in
highlighting schizophrenia as a leading contributor to disease burden. Despite being a low
prevalence disorder, schizophrenia ranked the 12th most disabling disorder among 310 diseases
and injuries globally in 2016 (Charlson et al., 2018).
Symptoms of Schizophrenia:-
The symptoms of schizophrenia fall into three broad categories: positive symptoms, negative
symptoms, and cognitive symptoms. Positive symptoms are psychotic behaviors not seen in
healthy people. People with positive symptoms often "lose touch" with reality. These
symptoms can come and go. Sometimes they are severe and at other times hardly noticeable,
depending on whether the individual is receiving treatment. They include hallucination,
delusion, movement disorder, and thought disorder (Norquist et al., 1996). Negative symptoms
are associated with disruptions to normal emotions and behaviors. These symptoms are harder
to recognize as part of the disorder and can be mistaken for depression or other conditions.
These symptoms include flat affect, lack of pleasure in everyday life, lack of ability to begin
and sustain planned activities, speaking little, even when forced to interact. Cognitive
symptoms are subtle. Like negative symptoms, cognitive symptoms may be difficult to
recognize as part of the disorder. Often, they are detected only when other tests are performed.
Cognitive symptoms include poor “executive functioning, trouble focusing or paying attention,
problems with working memory. Cognitive symptoms often make it hard to lead a normal life
and earn a living. They can cause great emotional distress (Mcgurk et al., 2004).
Neuroimunology of Schizophrenia:-
Inflammation and the central nervous system (CNS) A connection between inflammatory
factors and the development of ‘mental maladies’ was first voiced by Esquirol upon the
epidemic appearance of psychiatric disorders in 1845 (Bayer et al., 1999). Since then, a steady
stream of patients have been described displaying symptoms suggestive of acute schizophrenia
but also presented with, or later developed, the clinical hallmarks of multisystem encephalitis
(Crow TJ et al., 1985). Inflammation is a complex homeostatic cellular response designed to
protect an organism from potentially harmful environmental stimuli, such as infection.
Immune-modulatory mechanisms regulating the type, extent, and outcome of any
inflammatory response exist both in the periphery and CNS and involves either the up-or down-
regulation of pro-and or anti-inflammatory cytokines or their receptors. Cytokines are a super-
family of low-molecular-weight proteins secreted by a variety of cell types and have wide-
ranging functions within the innate and adaptive inflammatory response, Borish et al.,(2006).
Evidence demonstrates that the pathophysiology of schizophrenia could be associated with
cytokine abnormalities (Potvin et al., 2008).
Specifically, pro-inflammatory cytokines are involved in central nervous system (CNS)
inflammation processes, disturbing the homeostasis and contributing to additional tissue injury
(Müller et al., 2015). The increase of pro-inflammatory cytokines levels and their soluble
receptors in human samples such as serum, plasma, or cerebrospinal fluid (CSF) was reported
in several studies (Debnath and Berk, 2014; Potvin et al., 2008; Wu et al., 2016). On the other
hand, anti-inflammatory cytokines that down-regulate the inflammatory response are also
altered in schizophrenia (Müller and Schwarz, 2010). Another important aspect pointing
towards the involvement of immune system abnormalities in schizophrenia vulnerability is the
presence of specific cytokine gene polymorphisms that may result in inflammatory events that
putatively modulate the development of the schizophrenia syndrome by neurodevelopmental
or neurodegenerative abnormalities (Fan et al., 2007).
For example, the polymorphisms in the interleukin-1 (IL-1) or-6 genes have been associated
with schizophrenia, with increasing blood levels of both cytokines (Debnath and Berk, 2014;
Katila et al., 1999).
The ''cytokine hypothesis'' and ''two-hit hypothesis'' of schizophrenia have suggested that
inflammation is an important factor in schizophrenia. Cytokine hypothesis suggestive of
maternal infection, obstetric complications, neonatal hypoxia, and brain injury all recruit
cytokines to mediate inflammatory processes. Abnormal expression levels of specific cytokines
such as epidermal growth factor, interleukins (ILs), and neuregulin-1 are found both in the
brain and peripheral blood of patients with schizophrenia (Feigenson et al.,2014). Accordingly,
cytokines have been proposed to transmit peripheral inflammatory signals to immature brain
tissue through the developing blood–brain barrier, perturbing structural and phenotypic
development of the brain. The "Two-hit" hypothesis has gained increasing attention. In this
model, genetic or environmental factors disrupt early central nervous system (CNS)
development (Watanabe et al., 2010). These early disruptions produce long-term vulnerability
to a "second hit" that then leads to the onset of schizophrenia symptoms. The cell-cell signaling
pathways involved in non-axial induction, morphogenesis, and differentiation in the brain, as
well as in the limbs and face, could be targets for a "first hit" during early development. These
same pathways, redeployed for neuronal maintenance rather than morphogenesis, may be
targets for a "second hit" in the adolescent or adult brain. Furthermore, dysregulation of cell-
cell signaling by a "first hit" may prime the CNS for a pathologic response to a "second hit"
via the same signaling pathway (Monji et al., 2009.). Thus, parallel disruption of cell-cell
signaling in both the developing and the mature CNS provides a plausible way of integrating
genetic, developmental, and environmental factors that contribute to vulnerability and
pathogenesis in schizophrenia.
Infectious agents such as cytomegalovirus, influenza, and many others have been discussed to
be involved in schizophrenia, but results from animal models of schizophrenia indicate that not
a certain virus or other infectious agent but the immune response itself determines the risk for
schizophrenia: immune stimulants such as, which mimic a bacterial and viral infection,
respectively, both lead to typical behavior alterations in the offspring of animals (Torrey et al.,
2006).
Another line of evidence demonstrates that chronic stress is associated with immune activation.
The vulnerability-stress-inflammation model of schizophrenia includes the contribution of
stress based on increased genetic vulnerability for the pathogenesis of schizophrenia, because
stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-
inflammatory state. Immune alterations influence dopaminergic, serotonergic, noradrenergic,
and glutamatergic neurotransmission. The activated immune system, in turn, activates the
enzyme indoleamine 2, 3-dioxygenase (IDO) of the tryptophan kynurenine metabolism which
influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites
such as kynurenic acid (Pedraz et al., 2020).
Another neural system relevant for the stress response and centrally implicated in the
pathophysiology of schizophrenia is dopamine. Contemporary accounts of the dopamine
hypothesis increasingly suggest that dopamine dysregulation is a downstream consequence of
dysregulation in other systems, eg, falsely signaling salient states and triggering dopamine
release (Weinstein et al., 2017, Howes et al., 2009) Stress elevates striatal dopamine release in
animals and humans, and an impaired ability to regulate psychosocial stress has been suggested
as one of the upstream triggers leading to hyper-dopaminergic state and positive symptoms in
schizophrenia (Mizrahi et al., 2012).
The function of the glutamatergic system is closely related to the immune system and
tryptophan-Kynurenine metabolism, both of which seem to play a key role in the
pathophysiology of schizophrenia.
Inflammatory Markers
Procalcitonin:-
Procalcitonin (PCT) is a prohormone of calcitonin released by hepatocytes, kidney cells,
myocytes, adipocytes, neurons, and leukocytes, often in response to bacterial infections but
also in response to tissue injury. PCT is a 14 kDa acute phase protein encoded by the Calc-I
gene. During bacterial infections, PCT levels increase over 1000 times in the bloodstream
(Nobre et al, 2008). The explanation for such elevation remains unclear, but the presence
of bacterial endotoxins or pro-inflammatory cytokines, such as IL-1β, and IL-8, may stimulate
transcription factors that regulate the expression of the PCT gene Calc-1. Even though other
overt inflammatory conditions, such as active SLE, also exhibit increased blood levels of PCT.
(Matwiyoff et al., 2012).
In Simon et al’s study (2004), procalcitonin has been suggested as a better marker of
inflammation in sepsis due to its higher sensitivity and specificity. It is therefore often classified
as an acute phase reactant. Procalcitonin is an established marker of inflammation which has
not been well studied in context with schizophrenia. Patients suffering from schizophrenia have
been found to have elevated levels of procalcitonin compared to healthy individuals.
However, both the chronicity of illness and medication are strong confounding factors to
conclude on the relevance of PCT as a biomarker for schizophrenia. A mechanistic explanation
for the absence of increased levels of PCT levels in chronic schizophrenia is that most cytokines
capable of modulating the transcription process of PCT (i.e. IL-1β and IL-6) tend to 'normalize'
according to the disease and the use of antipsychotics (Campos et al., 2016).
In a study by de Campos et al, 2015, patients with sepsis presented increased PCT serum levels
compared with other groups. PCT serum levels in patients with schizophrenia did not differ
significantly from healthy controls. Although several studies have pointed out a pro-
inflammatory profile, PCT levels did not increase in patients with schizophrenia, suggesting
that not all inflammatory markers increase in this condition. A similar finding has been reported
for patients who were diagnosed with bipolar affective disorder. In the study Patients with
sepsis showed higher levels of PCT compared with other groups. Regardless of mood status,
Bipolar disorder patients presented similar plasma levels of PCT compared with healthy control
subjects (Barbosa et al., 2013.)
Varun et al., (2018) studied procalcitonin and CRP as peripheral inflammatory markers in
antipsychotic drug-free schizophrenia patients. It showed a subgroup of patients 17/34 (50%)
have either elevated PCT or CRP levels. The study reports evidence of inflammation by either
PCT or CRP or both amounting to 50%, which is in agreement with previous studies
(Fernandes et al., 2016, Miller et al., 2014) It indicates only a subgroup of patients have
inflammation. This study is the first to report PCT values in antipsychotic drug-free patients
with schizophrenia. On the other hand, these results might indicate that only a subset of patients
with schizophrenia presents a pro-inflammatory status as evidenced by the elevated PCT levels.
Procalcitonin in contrast to CRP is known to have a higher sensitivity and specificity, though
PCT generally used to study sepsis, has recently gained increasing value as an inflammatory
marker in conditions such as inflammatory Bowel Disease (Chung et al., 2016)
Although PCT thresholds are well defined in sepsis, there is no universally accepted threshold
value for PCT in non-sepsis conditions. Published literature suggests that baseline levels of
PCT in most adults are<10 pg/mL and are not within the detectable range (Taylor et al., 2017).
CRP:-
C-reactive protein (CRP) is an acute-phase inflammatory protein produced by the liver
hepatocytes, smooth muscle cells, macrophages, endothelial cells, lymphocytes, and
adipocytes. CRP levels rise to 1,000 fold at the site of infection or inflammation. The level of
CRP increases drastically in case of any type of inflammation, and thus its elevated levels are
usually observed in a variety of infections and inflammatory conditions like and the
inflammation associated with rheumatic fever, However, an elevated level of CRP in the blood
is considered to be the risk factor for the cardiovascular diseases, diabetes, and other metabolic
dysfunction (Ernst et al., 2010). A CRP test measures the amount of CRP in the blood to detect
inflammation due to acute conditions or to monitor the severity of disease in chronic conditions
(Salem et al., 2007).
In addition, it is also known to be associated with depression and cognitive dysfunction

(Karogh et al., 2014). A recent meta-analysis has concluded that increased CRP levels were
associated with positive but not negative symptoms in schizophrenia. In one case-control study,
hs-CRP levels were associated with insidious psychosis onset, duration of illness, and chronic
schizophrenia course with deterioration (Fernandes et al., 2016).
Abnormal CRP levels have been associated with increased aggressive behavior in
Schizophrenia inpatients in one study but this has not been replicated in other Schizophrenia
populations. Increased CRP levels have been associated with impaired sensory gating in one
small sample of stabilized Schizophrenia individuals (Fond et al., 2018).
CRP has been robustly associated with the Schizophrenia risk, however, it remains unclear if
this association may be due to confounding factors. However, tobacco smoking, increased gut
permeability, infections HSV virus or endo-retrovirus, candida Albicans sleep disturbances,
dental care, and periodontal diseases and impaired physical activity may be all confounding
factors for this association. It should be underlined that increased CRP has been associated with
social withdrawal in the general population, social withdrawal being one of the prodromal
symptoms of schizophrenia in adolescents (Fond at., 2018).
The evidence also suggests that child abuse causes long-lasting alterations in the HPA axis,
hippocampal function, and dopaminergic neurotransmitter systems, all of which are implicated
in psychosis (Cicchetti & Walker., 2001, Read et al., 2001). One study reported that childhood
abuse diminished cortisol response, which was amplified with increasing age and independent
of other variables including psychiatric illness (Carpenter et al., 2009). There are several
studies on childhood trauma and depression that link trauma with altered HPA axis activity, in
addition to immune activation and alterations in hippocampal volume.
In Fernandes et al, study (2016) suggesting that the greater the severity of positive symptoms,
the greater the increase in CRP levels, there was no relationship between CRP levels and
negative symptoms. Furthermore, there was a negative relationship between CRP levels and
age in the drug-naive or -free subjects, meaning that the greater the age, the smaller the
difference in CRP between drug-naive or drug-free subjects with Schizophrenia and healthy
controls. It was also found a positive relationship between BMI and CRP levels regardless of
the use of antipsychotics, meaning that the higher the BMI, the higher CRP levels were in
persons with Schizophrenia when compared with controls.
Inconsistent findings have been found concerning the association between abnormal CRP,
current depression, and antidepressant consumption in Schizophrenia, with one study
suggesting that increased CRP levels were associated with depressive symptoms, and one other
that it was associated with antidepressant consumption. This discrepancy may be due to
different antidepressant administrations, as the different classes of antidepressants have been
associated with various anti-inflammatory properties (Brien et al, 2006).
Increased CRP has been associated with high nicotine dependence in Schizophrenia subjects.
This finding was not consistent with the hypothesis that nicotine dependence would be
associated with lower peripheral inflammation due to the in vitro anti-inflammatory effects of
nicotine. As increased CRP and nicotine dependence have both been associated with cognitive
impairment, it remains also to be determined if inflammation mediates the association between
nicotine dependence and cognitive impairment in Schizophrenia smokers (Fond et al., 2017).
Increased CRP levels have been associated with a wide range of impaired cognitive functions.
While many have suggested that anti-inflammatory add-on therapy may be effective in
Schizophrenia subjects, no study has explored to date if adding anti-inflammatory agents to
conventional treatment may improve cognitive function in Schizophrenia subjects with
cognitive deficits and inflammatory disturbances (Alley de et al., 2008).
The physical health studies have confirmed that increased CRP levels were a predictor of
metabolic syndrome and cardiovascular risk in Schizophrenia subjects (Aronson et al., 2004).
Increased CRP has been associated with decreased 25-OH vitamin D levels, which may suggest
that supplementing vitamin D may improve the inflammatory status and cardiovascular risk in
Schizophrenia subjects with hypovitaminosis D (Mirhosseini et al., 2018).
In most of the earlier studies, the effects specifically on CRP level were not studied. This is to
be considered as an important limitation of these studies. It is still not very clear how
psychotropic medicine influences the immune system and CRP. Some of the studies have
revealed that antipsychotic drugs do modulate the level of CRP (Singh et al., 2014). One study
suggests that there is a positive correlation between hs-CRP levels and severity of positive
symptoms of both first episodes of psychosis and schizophrenia (Bolu et al., 2019.).
IL-6:-
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-
inflammatory myokine. In humans, it is encoded by the IL6 gene. Besides, osteoblasts secrete
IL-6 to stimulate osteoclast formation. Smooth muscle cells in the tunica media of many blood
vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6 is an important mediator of
fever and the acute phase response. It is capable of crossing the blood-brain barrier (Johnson
et al., 1997) and initiating the synthesis of PGE2 in the hypothalamus, thereby changing the
body's temperature set point. In muscle and fatty tissue, IL-6 stimulates energy mobilization
that leads to increased body temperature (Goetze et al., 2011). IL-6 can be secreted by
macrophages in response to specific microbial molecules, referred to as pathogen-associated
molecular patterns (PAMPs). These PAMPs bind to an important group of detection molecules
of the innate immune system, called pattern recognition receptors (PRRs), including Toll-like
receptors (TLRs). These are present on the cell surface and intracellular compartments and
induce intracellular signaling cascades that give rise to inflammatory cytokine production
(Kunz et al., 2011).
IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as
diabetes, (Kristiansen et al., 2005) atherosclerosis depression (Dowlati et al, 2010), and
Alzheimer's Disease (Gadient et al., 1997). The induction of epigenetic modification by IL-6
has been proposed as a mechanism in the pathology of schizophrenia through the hyper
methylation and repression of the GAD67 promoter (Kundakovic et al., 2009).
Figure-1. Demonstration of Pleiotropic functions of IL-6. ADAMTS, a disintegrin and

metalloproteinase with thrombospondin motifs (ADAMTS) matrix metalloproteinase
(MMPs), receptor activator of nuclear factor kappa-B ligand (RANKL), vascular
endothelial growth factor (VEGF), regulatory T cells(T-reg), Th17, T helper 17 cells
(Hashizume et al., 2015 ).
In many studies finding an elevation in serum levels of IL-6 is consistent with the majority of
studies of schizophrenia, although some other groups have reported no significant differences
between patients and controls. Elevated plasma levels of IL-6 have been noted in patients with
autoimmune diseases and it is thought that IL-6 may constitute one factor in the development
of autoimmune (Zhang et al., 2002). Therefore, the study showed that increased serum IL-6
levels may be involved in the development of the autoimmune response in schizophrenia.
There is now evidence that typical and atypical antipsychotic drugs have complex in-vivo
immune-modulatory effects in schizophrenic subjects Repeated administration of typical
antipsychotic drugs may suppress plasma IL-6 and sIL-6R, whereas repeated administration of
these drugs does not significantly alter plasma sIL-2R concentrations. These findings suggest
that typical antipsychotic drugs have immunosuppressive effects in vivo through suppression
of IL-6 related mechanisms (Lin et al., 1998.).
Among persons with schizophrenia, IL-6 levels were also significantly correlated with taking
anti-inflammatory medications and worse mental and physical well-being. Across both
schizophrenic and healthy control groups, IL-6 levels were significantly higher among women,
individuals with more depressive symptoms, and higher BMI (Lee et al., 2017).
Treatment with some antipsychotic agents, such as clozapine and olanzapine, may lead to
opposing effects on inflammation possibly through their propensity to generate metabolic
syndrome with its consequent effect on the inflammatory system and its stress response.
However, there were not enough studies on clozapine and olanzapine to substantiate this
assumption.
IL-10:-
IL-10 is an important Th2-type cytokine, produced by activated macrophages, T regulatory, B

regulatory, and Th2 lymphocytes, and inhibits expression of other pro-inflammatory cytokines
such as interferon-gamma (IFN-γ), IL-2, and tumor necrosis factor-alpha (TNF-α) in Th1
cells. Interestingly, Th3 cells, involved in mucosal immunity and protection, produce IL-10
(Severance et al., 2013, Miller et al., 2011) During infection, it inhibits the activity of Th1 cells,
NK cells, and macrophages, all of which are required for optimal pathogen clearance but also
contribute to tissue damage (Couper et al., 2008).
Hence, IL-10 contributes to dampening the immune and inflammatory response, being a potent
anti-inflammatory mediator (Moore et al., 2001), IL-10 determines the balance between
inflammatory and anti-inflammatory responses (Potvin et al., 2008). Also, IL-10 may be part
of the compensatory anti-inflammatory response syndrome, a counter-regulatory response to
the primary inflammatory response (Woiciechowsky et al., 1999). Also, previous studies have
found that IL-10 and IL-10 receptors are synthesized in the brain including microglia and
astrocyte. Hence, they are also considered to be an important modulator of inflammatory
response in the central nervous system (CNS) (Strle et al., 2001) functioning to maintain a
balance between pro-and anti-inflammatory cytokine levels in the CNS (Sawada et al., 1999).
Several studies have shown that activation of the inflammatory response system plays a pivotal
role in the pathogenesis of schizophrenia, including the promotion of Th10 (Pedrini et al.,
2012).
Based on the role of IL-10 in anti-inflammation, decreased IL-10 supports the hypothesis that
schizophrenia is accompanied by an activated macrophage immune response system, maybe
through a Th1 response rather than an antibody-mediated response (Smith et al., 1995).
Several previous studies have shown a relationship between IL-10 and Schizophrenia, with
contradictory results. For example, Maes et al.(2002) reported that patients with Schizophrenia
exhibited significantly increased IL-10 serum levels. Moreover, increased serum levels of IL-
10 were observed in Schizophrenia patients, specifically in more severe cases (Cazzullo et
al.,1998). However, some authors failed to replicate these findings in patients with
Schizophrenia or even found decreased serum IL-10 levels in paranoid Schizophrenia or
patients with Schizophrenia at a late stage (Kubistova et al., 2012). A recent study found no
significant differences in IL-10 gene expression in peripheral blood cells between patients with
schizophrenia and healthy controls (Freudenreich et al., 2010). Thus, the picture emerging is
that IL-10 levels deserve further examination in the peripheral blood of patients with
Schizophrenia.
Hong Xiu et al (2014) reported that IL-10 levels were significantly decreased in these first
episode drug naïve (FEDN) schizophrenia patients, and second, a significantly negative
association between IL-10 and PANSS clinical phenotypes was found, including negative and
cognitive symptoms. Based on this finding of decreased serum levels of IL-10 were consistent
with previous studies (Pedrini et al., 2012). However, some studies failed to replicate the results
in both medicated and unmediated (Kubistova et al., 2012) or even found increased IL-10 levels
in patients with Schizophrenia (Kunz et., 2011). Numerous factors may have contributed to
these discrepancies, such as differences in testing material (serum vs plasma), exposure to
treatment (naive vs medicated), sampling of patients in different stages of (acute vs chronic or
active phase vs remission), different illness duration, age at onset, and different ethnic origins
or genetic backgrounds of the populations studied.
There was a significant negative relationship between IL-10 and the PANSS negative and
cognitive sub score in clinical symptoms in Schizophrenia. A few studies have linked serum
levels of inflammatory cytokines and clinical severity in Schizophrenia. For example, a
previous study found that IL-1Ra was significantly correlated with PANSS negative symptoms
in schizophrenia (Hope et al., 2013). There is evidence that the negative/deficit symptom
complex of Schizophrenia may be associated with low dopamine activity in the prefrontal
cortex (Weinberger et al., 1988). Recent studies have shown that injection of LPS into the
substantia nigra (SN) induced a selective loss of dopaminergic neurons, but IL-10 protects
against inflammation-mediated degeneration of dopaminergic neurons substantia nigra (SN)
(Arimoto et al., 2007). Thus, the decreased IL-10 may alter the central dopamine function and
further affect the negative symptoms in Schizophrenia. However, this is only our speculation;
the interaction between IL-10 and the dopamine system and how they relate to negative
symptoms of Schizophrenia need to be explored with further detailed investigations.
Further, cognitive impairment appears to be the core feature of schizophrenia (Goff et al.,
2011). Numerous studies have shown that activation of the peripheral innate immune system
induces the production of cytokines within the brain that can have deleterious effects on
cognition (Yirmiya et al., 2011). Inflammatory cytokines can negatively affect hippocampal
function by directly impairing long-term potentiation (LTP) (Hwang et al., 2013) and evidence
also shows that immune/inflammation response in the hippocampus may underlie the
pathophysiology of cognitive deficits in Schizophrenia(Pickering et al., 2007). Taken together,
these studies suggest that immune responses may play a role in cognitive impairment in
Schizophrenia.
Role of Antipsychotic on Inflammatory Marker:-

The pathophysiological underpinnings of inflammation and its potential role in schizophrenia
onset and maintenance have been previously discussed. Schizophrenia is a severe mental
illness, the pathophysiology for which is unclear. The “cytokine hypothesis” of schizophrenia
(Watanabe et al., 2010, Rodrigues-Amorim et al., 2017) suggests that pro-inflammatory
cytokines are involved in the pathogenesis of schizophrenia. It was suggested that neutralizing
the inflammation would be helpful in the treatment of schizophrenia cases, though a meta-
analysis has reported the use of NSAIDs to be of limited utility in the treatment of this disorder
(Nitta et al., 2013). This suggested that inflammation is present in only a subset of
schizophrenia patients. Identifying this subset of patients may help design targeted therapies
with a combination of anti-inflammatory drugs and anti-psychotics.
Studies on the effect of antipsychotic treatment on inflammation, and more specifically on
cytokine levels, have so far given mixed findings, showing an increase, a decrease, or
unchanged levels of cytokines after antipsychotic treatment (Mondelli et al., 2013). One
potential explanation for the mixed findings is that antipsychotic agents might exert different
effects on the immune system, having both a direct anti-inflammatory activity and an indirect
pro-inflammatory activity, mediated by their effect on weight-gain and increased adiposity.
Interestingly, this dual anti- and pro-inflammatory action of antipsychotics is supported by the
longitudinal study, who observed a decrease in IL1β and IL6 levels in the first weeks of
treatment with risperidone, followed by an increase back to baseline levels by the end of 6
months of treatment, which happened alongside a steady weight gain.
In vitro studies show that the blunted IFN-γ production is normalized after treatment with
antipsychotics. An increase of "memory cells" (CD4+CD45RO+ cells) – one of the main
sources of IFN-γ –was observed by different group's treatment. Additionally, an increase of
sIL-2R – which reflects an increase of activated, IL-2- and may induce effects – has been
described during antipsychotic treatment. The reduced sICAM-1 levels seen in schizophrenia
increase significantly during short-term antipsychotic therapy, and expression of the ligand
leukocyte function antigen-1 (LFA-1) increases significantly with antipsychotics. An increase
of TNF- α and TNF-α receptors during therapy with and other antipsychotics has been
observed repeatedly. Clozapine, however, seems to have divergent modulatory immune effects.
An elevation serum IL-18 levels were described in medicated schizophrenia patients. Since IL-
18 plays a pivotal role in type 1 immune response, this finding is consistent with other
descriptions of type 1 activation during antipsychotic treatment (Muller et al., 2012). Regarding
the type 2 response, several studies indicate that antipsychotic therapy is accompanied by a
functional decrease in the IL-6 system. Capuzzi et al. (2017) study suggests antipsychotics
produce anti-inflammatory effects in individuals with first-episode psychosis (FEP), although
the underlying mechanisms, involving neurons and several immune cells, remain unknown.
IL-6 and IL-2, and probably IL-1β, seem to be state markers, decreasing after antipsychotic
treatment, whilst TNF-α, IL-17, and IFN-γ might be considered trait markers.
Staple et al. (2018) study was done to test whether SGAs olanzapine and aripiprazole directly
affect cytokine expression in peripheral blood mononuclear cells (PBMC) without influence
from interfering clinical values or other cell types, we assessed mRNA levels of relevant pro-
and anti-inflammatory cytokines after ex vivo treatment with olanzapine and aripiprazole.
Treatment with either SGA decreased mRNA expression of pro-inflammatory cytokines IL-
1β, IL-6, and TNF-α significantly albeit the effect of aripiprazole was more pronounced than
that observed with olanzapine treatment. In contrast, both antipsychotics increased mRNA
expression of anti-inflammatory IL-10, olanzapine by the trend, aripiprazole significantly,
while no effect on TGF-β1 expression was detected.
AIMS, HYPOTHESIS AND OBJECTIVES
Aim: - To assess levels of serum procalcitonin, hs-CRP, IL-6, and 1L-10 levels at baseline and
after four weeks of olanzapine treatment in patients, with schizophrenia.
Objectives
1. To assess and compare the levels of serum procalcitonin, serum hs-CRP, IL-6, and IL-
10 at baseline in patients with schizophrenia and healthy controls.
2. To assess the levels of serum procalcitonin, hs-CRP, IL-6, and IL-10 at four weeks of
olanzapine treatment in patients with schizophrenia.
3. To study relationship between serum procalcitonin, hs-CRP, IL-6, and IL-10 with
PANSS and socio-demographic variables in patients with schizophrenia at baseline and
after four weeks of olanzapine treatment.
Null Hypotheses
1. There will be no significant difference between the baseline serum procalcitonin, hs-
CRP, IL-6, and IL-10 values in patients with schizophrenia and healthy controls.
2. There will be no significant difference between baseline, and four weeks of olanzapine
treatment in serum procalcitonin, hs-CRP, IL-6, and IL-10 values in patients with
schizophrenia.
3. There will be no significant relationship between serum procalcitonin, hs-CRP, IL-6,

and IL-10, with PANSS and socio-demographic variables in schizophrenia at baseline,
and after four weeks, of olanzapine treatment.
METHODOLOGY
Venue:
Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand.
Design:
It will be conducted on in-patients and outpatient at CIP and Sridhar Sharma Centre for
Investigation Medicine.
Sample Size:
Sample size consist of 15 patients diagnosed with schizophrenia according to ICD-10 DCR and
15 age and gender matched healthy individuals in 18 -50 years age group population. Prior
sample size calculation was done using G-power 3.1.9 considering the moderate effect
calculated as 15 in each group.
Inclusion Criteria for Experimental Group:-
1. Patients who received the diagnosis of schizophrenia according to ICD-10 DCR

criteria.
2. patients of both sex in 18-50 years of age group.
3. Patients who are drug naive or drug free from antipsychotics for past 1 month from all
psychotropic medicines.
4. The patients who had not taken antibiotics recently, anti-inflammatory,

immunosuppressive medication and suffering from chronic disorders recently within
15 days.
5. Those who give written informed consent for compliance and study purpose.
Exclusion Criteria for Experimental Eroup:-
1. Co-morbid medical illnesses, neurosurgical illnesses, other psychiatric illnesses, any

inflammatory disorder including both acute and chronic.
2. Patients with substance use disorder.
3. Noncompliance within medication during 4 weeks to be excluded.
4. Patients who are unwilling to give informed consent.
Inclusion Criteria for Controls:-
1. Healthy subject’s age and gender matched to experimental group.
2. Subjects who are willing to give informed consent.
3. GHQ-12 score less than or equal to 3.
Exclusion Criteria for Controls:-
1. Co-morbid Medical illnesses, neurosurgical illnesses, other psychiatric illnesses, any

inflammatory disorder including both acute and chronic.
2. Patients with substance use disorder.
3. Patients who are unwilling to give informed consent.
4. GHQ-12 score more than 3.
Tools for Assessment:-
1. Informed consent form

2. Socio-demographic and clinical data sheet.
3. The Positive and Negative Syndrome Scale for Schizophrenia (PANSS)
4. Clinical Global Impression-severity (CGI-S)
5. UKU side effect rating scale
6. General health questionnaire – 12
7. Laboratory measurement of serum procalcitonin, hs-CRP, IL-6, and IL-10.
Description of Tools:-
Informed Consent Form

Permission is taken from the participants before conducting the study. It contains information
sheet (to share information about the research i.e. introduction, main purpose, procedure,
duration, participant selection, voluntary participation and confidentiality of the study) and
certificate of consent (for signature if agree to take part).
Socio-demographic and Clinical Data Sheet
It is a semi-structured preforma consisting of socio-demographic variables like name, age, sex,

educational qualification, occupation, socioeconomic status, religion, marital status, family
type, residence and clinical variables like age of onset, duration of illness, treatment history,
and diagnosis.
Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987)
It's a 30 item rating instrument evaluating the presence or absence ans severity of positive and
negative and psychopathology of schizophrenia. This evaluates the patient based on severity
of positive, negative and general psychopathology features. All 30 items are rated on 70 point
scale. The PANSS is scored by summation of ratings across items, such that the potential ranges
are 7-49 for the Positive and Negative Scales and 16-112 for the General Psychopathology
Scale. The Composite Scale is arrived at by subtracting the negative from positive score, thus
yielding a bipolar index that ranges from -42 to +42. A direct interrelationship of modest size
was found between the Positive and Negative Scales, Suggesting that the two syndromes are
not independent. However, their common association with general schizophrenic pathology, as
described above, raised the possibility that severity of the disorder mediated the covariation
between two otherwise distinct scales. This proposition was supported by a partial correlation
which, upon extracting the shared variance from the General Psychopathology Scale, revealed
a significant inverse correlation between positive and negative scores. Thus, once the influence
of severity of illness was removed statistically, the Positive and Negative Scales tended to be
mutually exclusive. Because of the pervasive contribution of general severity of
psychopathology, of course, the two syndromes clinically can be expected to overlap to some
degree.
Clinical Global Impression Scale (CGI) (Guy, 1976)
The CGI was developed for use in NIMH-sponsored clinical trials to provide a brief, stand-
alone assessment of the clinician's view of the patient's global functioning prior to and after
initiating a study medication. The CGI is an instrument which is described and sample patient
scenarios are provided with scoring rationales and a practical charting system. The CGI-
Severity (CGI-S) is rated on the following seven-point scale: 1-normal, not at all ill; 2-
borderline mentally ill; 3-mildly ill; 4-moderately ill; 5-markedly ill; 6-severely ill; 7-among
the most extremely ill patients.
This rating is based upon observed and reported symptoms, behavior, and function in the past
seven days. Clearly, symptoms and behavior can fluctuate over a week; the score should reflect
the average severity level across the seven days.
CGI-S Guidelines
1 = Normal—not at all ill, symptoms of disorder not present past seven days
2 = Borderline mentally ill—subtle or suspected pathology
3 = Mildly ill—clearly established symptoms with minimal, if any, distress or difficulty in social
and occupational function
4 = Moderately ill—overt symptoms causing noticeable, but modest, functional impairment or
distress; symptom level may warrant medication
5 = Markedly ill—intrusive symptoms that distinctly impair social/occupational function or
cause intrusive levels of distress
6 = Severely ill—disruptive pathology, behavior and function are frequently influenced by
symptoms, may require assistance from others
7 = Among the most extremely ill patients—pathology drastically interferes in many life
functions; may be hospitalized.
UKU Side Effect Rating Scale (Lingjaerde et al., 1987)
A scale for rating the side effects of psychotropic drugs, discussing inter-observer reliability.
The scale itself and a manual for its administration are appended. The Committee of Clinical
Investigations (UKU) scale is used to rate psychic (e.g., depression, failing memory,
concentration difficulty), neurological (e.g., rigidity, tremor, epileptic seizure), and autonomic
(e.g., nausea, diarrhea, tachycardia) side effects, plus others. The scale was used on patients
diagnosed as schizophrenic, demented, neurotic, or as having personality and affective
disorders or reactive and paranoid psychoses.
General health questionnaire (Goldberg and Hiller., 1992)
The General Health Questionnaire (Goldberg, 1992) is a screening device for identifying
minor psychiatric disorders in the general population and within community or non-psychiatric
clinical settings such as primary care or general medical out-patients. Suitable for all ages from
adolescent upwards (not children), it assesses the respondent’s current state and asks if that
differs from his or her usual state. Questionnaire consists of 12 items each with a bi-modal or
four-point likert scale for responses. It has a sensitivity of 89% and specificity of 80%.
The General Health Questionnaire (Goldberg and Hiller, 1992) is a screening device for
identifying minor psychiatric disorders in the general population and within community or non-
psychiatric clinical settings such as primary care or general medical out-patients. Suitable for
all ages from adolescent upwards (not children), it assesses the respondent’s current state and
asks if that differs from his or her usual state. Questionnaire consists of 12 items each with a
bi-modal or four-point Likert scale for responses. It has a sensitivity of 89% and specificity of
80%.
ELISA for Assessing Serum procalcitonin, hs-CRP, IL-6, and IL-10 Levels
Serum procalcitonin, hs-CRP, IL-6, and IL-10 levels were measured using the quantitative
sandwich enzyme immunoassay technique. This assay employs the quantitative sandwich
enzyme immunoassay technique. 5 ml of venous blood was withdrawn under complete aseptic
conditions from all with schizophrenia on baseline and after 4 weeks of olanzapine treatment
and healthy subjects. Samples were left to clot for 1 hour and then were centrifuged for 15 min.
The serum were stored in aliquots at -50 *C until the assay of procalcitonin, hs-CRP, IL-6, and
IL-10 in the serum is completed. Repeated freezing and thawing was avoided. It was processed
after all samples collection. The identity of all subjects was indicated by a code number, which
was maintained by the investigator until all biochemical analyses complete. Serum
procalcitonin, hs-CRP, IL-6, and IL-10 levels was measured using the quantitative sandwich
enzyme immunoassay technique.
Procedure for Data Collection
The study was conducted in CIP after getting approval from institute ethics committee. Those
patients, who fulfill the inclusion and exclusion criteria was explained in detail regarding study
and informed consent was taken. Patients with drug naive or drug free (at least 4 weeks of oral
medication) acute schizophrenia and chronic schizophrenia meeting the inclusion and
exclusion criteria were recruited from inpatient and outpatient department of Central Institute
of Psychiatry (CIP), Kanke, Ranchi. Normal healthy controls meeting the inclusion and
exclusion criteria matched for age and sex were recruited. Written informed consent was taken
after explaining the procedure in detail.
Relevant socio-demographic data were collected from all the participants on the socio-
demographic data sheet. Normal healthy controls were screened by administering GHQ- 12.
Subject were rated on PANSS, CGI-S, and UKU side effect rating scale and after overnight
fast 5 ml of venous blood was collected under aseptic precautions at baseline. Patients, was
started on olanzapine treatment as per decision of the treating team. Treatment along with
dosage was clinically determined by treating team based on effectiveness of the drug, patient
tolerability and response to treatment. After four weeks of olanzapine treatment, subsequently
they were again rated on PANSS, CGI-S, UKU side effect rating scale and blood samples were
taken after an overnight fast for assessment of laboratory variables. 5 ml of venous blood
samples was taken from age and gender matched healthy controls after an overnight fasting
using venipuncture K-2 EDTA vacutainer and serum was separated by centrifugation using
pipet within 30 min. The collected serum was stored at -50°C using aliquot tube. Serum
analysis of serum procalcitonin, hs-CRP, IL-6, and IL-10 levels was done using sandwich
enzyme linked immunosorbent serologic assay (ELISA).
Statistical Analysis
All the collected data were analyzed using SPSS version 25.0.
The frequency counts of the categorical variables were done; and the mean and standard
deviation of the continuous variables were calculated across the sample.
Chi square test was applied to compare the categorical data.
Independent sample t-tests were applied to compare continuous data between two groups and
ANOVA was applied to compare continuous data among two groups.
Pearson’s correlation was used to detect the relationship between variables in the study groups.
RESULTS
General Consideration
The present study was conducted at Central Institute of Psychiatry (CIP), Kanke,
Ranchi. 15 drug naïve/drug free schizophrenia patients were included in this study.
Written informed consent was taken after explaining the procedure in details.
Upon entering the study they were rated on Positive and Negative Syndrome Scale
(PANSS) and Clinical global impression scale (CGI). Baseline blood samples were
taken to measure the serum procalcitonin, hs-CRP, IL-6, and IL-10 levels and patients
were put on olanzapine treatment by the treating team. After 4 weeks of olanzapine
treatment, patients were again rated on Positive and Negative Syndrome Scale
(PANSS), Clinical global impression scale (CGI) and UKU side effect rating
scale,Blood samples were again drawn to measure serum procalcitonin, hs-CRP, IL-6,
and IL-10 levels.
Table 1: Comparison of age and education between study group and normal
healthy control group
Study group (N=15) Healthy controls

Variables Mean ± SD (N=15) Mean ±
SD t df p
Age (in years) 29.46± 7.42 30.06 ± 6.78 .44 28 .81
Education
(in years) 9.26 ± 4.28 10.26 ± 4.90 .38 28 .51
Table 1. Shows comparison age and education between study group and normal healthy
controls group. The mean age of patients in the study group was 29.46 ± 7.42 years and
that of normal healthy controls was 30.06 ± 46.78 and there was no statistically significant
difference between them. The mean number of years of education of the study group was
9.26 ± 4.28 and it was not significantly different from that of normal healthy controls
(10.26 ± 4.90).
Table-2: Comparison of socio-demographic and clinical variables between study

group and healthy control group
Study group
Healthy controls
(N=15)
Variables (N=15) df Fisher’s
n (%) n (%) Exact
12 (80)
Rural 12 (80)
Residence 1 1.00
03 (20)
Urban 03 (20)
09 (60)
Male 09 (60)
Sex 1 1.00
06 (40)
Female 06 (40)
Married 06 (40) 10 (66.6)

Marital status 1 0.27
Unmarried 09 (60) 05 (33.4)
Hindu 12 (80.0) 11 (73.4)

Religion 1 1.00
Others 03 (20.0) 04 (26.6)
Table 2. Shows comparison of socio-demographic variables among study group and healthy
control group. Out of 15 subjects with study group population, a majority were male (60%)
unmarried (60%), Hindu (80.0%), and coming from a rural background (80%) and which
was similar to that of the healthy control group represented by male (60%), married (66.6%),
Hindu (73.4%), coming from a rural background (80%). No significant difference was found
in these parameter between the study group and healthy controls.
Table-3: Clinical characteristics of cases
Cases (N=15)
Variables (Mean ± SD) Range
Age of onset (in years) 25.06 ± 7.29 18 - 44
Duration of illness (in months) 53.13 ± 39.80 2 - 144
Table 3:-shows the data of clinical characteristics amongst cases. Patients had an average age
of onset of illness being 25.06 ±7.29 years which had a range of 18 - 44 years. The average
duration of illness amongst the cases was found to be 53.13 ± 39.80 months with a range of 2
- 144 months.
Table-4: Clinical variables in study group
Study group (N=15)
Variables n (%)
Acute 1 (6.7)
Mode of onset
Insidious 14 (93.3)
Continues 15 (100)
Clinical course Episodic 0 (0)
Clinical progress Deteriorating 15 (100)
Improving 0 (0)
Table 4. Shows clinical characteristic among study group. In the study group, 14 patients
(93.3%) had an insidious onset of illness. 15 patients (100%) had continues course of illness. 15 patients
(100%) had deteriorating progression of illness.
Table 5: Comparison between biochemical variables of the study group and healthy
controls
Study group Healthy controls
Variable (Baseline) (N=15) (Baseline) (N=15) t df p

Mean ± SD Mean ± SD
Serum PCT
0.63 ± 0.02 0.63 ± 0.39 0.35 28 0.97
(ng/ml)
Serum
hs-CRP level 1.06 28 0.29
(mg/ml) 3.26 ± 4.30 1.94 ± 2.28
Serum IL-6 1.71 28 0.09

(pg/ml) 31.08 ± 59.69 4.70 ± 1.40
Serum IL-10
(pg/ml) 24.31 ± 15.97 19.21 ± 3.27 1.21 28 0.23
PCT- procalcitonin, hs –CRP - high-sensitivity C-reactive protein, IL-6- interleukin 6 IL-10-

interleukin 10
Table 5. Shows comparison of biochemical variables between the study group and healthy
controls. The mean value of serum PCT levels in the study group was 0.63 ± 0.02 pg/ml
and that of healthy controls was 0.63 ± 0.39 pg/ml. The mean value of serum hs-CRP levels
in the study group was 3.26 ± 4.30 mg/ml and that of healthy controls was 1.94 ± 2.28
mg/ml. The mean value of serum IL-6 levels in the study group was 31.08 ± 59.69 pg /ml
and that of healthy controls was 4.70 ± 1.40 pg/ml. The mean value of serum IL-10 levels
in the study group was 24.31 ± 15.97 pg /ml and that of healthy controls was 19.21± 3.27
pg/ml. The comparison between the two groups was not statistically significant.
Table 6: Comparison between serum procalcitonin, hs-CRP, IL-6, IL-10 levels in
study group patients at baseline and after one-month treatment with olanzapine
(N=15)
Variables Baseline After 4 weeks of t p

Mean ± SD olanzapine Rx (df=14)
Mean ± SD
Serum PCT (ng/ml) 0.05 ± 0.02 0.55
0.63 ± 0.02 0.58
Serum hs-CRP (mg/ml) 1.05 ± 1.95 1.75 0.10
3.26 ± 4.20
Serum IL-6 (pg/ml) 31.08 ± 59.69 7.16 ± 5.46 1.54 0.14
Serum IL-10 (pg/ml) 21.31 ± 15.97 19.49 ± 2.75 1.17 0.26
PANSS Positive 20.53 ± 8.10 12.40 ± 4.27 5.35 0.001***
PANSS Negative 18.46 ± 7.17 11.00 ± 4.69 5.65 0.001***
PANSS GPS 32.06 ± 5.92 20.80 ± 2.65 7.35 0.001***
PANSS Total 71.73 ± 12.07 44.20 ± 8.14 9.91 0.001***
PCT- procalcitonin, hs –CRP - high-sensitivity C-Reactive Protein, IL-6- Interleukin 6 IL-10-
Interleukin 10, GPS- General Psychopathology scores.
Table 6. Shows comparison of PANSS scores and serum PCT, hs-CRP, IL-6, IL-10 levels at
baseline and after one month of olanzapine treatment in study group patients. The mean serum
PCT level was 0.63 ± 0.02 at baseline and 0.05 ± 0.02, after one month of olanzapine treatment.
The mean serum hs-CRP level was 3.26 ± 4.20 at baseline and 1.05 ±1.95 after one month of
olanzapine treatment. The mean serum IL-6 level was, 31.08 ± 59.69 at baseline and 7.16 ±
5.46, after one month of olanzapine treatment. The mean serum IL-10 level was 21.31 ± 15.97
at baseline and 19.49 ± 2.75 after one month of olanzapine treatment. No significant difference
were found in the serum levels of PCT, hs-CRP, IL-6, IL-10 at baseline and after 4 weeks of
treatment with olanzapine. The mean PANSS positive was 20.53 ± 8.10 at baseline and 12.40
± 4.27 after one month of olanzapine treatment. The comparison between two group was
statistically significant (p=.001***). The mean PANSS Negative was 18.46 ± 7.17 at baseline
and 11.00 ± 4.69, after one month of olanzapine treatment. The comparison between two group
was statistically significant (p=.001***). The mean PANSS GPS was 32.06. ± 5.92 at baseline
and 20.80 ± 2.65 after one month of olanzapine treatment. The comparison between two group
was statistically significant (p=.001***). The mean PANSS Total was 71.73 ± 12.07 at baseline
and 44.20 ± 8.14 after one month of olanzapine treatment. The comparison between two group
was statistically significant (p=.001***).
Table 7: Correlation between socio-demographic variables, biochemical variables,
and procalcitonin, hs-CRP, IL-6, IL-10 (N=15)
Variables Serum Serum Serum Serum Serum Serum Serum Serum
Procalcitonin hs-CRP IL-6 IL-10 Procalcitoni hs-CRP IL-6 IL-10
Pre Pre Pre Pre n Post Post Post Post
Age r 0.59 0.08 0.08 0.08 0.24 0.19 0.07 0.04
p 0.02* 0.77 0.76 0.76 0.38 0.49 0.77 0.86
Educati r 0.12 .411 0.03 0.54 0.02 0.22 0.20 0.18

on
p 0.67 0.12 0.89 0.04* 0.94 0.41 0.46 0.51
Age of r 0.66 0.11 0.13 0.07 0.02 0.01 0.001 0.24

onset
p 0.01** 0.69 0.62 0.80 0.92 0.96 0.99 0.38
Duratio r 0.13 0.06 0.10 0.03 0.47 0.40 0.18 0.41

n of
p 0.64 0.81 .070 0.90 0.07 0.13 0.51 0.12
illness
*P≤0.05 **P≤0.01
Table no 7:- Shows correlation between socio-demographic variables, and biochemical variables at
baseline and after treatment with Olanzapine for 4weeks A significant positive correlation is
present between age with a level of procalcitonin at baseline (p=0.02*) between education with IL-
10 level at baseline (p=0.04**) and between the age of onset with procalcitonin at baseline
(p=0.01***).
Table 8: Correlation between clinical global impressions variables and biochemical
variables (N=15)

Procalciton hs-CRP IL-6 IL-10 Procalcitonin hs-CRP IL-6 IL-10
in Pre Pre Pre Pre Post Post Post Post
CGI r 0.10 0.09 0.26 0.01 0.19 0.46 0.04 0.14

Severity
of Illness
p 0.71 0.72 0.34 0.96 0.48 0.07 0.87 0.62
CGI r 0.03 0.46 0.24 0.25 0.16 0.18 0.26 0.19
Global
Improve p 0.89 0.08 0.37 0.35 0.56 0.50 0.33 0.48
ment
CGI r 0.08 0.37 0.14 0.42 0.17 0.14 0.11 0.17
Efficacy p 0.76 0.17 0.60 0.11 0.53 0.61 0.68 0.53
Index
Table no 8:- Shows correlation between CGI variables and biochemical variables, at baseline and
after treatment with olanzapine for 4 weeks No significant correlation is present between CGI
severity of illness, CGI global improvement, CGI efficacy index with the level of procalcitonin,
hs-CRP, IL-6, IL-10 at baseline, and after treatment with Olanzapine for 4 weeks.
Table 9: Correlation between baseline clinical variables (PANSS) and biochemical

variables (N=15)
Variables Serum Serum hs- Serum Serum
Procalcitonin CRP Pre IL-6 Pre IL-10 Pre
Pre
PANSS r 0.01 0.51 0.08 0.35
Positive Pre
p 0.94 0.05 0.75 0.19
PANSS r 0.17 0.25 0.06 0.19

Negative Pre
p 0.52 0.35 0.81 0.49
PANSS GPS r 0.21 0.44 0.21 0.02

Pre
p 0.44 0.09 0.44 0.92
PANSS Pre r 0.25 0.07 0.23 0.12

Total
p 0.35 0.79 0.40 0.65
*P≤0.05 ,GPS- General Psychopathology scores

Table no 9:- Shows correlation between PANSS variables and biochemical variables, at baseline. No
significant correlation is present between PANSS and biochemical variables.
Table 10: Correlation between post olanzapine treatment clinical variables (PANSS)
and biochemical variables (N=15)
Variables Serum Serum hs- Serum Serum
Procalcitonin CRP Post IL-6 Post IL-10 Post
Post
PANSS Positive Post r 0.19 0.32 0.16 0.08
p 0.48 0.23 0.55 0.77
PANSS Negative Post r 0.18 0.39 0.14 0.07
p 0.52 0.14 0.61 0.80
PANSS GPS Post r 0.01 0.06 0.13 0.01
p 0.96 0.81 0.63 0.97
PANSS Total Post r 0.00 0.03 0.12 0.00
p 0.98 0.90 0.65 0.99
GPS- General Psychopathology scores
Table no 10: Shows correlation between PANSS variables and biochemical variables after 4 weeks
of treatment with Olanzapine. No significant correlation is present between PANSS and
biochemical variables after 4 weeks of treatment with olanzapine.
Table 11: Correlation between UKU side effect rating scale and biochemical variables
Procalcitonin hs- CRP IL-6 IL-10 Procalcitonin hs- CRP IL-6 IL-10
Pre Pre Pre Pre Post Post Post Post
UK Psychic r 0.29 0.31 0.30 0.04 0.09 0.18 0.26 0.48
SE
p 0.29 0.25 0.27 0.88 0.74 0.50 0.34 0.06
UKU r 0.21 0.60 0.37 0.23 0.09 0.03 0.03

Neurological 0.54
SE p 0.43 0.02* 0.16 0.04* 0.39 0.73 0.90 0.91
UKU r 0.04 0.05 0.21 0.19 0.13 0.17 0.18 0.33

Autonomic
SE p 0.86 0.85 0.44 0.49 0.64 0.54 0.52 0.21
UKU r 0.03 0.26 0.77 0.61 0.15 0.14 0.09 0.005

Other SE
p 0.89 0.34 0.001*** 0.02* 0.57 .60 0.74 0.98
*P≤0.05, ***P≤0.001 UKU: - UKU= udvalg for kliniske undersøgelser side-effect rating scale.
Table no 11: Shows correlation between UKU side effect variables and biochemical variables, at
baseline and post olanzapine treatment. Significant negative and positive correlation is present
between UKU neurological side effect with the hs-CRP level at baseline (p=0.02*), between
UKU neurological side effect with IL-10 level at baseline (p=0.04*), significant positive
correlation between UKU other side effectswith IL-6 level at baseline (p=0.001***) and between
UKU other side effects with IL-10 level at baseline (p=0.02*).
Table-12: Treatment emergent side effects in the study group
Count (n=15) (%)
UKU Psychic Nil 09 60

Mild 06 40
UKU Neurologic Nil 03 20
Mild 12 80
UKU Autonomic Nil 12 80
Mild 3 20
UKU Other Nil 11 73
Mild 4 26
UKU= Udvalg for Kliniske undersøgelser Side-Effect Rating Scale
Table 12: Depicts treatment emergent side effects in the study group. The most frequent
side effects in the patient group were neurologic (tremor, hypokinesia and rigidity)
followed by others (weight gain) and psychic (sedation).
Table no 13: Correlation between biochemical marker (serum procalcitonin, hs-CRP,

serum IL-6, IL-10) level after 4 weeks of olanzapine treatment
Variables Serum Serum Serum IL-6 Serum IL-10
Procalcitonin hs-CRP post post
post post
Serum procalcitonin r 1 0.56 0.30 0.22
post
p 0.02* 0.27 0.42
Serum hs-CRP r 1 0.18 0.16

0.56
post p 0.02* 0.51 0.56
Serum IL-6 r 0.30 0.18 1 0.04
post p 0.27 0.51 0.86
Serum IL-10 r 0.22 0.16 0.04 1
post p 0.42 0.56 0.86
*P≤0.05
Table no 13: Shows correlation between biochemical parameters. Significant positive correlation
is present between serum pro calcitonin and hs-CRP (p=0.02*)
DISCUSSION
1) Methodological Consideration:-
This was a prospective, hospital-based study which was conducted at the Central Institute of
Psychiatry on 13 inpatients, who got admitted in the respective wards of the hospital, and 2
outpatients, those who are attending clinical outpatient service at CIP regularly. This study
group consisted of 15 patients with schizophrenia fulfilling the criteria as per ICD-10 DCR
(WHO, 1993) and who are drug naïve/ drug free.
Drug naïve cases represent a population who have never been exposed to an antipsychotic drug,
presenting with psychotic symptoms. In contrast, drug-free cases were previously treated but
currently not taking medication. The drug-free cases were actively psychotic at the time of
presentation and differed from drug naïve cases only by the finding that they were exposed to
an antipsychotic drug in the past. So one month of abstinence from antipsychotics was chosen
as the minimum period for the selection of drug-free cases to cover for effects of previous
medication. However, both groups had similar psychotic symptoms and did not significantly
differ in their clinical presentation. This indicates that our study subjects had two distinct
patient populations- drug naïve and drug-free cases. However, there was no significant
difference in inflammatory markers between the groups, though the trend was slightly higher
in the drug-free cases.
Patients having any other comorbid psychiatric disorder or any significant neurological or
medical illness (including a history of significant head injury, epilepsy, inflammatory disease,
or other chronic disorder), substance dependence, endocrine disorders, or pregnancy states
were excluded because these conditions are known to alter the phenomenology and course of
the disorder as well as levels of these markers. The oxidative stress status of the body varies
with age. Levels of oxidative stress increase with age, as antioxidant capacity decreases.
Keeping this in mind, a narrow age range of 18-50 years was chosen (Barnett et al., 1995).
Only neuroleptic-naive patients were included in the study, as neuroleptics themselves are
known to induce oxidative stress (Cadet and Perumal, 1990), which in turn influence the
expression of many inflammatory factors. The inflammation triggered by oxidative stress is
the cause of many chronic diseases (Hussain et al., 2016).
2) Discussion of Results:
a) Description of Sample Population:-
The study subjects were recruited from amongst the inpatients admitted to the Central
Institute of Psychiatry and outpatient, those who are attending clinical outpatient
service at CIP regularly.
In this study, the mean age of schizophrenia patients was 29.46 ± 7.42 years, and in
healthy controls, was 30.06 ± 6.78 years. The cases and controls were matched for age
and we found no statistical difference between the two groups. Our sample had an
almost equal distribution of male and female subjects in cases and controls (60% and
40%, respectively).
The sample population was described based on frequency distribution in terms of

religion, marital status, and sex. Majority of the patients were males (60%) and of Hindu
religion (80%). A larger male representation is noted by several studies which have
found a higher incidence of schizophrenia in men versus women (Ochoa et al., 2012).
Patients and control groups differed significantly in terms of their marital status,
wherein, in comparison to 66.6% of controls, only 40% of schizophrenia patients were
married (Table-2).
In our study sample, the majority were educated in both cases and controls with mean
years of education being 9.26 ± 4.28 years and 10.26 ± 4.90 years for schizophrenia
patients and healthy controls respectively (Table-1). There was no significant difference
in years of education between study group patients and healthy control groups.
b) Clinical Characteristics:-
Among the clinical variables, the mean age of onset of schizophrenia was 25.06 ± 7.29
years which was similar to previous studies which suggest that onset before puberty was
associated initially with profound structural abnormalities within the parietal and frontal
regions and later incorporating temporal regions post-adolescence. It suggests that
structural changes represent an acceleration of normal maturational processes in childhood
and adolescence involving those regions that are programmed to mature at that time. The
onset of schizophrenia at these critical periods is likely to disrupt the normal processes of
maturation of both brain gray matter (GM) and white matter (WM) in these regions, with
associated disruption to the maturation of relevant functions (Gogtay et al., 2011).
The available evidence is consistent with the presence of subtle regionally and temporally
specific neurobiological changes through the course of psychosis, involving early as well
as later neurodevelopmental changes that are disrupted with the onset of psychosis. These
changes involve the acceleration of normal brain maturational processes that appear to be
endophenotypic and influenced by individual genes in an age-specific manner (Pantelis et
al., 2005).
In our study, the average total duration of illness was 53.13 ± 39.80 months, which is similar
to the earlier studies. As the study reported schizophrenia patients had a total duration of
illness of more than 5 years in 72.3% of the subjects (Solanki et al., 2008).
Thus, it can be summarized that the patients in the different experimental groups share
similar socio-demographic and clinical characteristics and that these features are
comparable to those from other studies that had been published in this country.
3) Comparison of Baseline Biochemical Levels:-
The choice of the test was based on the ability of the kit to detect very low levels since
schizophrenia was not considered as a disease with pronounced inflammation as compared
to sepsis. The threshold for CRP was chosen at 5.0 mg/lit, based on universal acceptance
of this cut-off value for inflammation (Gabay et al., 1999). Although procalcitonin
thresholds are well defined in sepsis, there is no universally accepted threshold value for
procalcitonin in non-sepsis conditions. Published literature suggests that baseline levels of
procalcitonin in most adults are<10 ng/mL and are not within the detectable range (Taylor
et al., 2017). Therefore, we used 12.8 pg/mL as the threshold value for procalcitonin
positivity based on our kit ability and referential range to detect inflammation. The
threshold for IL-6, IL-10 was chosen at <2.0 pg/ml, <4.9 pg/ml respectively, based on
universal acceptance of this cut-off value for inflammation (Shintani et al., 1991, Pillinger
et al., 2019). The threshold for positivity of procalcitonin, hs-CRP, IL-6, and 1L-10 was
used to identify patients presenting with inflammation, and thus group the cases into
inflammatory or non-inflammatory subtype.
In our study, the Procalcitonin levels were 0.63 ± 0.02 ng/ml in study group where as it was
0.63 ± 0.39 ng/ml in healthy control group. Procalcitonin serum levels in patients with
schizophrenia did not differ significantly from healthy controls (de Campos et al., 2015).
Previous literature also suggests procalcitonin was also found to be elevated in 30.7% of
schizophrenia cases higher than previously reported (Varun et al., 2018). The present study
shows that the serum procalcitonin levels were slightly identical in healthy controls and the
schizophrenia group at baseline (Table-5). In a recent meta-analysis, it was found that
procalcitonin levels did not increase in patients with schizophrenia, suggesting that not all
inflammatory markers increase in this condition (Campos et al., 2015). A similar finding
has been reported for patients who were diagnosed with bipolar disorder (Barbosa et al.,
2013) there were no significant differences in the levels of procalcitonin between patients
and controls in a pooled analysis (Campos et al., 2015), which is comparable to our results.
Serum hs-CRP levels in schizophrenia group was 3.26 ± 4.30 mg/ml and 1.94 ± 2.28 pg/ml
in healthy control group (Table-5). In a meta-analysis of serum CRP levels in
Schizophrenia patients, Miller et al. (2014) found that there was a 28% prevalence of an
elevated CRP level in patients with schizophrenia and related disorders. They found
significantly elevated levels of CRP in schizophrenia patients compared to healthy controls
(Miller et al., 2014). A study by Fernandes et al., (2016) suggest CRP levels were
moderately increased in persons with schizophrenia regardless of the use of antipsychotics
and did not change between the first episode of psychosis and with progression of
Schizophrenia. In recent study, CRP was found to be significantly elevated in
approximately 33.3% of study group cases which is consistent with findings from previous
studies (Varun et al., 2018). In contrast, this study reports evidence of inflammation by
CRP, in 4 out of 5 patient which is in agreement with previous reports indicating only a
subgroup of patients have inflammation. The difference in positive rates of CRP with
procalcitonin could be possibly explained by the heterogeneous nature of the disorder
contributed by genetic and environmental factors.
In our study the serum IL-6 levels in schizophrenia group was 31.08 ± 59.69 pg/ml and
4.70 ± 1.40 pg/ml in healthy control group (Table-5). As previous literature suggests
compared to healthy controls drug-free schizophrenia patients exhibited higher
plasma concentrations of IL-6 (Zhang et al., 2002). However, there was no statistically
significant difference between healthy controls and the schizophrenia group at baseline.
Our study found increased levels of serum IL-6 in all the 15 schizophrenia group patients,
indicating presence of inflammation in schizophrenia. Our finding of an elevation in serum
levels of IL-6 is consistent with the majority of studies of schizophrenia (Kammen et al.,
1999). Elevated plasma levels of IL-6 have been noted in patients with autoimmune
diseases, It is thought that IL-6 may constitute one factor in the development of
autoimmune states (Hirano et al., 1996) Therefore, our present study showed that increased
serum IL-6 levels may be involved in the development of the autoimmune response in
schizophrenia.
Serum IL-10 levels in schizophrenia group was 24.31 ± 15.97 mg/ml and 19.21 ± 3.27
pg/ml in healthy control group (Table-5). A recent study found no significant differences
in IL-10 level in peripheral blood cells between patients with schizophrenia and healthy
controls (Freudenreich et al., 2010). Several previous studies reported that patients with
schizophrenia exhibited significantly increased IL-10 serum levels compared to healthy
control (Maes et al., 2002). Our study found increased levels of serum IL-10 in all the 15
schizophrenia group patients, indicating presence of inflammation in schizophrenia. Meas
et al., (2002) which reported that patients with schizophrenia exhibited significantly
increased IL-10 serum levels. Moreover, increased serum levels of IL-10 were observed in
schizophrenia patients, specifically in more severe cases (Cazzullo et al., 1998). However,
some authors failed to replicate these findings in patients with Schizophrenia or even found
decreased serum IL-10 levels in paranoid schizophrenia or patients with schizophrenia at a
late stage (Kubistova et al., 2012). Other studies reported that IL-10 levels were
significantly decreased in these first episode drug naïve (FEDN) patients compared to
healthy controls (Hong et al., 2014). Thus, the picture emerging is that IL-10 levels deserve
further examination in the peripheral blood of patients with schizophrenia.
4. Effect of Treatment on Psychopathology:-
In the schizophrenia patient group, the severity of symptoms and effect of Olanzapine
treatment on psychopathology was assessed by the PANSS scale. The mean PANSS positive
was 20.53 ± 8.10 at baseline and 12.40 ± 4.27 after one month of Olanzapine treatment. The
comparison between baseline and after one-month Olanzapine treatment was statistically
significant. The mean PANSS Negative was 18.46 ± 7.17 at baseline and 11.00 ± 4.69, after
one month of Olanzapine treatment. The comparison between baseline and after one-month
Olanzapine treatment was statistically significant. The mean PANSS GPS was 32.06 ± 5.92
at baseline and 20.80 ± 2.65 after one month of Olanzapine treatment. The comparison
between baseline and after one-month Olanzapine treatment was statistically significant.
The mean PANSS total was 71.73 ± 12.07 at baseline and 44.20 ± 8.14 after one month of
Olanzapine treatment. The comparison between the two groups was statistically significant.
This indicates a significant improvement in the PANSS scores after 4-weeks of treatment
with Olanzapine. Olanzapine in this study demonstrated superior antipsychotic efficacy,
significantly reduced the positive symptoms, negative symptoms, and cognitive symptoms
of schizophrenia. This is similar to a study conducted by Conley and Mahmoud (2001)
which compared the treatments of Olanzapine and Risperidone to 134 patients who were
hospitalized. The patients were treated with Risperidone and Olanzapine with a flexible dose
for 6 weeks. In both the groups, there was also a significant difference in the scores of
PANSS for the positive scale, the negative scale, the general psychopathology scale, and the
total score of PANSS at the end of the 6th weeks.
5. Effect of Olanzapine Treatment on Procalcitonin, hs-CRP, IL-6, IL-10 Levels:-

The biochemical parameters were measured twice in the study group, once at baseline and
once after 4 weeks of Olanzapine treatment (Table-6). To the best of our knowledge, there
have been no previous longitudinal studies in the schizophrenia population measuring drug
naïve/drug free serum procalcitonin level and comparing with post antipsychotics treatment
level, In the present study, the mean serum procalcitonin level was 0.63 ± 0.02 at baseline
and 0.05 ± 0.02 after one month of Olanzapine treatment. No significant change was found
in the serum procalcitonin levels in schizophrenia patients. In one recent study,
Procalcitonin was also found to be elevated in 30.7% of schizophrenia cases, higher than
previously reported. This is possibly due to the sampling of patients devoid of medication
effects (Varun et al., 2018).
The mean serum hs-CRP level was 3.26 ± 4.20 at baseline and 1.05 ± 1.95 after one month
of Olanzapine treatment. However, no significant change was found in the serum hs-CRP
in schizophrenia patients. Some of the studies have revealed that antipsychotic drugs do
modulate the level of CRP (Singh et al., 2014). In Olanzapine-treated patients, the baseline
and three-month post-treatment CRP medians were not significantly different (0.3 and
0.4 mg/L, respectively). The antipsychotic effects on metabolic syndrome may indirectly
increase CRP levels post-treatment. The literature has largely ignored the possible effects
of antipsychotics on CRP and other inflammatory markers (Diaz et al., 2010).
The mean serum IL-6 level was 31.08 ± 59.69 at baseline and 7.16 ± 5.46, after one month
of Olanzapine treatment. However, no significant correlation was found between changes
in the serum IL-6 level. Previous literature suggests that typical and atypical antipsychotic
drugs have complex in-vivo immune-modulatory effects in schizophrenic subjects.
Repeated administration of typical antipsychotic drugs may suppress plasma IL-6 and sIL-
6R, whereas repeated administration of these drugs does not significantly alter plasma sIL-
2R concentrations. These findings suggest that typical antipsychotic drugs have
immunosuppressive effects in vivo through suppression of IL-6 related mechanisms (Lin
et al., 1998). Treatment with some antipsychotic agents, such as Clozapine and Olanzapine,
may lead to opposing effects on inflammation possibly through their propensity to generate
metabolic syndrome with its consequent effect on the inflammatory system and its stress
response. Pro-inflammatory cytokine level decreases were found for interleukin-1 β levels
and interferon-γ and a statistical trend towards a decrease in interleukin-6 and tumor
necrosis factor-α levels. The meta-analysis provides evidence that antipsychotic treatment
has an anti-inflammatory effect and could normalize immune balance dysfunction in
schizophrenia. Interleukin-6 level normalization could be a marker of illness equilibration
and thus be used in clinical practice (Romeo et al., 2018). Meas et al., (2000) reported no
significant effects of prolonged treatment with atypical antipsychotics on serum IL-6R
concentrations, although there was a trend toward increases in serum IL-6.
The mean serum IL-10 level was 21.31 ± 15.97 at baseline and 19.49 ± 2.75 after one month
of Olanzapine treatment. However no significant change was found in the levels of serum
IL-10 in schizophrenia patients. Previous literature was suggestive of a decline of IL-10
levels significantly in these first episode drug naïve (FEDN) schizophrenia patients (Hong
et al., 2014). The finding that IL-1RA and IL-10 levels were decreased after treatment with
atypical antipsychotics suggests that these molecules might be involved in the therapeutic
response to atypical antipsychotics treatment. Indeed, reduction in IL-10 was significantly
correlated with symptom improvement, although it is consistent with others that have
shown mixed responses as we have found in our study.
6. Correlation of Procalcitonin, hs –CRP, IL-6, IL-10 Levels with Clinical and other
Parameters:-
A significant positive correlation is present between current age of patient of schizophrenia,
age of schizophrenia with the level of procalcitonin at baseline, which suggests a possible role
of age concerning procalcitonin, as the age increases, baseline procalcitonin level also elevates.
A positive correlation was also found between education and IL-10 level at baseline, which
suggests the possible role of education in causing inflammation. Friedman and Herd (2010)
study reported the explanation behind the association between education and peripheral
inflammation. They postulated that higher education reduces the risk for low income status,
thus leading to reduced peripheral inflammation, It also explains the link between income
and inflammatory markers. One possibility is that there are higher rates of illness and
health-damaging behaviors among the poor that are responsible for higher levels of
inflammation.
In our study, we could not find any significant correlation between CGI severity of illness,
CGI global improvement, CGI efficacy index and serum procalcitonin, hs-CRP, IL-6, IL-
10 levels at baseline and four weeks of Olanzapine treatment, and the correlation wasn't
statistically significant.
The biochemical parameters, namely, procalcitonin, hs-CRP, IL-6, IL-10 levels were
correlated with PANSS, both at baseline and after four weeks of Olanzapine treatment. A
positive correlation was seen between the PANSS positive serum hs-CRP, levels
individually at baseline, hinting that the greater the severity of positive symptoms, the
greater the increase in CRP levels which corresponds with the previous study result. In
Chang et al., (2019), concluded that CRP was significantly associated with the PANSS
positive subscale. Our results are similar to the previous study which conclude that
abnormal CRP levels are significantly associated with formal thought dysfunction and
positive psychotic symptom (Fernandes et al., 2016). No significant correlation was seen
between the PANSS positive, negative, general psychopathology, and total score with
serum procalcitonin, IL-6, IL-10 levels at baseline and 4 weeks of Olanzapine treatment
and the correlation wasn’t statistically significant.
In our study, correlation using UKU side effect variables and biochemical variables were
suggestive of significant positive correlation UKU neurological side effect with the hs-CRP
level at baseline, which suggest in absence of drug effect hs-CRP levels would be
significantly higher in individuals with a neurological disorder or having neurological sign
and symptoms (Table-11). A recent study suggested that elevated CRP levels in both the
serum and CSF were prominent in Parkinson's patients (Qiu et al., 2019).
Negative correlation between UKU neurological side effect with IL-10 level at baseline,
suggest in absence of drug effect elevation of IL-10 levels may have a neuroprotective
mechanism, and have less chance of developing the neurological disorder. Recent literature
suggests the elevation of IL-10 and the significant correlation between IL- 10 and IL- 12,
a pro-inflammatory cytokine, may suggest that immunological disturbances and
neuroprotective mechanisms are involved in patients with Parkinson's disease (Rentzos et
al., 2009). Also, there was a positive correlation between UKU other side effects (weight gain)
with IL-6 and IL-10 level at baseline. This indicates that in the absence of medications, IL-
6, IL-10 or other cytokine levels would be significantly altered in individuals with others
systemic disease of skin rash, metabolic complication hormonal and sexual dysfunction.
A significant positive correlation was also seen between serum procalcitonin and hs- CRP
suggesting the rise or fall of hs-CRP levels and procalcitonin level occur synergistically.
As previous literature suggests CRP and PCT production are stimulated by bacterial
products and interleukins such as IL-6 (Simon et al., 2004). In contrast, Varun et al., (2018)
study reports evidence of inflammation by either PCT or CRP or both amounting to 50%
in the schizophrenia population. In one study both serum procalcitonin and CRP values in
cases with sepsis, severe sepsis, and septic shock were significantly higher than that of the
cases with systemic inflammatory response syndrome (SIRS) and without systemic
inflammatory response syndrome (SIRS).
7. Side Effect Profile:-

In our study, we found a significant prevalence of psychic, neurological, autonomous
adverse effects and other side effects after four weeks of Olanzapine treatment. Based on
the UKU side effect rating scale, we observed the most frequent side effects in the study
group were neurologic (tremor, hypokinesia, and rigidity) followed by psychic (sedation)
and another side effect (weight gain).
Side effects are consistently based on previous studies which indicate Olanzapine generally
has a mild-to-minimal risk of causing extrapyramidal side effects (EPS), however, the risk
is dose-dependent. In a study evaluating the D2 and 5-HT2 occupancy of Olanzapine,
extrapyramidal side effects (EPS) were noted to occur in patients treated with Olanzapine
at dosages of > 20 mg/day (Kapur et al., 1998).
The psychic side effects observed on Olanzapine treatment was sedation. A recent study
indicates that Olanzapine is also associated with a moderate risk of transient somnolence
(Tandon, 2002).
Another side effect found in our study was weight gain. Tandon (2002) study suggest that
except for Clozapine, Olanzapine has been associated with a higher degree of weight gain
than other available atypical antipsychotics. At 10 weeks, Olanzapine at standard doses
may produce between 4 and 4.5 kg of weight gain. Weight gain with Olanzapine does not
appear to be dose-related within the therapeutic dosage range of 5 to 20 mg/day, and weight
changes tend to plateau at 7- 8 kg after about 40 weeks of treatment.
SUMMARY AND CONCLUSION
Following are the salient features in our study:

 The mean age of onset of the illness for schizophrenia in the present study was
(25.06 ± 7.29) years. The mean duration of illness was (53.13 ± 39.80) in
months.
 The mean baseline PANSS total score in schizophrenia patients was (71.73 ±
12.07) and (44.20 ± 8.14) after 4 weeks of olanzapine treatment.
 There was no statistically significant difference in levels of serum procalcitonin,
hs-CRP, IL-6, and IL-10 at baseline in schizophrenia patients as compared to
healthy controls.
 There was a no statistically significant difference between serum procalcitonin,
hs-CRP, IL-10, IL-6 levels at baseline and after 4 weeks of olanzapine treatment
in patients.
 There was statistically significant improvement in terms of positive, negative
and general psychopathology in schizophrenia patients after 4 weeks of
olanzapine treatment.
 There was a significant negative and positive correlation between age, age of
onset and procalcitonin levels at baseline.
 No significant correlation was found between CGI scores and PANSS score with
levels of serum procalcitonin, hs-CRP, IL-6, and IL-10.
 No significant correlation was found between CGI scores and PANSS score with
levels of serum procalcitonin, hs-CRP, IL-6, and IL-10.
 There was a significant positive correlation between CRP level and
procalcitonin levels.
 There was a significant positive and negative correlation between UKU side
effect scores and hs-crp, IL6, IL-10 levels at baseline.
In conclusion, the findings of our study suggest that there was no significant difference
between patients of schizophrenia and healthy controls in terms of serum procalcitonin,
hs-CRP, IL-6, and IL-10. Also, Olanzapine treatment had no significant alterations on
serum procalcitonin, hs-CRP, IL-6, IL-10 levels in schizophrenia patients.
LIMITATIONS
 Our sample size was modest which is liable to errors, making it difficult to
generalize the result.
 This study examined a specific segment of population drawn out of a purposive
method of sampling. Therefore, the conclusions derived from the study might
not hold true for all patients with schizophrenia. This study needs to be replicated
in other population.
 Treatment was controlled, including varying dosages of medications used.
Effect of drugs on the biomarkers could be varied and hence could confound the
results.
 We examined procalcitonin with other inflammatory marker in serum, and the
range of procalcitonin levels in our study was quite broad, reducing the
reliability of the study.
 Most of the subjects belonged to lower socio-economic stratus so results cannot
be generalized to the entire population.
FUTURE DIRECTIONS
1. Future studies should take a larger sample size for study to get more reliable
results.
2. In future study other confounding factors may be considered in order to get more
comprehensive findings.
3. Moreover, further studies are needed to factor in the heterogenicity of
psychotropic drugs used as they can induce changes in the biochemical markers
being assessed.
4. Future research is needed to identify other factors associated with inflammation
in schizophrenia as well their relationships with inflammation, whether.
5. In future, studies should be conducted in different parts of the world with
different population dynamics can give results which can be generalized.
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interleukin-6 in schizophr Psychiatry Res. 1999 Oct 11; 87(2-3): 129- 36.
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protein as peripheral inflammatory markers in antipsychotic drug-free schizophrenia
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Watanabe Y, Someya T, Nawa H. Cytokine hypothesis of schizophrenia pathogenesis:
evidence from human studies and animal models. Psychiatr Clinical Neurosci 2010 Jun;
64(3): 217- 30.
Weinberger DR, Berman KF. Speculation on the meaning of cerebral metabolic hypofrontality
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APPENDICES
APPENDIX-I
GOVERNMENT OF INDIA
RANCHI-834006
INFROMED CONSENT FORM

Title: COMPARISON OF SERUM PROCALCITONIN, hs-CRP, IL-6, IL-10 LEVELS
AT BASELINE AFTER 2 AND 4 WEEKS OF OLANZAPINE IN PATIENTS WITH
SCHIZOPHERNIA
Investigators’ Details:
1. DR. AMANULLAH GHORI, MBBS
2. PROF. (DR.) BASUDEB DAS, MD.
3. PROF.(DR.) K.K. KSHITIZ, MD
4. DR. ANIRUDDHA MUKHERJEE, MD.
Participant Details:
1. Name:
2. Age/Date of Birth:
3. Name of the Informant/Guardian/Caregiver:
4. Address:
Probable Finding Agency:
Patient/Guardian/Caregiver Consent Form
Part I: Information Sheet for Patient and/or Guardians/Caregivers

1. Purpose of Study: You are requested to participate in the above mentioned study. You
can read and understand this information before consenting for the study and can read
this information even after that all the times. Ensure that you understand the information
provided to you. (Please provide a brief about aims and objectives of the study)
2. Process of Study: In this study, data would be collected by propoer and detailed
evaluation of patients attending OPD and/or admitted to the hospital as per the inclusion
and exclusion criteria mentioned and further statistical analysis would be performed to
test the hypotheses.
3. Risk from the Study : Nil
4. Benefits from the Study: In this study, we would assess ___________________
i. _________________________________________________________
________ Which would help develop and execute appropriate
pharmacological and better management of these patients.
5. Complications: Nil
6. Compensation: Nil
7. Confidentiality: Your participation in this study would be kept confidential. No
data/part of data would be published with your name in it. By signing this consent from,
you authorize investigative agency and Institute Ethics Committee to share the records
related to you.
8. Rights of the Participants: For receiving treatment at CIP, Ranchi in future, you and
your family has the right to withdraw your consent from the study during any part of
the study without any reason.
9. Options for Participation in the Study: You can continue with the usual treatment
what you have been receiving from CIP, Ranchi.
You can ask for more/further information during and/or after the completion of the
study.
Part 2 :Patient/Guardian/Caregiver Consent
I have read and have been explained the information contained in this form. I was given
chance to ask and put forth questions related to the study. I have been made satisfied
completely.
I hereby give my consent for participation in the Study.
Name of the Patient:
Signature/Left Thumb Impression of Patient/Caregiver:
Date:
Relationship with the patient:
Testimony of the Investigator:

I, , Investigator have explained to the
patient/caregiver in the language in which they are conversant. I have explained the procedure,
benefits and harm of the study to them.
Signature of the Investigator: Signature of the Witness:

Name of the Investigator: Name of the Witness
Date: Date:
APPENDIX-II
GOVERNMENT OF INDIA
RANCHI-834006
SOCIO-DEMOGRAPHIC AND CLINICAL DATA SHEET
CRF no.:
Name:
Father’s Name:
Age: Sex:
Religion: Residence (Rural/Urban/Semi-urban):
Education Status: Occupation:
Marital Status: Family Income

(Approx.): Handedness:
Clinical Diagnosis (with ICD-10 code):
Age of onset: Duration of illness:
Mode of onset: Clinical course:
Clinical Progress:
Past History, Significant: 1. Yes 2. No
Family history, Significant: 1. Yes 2. No
Birth and Developmental history, Significant: 1. Yes 2. No
APPENDIX-III
GOVERNMENT OF INDIA
RANCHI-834006
POSITIVE AND NEGATIVE SYNDROME SCALE
1 2 3 4 5 6 7
Absent Minimal Mild moderate Moderate severe Severe Extreme

ITEM BASELINE 4 WEEKS
P1 Delusion
P2 Conceptual disorganization
P3 Hallucinatory behaviour
P4 Excitement
P5 Grandiosity
P6 Suspiciousness/Persecution
P7 Hostility
N1 Blunted affect
N2 Emotional withdrawal
N3 Poor Rapport
N4 Passive / Apathetic Social withdrawal
N5 Difficulty in abstract thinking
N6 Lack of spontaneity & flow of conversation
N7 Stereotyped thinking
G1 Somatic concern
G2 Anxiety
G3 Guilt feelings
G4 Tension
G5 Mannerisms & posturing
G6 Depression
G7 Motor retardation
G8 Uncooperativeness
G9 Unusual thought content
G10 Disorientation
G11 Poor attention
G12 Lack of judgment & insight
G13 Disturbance of volition
G14 Poor impulse control
G15 Pre-occupation
G16 Active social avoidance
Kay, S. R., Fiszbein, A. & Opler, L. A. (1987). The positive and negative syndrome
scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13(2), 261-276.
APPENDIX-IV
GOVERNMENT OF INDIA
RANCHI-834006
GENERAL HEALTH QUESTIONNAIRE – 12
1. Have you recently been able to concentrate on whatever you are doing?
a. Better than usual
b. Same as usual
c. Less than usual
d. Much less than usual
2. Have you recently lost much sleep over worry?
a. Not at all
b. Not more than usual
c. Rather more than usual
d. Much more than usual
3. Have you recently felt you are playing a useful part in things?
a. More than usual
b. Same as usual
c. Less than usual
d. Not at all
4. Have you recently felt capable of making decisions about things?
a. More than usual
b. Same as usual
c. Less than usual
5. Have you recently felt constantly under strain?
a. Not at all
6. Have you recently felt you could not overcome your difficulties?
a. Not at all
7. Have you recently been able to enjoy your normal day-to-day activities?
a. More than usual
b. Same as usual
c. Less than usual
d. Much, less than usual
8. Have you recently been able to face up your problem?
a. More than usual
b. Same as usual
c. Less than usual
9. Have you recently been feeling unhappy and depressed?
a. Not at all
10. Have you recently been losing confidence?
a. Not at all
11. Have you recently been thinking yourself as a worthless person?
a. Not at all

12. Have you recently been feeling reasonable happy all things considered?
a. More than usual
b. Same as usual
c. Less than usual
Goldberg, D., & Williams, P. (2000). General health questionnaire (GHQ).

Swindon, Wiltshire, UK: nferNelson.
APPENDIX-V
GOVERNMENT OF INDIA
RANCHI-834006
CLINICAL GLOBAL IMPRESSION(CGI)
Severity of Illness:
0 = Not assessed
1 = Normal; Not at all ill 2 = Borderline mentally ill 3 =Mildly ill
4 = Moderately ill 5 = Severely ill
6=Severely ill 7 = Among the most extremely ill
patients
Global Improvement:
0 = Not assessed
1 = Very much improved 2 = Much improved
3 = Minimally improved 4 = No change
5 = Minimally worse 6 = Much worse
7 = Very much worse
Efficacy Index:
Side Effects
None No interference Significant Outweighs
Effects
Marked 1 2 3 4
Moderate 5 6 7 8
Minimal 9 10 11 12
Unchanged/ 13 14 15 16
worsened
Refrence:- Guy W. ECDEU manual for psychopharmacology. DHEW publication no. (ADM)
Rockville, MD: U.S. Department of Health, Education and Welfare; 1976. Clinical global impression;
pp. 76–338.
APPENDIX-VI
GOVERNMENT OF INDIA
RANCHI-834006
THE UKU SIDE EFFECTS RATING SCALE FOR THE REGISTRATION OF
UNWANTED EFFECTS OF PSYCHOTROPICS
PSYCHIC
CATEGORY SYMPTOM SCORES CASUAL

O RELATIO
F SIDE EFFECTS N
1.1 Concentration Difficulties
1.2 Asthenia/Lassitude/lncreas
ed Fatigability
1.3 Sleepiness/Sedation
1.4 Failing Memory
1.5 Depression
1.6 Tension/lnner Unrest
1.7 Increased Duration of

Sleep
1.8 Reduced Duration of Sleep
1.9 Increased Dream Activity
1.10 Emotional indifference
NEUROLOGIC
CATEGORYOF SYMPTOMS SCORE CASUAL

RELATIO
SIDE EFFECTS
N
2.1 Dystonia
2.2 Rigidity
2.3 Hypokinesia/Akinesia
2.4 Hyperkinesia logic
2.5 Tremor
2.6 Akathisia
2.7 Epileptic seizures
2.8 Paraesthesias
AUTONOMIC
CATEGORY OF SIDE SYMPTOMS SCORE CASUAL

EFFECTS RELATION
3.1 Accommodation
Disturbances
3.2 Increased Salivation
3.3 Reduced Salivation
3.4 Nausea/Vomiting
3.5 Diarrhoea
3.6 Constipation
3.7 Micturition Disturbances
3.8 Polyuria/Polydipsia
3.9 Orthostatic Dizziness
3.10 Palpitations/Tachycardia
3.11 Increased Tendency to

Sweating
OTHERS
CATEGORY OF SYMPTOMS SCORE CASUAL

SIDE EFFECTS RELATION
4.1 Rash
4.1a -Morbilliform
4.1b -Petechial
4.1c -Urticarial
4.1d -Psoriatic
4.1e -Cannot be classified
4.2 Pruritus
4.3 Photosensitivity
4.4 Increased Pigmentation
4.5 Weight gain
4.6 Weight loss
4.7 Menorrhagia
4.8 Amenorrhoea
4.9 Galactorrhoea
4.10 Gynaecomastia
4.11 Increased Sexual

Desire
4.12 Diminished Sexual

Desire
4.13 Erectile Dysfunction
4.14 Ejaculatory
Dysfunction
4.15 Orgastic Dysfunction
4.16 Dry Vagina
4.17 Headache
4.17a -Tension headache
4.17b -Migraine
4.17c -0ther forms
4.18 Physical Dependence
4.19 Psychic Dependence
GLOBAL ASSESSMENT OF THE INTERFERENCE BY ASSESED BY

EXISTING SIDE EFFECTS WITH THE PATIENT'S
PATIENT DOCTOR
DAILY PERFORMANCE:
0 No side effects
1 Mild side effects that do not interfere with the

patient's performance
2 Side effects that interfere moderately with the

3 Side effects that interfere markedly with the

CONSEQUENCE
0 No action
1 More frequent assessment of the patient, but no reduction of dose, and/or

occasional drug treatment of side effects
2 Reduction of dose and/or continuous drug, treatment of side effects
3 Discontinuation of drug or change to another preparation
Refrences :- Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side
effect rating scale: A new comprehensive rating scale for psychotropic drugs and a cross‐
sectional study of side effects in neuroleptic‐treated patients. Acta Psychiatrica
Scandinavica. 1987 Jun 1;76(s334):1-00.

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COMPARISON OF SERUM PROCALCITONIN, hs-CRP, IL-6,

AND IL-10 LEVELS AT BASELINE AND AFTER 4 WEEKS OF

Under the Guidance of

CENTRAL INSTITUTE OF PSYCHIATRY

OF OLANZAPINE TREATMENT IN PATIENTS WITH SCHIZOPHERNIA” has been conducted by me

Professor of Biochemistry and Dr. Aniruddha Mukherjee, M.D., Associate Professor of

requirements of the Diploma in Psychological Medicine.

to any university previously before this date.

Place: Ranchi (Dr. Amanullah Ghori)

Dr.Aniruddha Mukherjee, MD Dr. K.K. Kshitiz, MD

Prof. (Dr.) Basudeb Das, MD

Dr. Amanullah Ghori

AIM, HYPOTHESIS AND OBJECTIVES 18

SUMMARY AND CONCLUSION 44

Despite research over few decades pathophysiology of schizophrenia remains poorly

In addition, it is also known to be associated with depression and cognitive dysfunction

Figure-1. Demonstration of Pleiotropic functions of IL-6. ADAMTS, a disintegrin and

IL-10 is an important Th2-type cytokine, produced by activated macrophages, T regulatory, B

Role of Antipsychotic on Inflammatory Marker:-

3. There will be no significant relationship between serum procalcitonin, hs-CRP, IL-6,

Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand.

Inclusion Criteria for Experimental Group:-

1. Patients who received the diagnosis of schizophrenia according to ICD-10 DCR

2. patients of both sex in 18-50 years of age group.

4. The patients who had not taken antibiotics recently, anti-inflammatory,

1. Co-morbid medical illnesses, neurosurgical illnesses, other psychiatric illnesses, any

2. Patients with substance use disorder.

3. Noncompliance within medication during 4 weeks to be excluded.

4. Patients who are unwilling to give informed consent.

Inclusion Criteria for Controls:-

1. Healthy subject’s age and gender matched to experimental group.

2. Subjects who are willing to give informed consent.

3. GHQ-12 score less than or equal to 3.

Exclusion Criteria for Controls:-

1. Co-morbid Medical illnesses, neurosurgical illnesses, other psychiatric illnesses, any

2. Patients with substance use disorder.

3. Patients who are unwilling to give informed consent.

4. GHQ-12 score more than 3.

Tools for Assessment:-

1. Informed consent form

Informed Consent Form

It is a semi-structured preforma consisting of socio-demographic variables like name, age, sex,

Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987)

2 = Borderline mentally ill—subtle or suspected pathology

UKU Side Effect Rating Scale (Lingjaerde et al., 1987)

Procedure for Data Collection

Study group (N=15) Healthy controls

Age (in years) 29.46± 7.42 30.06 ± 6.78 .44 28 .81

Table-2: Comparison of socio-demographic and clinical variables between study

Married 06 (40) 10 (66.6)

Hindu 12 (80.0) 11 (73.4)

Table-4: Clinical variables in study group

Study group (N=15)

Clinical course Episodic 0 (0)

Clinical progress Deteriorating 15 (100)

Study group Healthy controls

Variable (Baseline) (N=15) (Baseline) (N=15) t df p

Serum IL-6 1.71 28 0.09

PCT- procalcitonin, hs –CRP - high-sensitivity C-reactive protein, IL-6- interleukin 6 IL-10-

Variables Baseline After 4 weeks of t p

p 0.02* 0.77 0.76 0.76 0.38 0.49 0.77 0.86

Educati r 0.12 .411 0.03 0.54 0.02 0.22 0.20 0.18