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Specific Aim:

The improved understanding of schizophrenia as a neurobiological disorder and the recognition that intervention
is needed as early as possible following the onset of illness offers the potential to optimize long-term treatment
outcomes. The two main challenges facing intervention at the prodromal phase of psychosis are correct early
diagnosis and time to initial intervention. First episode psychosis (FES) is typically preceded by subtle premorbid
signs, early signs are often vague and not consistent making diagnosis and timely treatment a challenge.

Recent advances in psychiatry have shown that inflammatory processes might be responsible for psychopathology
related to first-episode psychosis. Studies have shown that both acute-phase inflammatory marker C-reactive
protein (CRP) and chronic phase inflammatory markers erythrocyte sedimentation rate (ESR) are elevated in
patients with schizophrenia, chemokines which derive inflammatory process are implicated in pathogenesis and
more recently research has suggested other markers including neutrophil/lymphocyte ratio (NLR),
platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) were significantly increased in the relapse
period of disease when compared with the remission period in the same patients.

The aim of our study is to identify any changes in inflammatory markers in first-episode psychosis versus control
subjects. We plan to gather retrospective data and look closely at markers including white blood cell count
(WBC)/leukocyte count, WBC differential measuring neutrophils, lymphocytes, monocytes, eosinophils, and
basophils. We also plan to measure platelet count and derive neutrophil/lymphocyte ratio (NLR),
platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR).

We plan to include patients who came with first-episode psychosis, coded as unspecified psychosis, not due to a
substance or known physiological condition (ICD-9 CM 298.9, and ICD-10 F 29). We will limit our study to ages
15-30 years of age as the majority of new-onset psychosis will fall in this age group. We will only be looking at the
first onset of psychosis and the associated labs, we will not look into follow up lab values, or subsequent visits
related to psychosis.

We plan to measure differences of patient groups with the control group, healthy subjects who presented for a
visit without any history of psychosis, no previous history of substance use disorder, and meet exclusion criteria
provided below. We will also look at differences in time to readmission, and length of stay in FES patients versus
control subjects.

Exclusion criteria applied to both FEP and control group:

Previous history of traumatic brain injury (completed Sid)
Functional Neurological Symptom Disorder( completed Sid)
Delirium (completed Sid)
Organic causes of psychosis (specifically hypo and hyperthyroidism; seizure disorders) ​FIND OTHER CAUSES
Ongoing or recent Infection (brain encephalitis, Lyme’s disease, ​etc.)
Medication-induced psychosis (specifically corticosteroids, ACE inhibitors, Beta-blockers, anabolic steroids,
Efavirenz, H2 receptor antagonists, Interferon, Isotretinoin, Isoniazid, Levetiracetam, Estrogens and Progestins, and
Valproate) (Abbass on it)
Neurological disorders including brain tumors, strokes, HIV and some brain diseases such as Parkinson’s,
Alzheimer’s, Huntington's disease, Multiple sclerosis, and dementia.
Recent surgical procedures (figure this out) Suman can exclude easily via billing so no need to code individually
Previous history of mental disorder that can lead to psychosis. (Please see excel sheet for complete listing)
(completed Sid)
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Specific Aim​:

First episode psychosis is typically preceded by subtle premorbid signs, early signs are often
vague and not consistent making diagnosis and timely treatment a challenge. The aim of the
study is to identify any changes in lab values related to first episode of psychosis. Recent
advances in psychiatry has shown that inflammatory process might be responsible for
psychopathology related to first episode psychosis. Studies have shown that both acute phase
inflammatory marker CRP and chronic phase inflammatory markers ESR are elevated in
patients with schizophrenia.

About 3 out of 100 people will experience psychosis at some time in their lives. Studies have
also shown that inflammatory markers can predict poor treatment response and prognosis, and
has potential for newer modality or early interventions for psychosis.

Significance​:

The improved understanding of schizophrenia as a neurobiologic disorder and the recognition

that intervention is needed as early as possible following the onset of illness offer the potential
to optimize long-term treatment outcomes. The two main challenges facing intervention at the
prodromal phase are correct diagnosis and interventions that offer benefit with minimal risk of
unwanted effects on the developing brain.

The inflammatory hypothesis is typically hypothesized in the pathogenesis of schizophrenia.

The objective of this study was to compare inflammatory markers during relapse and remission
periods in patients with schizophrenia.

Patients with schizophrenia are much more likely to develop metabolic abnormalities. These
include type II diabetes mellitus, cardiovascular disease, hypertension, and dyslipidemia
compared to the general population. These comorbidities account for 60% of the mortality rate
in schizophrenia.

One study concluded that schizophrenia in young adults (<35 years old) is accompanied by
increased IL-6 and sIL-2R secretion; and subchronic treatment with clozapine increases sIL-2R
levels. Increased plasma sIL-2R may be one mechanism by which neuroleptics exhibit their
immunosuppressive effects.

Studies also show chemokines, which derive inflammation processes are implicated in
pathogenesis of schizophrenia, study suggested the role of CCR5-A55029G polymorphism,
CCR2-V64IWT:CCR5-A55029GA and CCR2-V64I64I:CCR5-A55029GA haplotypes as possible
markers.

Another study calculated the inflammation score based on levels of C-reactive protein,
Pentraxin 3, IgG antibodies to gliadin, casein, and Saccharomyces cerevisiae measured in
blood samples, and concluded that chronic schizophrenia group showed significant elevations in
the combined inflammation score compared with controls.

To the best of our knowledge; there was one such study done at Ondokuz Mayis University. The
study analyzed the complete blood count (CBC) of 105 patients diagnosed with schizophrenia
who were hospitalized due to psychotic relapse between 2012 and 2016 and 105 healthy
control subjects were retrospectively analyzed. MLR and PLR were found to be significantly
higher in the remission period when compared with the control group. NLR, PLR and MLR
values were significantly increased in the relapse period when compared with the remission
period of the same patients. This finding also support the inflammation hypothesis of
schizophrenia.

Method​:

We will review the retrospective data in the electronic medical records examining the metabolic
and blood count abnormalities of patients with first episode psychosis. We plan to include
patients ages 15-30 years of age as majority of new onset psychosis will fall in this age group.

Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR)
of the patients during relapse period were found to be significantly higher when compared with the control
group.

OR/AND

Comparison of Neutrophils, platelets, lymphocytes, and ANC measurements between first episode
psychosis and control group.

Exclusion criteria​:

Previous history of traumatic brain injury

Functional Neurological Symptom Disorder

Delirium

Organic causes of psychosis (specifically hypo and hyperthyroidism;, seizure disorders, )

Infections ( brain encephalitis, Lymes disease, etc.)

Postnatal depression,
Medication-induced psychosis (specifically corticosteroids, ACE inhibitors, Beta blockers,
anabolic steroids, Efavirenz, H2 receptor antagonists, Interferon, Isotretinoin, Isoniazid,
Levitriacetam, Estrogens and Progestins, and Valproate)

Recent or previous history of substance use including cannabis, stimulants, hallucinogens,

sedatives/hypnotics.

Alcohol use disorder, or hospitalization related to intoxication from alcohol, and or withdrawal
related to alcohol.

Intellectual disability, as precise history cannot be elucidated in this population

Neurological disorders including brain tumors, strokes, HIV and some brain diseases such as
Parkinson’s, Alzheimer’s, Huntington's disease, Multiple sclerosis, and dementia.

Recent surgical procedures

Previous history of any mental disorders that can lead to psychosis, including MDD, PTSD,
Bipolar disorder, OCD, Autism, Schizoid personality disorder, Schizophreniform personality
disorder

HIstory of physical, emotional or sexual trauma

Control Group:

Healthy individuals with no previous history of any mental disorders, and no substance use
issues.

Secondary Goal​:

We will measure hemoglobin changes (e.g. Hematocrit) in patients with first episode psychosis,
and compare it with the control group. Previously changes in hemoglobin have been implicated
in causing psychosis.

​References:

https://www.ncbi.nlm.nih.gov/pubmed/30472508

-Cortisol and Inflammatory Biomarkers Predict Poor Treatment Response in First Episode Psychosis
https://academic.oup.com/schizophreniabulletin/article/41/5/1162/1920436

-Inflammation and metabolic changes in first episode psychosis: Preliminary results from a longitudinal
study. https://www.sciencedirect.com/science/article/pii/S0889159115001555
-The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset
psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial.
https://www.ncbi.nlm.nih.gov/pubmed/30322824

-Meta-Analysis of Total and Differential White Blood Cell Counts in Schizophrenia.

https://www.ncbi.nlm.nih.gov/pubmed/31850530

-First-Episode Psychosis: An Inflammatory State? https://www.karger.com/Article/Abstract/356536

- Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia:
Relationship to Psychopathology and Treatment. ​https://www.ncbi.nlm.nih.gov/pubmed/31504969

-Correlations between immune and metabolic serum markers and schizophrenia/bipolar disorder
polygenic risk score in first-episode psychosis. ​https://www.ncbi.nlm.nih.gov/pubmed/31749237

-Does early diagnosis and treatment of schizophrenia lead to improved long-term outcomes?.
http://www.jneuropsychiatry.org/peer-review/does-early-diagnosis-and-treatment-of-schizophrenia-lea
d-to-improved-longterm-outcomes-neuropsychiatry.pdf
- Five years of specialised early intervention versus two years of specialised early
intervention followed by three years of standard treatment for patients with a
first episode psychosis: randomised, superiority, parallel group trial in
Denmark (OPUS II).​ https://www.ncbi.nlm.nih.gov/pubmed/28082379

-Early recognition and prevention of schizophrenia and other psychoses.

https://www.ncbi.nlm.nih.gov/pubmed/31858162

-Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a

critical review and meta-analysis.
https://www.uptodate.com/contents/first-episode-psychosis/abstract/4

-Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of

clozapine.

-Inflammatory Markers in Recent Onset Psychosis and Chronic Schizophrenia.

-Chemokine gene variants in schizophrenia

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