Withania Somnifera: an Immunomodulator and Anti-inflammatory Agent for Schizophrenia

Study Overview
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Brief Summary
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Withania somnifera (WSE; Ashwagandha in Ayurveda) extracts have been used as an adaptogen or to build resistance to stress or diseases in indigenous medical systems in India for centuries. Modern scientific data for WSE indicate several bioactive molecules (withanolides, withanosides, indosides, withaferin-A, others) with significant immunomodulatory, anti-inflammatory and stress reducing properties. This study will examine whether a standardized extract of Withania Somnifera (WSE; Sensoril®) will improve total, positive, negative symptoms, and stress in patients with schizophrenia. The study will examine whether WSE reduces PANSS positive and negative symptoms and stress scores in subjects, and whether these improvements are mediated by changes in inflammatory immune indices. An additional aim will determine if patients receiving WSE will have fewer adjustments to their psychotropic medications that those assigned to placebo. The study will examine whether WSE will re-balance Th1/Th2 ratios (cytokine measures) and mediate a reduction of elevated hs-CRP levels. It is hypothesized that those subjects whose Th1/Th2 ratios normalize will likely have a greater magnitude of clinical improvement versus those subjects whose immune ratios remain unbalanced. The proposal is a 12-week, double-blind, placebo-controlled RCT of WSE added to antipsychotic medications in approximately 60 or more patients with schizophrenia with an exacerbation of symptoms. If efficacy is affirmed, this low cost extract could be studied further, and used quite readily across low, middle and high income countries.

Detailed Description
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The primary aim is to determine whether a standardized extract of Withania somnifera will reduce psychopathology scores (PANSS total) and stress scores(PSS total) in persons with schizophrenia? The study will also determine whether WSE reduces measures of positive and negative and general symptoms of schizophrenia (PANSS subscale scores)? Another primary aim will be to determine if changes in antipsychotic and/or other psychotropic medications (lithium, anticonvulsants, antidepressants, anxiolytic agents or hypnotics) (examples: dosage escalation or reductions or switch or stoppage) will favor the group receiving the standardized Withania somnifera extract versus those receiving placebo. Even though we expect changes in antipsychotic medications to occur when patients experience an exacerbation of psychotic symptoms (or other psychiatric symptoms), we hypothesize that those receiving the standardized Withania somnifera extract will experience fewer medication adjustments then those assigned to placebo. A secondary aim is to determine whether WSE will rebalance TH1/TH2 ratios (cytokine measures) and mediate a reduction of elevated hs-CRP levels? The study will assess whether those subjects whose TH1/TH2 ratios normalize have a greater magnitude of clinical improvement vs. those subjects whose immune ratios remain unbalanced. Similarly, the study will assess whether reduction of hsCRP levels correlate with improvements in PANSS total and subscale scores or the PSS total scores. Eighty or more patients with DSM IV TR (or if instituted by the study initiation: DSM V) schizophrenia or schizoaffective disorder will be screened and 60 or more eligible patients will be enrolled in a 12 week placebo controlled double blind study. Subjects who have experienced an exacerbation of positive symptoms (delusions, hallucinations, etc). Subjects receiving medications that affect the immune-inflammatory system will be excluded and those receiving antibiotics, antiviral or anti-parasitic medications will be excluded. Base line laboratory and EKG examination will be carried out to establish eligibility for study participation. In addition specific laboratory analyses of immune markers namely interleukin-2, interferon gamma, interleukin-4, interleukin 6 and high sensitivity C-Reactive Protein will be carried out. Sixty or more patients will be randomly assigned to receive either WSE or matching placebo starting with 1 capsule of 250 mg strength twice a day (total daily dose = 500 mg) for the first week which will be increased to 2 capsules of 250 mg twice daily (total daily dose = 1000 mg) for a total treatment period of 12 weeks. An assessment of psychopathology (PANSS) and stress will be carried out at each scheduled visit. Assessments of safety including vital signs and treatment emergent adverse events will also be carried out at each visit. Immune-inflammatory markers will be re-assessed at the final visit.

Official Title
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Sensoril® (Ashwagandha), an Immunomodulator and Anti-inflammatory Agent for Schizophrenia: A Parallel Group, Randomized Double Blind, and Placebo Controlled Study

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Sensoril®
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males or females (≥ 18 years, to 75 years) DSM IV TR diagnosis of schizophrenia or schizoaffective disorder (If officially instituted by study initiation: DSM V diagnoses will be used). Ability to provide informed written consent PANSS total score ≥ 60, positive symptom cluster, (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility and unusual thought content with at least 2 items scoring ≥ 4, or one of these items scoring ≥ 5, on a scale ranging from 1 = absent to 7 = extreme Current symptom exacerbation ≥ 2 weeks, but ≤ 1 year Receiving anti-psychotic medications for ≥ 4 weeks For women of child bearing age, a negative pregnancy test at screening. Exclusion Criteria: Testing positive for illicit substances (marijuana or alcohol use will be assessed on a case by case basis, caffeine and nicotine are excepted) Receiving pharmacological treatment for addictions (naltrexone, suboxone, acamprosate, others) will be reviewed on a case by case basis Seriously unstable medical illnesses Pregnant or breast feeding women Known allergy or history of serious adverse event with WSE Subjects who may require imminent hospitalization (examples: suicidal or aggressive behavior) Currently receiving antibiotics, anti-viral, or anti-parasitic medications Currently receiving immunosuppressive medications (e.g. corticosteroids, chemotherapy or transplantation or HIV/AIDs associated drugs). Currently receiving NSAIDs or Aspirin (>81 mg/day) on a daily basis or PRN use > 2x/week (in the last 4 weeks).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sensoril®<br>Sensoril® is a proprietary extract of Withania Somnifera | Drug: Sensoril®<br>* Sensoril® is a proprietary extract of Withania Somnifera. Each Sensoril® capsules will contain 250 mg of standardized extract of Withania Somnifera<br>* Other names: Ashwagandha;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Each Placebo capsule comprises inert ingredients; microcrystalline cellulose NF 102, croscarmellose Sodium NF, silicon Dioxide, Fumed NF (Cab-0-sil), magnesium sterate, NF matched in appearance and fill weight to Sensoril® capsules. Moreover, based on past experience, we will expose the placebo capsules to covered sachets containing Sensoril, so that the smell permeates the placebo capsules which then smell like the Sensoril capsules.<br>* Other names: Sugar Pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Syndrome Scale (PANSS) | The Positive and Negative Syndrome Scale (PANSS) measures symptom severity in patients with psychotic illnesses. It yields a total score as well as subscores for Positive symptoms, Negative symptoms and General symptoms. PANSS Positive subscale consists of 7 Items - (minimum score = 7, maximum score = 49) - Higher values represent a worse outcome. PANSS Negative subscale consists of 7 Items - (minimum score = 7, maximum score = 49) - Higher values represent a worse outcome. General Psychopathology subscale consists of 16 items - (minimum score = 16, maximum score = 112) - Higher values represent a worse outcome. PANSS Total Score - The 3 subscales scores are summed to compute a PANSS Total score. The minimum PANSS total score = 30, maximum = 210 - Higher values represent a worse outcome | Baseline and 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perceived Stress Scale (PSS) | The Perceived Stress Scale (PSS) was developed to measure the degree to which situations in one's life are appraised as stressful. Perceived Stress Scale Scoring Each item is rated on a 5-point scale ranging from never (0) to very often (4). Positively worded items are reverse scored, and the ratings are summed, with higher scores indicating more perceived stress. PSS-10 scores are obtained by reversing the scores on the four positive items: For example, 0=4, 1=3, 2=2, etc. and then summing across all 10 items. Items 4, 5, 7, and 8 are the positively stated items. Total score can range from 0 to 40. Scores around 13 are considered average. Scores of 20 or higher are considered high stress, | Baseline and 12 weeks or end of treatment | 
| Clinical Global Impression Scale (CGI-S) - Severity | The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Possible ratings are: 0 = not assessed, 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 - The higher the score the worse outcome | Baseline and 12 weeks or end of study | 
| Number of Participants With a Score of 1, 2, or 3 on the Clinical Global Impression Improvement Scale | The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. and rated as: Possible ratings are: 1= Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5= Minimally worse, 6= Much worse, 7=Very much worse. The higher the score the worse outcome | 12 weeks | 
| Immune Marker IL-2 | Changes in immune marker IL-2 will be assessed in response to study medication. | Baseline and 12 weeks or end of study | 
| Immune Marker IL-4 | Changes in immune marker IL-4 will be assessed in response to study medication. | Baseline and12 weeks or end of study | 
| Immune Marker IL-6 | Changes in immune marker IL-6 will be assessed in response to study medication. | Changes from Baseline in Immune markers at 12 weeks or end of study | 
| Immune Marker IFN-Y (Gamma) | Changes in immune marker IFN-Y (gamma) will be assessed in response to study medication. | Baseline and 12 weeks or end of study | 
| Immune Marker Hs-CRP (High Sensitivity C Reactive Protein) | Changes in immune marker hs-CRP (high sensitivity C Reactive Protein) will be assessed in response to study medication. hsCRP - mg/L | Baseline and 12 weeks or end of study | 
| Immune Marker S-100B | Changes in immune marker S-100B will be assessed in response to study medication. Elisa Sensitivity 2.7 picogm/ml Range 2.7 to 2000 picogm/ml | Baseline and 12 weeks or end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Sensoril, Withania Somnifera extract, Total/ Positive / Negative Symptoms, Stress, Inflammation, Immunomodulation