Clinical trial NCT01793935: Withania Somnifera: an Immunomodulator and Anti-inflammatory Agent for Schizophrenia
Official title: Sensoril® (Ashwagandha), an Immunomodulator and Anti-inflammatory Agent for Schizophrenia: A Parallel Group, Randomized Double Blind, and Placebo Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Schizophrenia
Schizoaffective Disorder
Keywords: Schizophrenia
Sensoril
Withania Somnifera extract
Total/ Positive / Negative Symptoms
Stress
Inflammation
Immunomodulation
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2013-02-18
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Adult males or females (≥ 18 years, to 75 years)
2. DSM IV TR diagnosis of schizophrenia or schizoaffective disorder (If officially instituted by study initiation: DSM V diagnoses will be used).
3. Ability to provide informed written consent
4. 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
5. Current symptom exacerbation ≥ 2 weeks, but ≤ 1 year
6. Receiving anti-psychotic medications for ≥ 4 weeks
7. For women of child bearing age, a negative pregnancy test at screening.

Exclusion Criteria:

1. Testing positive for illicit substances (marijuana or alcohol use will be assessed on a case by case basis, caffeine and nicotine are excepted)
2. Receiving pharmacological treatment for addictions (naltrexone, suboxone, acamprosate, others) will be reviewed on a case by case basis
3. Seriously unstable medical illnesses
4. Pregnant or breast feeding women
5. Known allergy or history of serious adverse event with WSE
6. Subjects who may require imminent hospitalization (examples: suicidal or aggressive behavior)
7. Currently receiving antibiotics, anti-viral, or anti-parasitic medications
8. Currently receiving immunosuppressive medications (e.g. corticosteroids, chemotherapy or transplantation or HIV/AIDs associated drugs).
9. Currently receiving NSAIDs or Aspirin (\>81 mg/day) on a daily basis or PRN use \> 2x/week (in the last 4 weeks).

Primary outcomes:
measure: Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline and 12 Weeks
Secondary outcomes:
measure: Perceived Stress Scale (PSS)
timeFrame: Baseline and 12 weeks or end of treatment
measure: Clinical Global Impression Scale (CGI-S) - Severity
timeFrame: Baseline and 12 weeks or end of study
measure: Number of Participants With a Score of 1, 2, or 3 on the Clinical Global Impression Improvement Scale
timeFrame: 12 weeks
measure: Immune Marker IL-2
timeFrame: Baseline and 12 weeks or end of study
measure: Immune Marker IL-4
timeFrame: Baseline and12 weeks or end of study
measure: Immune Marker IL-6
timeFrame: Changes from Baseline in Immune markers at 12 weeks or end of study
measure: Immune Marker IFN-Y (Gamma)
timeFrame: Baseline and 12 weeks or end of study
measure: Immune Marker Hs-CRP (High Sensitivity C Reactive Protein)
timeFrame: Baseline and 12 weeks or end of study
measure: Immune Marker S-100B
timeFrame: Baseline and 12 weeks or end of treatment
Other outcomes:
measure: Vital Signs - Weight
timeFrame: Baseline and 12 weeks or end of study
measure: Vital Signs - Body Mass Index
timeFrame: Baseline and 12 weeks or end of study
measure: Vital Signs - Blood Pressure Systolic and Diastolic
timeFrame: Baseline and 12 weeks or end of study
measure: Vital Signs - Pulse
timeFrame: Baseline and 12 weeks or end of study
measure: Vital Signs - Temperature
timeFrame: Baseline and 12 weeks or end of study
measure: Laboratory Analytes
timeFrame: Change from Baseline in Laboratory Analytes at 12 weeks or end of study
Locations:
city: Pittsburgh
country: United States
facility: Western Psychiatric Institute & Clinic
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: KN Roy Chengappa, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chengappa KNR, Brar JS, Gannon JM, Schlicht PJ. Adjunctive Use of a Standardized Extract of Withania somnifera (Ashwagandha) to Treat Symptom Exacerbation in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry. 2018 Jul 10;79(5):17m11826. doi: 10.4088/JCP.17m11826.