Withania Somnifera: an Immunomodulator and Anti-inflammatory Agent for Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional

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.
    

Intervention name(s): Sensoril®; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Sensoril® is a proprietary extract of Withania Somnifera. Each Sensoril® capsules will contain 250 mg of standardized extract of Withania Somnifera; 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.
Other intervention name(s): Ashwagandha; "Sugar Pill"
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; Sensoril; Withania Somnifera extract; Total/ Positive / Negative Symptoms; Stress; Inflammation; Immunomodulation