Re: Ashwagandha Beneficial for Symptom Exacerbation in Schizophrenia

Ashwagandha (Withania somnifera, Solanaceae) Immune-inflammatory Dysregulation Schizophrenia Date: 12-14-2018 HC# 111851-606 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. July 2018;79(5): 17m11826. doi: 10.4088/JCP.17m11826. Immune-inflammatory dysregulation has been linked with the exacerbation of symptoms in patients with schizophrenia. There is some evidence that adjunctive treatment with non-steroidal anti-inflammatory drugs (NSAIDS) may be beneficial; however, NSAIDS may cause adverse effects (AEs). Ashwagandha (Withania somnifera, Solanaceae) root extract has demonstrated immunomodulatory and anti-inflammatory activity. The purpose of this randomized, double-blind, placebo-controlled study was to evaluate the effect of ashwagandha on recently exacerbated symptoms in patients with schizophrenia. Outpatients (n=66, aged 18-75 years) with schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) and Mini-International Neuropsychiatric Interview participated in this study conducted from April 2013 to July 2016 at the ambulatory clinics associated with the Comprehensive Recovery Services of Western Psychiatric Institute Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Other inclusion criteria were a Positive and Negative Syndrome Scale (PANSS) total score ≥ 60 and ≥ 5 on any one item or a score ≥ 4 on any two items in the positive cluster or unusual thought content; symptom exacerbation for ≥ 2 weeks but ≤ 1 year; and taking antipsychotics for ≥ 4 weeks. Excluded patients had unstable medical disorders; needed immediate psychiatric hospitalization; were pregnant or used illicit drugs; were allergic to ashwagandha; or were taking antibiotics, antivirals, antiparasitics, immunosuppressive therapy, or daily NSAIDs. The duration of the trial was 12 weeks. Patients were randomized to receive 500 mg/day of either ashwagandha extract (Sensoril; Natreon, Inc.; New Brunswick, New Jersey) or placebo for one week, and then 1000 mg/day ashwagandha extract or placebo for an additional 11 weeks. The ashwagandha capsules contained inactive ingredients and "a minimum concentration of the critical bioactive withanolide glycosides and carrier oligosaccharides but only traces of withaferin A (US Patent 7318938)." The placebo capsules contained "the same inactive ingredients" and were stored with closed sachets of ashwagandha for several days to imbue the capsules with the characteristic odor of ashwagandha. Physicians were permitted to increase the dosage of the antipsychotic drug or add a second medication; however, patients were discontinued from the study if they were switched to a different antipsychotic drug. The primary endpoint was the change from baseline on the four PANSS scales (total score, positive, negative, and general symptom score). Secondary outcome measures included the Perceived Stress Scale (PSS), Clinical Global Impressions (CGI), and serum levels of the inflammatory markers high-sensitivity C-reactive protein; S100 calcium binding protein B; the cytokines interleukin (IL)-2, IL-4, IL-6; and interferon gamma. The proportion of patients with ≥ 20% improvement on the PANSS and PSS, time to onset of improvement on the PANSS and PSS, and the proportion of patients with improvements on the CGI were calculated. There were no significant differences between groups at baseline. A total of 59 patients completed the study (n = 28 [84.9%] in the ashwagandha group and n = 31 [93.9%] in the placebo group). Treatment adherence rate was not significantly different between the groups. The ashwagandha group had significantly better outcomes on the PANSS negative (P = 0.001), total (P = 0.001), and general (P = 0.003) symptom scores compared with placebo. Cohen's d statistic indicated a high treatment effect for PANSS negative and PANSS total score (d = 0.83 for both) and a moderate treatment effect for general symptom score (d = 0.76). There was no significant difference between groups for the PANSS positive symptom scores (P = 0.055); however, post-hoc analysis revealed that the ashwagandha sub-group with the highest PANSS negative symptom scores at baseline had a significantly greater improvement than that cohort in the placebo group (P = 0.002). The ashwagandha group had significant improvements in the PSS score compared with placebo (P = 0.022; d = 0.58). Significant improvements in PANSS and PSS scores began after four weeks of treatment. Compared to the placebo group, the ashwagandha group had significantly more patients who achieved ≥ 20% improvement on total PANSS (P = 0.013), negative PANSS (P = 0.002), general PANSS (P = 0.013), and PSS (P = 0.012) scores. The dosage of the antipsychotic drug was increased, or another medication was added, in 27.3% of the placebo group and 6.1% of the ashwagandha group (P = 0.044). There were no significant changes in serum levels of inflammation markers or cytokines. There were no correlations between serum levels of the inflammation markers and PANSS scores. The incidence of AEs did not significantly differ between groups. The authors conclude that the results of this early study suggest a standardized extract of ashwagandha as an adjunct to antipsychotic therapy "provides significant benefits, with minimal side effects, for negative, general, and total symptoms and stress in patients with recent exacerbation of schizophrenia." Limitations of the study include the small sample size, relatively short duration, and the use of several different antipsychotic medications. Additional studies are needed to confirm these findings and determine the optimal dosage of ashwagandha. The ashwagandha and placebo capsules were provided by Natreon, Inc. This organization had no role in conducting the study, data analysis, or reporting of the results. —Heather S. Oliff, PhD