Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled trial (a Positive and Negative Syndrome Scale, five-factor analysis)

Treating schizophrenia patients who fail to respond to antipsychotics is a major challenge, and the percentage of treatment-resistant patients is estimated to be 20-25 %. Recent studies indicate that yokukansan (YKS; D2 and 5HT1A partial agonist and 5HT2A and glutamate antagonist) to be safe and useful in treating behavioral and psychological symptoms associated with dementia and other neuropsychiatric conditions. We aimed at evaluating both the efficacy and safety of YKS in patients with treatment-resistant schizophrenia.This randomized, multicenter, double-blind, placebo-controlled study was conducted between May 2010 and August 2012. One hundred twenty antipsychotic-treated inpatients from 34 psychiatric hospitals in Japan were included. Patients were randomized to adjuvant treatment with YKS 7.5 g/day or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) with five factors [excitement/hostility (P4, P7, G8, and G14), depression/anxiety (G1, G2, G3, G4, and G6), cognition (P2, N5, N7, G5, G10, G11, G12, G13, and G15], positive (P1, P3, P5, P6, and G9), and negative (N1, N2, N3, N4, N6, G7, and G16]]. Other assessments included, Clinical Global Impression-Severity (CGI-S), Global Assessment of Functioning (GAF), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The primary efficacy outcome was the change in PANSS five-factor scores. The secondary outcomes were changes in the scores of CGI-S. The analysis was made on a modified intention to treat basis with the help of a last observation carried forward method.YKS showed a tendency of superiority to placebo in reducing total all PANSS five-factor scores in treatment-resistant schizophrenia, but the difference was not statistically significant in total, depression/anxiety, cognition, positive, and negative factors. However, compared to the placebo group, the YKS group showed statistically significant improvements in the PANSS excitement/hostility factor scores (p0.05). No substantial side effects were recorded.The results of the present study indicate YKS to be a potential adjunctive treatment strategy for treatment-resistant schizophrenia, particularly to improve excitement/hostility symptoms.