Efficacy of glutamate-GABA modulator riluzole for the treatment of cognitive and psychotic symptoms in 22q11.2 deletion syndrome: A placebo-controlled crossover trial.

Individuals with 22q11.2 deletion syndrome are susceptible to psychosis and cognitive impairments. These symptoms have been linked to a disruption in the balance of glutamate (excitatory) to GABA (inhibitory) transmission. This clinical trial aimed to determine whether the glutamate and GABA-modulating drug riluzole reduces psychotic or cognitive symptoms within 22q11.2 deletion syndrome. 32 participants with a 22q11.2 deletion and psychotic and/or cognitive symptoms were enrolled in this placebo-controlled, fixed-order crossover trial. Participants received placebo for 8 weeks, followed by 8 weeks of 100mg/day riluzole. The Positive and Negative Syndrome Scale (PANSS) and Pennsylvania Computerized Neurocognitive Battery (CNB) were used to assess psychotic and cognitive symptoms, with PANSS total and subscale scores and CNB accuracy and reaction time as primary outcome measures. Correcting for family-wise error rate, riluzole improved performance on executive function (p = 0.036), social cognition (p = 0.041), and non-verbal reasoning (p = 0.005) tasks in comparison to baseline. Following correction, no significant effects of riluzole were found on the PANSS total score and subscales, or on accuracy and reaction time on the CNB compared to placebo. Exploratory analyses of individual PANSS items indicated that riluzole reduced anxiety (p = 0.001) and impairments in abstract thinking (p = 0.039) compared to baseline. Our results suggest riluzole may have beneficial effects on mental health and cognition. Further research is needed to confirm these findings and establish a responsive phenotype.