Simvastatin Augmentation for Patients With Early-Phase Schizophrenia-Spectrum Disorders: A Double-Blind, Randomized Placebo-Controlled Trial

Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this proinflammatory status may improve clinical presentation. +imvastatin crosses the blood-brain barrier, has anti-inflammatory and neuroprotective effects and reduces metabolic s:+ ndrome. In this study, we investigated if 12 months of simvastatin augmentation can improve symptoms and cognition in patients with early SSD. This double-blind placebo-controlled trial included 127 SSD patients across the Netherlands, <3 years after their diagnosis. From these, 119 were randomly assigned 1:1 to simvastatin 40 mg (n = 61) or placebo (n = 58), stratified for sex and study site. Primary outcomes were symptom severity and cognition after 12 months of treatment. Depression, symptom subscores, general functioning, metabolic syndrome, movement disorders, and safety were secondary outcomes. Intention to treat analyses were performed using linear mixed models and ANCOVA. No main effect of simvastatin treatment was found on total symptom severity after 12 months of treatment as compared to placebo (X-2(1) = 0.01, P = .90). Group differences varied over time (treatment*time X-2(4) = 11.2; P = .025), with significantly lower symptom severity in the simvastatin group after 6 months (mean difference = -4.8; P = .021; 95% CI: -8.8 to -0.7) and at 24 months follow-up (mean difference = -4.7; P = .040; 95% CI: -9.3 to -0.2). No main treatment effect was found for cognition (F(1,0.1) = 0.37, P = .55) or secondary outcomes. SAEs occurred more frequently with placebo (19%) than with simvastatin (6.6%). This negative finding corroborates other large scale studies on aspirin, minocycline, and celecoxib that could not replicate positive findings of smaller studies, and suggests that anti-inflammatory augmentation does not improve the clinical presentation of SSD.

Automated summary

This study found that augmentation with simvastatin did not significantly affect total symptom severity in early SSD patients after 12 months of treatment, but did show lower symptom severity in the simvastatin group at 6 and 24 months. There was no main treatment effect on cognition and secondary outcomes. Adverse events occurred more frequently in the placebo group compared to the simvastatin group.