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

Abstract

Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this pro-inflammatory status may improve clinical presentation. Simvastatin crosses the blood-brain barrier, has anti- inflammatory and neuroprotective effects and reduces metabolic syndrome. 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 (X2(1) = 0.01, P = .90). Group differences varied over time (treatment*time X2(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.

Keywords: RCT; inflammation; schizophrenia; simvastatin; symptoms.

Fig. 1.

Trial profile. *In case of familial risk for muscular disorders or previously experienced muscle toxicity when taking medication similar to simvastatin, creatine kinase (CK) levels will be checked (as recommended by the Dutch Farmacotherapeutisch Kompas).

Fig. 2.

Mean symptom severity (PANSS total score) for the simvastatin and placebo group. Means are estimated by a linear mixed model and displayed with standard errors. Data are displayed per visit for the active treatment phase (0–12 mo; continuous line) and follow up phase (24 mo; dashed line).

Fig. 3.

Mean change of cognitive functioning during the active treatment phase (0–12 mo). Mean Z-scores with standard errors are displayed for the composite cognition score and for the 6 subtasks of the BACS.

Fig. 4.

(a) Mean symptom severity (PANSS total score) for the adherent and non-adherent participants within the simvastatin group Means are estimated by a linear mixed model, with standard error. Data are displayed per visit for the active treatment phase (0–12 mo). Adherence to study medication (simvastatin) was defined as >20% reduction of LDL-cholesterol, compared to baseline, throughout the study. (b) Mean LDL-cholesterol levels for the simvastatin and placebo group. Means are depicted, with standard error. Data are displayed per visit for the active treatment phase (0–12 mo).