Randomized double-blind inpatient study of a gluten-free diet for negative symptoms in people with schizophrenia

BACKGROUND: There are no FDA-approved treatments for negative symptoms in schizophrenia and related disorders (SRD). In an SRD subgroup with systemic and central inflammation and elevated anti-gliadin immunoglobulin G antibodies (AGA IgG+), previous findings suggested that a gluten-free diet (GFD) improved negative symptoms. METHODS: We conducted a five-week double-blind randomized placebo-controlled inpatient trial comparing a GFD versus a gluten-containing diet (GCD) in people with SRD and elevated AGA IgG+ (N = 39; n = 21 GFD and n = 18 GCD). The Clinical Assessment Interview for Negative Symptoms Motivation and Pleasure (CAINS MAP) scale measured the primary outcome of negative symptoms. Secondary outcomes evaluated other symptom domains and serum kynurenine pathway metabolites. Also, we explored inflammatory markers and, in n = 20 participants, measured cerebral blood flow (CBF) using Arterial Spin Labeling, and neurochemistry using magnetic resonance spectroscopy. OUTCOMES: Relative to a GCD, a GFD was associated with a modest decrease in CAINS MAP scores (df = 31.2.1, F = 2.96, p = 0.035); decrease in kynurenic acid (KYNA; df = 32, F = 9.51, p = 0.0042) and kynurenine (df = 32, F = 11.45, p = 0.0019); and increase in CBF and total creatine in frontal brain regions. KYNA and CAINS MAP change scores were correlated (r = 0.350, p = 0.039) while cognition was not impacted. DISCUSSION: Our preliminary data suggests that a GFD may be associated with modest improvements on experiential negative symptoms within an SRD subgroup. A GFD may be associated with reductions in kynurenine pathway metabolites and increased CBF. Larger and longer studies are needed to confirm negative symptom efficacy in this AGA IgG+ SRD subgroup.