Abstract
Background
Early intervention and management of Generalised Anxiety Disorder (GAD) is essential to effectively reduce both symptom severity and the risk of developing other psychiatric disorders. However, current first-line treatments are only about 50% effective, with high rates of relapse and many adverse effects. Psychedelic medicines, such as psilocybin, have emerged as promising medications for treatment-refractory mood and anxiety disorders. However, between a third to a half of clinical trial participants fail to respond to psychedelic therapies, subjecting them to intensive but ultimately successful treatments and delaying more effective treatment strategies.
A recent Phase II clinical trial examining the efficacy of psilocybin assisted therapy (PAT) for the treatment of GAD found that 44% of participants with GAD responded to treatment with 27% of participants achieving symptom remission at 11 weeks after commencing treatment (primary endpoint). Thus, there is a need to identify which individuals with GAD are likely to respond to PAT and direct probable non-responders to alternate therapies.
Aims & Objectives
We aimed to identify potential blood biomarkers of PAT treatment-response using a multi-omic approach.
Method
Following a 6-week treatment regime of PAT, whole blood was collected from 11 participants with GAD who responded to PAT at primary endpoint (≥50% reduction in HAM-A score) and 13 PAT non-responders. Total RNA and genomic DNA was isolated from the blood. RNAseq at 50 million reads/sample was used to measure differential gene expression and Infinium MethylationEPIC v2.0 bead chips were used to identify differential DNA methylation in the samples. Variation in gene sequence was examined using NGS whole genome sequencing at 30x coverage.
Results
Following FDR correction, 5 genes were found to be differentially expressed in PAT responders vs non-responders: CTXN2-AS1 (F.C. log2 = 4.6; q < 0.001), DUT-AS1 (F.C. log2 = 2.6; q < 0.001), HLA-V (F.C. log2 = -4.8; q < 0.001), PARP16 (F.C. log2 = 0.3 q < 0.05), and SAXO2 (F.C. log2 = -2.52; q < 0.05). Cluster analysis identified the expression levels of a panel of 4 genes: CTXN2-AS1, DUT-AS1, HLA-V and PARP16, were able to separate 45% of the participants with GAD that responded to PAT at primary endpoint from all other participants.
Discussion & Conclusions
This is a first of its kind, multi-omic study of psychedelic treatment for a mental illness in a clinical cohort. We have identified a panel of 4 genes that may be useful in identifying whether a patient with GAD is likely to respond to PAT. Further study is needed to validate these genes as treatment response biomarkers in a larger cohort, and to determine whether these or other genes predict treatment response prior to commencing PAT.