Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD

Abstract

Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, P=0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, P=0.028 and P=0.017, P=0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, P=0.048), and with months of treatment (P=0.002, P=0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.

Genetics of ADHD: What Should the Clinician Know?

“…Since therapy is mainly based on improvement of dopaminergic neurotransmission, it is plausible to expect a stronger effect of genes involved in the mediation of dopaminergic effects. Smaller studies have shown that polymorphisms in genes of catecholaminergic neurotransmission [66] or the SNARE complex of the synapse can indeed predict the response to stimulant therapy [67].…”

A Review of Heterogeneity in Attention Deficit/Hyperactivity Disorder (ADHD)

“…For instance, the treatment response of methylphenidate was suggested to rely on inter-individual variability in the amount of dopamine released by neurons (Volkow et al, 2002; Berridge et al, 2006; Hannestad et al, 2010). Certain polymorphisms, such as the 40-pb variable number tandem repeat polymorphism, noradrenaline, and serotonin transporter genes, were also suggested to be associated with the treatment response to methylphenidate (Winsberg and Comings, 1999; Yang et al, 2004; Thakur et al, 2010; Froehlich et al, 2011b; Bidwell et al, 2017; da Silva et al, 2018). However, recent meta-analyses did not support this polymorphism association hypothesis (Kambeitz et al, 2014; Bonvicini et al, 2016).…”

Recent developments in the genetics of attention‐deficit hyperactivity disorder

“…The latter argument, in particular, suggests that scientists’ methods are currently no better than a random selection of genes when it comes to putting together plausible biologically motivated gene sets . While such candidate‐driven association studies have generated initial promising results and applications (e.g., in the pharmacogenomics of methylphenidate treatment), most recent studies have concentrated on whole‐genome genotyping.…”