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

• Published in: Molecular psychiatry Vol. 23; no. 6; pp. 1446 - 1452
• Main Authors: da Silva, B S, Cupertino, R B, Rovaris, D L, Schuch, J B, Kappel, D B, Müller, D, Bandeira, C E, Victor, M M, Karam, R G, Mota, N R, Rohde, L A, Contini, V, Grevet, E H, Bau, C H D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2018; Nature Publishing Group
• Subjects: 38/77; 631/208; 692/53/2423; Adult; Analysis; Attention Deficit and Disruptive Behavior Disorders - complications; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit hyperactivity disorder; Behavioral Sciences; Biological Psychology; Blood proteins; Care and treatment; Central Nervous System Stimulants; Childhood mental disorders; Dosage and administration; Exocytosis; Exocytosis - genetics; Exocytosis - physiology; Female; Genes; Genetic aspects; Genetic polymorphisms; Genetic research; Humans; Hyperactivity; Male; Medicine; Medicine & Public Health; Messenger RNA; Methylphenidate; Methylphenidate - pharmacology; Methylphenidate - therapeutic use; mRNA; Neurosciences; Oppositional defiant disorder; original-article; Outcome Assessment (Health Care); Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Polymorphism, Genetic; Practice guidelines (Medicine); Psychiatry; RNA; Short term; SNAP receptors; Stimulants; Synaptotagmin; Synaptotagmin I - genetics; Synaptotagmin I - metabolism; Syntaxin 1 - genetics; Syntaxin 1 - metabolism; Treatment Outcome; Vesicle-Associated Membrane Protein 2 - genetics; Vesicle-Associated Membrane Protein 2 - metabolism
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2017.90

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 FDR =0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction ( P =0.007, P FDR =0.028 and P =0.017, P FDR =0.048, respectively). SYT1 -rs2251214 was also associated with short-term treatment persistence ( P =0.018, P FDR =0.048), and with months of treatment ( P =0.002, P FDR =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.