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855. Response to Methylphenidate and Atomoxetine in Children with ADHD: Pharmacogenetic Predictors
Biological Psychiatry
Saturday Abstracts
received rapastinel for the present study at no cost and she was reimbursed for travel and time to present findings to Allergan after the findings were submitted for publication to American Journal of Psychiatry as a "letter to the editor." Keywords: Obsessive Compulsive Disorder (OCD), Rapastinel, GLYX-13, Ketamine, NMDAR
854. Phase 2 Multisite Double-Blind Placebo-Controlled Trial of TNX-102 Sl in Military-Related Posttraumatic Stress Disorder (PTSD): Mediators and Moderators of Treatment Response Gregory Sullivan1, Judith Gendreau1, R Michael Gendreau2, Jean Engels3, Perry Peters1, Ashild Peters1, and Seth Lederman1 1 3
Tonix Pharmaceuticals, Engels Consulting
Inc,
2
Gendreau
Consulting,
Background: Evidence-based pharmacotherapies are lacking for military-related PTSD. TNX-102 SL* is a proprietary formulation of cyclobenzaprine (CBP) for bedtime sublingual administration that bypasses first pass metabolism and antagonizes 5-HT2A, 1-adrenergic and histaminergic-1 receptors. It is hypothesized to improve PTSD via effects on core symptoms of sleep disturbance and hyperarousal. Methods: Efficacy and safety of TNX-102 SL was investigated in a PTSD population with military-related traumas since 2001 at 24 U.S. clinical sites. Patients were randomized to 12-week treatment with placebo, TNX-102 SL 2.8 mg (TNX2.8) or 5.6 mg (TNX5.6). Results: The primary efficacy analysis comparing TNX2.8 (n590) to placebo (n592) was not significant. Yet TNX5.6 (n549) demonstrated a strong trend towards greater improvement in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at Week 12 (p50.053, MMRM; effect size50.36); sensitivity analyses were significant. Improvements in sleep and hyperarousal occurred early and appeared to mediate therapeutic response. Moderator analyses indicated those with combat PTSD and greater baseline severity were most likely to respond to TNX5.6. The most common adverse event (AE) in the TNX-102 SL arms was tongue numbness (39% in TNX2.8; 36% in TNX5.6), which was generally transient, and never severe. Systemic AEs of somnolence, sedation, headache appeared dose-dependent; rates in TNX5.6 mg were 16%, 12%, 12%, respectively. Conclusions: TNX5.6 mg demonstrated activity over placebo in this multicenter trial in a population with military-related PTSD, one not generally responsive to pharmacotherapies. Mediators and moderators of treatment response unique to TNX-102 SL will be discussed. Supported By: Tonix Pharmaceuticals, Inc. Keywords: PTSD - Posttraumatic Stress Disorder, Cyclobenzaprine, Sleep disturbances, Extinction, Recovery
855. Response to Methylphenidate and Atomoxetine in Children with ADHD: Pharmacogenetic Predictors Mark Stein1, Jeffrey Bishop2, Edwin Cook Jr.3, Chuan Zhou4, and Jeffrey Newcorn5
S346
University of Washington Seattle, 2University of Minnesota, 3University of Illinois at Chicago, 4University of Washington, 5Icahn School of Medicine 1
Background: Despite inconsistent findings from studies using diverse methodologies and populations, commercial genotyping services have been marketed which recommend specific ADHD treatments. We sought to examine the relationship between several candidate and metabolism genes (DAT1,Drd4, ADRA1, COMT, CYP2D6) and response in children who are treated with OROS methylphenidate (MPH) and atomoxetine (ATX) in a crossover study. Methods: Children (n 5 191) with ADHD, ages 6-17 (mean 10.5), participated in a double blind, double-dummy, crossover study comparing MPH (mean dose 54 mg) and ATX (mean dose 1.35 mg/kg). Medication was titrated using a flexible, stepped dose optimization for 3-7 weeks with 2 weeks on optimal dose. Primary outcome was ADHD RS and CGI completed by blind raters. Results: The largest number of youth responded to both medications (49%), with a mean reduction in ADHD RS of 15.5 to ATX and 19.1 to MPH. None of the genetic markers were associated with an excellent response to MPH or ATX (i.e., 50% reduction in ADHD symptoms). However, significant associations between nonresponse (, 30 reduction in ADHD symptoms) to ATX and CYP2d6 were detected. Specifically, odds of non-responding to ATX is 2.4 times higher for CPY2D6 poor metabolizers compared to a non-poor metabolizer. Conclusions: In a crossover study of children with ADHD treated for several weeks, dopaminergic and adrenergic genes were not associated with response to either stimulant or nonstimulant medication, although genetic variation in cytochrome P-450 2d6 pathway was associated with non-response to ATX. Supported By: RO1 MH70564-01 Keywords: ADHD, Pharmacogenetics
856. Methylphenidate vs. Atomoxetine in Youth with ADHD: Comparative Effectiveness and Preference following Treatment with both Medications Jeffrey Newcorn1, Beth Krone2, Tom Hildebrandt2, and Mark Stein3 1 3
Mt. Sinai School of Medicine, 2Icahn School of Medicine, University of Washington Seattle
Background: The majority of youth with ADHD treated with psychostimulant medication experience significant improvement, but a smaller number achieve normalized function. The availability of FDA-approved non-stimulants offers therapeutic alternatives, but more information is needed to guide treatment selection and algorithm development. We compared OROS methylphenidate (MPH) (long-acting stimulant) and atomoxetine (ATX) (nonstimulant) in a randomized, double-blind, crossover study ( 6 weeks each, separated by a two week placebo washout) Methods: Multiple-group latent growth curve models were used to estimate the effects of drug (ATX vs. MPH) on block 1 and block 2 changes in ADHD symptoms. Latent transition analyses examined the effect of order on responder status.
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal
Saturday Abstracts
received rapastinel for the present study at no cost and she was reimbursed for travel and time to present findings to Allergan after the findings were submitted for publication to American Journal of Psychiatry as a "letter to the editor." Keywords: Obsessive Compulsive Disorder (OCD), Rapastinel, GLYX-13, Ketamine, NMDAR
854. Phase 2 Multisite Double-Blind Placebo-Controlled Trial of TNX-102 Sl in Military-Related Posttraumatic Stress Disorder (PTSD): Mediators and Moderators of Treatment Response Gregory Sullivan1, Judith Gendreau1, R Michael Gendreau2, Jean Engels3, Perry Peters1, Ashild Peters1, and Seth Lederman1 1 3
Tonix Pharmaceuticals, Engels Consulting
Inc,
2
Gendreau
Consulting,
Background: Evidence-based pharmacotherapies are lacking for military-related PTSD. TNX-102 SL* is a proprietary formulation of cyclobenzaprine (CBP) for bedtime sublingual administration that bypasses first pass metabolism and antagonizes 5-HT2A, 1-adrenergic and histaminergic-1 receptors. It is hypothesized to improve PTSD via effects on core symptoms of sleep disturbance and hyperarousal. Methods: Efficacy and safety of TNX-102 SL was investigated in a PTSD population with military-related traumas since 2001 at 24 U.S. clinical sites. Patients were randomized to 12-week treatment with placebo, TNX-102 SL 2.8 mg (TNX2.8) or 5.6 mg (TNX5.6). Results: The primary efficacy analysis comparing TNX2.8 (n590) to placebo (n592) was not significant. Yet TNX5.6 (n549) demonstrated a strong trend towards greater improvement in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at Week 12 (p50.053, MMRM; effect size50.36); sensitivity analyses were significant. Improvements in sleep and hyperarousal occurred early and appeared to mediate therapeutic response. Moderator analyses indicated those with combat PTSD and greater baseline severity were most likely to respond to TNX5.6. The most common adverse event (AE) in the TNX-102 SL arms was tongue numbness (39% in TNX2.8; 36% in TNX5.6), which was generally transient, and never severe. Systemic AEs of somnolence, sedation, headache appeared dose-dependent; rates in TNX5.6 mg were 16%, 12%, 12%, respectively. Conclusions: TNX5.6 mg demonstrated activity over placebo in this multicenter trial in a population with military-related PTSD, one not generally responsive to pharmacotherapies. Mediators and moderators of treatment response unique to TNX-102 SL will be discussed. Supported By: Tonix Pharmaceuticals, Inc. Keywords: PTSD - Posttraumatic Stress Disorder, Cyclobenzaprine, Sleep disturbances, Extinction, Recovery
855. Response to Methylphenidate and Atomoxetine in Children with ADHD: Pharmacogenetic Predictors Mark Stein1, Jeffrey Bishop2, Edwin Cook Jr.3, Chuan Zhou4, and Jeffrey Newcorn5
S346
University of Washington Seattle, 2University of Minnesota, 3University of Illinois at Chicago, 4University of Washington, 5Icahn School of Medicine 1
Background: Despite inconsistent findings from studies using diverse methodologies and populations, commercial genotyping services have been marketed which recommend specific ADHD treatments. We sought to examine the relationship between several candidate and metabolism genes (DAT1,Drd4, ADRA1, COMT, CYP2D6) and response in children who are treated with OROS methylphenidate (MPH) and atomoxetine (ATX) in a crossover study. Methods: Children (n 5 191) with ADHD, ages 6-17 (mean 10.5), participated in a double blind, double-dummy, crossover study comparing MPH (mean dose 54 mg) and ATX (mean dose 1.35 mg/kg). Medication was titrated using a flexible, stepped dose optimization for 3-7 weeks with 2 weeks on optimal dose. Primary outcome was ADHD RS and CGI completed by blind raters. Results: The largest number of youth responded to both medications (49%), with a mean reduction in ADHD RS of 15.5 to ATX and 19.1 to MPH. None of the genetic markers were associated with an excellent response to MPH or ATX (i.e., 50% reduction in ADHD symptoms). However, significant associations between nonresponse (, 30 reduction in ADHD symptoms) to ATX and CYP2d6 were detected. Specifically, odds of non-responding to ATX is 2.4 times higher for CPY2D6 poor metabolizers compared to a non-poor metabolizer. Conclusions: In a crossover study of children with ADHD treated for several weeks, dopaminergic and adrenergic genes were not associated with response to either stimulant or nonstimulant medication, although genetic variation in cytochrome P-450 2d6 pathway was associated with non-response to ATX. Supported By: RO1 MH70564-01 Keywords: ADHD, Pharmacogenetics
856. Methylphenidate vs. Atomoxetine in Youth with ADHD: Comparative Effectiveness and Preference following Treatment with both Medications Jeffrey Newcorn1, Beth Krone2, Tom Hildebrandt2, and Mark Stein3 1 3
Mt. Sinai School of Medicine, 2Icahn School of Medicine, University of Washington Seattle
Background: The majority of youth with ADHD treated with psychostimulant medication experience significant improvement, but a smaller number achieve normalized function. The availability of FDA-approved non-stimulants offers therapeutic alternatives, but more information is needed to guide treatment selection and algorithm development. We compared OROS methylphenidate (MPH) (long-acting stimulant) and atomoxetine (ATX) (nonstimulant) in a randomized, double-blind, crossover study ( 6 weeks each, separated by a two week placebo washout) Methods: Multiple-group latent growth curve models were used to estimate the effects of drug (ATX vs. MPH) on block 1 and block 2 changes in ADHD symptoms. Latent transition analyses examined the effect of order on responder status.
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal