Latin American Psychopharmacology Update: INNOVATIVE TREATMENTS IN PSYCHIATRY INNOVATIVE TREATMENTS IN PSYCHIATRY

Metadoxine (pyridoxol L-2-pyrrolidone-5-carboxylate) is an ion-pair salt of pyridoxine (vitamin B6) and 2-pyrrolidone-5-carboxylate (PCA, also known as L-PGA). Metadoxine modulates GABAergic activity, and does not increase levels of brain neurotransmitterssuch as dopamine, norepinephrine and serotonin. In animal studies, Metadoxine has shown no signs of abuse or addiction potential.Metadoxine Extended Release (MDX) is a novel, immediate release and sustained release formulation in a bi-layer tablet.Placebo-controlled studies of MDX in adults with ADHD produce a consistent signal of efficacy, and analysis of secondary endpoints andsub-scales suggest an impact on attention and cognitive function. No treatment-emergent serious adverse events or any meaningful differencesin adverse events profile between the drug and placebo groups have been observed so far. A phase III 10-week, randomized, multicenter,placebo-controlled, double-blind, parallel group, study of MDX once daily in adults with ADHD was recently launched. The design of thestudy will be discussed.Findings to date also suggest that MDX could improve attention and cognition in Fragile X Syndrome (FXS), a rare neuro-genetic disease andthe most common inherited form of autism. Furthermore, pre-clinical studies in an animal model of Fragile X Syndrome demonstratedimprovements in behavioral outcomes with metadoxine treatment.A phase II 6-week, randomized, multicenter, placebo-controlled, double-blind, parallel group, study of MDX once daily in adults andadolescents with FXS was recently completed. Subjects had molecular confirmation of FXS (greater than or equal to 200 CGG repeats) andwere between 14 and 55 years. The study was conducted at 12 sites in the US and 1 site in Israel. Results of this study will be presented.Preclinical and clinical evidence demonstrates that MDX has a unique mechanism of action and consistent procognitive effects. Results fromongoing and recently completed studies in ADHD and FXS may provide important information about a novel and highly differentiatednonstimulant drug candidate.Learning Objectives:  Participants will learn about a new drug candidate, Metadoxine Extended Release (MDX), as a novel potential treatment for ADHDand;  Participants will learn about the pharmacological profile of Metadoxine Extended Release (MDX), a monoamine-independentGABA modulator. Prior publications / presentations  Rubin J, et al. Metadoxine in ADHD and fragile X syndrome: a novel mechanism of action. Poster 1364 presented at: Society ofBiological Psychiatry 69th Annual Scientific Meeting; May 10, 2014; New York, NY.  Manor I et al. A randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerabilityof extended-release metadoxine in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2012; 73(12):1517-1523.  Manor I et al. Attention Benefits after a single dose of Metadoxine Extended Release in Adults with Predominantly InattentiveADHD. Postgrad Med 2014; 126(5): 1-10.  Adler L et al. Randomized Controlled Trials of Metadoxine Extended Release in Adults with Attention-Deficit/HyperactivityDisorder. Symposium presented at AACAP 61st Annual Meeting; October 22, 2014; San Diego, CA. DASOTRALINE: A NOVEL DRUG CANDIDATE FOR THE TREATMENT OF ADHDRobert Goldman, Kenneth S. Koblan, Seth C. Hopkins, Antony LoebelSunovion Pharmaceuticals, Inc. Abstract Several classes of drugs have demonstrated efficacy in the treatment of ADHD, including shortand long-acting stimulant andnon-stimulant medications. However, there continues to be a need for additional treatment options that may offer a more differentiated clinicalprofile than current agents. Dasotraline [(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine], currently in development foradult and pediatric ADHD, is a potent inhibitor of human DA transporters (DAT; dopamine uptake IC50 3 nM) and NE transporters (NET;norepinephrine uptake IC50 4 nM), and a weaker inhibitor of human serotonin transporters (SERT; serotonin uptake IC50 15 nM; data-on-file, 2014). In humans, dasotraline has a tmax of 10-12 hours, a terminal elimination half-life (t1⁄2) of 47-77 hours, and achieves steady stateplasma concentration by 2 weeks of daily dosing. A clinical trial has been completed in adults meeting DSM-IV-TR criteria for ADHD whowere randomized, without titration, to 4 weeks of double-blind, once-daily treatment with fixed doses of dasotraline 4 mg/d (N=114), 8 mg/d(N=107), or placebo (N=110). On the ADHD Rating Scale, Version IV (ADHD RS-IV) total score, significant LS mean improvement wasobserved at Week 4 for dasotraline 8 mg/d versus placebo (-13.9 vs -9.7; P=0.019), with trend level significance for 4 mg/d (-12.4; P=0.076).LS mean improvement in a modified CGI-S scale was significantly greater at Week 4 for dasotraline 8 mg/d versus placebo (-1.1 vs -0.7;P=0.013), and for 4 mg/d (-1.1 vs -0.7; P=0.021). The most frequent adverse events reported were insomnia, decreased appetite, nausea, anddry mouth. The pharmacokinetic and pharmacodynamic characteristics of dasotraline suggest that it may have a favorable therapeutic profilefor the treatment of ADHD, offering once-per-day dosing that provides sustained inhibition of DA and NE reuptake throughout the 24 hourdosing interval, with possible low risk of abuse potential due to its delayed tmax. The results of this first clinical trial provide preliminaryevidence indicating that once-daily dosing with dasotraline, a long-acting, dual monoamine reuptake inhibitor, may be a safe and efficacioustreatment for adult ADHD.Learning objectives:1. Participants will learn about the efficacy and tolerability of dasotraline in adult patients diagnosed with ADHD.2. Participants will learn about the pharmacokinetic profile of a dasotraline, a new drug candidate for the treatment of ADHD.Several classes of drugs have demonstrated efficacy in the treatment of ADHD, including shortand long-acting stimulant andnon-stimulant medications. However, there continues to be a need for additional treatment options that may offer a more differentiated clinicalprofile than current agents. Dasotraline [(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine], currently in development foradult and pediatric ADHD, is a potent inhibitor of human DA transporters (DAT; dopamine uptake IC50 3 nM) and NE transporters (NET;norepinephrine uptake IC50 4 nM), and a weaker inhibitor of human serotonin transporters (SERT; serotonin uptake IC50 15 nM; data-on-file, 2014). In humans, dasotraline has a tmax of 10-12 hours, a terminal elimination half-life (t1⁄2) of 47-77 hours, and achieves steady stateplasma concentration by 2 weeks of daily dosing. A clinical trial has been completed in adults meeting DSM-IV-TR criteria for ADHD whowere randomized, without titration, to 4 weeks of double-blind, once-daily treatment with fixed doses of dasotraline 4 mg/d (N=114), 8 mg/d(N=107), or placebo (N=110). On the ADHD Rating Scale, Version IV (ADHD RS-IV) total score, significant LS mean improvement wasobserved at Week 4 for dasotraline 8 mg/d versus placebo (-13.9 vs -9.7; P=0.019), with trend level significance for 4 mg/d (-12.4; P=0.076).LS mean improvement in a modified CGI-S scale was significantly greater at Week 4 for dasotraline 8 mg/d versus placebo (-1.1 vs -0.7;P=0.013), and for 4 mg/d (-1.1 vs -0.7; P=0.021). The most frequent adverse events reported were insomnia, decreased appetite, nausea, anddry mouth. The pharmacokinetic and pharmacodynamic characteristics of dasotraline suggest that it may have a favorable therapeutic profilefor the treatment of ADHD, offering once-per-day dosing that provides sustained inhibition of DA and NE reuptake throughout the 24 hourdosing interval, with possible low risk of abuse potential due to its delayed tmax. The results of this first clinical trial provide preliminaryevidence indicating that once-daily dosing with dasotraline, a long-acting, dual monoamine reuptake inhibitor, may be a safe and efficacioustreatment for adult ADHD.Learning objectives:1. Participants will learn about the efficacy and tolerability of dasotraline in adult patients diagnosed with ADHD.2. Participants will learn about the pharmacokinetic profile of a dasotraline, a new drug candidate for the treatment of ADHD. DISCOVERY AND DEVELOPMENT OF EMB-001 FOR THE TREATMENT OF SUBSTANCE USEDISORDERSMichael Detke, Nicholas Goeders, Glenn Guerin, Carol Gloff, Gary Connor, Doug FeltnerLSU Health Sciences Center, Embera NeuroTherapeutics, Embera NeuroTherapeutics, AbbVie Inc., Embera NeuroTherapeutics, IndianaUniversity School of Medicine Abstract Background: EMB-001 is a combination of two FDA-approved drugs: metyrapone, a cortisol synthesis inhibitor, and oxazepam,a benzodiazepine. Metyrapone is approved for one day only as a test; oxazepam is approved for various anxiety disorders. We hypothesizedthat a combination of drugs working by different stress-related mechanisms may be useful for the treatment of substance use disorders, atdoses that minimize the safety/tolerability risks of each individual drug.Background: EMB-001 is a combination of two FDA-approved drugs: metyrapone, a cortisol synthesis inhibitor, and oxazepam,a benzodiazepine. Metyrapone is approved for one day only as a test; oxazepam is approved for various anxiety disorders. We hypothesizedthat a combination of drugs working by different stress-related mechanisms may be useful for the treatment of substance use disorders, atdoses that minimize the safety/tolerability risks of each individual drug. Methods: We summarize a range of preclinical and clinical data supporting the potential utility of EMB-001 for the treatment of substance use disorders including a pilot human study in cocaine dependent subjects, including measures of cocaine use and craving. New safety datafrom a Phase 1 study will be available in time for the meeting.Results: Metyrapone and oxazepam together reduce cocaine self-administration in rats at doses where each is ineffective alone (Goeders,2008). A formal dose-finding study in rats confirmed the effective doses in EMB-001 are lower than the effective doses of each drug alone.EMB-001 also reduces nicotine self-administration in rats (Goeders, 2012), and attenuates cocaine and methamphetamine cue reactivity inrats (Keller, 2013).In five trials, (O’Dwyer 1995; Murphy 1998; Eriksson, 2001; Jahn, 2004; Rogoz 2004) metyrapone was generally safe and well-tolerated at500-4000 mg/day for 2-8 weeks. A human study of EMB-001 in cocaine dependence (Kablinger, 2012) showed a significant reduction incocaine use and EMB-001 was generally well-tolerated.Conclusions: Preclinical data demonstrate that EMB-001 is effective in several animal models of drug addiction. A pilot human studysuggested efficacy in cocaine dependent subjects, with reduced cocaine use at endpoint. New data from a Phase 1 combined single/multipleascending dose GCP-compliant study to assess safety will be presented, along with plans for Phase 2 efficacy studies in cocaine use disorderand tobacco use disorder.No pharmaceutical treatments are currently available for cocaine use disorder, and treatments for tobacco use disorder are only effectiveapproximately 25% of the time. This pharmacological intervention has potential to treat methamphetamine use disorder as well, for which noFDA-approved treatments exist. PH94B NASAL SPRAY AS A PRN TREATMENT FOR SOCIAL ANXIETY DISORDER: A PHASE 3PILOT TRIALMichael Liebowtiz, Ann Draine, Louis Monti, Rita HanoverColumbia University, Medical Research Network, Pherin Pharmaceuticals, Westport Compass Abstract Social Anxiety Disorder (SAD) is a prevalent anxiety disorder that is often chronic and disabling. Several medications have beenapproved for this condition, but they require sustained treatment, are of limited help for many affected individuals, and often have troublingside effects. Cognitive behavior therapy (CBT) is also helpful but many individuals do not participate or fully benefit.Given the predictable occurrence of the performance and social encounters many individuals with SAD dread and avoid, an effective rapidlyacting treatment for the symptoms of SAD that could be used just before such events could be highly useful. PH94B is a synthetic neurosteroiddeveloped by Pherin Pharmaceuticals that is delivered intranasally in low microgram doses and acts via nasal chemosensory receptors torapidly affect brain structures such as hypothalamus, amygdala, prefrontal cortex and hippocampus. We have previously presented data toshow that PH94B rapidly and transiently relieved symptoms of generalized anxiety disorder (GAD). PH94B was also shown in a Phase 2double blind placebo controlled trial to be significantly more effective than placebo in reducing public speaking and social interaction anxietyduring clinic challenges of individuals with SAD. The next logical step was to ascertain whether PH94B would be reduce public speaking andsocial interaction anxiety and avoidance in people with SAD using the medication as needed in their daily lives. Given that prior clinicalstudies of PH94B involved only women, we also wanted to evaluate the effectiveness of PH94B in both sexes. Women were given the samedosage as used in our study, while men were given twice the dose.The study reported here was a Phase 3 pilot/feasibility trial to test a methodology for comparing PH94B and placebo used on a PRN basis byindividuals meeting DSM 5 criteria for SAD. Subjects meeting study inclusion and exclusion criteria carried a diary for 2 weeks during whichthey recorded any anxiety producing social or performance events, and rated the severity of their anxiety on the 0-100 SUDS scale. ThoseSocial Anxiety Disorder (SAD) is a prevalent anxiety disorder that is often chronic and disabling. Several medications have beenapproved for this condition, but they require sustained treatment, are of limited help for many affected individuals, and often have troublingside effects. Cognitive behavior therapy (CBT) is also helpful but many individuals do not participate or fully benefit.Given the predictable occurrence of the performance and social encounters many individuals with SAD dread and avoid, an effective rapidlyacting treatment for the symptoms of SAD that could be used just before such events could be highly useful. PH94B is a synthetic neurosteroiddeveloped by Pherin Pharmaceuticals that is delivered intranasally in low microgram doses and acts via nasal chemosensory receptors torapidly affect brain structures such as hypothalamus, amygdala, prefrontal cortex and hippocampus. We have previously presented data toshow that PH94B rapidly and transiently relieved symptoms of generalized anxiety disorder (GAD). PH94B was also shown in a Phase 2double blind placebo controlled trial to be significantly more effective than placebo in reducing public speaking and social interaction anxietyduring clinic challenges of individuals with SAD. The next logical step was to ascertain whether PH94B would be reduce public speaking andsocial interaction anxiety and avoidance in people with SAD using the medication as needed in their daily lives. Given that prior clinicalstudies of PH94B involved only women, we also wanted to evaluate the effectiveness of PH94B in both sexes. Women were given the samedosage as used in our study, while men were given twice the dose.The study reported here was a Phase 3 pilot/feasibility trial to test a methodology for comparing PH94B and placebo used on a PRN basis byindividuals meeting DSM 5 criteria for SAD. Subjects meeting study inclusion and exclusion criteria carried a diary for 2 weeks during whichthey recorded any anxiety producing social or performance events, and rated the severity of their anxiety on the 0-100 SUDS scale. Those who met predetermined criteria for event frequency and severity were then randomized to 2 weeks of PH94B or placebo, used on a PRN basisup to 4 times per day. Subjects were instructed how to self-administer PH94B or placebo intranasally 15 minutes before entering a fearedsituation, and how to record both their anticipatory anxiety prior to the event and their peak anxiety during the event in their paper diaries.After 2 weeks, subjects were crossed over to the opposite treatment for an additional 2 weeks. During the trial subjects were seen weekly forratings on the Liebowitz Social Anxiety Scale (LSAS) and CGI, and they also completed a patient global rating (PGI) and received newweekly diary forms and fresh bottles of medication.The predetermined primary outcome measure was a within subjects comparison of mean peak SUDs for all events recorded during the 2 weekson PH94B versus mean peak SUDS on placebo. Secondary outcome measures included total LSAS, PGI, CGI-S, CGI-I, HAMD-17 and HAM-A at the end of each treatment phase. When carry over effects between the two phases of treatment were observed, between groupscomparisons were conducted using data from the first 2 weeks of treatment.Thirty-one subjects were evaluated for the study, 23 were randomized to treatment, and 22 had sufficient exposure to both treatments to beincluded in efficacy assessments. The mean age of the 22 subjects was 40.2 years, the average age of onset of SAD was 10.3 years, there were11 male and 11 female subjects, and their mean baseline LSAS total score was 98, indicating severe SAD symptoms.The mean SUDS peak score for all patients receiving placebo was 58.4 vs 51.1 for PH94B, a difference of 7.3 points, which was statisticallysignificant (paired t 3.09, p=.006) with an effect size of .658 (Cohen's D) in favor of PH94B. Drug superiority over placebo on peak SUDSwas similar for males and females. There was a small carry over effect on this variable, such that PH94B followed by placebo showed asmaller difference in favor of drug than did placebo followed by PH94B. However, the carryover effect was not sufficient to nullify the overallsignificant difference between drug and placebo.On several secondary endpoints such as the LSAS and the PGI, the carry over effect of placebo being more effective following PH94B than when given as a first treatment, resulted in no overall difference between drug and placebo. However, when only the first 2 weeks of treatmentwere compared in between subject’s analyses, PH94B showed significant superiority to placebo on the LSAS and PGI. CGI-I, Ham D andHam A differences were not significant between treatments.Adverse effects were mild, and did not show drug placebo differences.Overall, despite the small study size, PH94B showed superiority to placebo in the whole sample on the primary outcome measure, and onseveral important secondary measures using between subjects comparisons of the first 2 week data. In addition, male and female subjectsseemed to both benefit from PH94B. The findings are important for several reasons. For one, if larger follow-up Phase 3 trials confirm ourfindings, PH94B could represent the first systematically studied PRN treatment for social anxiety disorder that could be used either asmonotherapy, or if effective on further testing, as an adjunctive treatment. Secondly, if PH94B's effectiveness is confirmed, it would furthervalidate the nasal chemosensory system as a novel pathway for administering medication. THE ANTIDEPRESSANT ACTIVITY OF BASIMGLURANT, A NOVEL MGLU5-NAM; ARANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY IN THE ADJUNCTIVETREATMENT OF MDDJorge Quiroz,Paul Tamburri, Dennis Deptula, Ludger Banken, Ulrich Beyer, Paulo Fontoura, Luca SantarelliRoche, Roche Innovation Center NY, Roche Innovation Center Basel, Switzerland Abstract Background: Therapies targeting the glutamatergic system are known to be efficacious in the treatment of mood disorders.Antagonism of the post-synaptic mGlu5 receptor is a novel approach to indirectly modulate glutamatergic (NMDA) function and has shownefficacy in a number of preclinical behavioral models of depression. Basimglurant is a potent and selective negative allosteric modulator ofthe mGlu5 receptor which has been comprehensively profiled in Ph1 and Ph2a trials. The main objectives of this Ph2b trial were to evaluatethe safety and efficacy of basimglurant modified release (MR) vs. placebo, as adjunctive therapy to ongoing antidepressant treatment inpatients with major depressive disorder (MDD) who showed inadequate response to at least one but no more than three treatment failureswithin the current episode.Methods: In this 9-week study (6-week double-blind treatment, 3-week post-treatment follow-up), adult patients with DSM-IV-TR diagnosisof MDD were randomized to basimglurant 0.5 mg/d, 1.5 mg/d, or placebo (adjunctive to ongoing SSRI or SNRI). The primary endpoint wasthe mean change from baseline in the Montgomery-Åsberg Depression Rating Scale Sigma total score (MADRS), as rated by the clinician atweek 6. Concomitantly, patient-rated MADRS scores were also collected and analyzed. Secondary endpoints included change in the QuickInventory of Depressive Symptomatology (QIDS-SR16), MADRS response (≥ 50% reduction in score from baseline), MADRS remission(score of ≤ 10), and Clinician and Patient Global Impression scales (CGI-I, PGI-I and CGI-S). Exploratory endpoints included change in theQuality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Sheehan Disability Scale (SDS). Due to theexploratory nature of this study, one-sided p values were estimated with no adjustment for multiplicity. Completers (observed cases)ANCOVA and ITT MMRM statistical analysis were performed.Results: 333 male and female patients were randomized in to the study. The primary endpoint for the study (clinician-rated MADRS) was notmet (p=0.127 ITT MMRM analysis); a trend for improvement was observed for basimglurant 1.5 mg vs. placebo (p=0.061 completersANCOVA analysis) while statistical significance was reached utilizing the patient-rated MADRS (p<0.025 in both analyses). Regarding thesecondary endpoints basimglurant 1.5 mg showed significant improvements vs. placebo in QIDS mean change from baseline (p=0.004 in bothanalyses), CGI-I mean score (p<0.039 in both analyses), PGI-I mean score (p<0.029 in both analyses). Significant improvements were alsoseen with in the patient-rated MADRS remission rate (p<0.024 both analyses), and to a lesser degree in the patient-rated MADRS response(p<0.1 both analyses). Lastly, significant improvements were observed in the Q-LES-Q-SF (p=0.011) and the SDS items 2-3 (p=0.047) (ITTMMRM). Basimglurant dosed at 0.5 mg showed no benefit over placebo in any of these measures. Withdrawal rates due to adverse eventswere 5.4%, 7.2% and 4.5% for basimglurant 0.5 mg, 1.5 mg, and placebo, respectively. The most common adverse event was dizziness (4%,23%, and 6%), mostly transient and of mild intensity. Mania (spontaneously resolved) lead to withdrawal of 2 patients from the study in the1.5 mg arm.Discussion: Adjunctive 1.5 mg/d basimglurant showed a consistent antidepressant effect across primary and secondary endpoints. Greatereffects were seen in patient-rated endpoints such as the patient-rated MADRS and the QIDS, which statistically separated from placebo atseveral time-points including week 6, while clinician-rated MADRS only separated at earlier time-points but not at day 42. Basimglurant 0.5mg/d was not effective compared to placebo. Study results should be considered in the context of the observed high placebo response in thistrial (47% on the clinician-mpedes observing statisticalseparation for active arms in adjunctive MDD treatment trials, minimizing the possibility of detecting true antidepressant effects. In this trial,nevertheless, basimglurant 1.5mg response rates were still consistently superior to placebo. Furthermore, basimglurant was overall safe andwell tolerated in combination with SSRI/SNRI with mild transient dizziness as the most common emergent adverse event. These resultswarrant further investigation of basimglurant in the treatment of MDD both in the adjunctive as well as monotherapy settings.Background: Therapies targeting the glutamatergic system are known to be efficacious in the treatment of mood disorders.Antagonism of the post-synaptic mGlu5 receptor is a novel approach to indirectly modulate glutamatergic (NMDA) function and has shownefficacy in a number of preclinical behavioral models of depression. Basimglurant is a potent and selective negative allosteric modulator ofthe mGlu5 receptor which has been comprehensively profiled in Ph1 and Ph2a trials. The main objectives of this Ph2b trial were to evaluatethe safety and efficacy of basimglurant modified release (MR) vs. placebo, as adjunctive therapy to ongoing antidepressant treatment inpatients with major depressive disorder (MDD) who showed inadequate response to at least one but no more than three treatment failureswithin the current episode.Methods: In this 9-week study (6-week double-blind treatment, 3-week post-treatment follow-up), adult patients with DSM-IV-TR diagnosisof MDD were randomized to basimglurant 0.5 mg/d, 1.5 mg/d, or placebo (adjunctive to ongoing SSRI or SNRI). The primary endpoint wasthe mean change from baseline in the Montgomery-Åsberg Depression Rating Scale Sigma total score (MADRS), as rated by the clinician atweek 6. Concomitantly, patient-rated MADRS scores were also collected and analyzed. Secondary endpoints included change in the QuickInventory of Depressive Symptomatology (QIDS-SR16), MADRS response (≥ 50% reduction in score from baseline), MADRS remission(score of ≤ 10), and Clinician and Patient Global Impression scales (CGI-I, PGI-I and CGI-S). Exploratory endpoints included change in theQuality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Sheehan Disability Scale (SDS). Due to theexploratory nature of this study, one-sided p values were estimated with no adjustment for multiplicity. Completers (observed cases)ANCOVA and ITT MMRM statistical analysis were performed.Results: 333 male and female patients were randomized in to the study. The primary endpoint for the study (clinician-rated MADRS) was notmet (p=0.127 ITT MMRM analysis); a trend for improvement was observed for basimglurant 1.5 mg vs. placebo (p=0.061 completersANCOVA analysis) while statistical significance was reached utilizing the patient-rated MADRS (p<0.025 in both analyses). Regarding thesecondary endpoints basimglurant 1.5 mg showed significant improvements vs. placebo in QIDS mean change from baseline (p=0.004 in bothanalyses), CGI-I mean score (p<0.039 in both analyses), PGI-I mean score (p<0.029 in both analyses). Significant improvements were alsoseen with in the patient-rated MADRS remission rate (p<0.024 both analyses), and to a lesser degree in the patient-rated MADRS response(p<0.1 both analyses). Lastly, significant improvements were observed in the Q-LES-Q-SF (p=0.011) and the SDS items 2-3 (p=0.047) (ITTMMRM). Basimglurant dosed at 0.5 mg showed no benefit over placebo in any of these measures. Withdrawal rates due to adverse eventswere 5.4%, 7.2% and 4.5% for basimglurant 0.5 mg, 1.5 mg, and placebo, respectively. The most common adverse event was dizziness (4%,23%, and 6%), mostly transient and of mild intensity. Mania (spontaneously resolved) lead to withdrawal of 2 patients from the study in the1.5 mg arm.Discussion: Adjunctive 1.5 mg/d basimglurant showed a consistent antidepressant effect across primary and secondary endpoints. Greatereffects were seen in patient-rated endpoints such as the patient-rated MADRS and the QIDS, which statistically separated from placebo atseveral time-points including week 6, while clinician-rated MADRS only separated at earlier time-points but not at day 42. Basimglurant 0.5mg/d was not effective compared to placebo. Study results should be considered in the context of the observed high placebo response in thistrial (47% on the clinician-mpedes observing statisticalseparation for active arms in adjunctive MDD treatment trials, minimizing the possibility of detecting true antidepressant effects. In this trial,nevertheless, basimglurant 1.5mg response rates were still consistently superior to placebo. Furthermore, basimglurant was overall safe andwell tolerated in combination with SSRI/SNRI with mild transient dizziness as the most common emergent adverse event. These resultswarrant further investigation of basimglurant in the treatment of MDD both in the adjunctive as well as monotherapy settings. ADVANCING LOW FIELD MAGNETIC STIMULATION (LFMS), A POTENTIAL RAPIDLY-ACTING ANTIDEPRESSANT INTERVENTIONAtul Pande, Andrew MillerTal Medical Abstract Low Field Magnetic Stimulation (LFMS) is a novel, non-invasive, neuromodulation technology being developed by Tal Medical.The mood elevating effect of LFMS were discovered serendipitously during proton echo-planar magnetic resonance spectroscopic imaging(EP-MRSI) study of bipolar depression patients, where patients reported mood improvement within minutes of exposure. This observationhas been replicated and expanded to Major Depressive Disorder with two sham-controlled trials published previously (Am J Psychiatry2004;161:93-98; Biol Psych 2014;76:186-93). The most recent trial was a double-blind sham-controlled trial study the effect of a single LFMStreatment in both MDD and Bipolar patients using a table top LFMS prototype device. Clinically meaningful mood improvement was observedfollowing LFMS treatment relative to sham treatment for both diagnostic subgroups for the primary outcomes, the VAS and the HDRS-17(3.1 point improvement over sham). Rapid improvement in mood was also observed using the Positive and Negative Affect Schedule (PANAS)scales as secondary measures. The time-varying magnetic field of LFMS induces a time-varying electric field in the brain. The electric fieldgenerated by the LFMS is much lower in magnitude (< 1 V/m) than the field used in repetitive transcranial magnetic stimulation (rTMS)treatment (> 100 V/m) and broadly extends throughout the cortex, unlike the more localized field used in rTMS. Importantly, LFMS doesnot directly induce the depolarization of neurons, unlike rTMS or ECT. There is no physical sensation associated with LFMS, which allowsfor robust blinding in clinical trials. Currently there is a 90 patient, multi-site clinical trial funded by the NIMH RAPID program ongoingwhich studies the effect of multiple LFMS treatments in MDD patients with a 4 week follow up period. Tal Medical is also launching a multi-site dose-optimization study of LFMS to investigate the effect of different LFMS treatment times and regimens.Low Field Magnetic Stimulation (LFMS) is a novel, non-invasive, neuromodulation technology being developed by Tal Medical.The mood elevating effect of LFMS were discovered serendipitously during proton echo-planar magnetic resonance spectroscopic imaging(EP-MRSI) study of bipolar depression patients, where patients reported mood improvement within minutes of exposure. This observationhas been replicated and expanded to Major Depressive Disorder with two sham-controlled trials published previously (Am J Psychiatry2004;161:93-98; Biol Psych 2014;76:186-93). The most recent trial was a double-blind sham-controlled trial study the effect of a single LFMStreatment in both MDD and Bipolar patients using a table top LFMS prototype device. Clinically meaningful mood improvement was observedfollowing LFMS treatment relative to sham treatment for both diagnostic subgroups for the primary outcomes, the VAS and the HDRS-17(3.1 point improvement over sham). Rapid improvement in mood was also observed using the Positive and Negative Affect Schedule (PANAS)scales as secondary measures. The time-varying magnetic field of LFMS induces a time-varying electric field in the brain. The electric fieldgenerated by the LFMS is much lower in magnitude (< 1 V/m) than the field used in repetitive transcranial magnetic stimulation (rTMS)treatment (> 100 V/m) and broadly extends throughout the cortex, unlike the more localized field used in rTMS. Importantly, LFMS doesnot directly induce the depolarization of neurons, unlike rTMS or ECT. There is no physical sensation associated with LFMS, which allowsfor robust blinding in clinical trials. Currently there is a 90 patient, multi-site clinical trial funded by the NIMH RAPID program ongoingwhich studies the effect of multiple LFMS treatments in MDD patients with a 4 week follow up period. Tal Medical is also launching a multi-site dose-optimization study of LFMS to investigate the effect of different LFMS treatment times and regimens. A SINGLE INTRAVENOUS DOSE OF THE NMDA RECEPTOR GLYCINE SITE MODULATOR NRX-1074 DOSE DEPENDENTLY REDUCED DEPRESSION SCORES WITHIN 24 HOURS IN SUBJECTSWITH MAJOR DEPRESSIVE DISORDER (MDD)Ronald Burch, Wen Yu, M. Amin Khan, Lee Bastin, Jeffrey Burgdorf, Joseph R MoskalNaurex, Inc. Abstract Background: NRX-1074 (threonyl-prolyl-2R-(2-benzyl)-prolyl-threonine amide) has the same tetrapeptide sequence as rapastinel(GLYX-13) except that the second Pro is benzylated. NRX-1074 is more potent in vitro, in animal models of antidepressant-like activity,NRX-1074 is more potent than GLYX-13 (100-fold) and orally active, and NRX-1074 does not exhibit a U-shaped dose-response like GLYX-13.Methods: This randomized, double blind, placebo controlled study enrolled 142 subjects with MDD at 12 United States study sites. Subjectswho were taking another antidepressant agent were required to discontinue all antidepressants for at least two weeks prior to receiving NRX-1074. Subjects received a single IV dose of placebo (N=52) or NRX-1074, 1 mg (23), 5 mg (54), or 10 mg (20), as monotherapy in order todetermine the dose at which antidepressant activity is observed in order to provide pharmacokinetic-pharmacodynamic correlation to providedose level guidance for oral administration. HDRS-17 and CGI-S scores, psychotomimetic effects (BPRS+), dissociative effects (CADSS)and other adverse events were monitored for 14 days.Results: Demographics and baseline HDRS-17 (25.2-26.9) and CGI-S (4.4-4.6) scores were not significantly among treatment groups. NRX-1074 demonstrated a dose dependent antidepressant effect within 24 hours. In response to 10 mg, HDRS-17 declined 5.4 points compared toplacebo (p=0.004) with an effect size of 0.7. CGI-S declined 0.9 points compared to placebo (p=0.0005). NRX-1074 did not induce significantchanges in dissociative (CADSS) or psychotomimetic (BPRS+) scores. Adverse events were mostly mild to moderate with similar incidenceto placebo and no discernible dose response.Conclusions: A single IV dose of NRX-1074 induced a rapid and significant antidepressant effect with clear dose-response without dissociativeor psychotomimetic side effects. NRX-1074 is undergoing repeat dose clinical trials using IV and oral dosing.Background: NRX-1074 (threonyl-prolyl-2R-(2-benzyl)-prolyl-threonine amide) has the same tetrapeptide sequence as rapastinel(GLYX-13) except that the second Pro is benzylated. NRX-1074 is more potent in vitro, in animal models of antidepressant-like activity,NRX-1074 is more potent than GLYX-13 (100-fold) and orally active, and NRX-1074 does not exhibit a U-shaped dose-response like GLYX-13.Methods: This randomized, double blind, placebo controlled study enrolled 142 subjects with MDD at 12 United States study sites. Subjectswho were taking another antidepressant agent were required to discontinue all antidepressants for at least two weeks prior to receiving NRX-1074. Subjects received a single IV dose of placebo (N=52) or NRX-1074, 1 mg (23), 5 mg (54), or 10 mg (20), as monotherapy in order todetermine the dose at which antidepressant activity is observed in order to provide pharmacokinetic-pharmacodynamic correlation to providedose level guidance for oral administration. HDRS-17 and CGI-S scores, psychotomimetic effects (BPRS+), dissociative effects (CADSS)and other adverse events were monitored for 14 days.Results: Demographics and baseline HDRS-17 (25.2-26.9) and CGI-S (4.4-4.6) scores were not significantly among treatment groups. NRX-1074 demonstrated a dose dependent antidepressant effect within 24 hours. In response to 10 mg, HDRS-17 declined 5.4 points compared toplacebo (p=0.004) with an effect size of 0.7. CGI-S declined 0.9 points compared to placebo (p=0.0005). NRX-1074 did not induce significantchanges in dissociative (CADSS) or psychotomimetic (BPRS+) scores. Adverse events were mostly mild to moderate with similar incidenceto placebo and no discernible dose response.Conclusions: A single IV dose of NRX-1074 induced a rapid and significant antidepressant effect with clear dose-response without dissociativeor psychotomimetic side effects. NRX-1074 is undergoing repeat dose clinical trials using IV and oral dosing. A RANDOMIZED PLACEBO-CONTROLLED ADJUNCTIVE TRIAL OF RILUZOLE INTREATMENT-RESISTANT MAJOR DEPRESSIVE DISORDERSanjay Mathew, Maurizio Fava, Ralitza Guerguieva, Gerard SanacoraBaylor College of Medicine, Massachusetts General Hospital, Yale Department of Psychiatry Abstract Background: Preclinical studies have shown that riluzole, a FDA-approved drug for amyotrophic lateral sclerosis, modulatesglutamate release and clearance, and has potent neuroprotective properties. Riluzole has shown antidepressant-like effects in rodent modelsused to screen for antidepressant activity. In addition, several small open-label clinical studies have suggested that riluzole has antidepressantand anxiolytic properties, even in patients resistant to conventional monoaminergic medications. The aim of this NIMH-sponsoredcollaborative study was to examine the antidepressant efficacy and safety of riluzole, by conducting the first double-blind, placebo-controlledtrial of this agent in adults with major depressive disorder (MDD) who were inadequately responsive to antidepressant medication.Methods: Patients were enrolled at three academic medical centers (Baylor College of Medicine, Massachusetts General Hospital, YaleUniversity School of Medicine), with oversight by a NIMH Data Safety and Monitoring Board. Patients were between the ages of 18-65,met DSM-IV criteria for MDD, and had at least a moderate level of depressive severity, indexed by an Inventory of DepressiveSymptomatology-Self Rated (IDS-SR) score of >20 and a Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher.Exclusion criteria included patients with serious suicide risk, unstable medical illness, substance use disorders within the last 6 months, lifetimehistories of bipolar disorder or psychotic disorders, and those who had failed to respond to 3 or more adequate antidepressant trials during thecurrent major depressive episode. Patients meeting initial eligibility criteria were assigned to one of 2 groups (A or B), depending on whetherthey were receiving concurrent antidepressant treatment at Screening. MDD patients not taking an antidepressant (Group A) were given a 8-week prospective trial of open-label sertraline (flexibly dosed to 150 mg/day). Following the 8 week sertraline treatment period, Group Apatients were eligible for a subsequent randomized, placebo-controlled double-blind phase if they continued to meet depressive severitythresholds and had < 50% decrease in the IDS-SR total score. Group B participants were individuals receiving an adequate dose of a SSRI,SNRI, or bupropion for at least 8 weeks, and were taking a stable dose for at least 4 weeks prior to randomization.A sequential parallel comparison design was used for the 56 day double-blind, randomized adjunctive, placebo-controlled trial, whichcomprised two phases of approximately 28 days each. Patients were randomized to adjunctive treatment with either riluzole (50 mg BID) orplacebo, with a 2:3:3 ratio for random assignment to the treatment sequences drug/drug, placebo/placebo, and placebo/drug, respectively.Clinical assessments were performed by trained raters every 7 days during the double-blind treatment period, followed by a 7 day taper period.The primary outcome was the change in the MADRS from baseline to the end of the double-blind treatment period. Secondary outcomesinclude the response rate, defined as at least a 50% improvement in MADRS compared to baseline. Safety and tolerability was assessed withthe Systematic Assessment for Treatment Emergent Events (SAFTEE-SI).Background: Preclinical studies have shown that riluzole, a FDA-approved drug for amyotrophic lateral sclerosis, modulatesglutamate release and clearance, and has potent neuroprotective properties. Riluzole has shown antidepressant-like effects in rodent modelsused to screen for antidepressant activity. In addition, several small open-label clinical studies have suggested that riluzole has antidepressantand anxiolytic properties, even in patients resistant to conventional monoaminergic medications. The aim of this NIMH-sponsoredcollaborative study was to examine the antidepressant efficacy and safety of riluzole, by conducting the first double-blind, placebo-controlledtrial of this agent in adults with major depressive disorder (MDD) who were inadequately responsive to antidepressant medication.Methods: Patients were enrolled at three academic medical centers (Baylor College of Medicine, Massachusetts General Hospital, YaleUniversity School of Medicine), with oversight by a NIMH Data Safety and Monitoring Board. Patients were between the ages of 18-65,met DSM-IV criteria for MDD, and had at least a moderate level of depressive severity, indexed by an Inventory of DepressiveSymptomatology-Self Rated (IDS-SR) score of >20 and a Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher.Exclusion criteria included patients with serious suicide risk, unstable medical illness, substance use disorders within the last 6 months, lifetimehistories of bipolar disorder or psychotic disorders, and those who had failed to respond to 3 or more adequate antidepressant trials during thecurrent major depressive episode. Patients meeting initial eligibility criteria were assigned to one of 2 groups (A or B), depending on whetherthey were receiving concurrent antidepressant treatment at Screening. MDD patients not taking an antidepressant (Group A) were given a 8-week prospective trial of open-label sertraline (flexibly dosed to 150 mg/day). Following the 8 week sertraline treatment period, Group Apatients were eligible for a subsequent randomized, placebo-controlled double-blind phase if they continued to meet depressive severitythresholds and had < 50% decrease in the IDS-SR total score. Group B participants were individuals receiving an adequate dose of a SSRI,SNRI, or bupropion for at least 8 weeks, and were taking a stable dose for at least 4 weeks prior to randomization.A sequential parallel comparison design was used for the 56 day double-blind, randomized adjunctive, placebo-controlled trial, whichcomprised two phases of approximately 28 days each. Patients were randomized to adjunctive treatment with either riluzole (50 mg BID) orplacebo, with a 2:3:3 ratio for random assignment to the treatment sequences drug/drug, placebo/placebo, and placebo/drug, respectively.Clinical assessments were performed by trained raters every 7 days during the double-blind treatment period, followed by a 7 day taper period.The primary outcome was the change in the MADRS from baseline to the end of the double-blind treatment period. Secondary outcomesinclude the response rate, defined as at least a 50% improvement in MADRS compared to baseline. Safety and tolerability was assessed withthe Systematic Assessment for Treatment Emergent Events (SAFTEE-SI). Results: Enrollment occurred between June 2011 and December 2014, with the final study visit completed in February 2015. Across the three sites, 104 patients were randomized, and 85 patients completed the 8 week double-blind placebo phase. The database lock is scheduledfor April 2015. The results of primary and key secondary analyses, including safety and tolerability information, will be presented. Discussion: The implications of this study on research and clinical practice will be discussed. As riluzole is now available as a generic medication, a positive trial would support its broader use for difficult-to-treat depression and spur further investigations into mechanisms ofaction.NCT01204918 Efficacy and Tolerability of Riluzole in Treatment Resistant Depression A DOUBLE-BLIND, DOUBLY-RANDOMIZED, PLACEBO-CONTROLLED STUDY OFINTRANASAL ESKETAMINE IN AN ADAPTIVE TREATMENT PROTOCOL TO ASSESS SAFETYAND EFFICACY IN TREATMENT-RESISTANT DEPRESSIONJaskaran SinghNeuroscience, TA, JanssenR&D;, LLC, Janssen Pharmaceutical Companies of JNJ Abstract Background: Esketamine and ketamine have been shown to produce rapid antidepressant action in patients with treatment-resistantdepression (TRD). The aim of the current study was to assess the efficacy, safety and dose response of intranasal esketamine in patients withTRD.Methods: This was a 2-Panel, doubly-randomized, double-blind, placebo-controlled, multicenter study. Panel A was conducted in the UnitedStates and Belgium and Panel B is currently ongoing in Japan. In both panels, each subject participated in up to 4 phases: a screening phaseof up to 4 weeks, a double-blind treatment phase which included two 1-week periods (Periods 1 and 2), a 9-week optional open-label treatmentphase and an 8-week posttreatment follow-up phase. Only Panel A double blind phase data are available, and will be presented at this time.Background: Esketamine and ketamine have been shown to produce rapid antidepressant action in patients with treatment-resistantdepression (TRD). The aim of the current study was to assess the efficacy, safety and dose response of intranasal esketamine in patients withTRD.Methods: This was a 2-Panel, doubly-randomized, double-blind, placebo-controlled, multicenter study. Panel A was conducted in the UnitedStates and Belgium and Panel B is currently ongoing in Japan. In both panels, each subject participated in up to 4 phases: a screening phaseof up to 4 weeks, a double-blind treatment phase which included two 1-week periods (Periods 1 and 2), a 9-week optional open-label treatmentphase and an 8-week posttreatment follow-up phase. Only Panel A double blind phase data are available, and will be presented at this time. The primary efficacy endpoint was the change from baseline to Day 8 in each period in the Montgomery-Asberg Depression Rating Scale (MADRS) total score combined. Safety and secondary efficacy endpoints were also assessed.Results: A total of 67 subjects with TRD were randomly assigned in a 3:1:1:1 ratio to one of four treatment groups: placebo (n=33), esketamine28 mg (n=11), esketamine 56 mg (n=11), or esketamine 84 mg (n=12) in Period 1. In Period 2, 28 placebo subjects who were eligible for re-randomization at the end of Period 1 were randomly assigned to placebo (n=6), esketamine 28 mg (n=8), esketamine 56 mg (n=9), oresketamine 84 mg (n=5) in a 1:1:1:1 ratio. Subjects were eligible for re-randomization if the patient-rated 16 item Quick Inventory ofDepressive Symptomatology (QIDS-SR16) total score was ≥11 at the end of Period 1. The analysis of Period 1 and Period 2, combined usingthe weighted combination test, showed that the mean change in MADRS total score in all three esketamine groups was statistically superiorto that obtained under placebo, based on a one-sided 0.05 significance level (p=0.021, p=0.001 and p<0.001 for esketamine 28 mg, 56 mg and84 mg respectively). The mean differences (SE) from placebo (after one week of treatment) were -4.2(2.09) for esketamine 28 mg, -6.3(2.07)for esketamine 56 mg, and -9.0(2.13) for esketamine 84 mg. The magnitude of effect size in Period 1 increases from a low Cohen’s D effectsize in the 28 mg dose group (0.43) to a high Cohen’s D effect size for the 56 (0.92) and 84 mg (1.19) dose groups.The most common TEAEs during the double-blind phase (≥10% of subjects in any group) were: dizziness, dissociation, headache, dysgeusia,nasal discomfort, nausea, hypoaesthesia oral, dissociative symptoms, tunnel vision, oropharyngeal pain, throat irritation, blurred vision,hypersomnia, feeling abnormal, insomnia, hypertension, vertigo, polyuria and sedation. No death was reported. Transient elevation in bloodpressure and heart rate was also observed on dosing days. The perceptual changes and dissociative symptoms measured by the Clinicianadministered Dissociative Symptom Scale (CADSS), suggest onset of these symptoms occurred shortly after the start of intranasal dosing andresolved by 2 hours postdose, and with repeated dosing these symptoms reduced significantly.Conclusions: Intranasal esketamine administered in doses of 28, 56 and 84 mg across the study period showed statistically and clinicallysignificant improvement of depressive symptoms in subjects with TRD, as demonstrated by the mean changes in the MADRS total score for the combined analysis of both periods. The doses evaluated were well tolerated and adverse events were similar to what has been observedpreviously with IV ketamine and eskatamine. NON-INVASIVE NEUROMODULATION WITH TRIGEMINAL NERVE STIMULATION IN MAJORDEPRESSIVE DISORDER AND OTHER CNS DISORDERSIan Cook, Andrew Leuchter, Christopher DeGiorgioUCLA Semel Institute for Neuroscience and Human Behavior, UCLA / NeuroSigma, UCLA Abstract Background: Modulation of brain activity via external Trigeminal Nerve Stimulation (eTNS) is an emerging therapy for CNSdisorders, with an excellent safety profile and significant improvements in seizures, mood, cognition, and anxiety reported in preliminary openstudies. Mechanistically, PET imaging findings showed acute, robust changes in cerebral perfusion in limbic and frontal regions. In a recently-completed dose ranging project, eTNS was examined under double-blind conditions in major depressive disorder (MDD) as an adjunct topharmacotherapy.Methods: Forty-three adults with MDD (age 23-65, avg 43.0 (11.5 sd), ATHF 1-10) completed at least six weeks of the trial (primary endpoint).Subjects stimulated the trigeminal nerve for 8 hours each night at home using custom patch electrodes placed on the forehead. Clinicaloutcomes were assessed with scales including the Beck Depression Inventory (BDI), Inventory of Depressive Symptomology (IDS-SR) andHamilton Depression Rating Scale (HDRS17). Medications remained constant throughout.Results: Symptom severity improved significantly for subjects receiving active stimulation (e.g., paired 2-tail t-test BDI 24.6 (8.5 sd) baselinevs 14.2 (7.3) week 6, p<0.00001). Subjects receiving active stimulation had significantly greater symptom improvement than subjectsBackground: Modulation of brain activity via external Trigeminal Nerve Stimulation (eTNS) is an emerging therapy for CNSdisorders, with an excellent safety profile and significant improvements in seizures, mood, cognition, and anxiety reported in preliminary openstudies. Mechanistically, PET imaging findings showed acute, robust changes in cerebral perfusion in limbic and frontal regions. In a recently-completed dose ranging project, eTNS was examined under double-blind conditions in major depressive disorder (MDD) as an adjunct topharmacotherapy.Methods: Forty-three adults with MDD (age 23-65, avg 43.0 (11.5 sd), ATHF 1-10) completed at least six weeks of the trial (primary endpoint).Subjects stimulated the trigeminal nerve for 8 hours each night at home using custom patch electrodes placed on the forehead. Clinicaloutcomes were assessed with scales including the Beck Depression Inventory (BDI), Inventory of Depressive Symptomology (IDS-SR) andHamilton Depression Rating Scale (HDRS17). Medications remained constant throughout.Results: Symptom severity improved significantly for subjects receiving active stimulation (e.g., paired 2-tail t-test BDI 24.6 (8.5 sd) baselinevs 14.2 (7.3) week 6, p<0.00001). Subjects receiving active stimulation had significantly greater symptom improvement than subjects randomized to the control condition (e.g., BDI -41.7% vs -10.9% t=-2.61 2-tail p=0.013).Conclusions: Significantly greater symptom reductions were achieved in the 6 weeks of acute eTNS treatment than in our control condition.These findings replicate open trial results, extend them under double-blind controlled conditions, and justify further development. Symptomimprovement did not differ across stimulation frequencies (‘doses’), suggesting that low doses of stimulation may lead to meaningful symptomimprovement in MDD, and that the cumulative integration of stimulation events may be an important determinant of clinical effects.Trigeminal Nerve Stimulation is a unique form of neuromodulation because can be delivered at home using a non-invasive system, or may bedeliverable with an implantable system that is under development. This novel approach to brain stimulation may have use as an adjunct topharmacotherapy once efficacy and tolerability are confirmed with additional studies. A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF THE ANTIDEPRESSANT EFFECTS OFTHE MGLU2 NEGATIVE ALLOSTERIC MODULATOR RG1578 IN PATIENTS WITHINADEQUATE RESPONSE TO ANTIDEPRESSANT THERAPYDaniel Umbricht, Markus Niggli, Patricia Sanwald-Ducray, Dennis Deptula, Rema Moore, Waltraud Grünbauer, Lauren Boak, Silvia Gatti,Paulo FontouraF. Hoffmann-La Roche, Ltd. Abstract Background: Abnormalities in glutamate transmission have been implicated in major depressive disorder (MDD). In particular,normal glutamate transmission may be disrupted via excessive autoinhibition through metabotrobic glutamate receptors type 2 (mGlu2).mGlu2 antagonists should correct this abnormal state and offer a therapeutic approach. We evaluated the antidepressant effects of the mGlu2negative allosteric modulator RG1578 in patients with an inadequate response to SSRIs or SNRIs.Methods: 310 patients with MDD and an inadequate response (inclusion criterion for severity of illness: MADRS ≥ 25, CGI ≥4) to up to twoantidepressant trials were randomized to double-blind treatment and with placebo (N=86), 5 mg (N=89), 15 mg (N=88) or 30 mg (N=47) ofRG1578 as an adjunct to ongoing treatment with an SSRI or SNRI. Patients completed 6 weeks treatment without major protocol violationsThe primary endpoint (MADRS) was assessed by fully blinded centralized raters. Secondary endpoints included the IDS-SR30, CPFQ, SDSand the CANTAB battery.Results:-MADRS total score did not differ significantly between any active treatment arm and placebo (placebo: -–mg: --observed for all secondary outcome measures.Background: Abnormalities in glutamate transmission have been implicated in major depressive disorder (MDD). In particular,normal glutamate transmission may be disrupted via excessive autoinhibition through metabotrobic glutamate receptors type 2 (mGlu2).mGlu2 antagonists should correct this abnormal state and offer a therapeutic approach. We evaluated the antidepressant effects of the mGlu2negative allosteric modulator RG1578 in patients with an inadequate response to SSRIs or SNRIs.Methods: 310 patients with MDD and an inadequate response (inclusion criterion for severity of illness: MADRS ≥ 25, CGI ≥4) to up to twoantidepressant trials were randomized to double-blind treatment and with placebo (N=86), 5 mg (N=89), 15 mg (N=88) or 30 mg (N=47) ofRG1578 as an adjunct to ongoing treatment with an SSRI or SNRI. Patients completed 6 weeks treatment without major protocol violationsThe primary endpoint (MADRS) was assessed by fully blinded centralized raters. Secondary endpoints included the IDS-SR30, CPFQ, SDSand the CANTAB battery.Results:-MADRS total score did not differ significantly between any active treatment arm and placebo (placebo: -–mg: --observed for all secondary outcome measures. Discussion: Adjunctive treatment with RG1578 was not associated with significant antidepressant effects in patients with MDD and inadequate response to antidepressants. ALKS 3831: A NOVEL DRUG CANDIDATE FOR THE TREATMENT OF SCHIZOPHRENIAElliot Ehrich, Mark Todtenkopf, Ying Jiang, Sanjeev Pathak, Anjana Bose, Daniel Deaver, Srdjan Stankovic, Bernard SilvermanAlkermes, Inc. Abstract The biology of the strong association between many atypical antipsychotics and adverse weight gain and metabolic dysfunctionhas not been fully elucidated. The same could be said for the high rate of co-occurrence between schizophrenia and substance abuse. As aconsequence, complexities of these associations present significant obstacles in the treatment and management of many patients withschizophrenia by limiting patient adherence and adversely impacting treatment outcomes.1,2 However, the role of the opioid system,specifically mu antagonism, for the treatment of substance abuse has been well established.3 As such, an antipsychotic designed to addressthese complexities through appropriate engagement of the opioid system and reward circuitry would present a substantive advancement in thetreatment of schizophrenia.Olanzapine (OLZ) is regarded as one of the most effective treatments for schizophrenia, but concerns with weight gain and adverse metaboliceffects prevent its use as part of a first line treatment paradigm, which is of particular importance for the treatment of early psychotic episodes.1Samidorphan (SAM), a novel opioid modulator, acts as an antagonist at mu opioid receptors. Nonclinical studies suggested that SAM may beuseful in mitigating or preventing OLZ-induced weight gain. Using a standard rodent model, it was demonstrated that co-administration ofSAM mitigated OLZ-induced weight gain, whereas naltrexone did not.4 In a subsequent study using non-human primates to investigate OLZ-induced changes in weight gain and metabolic effects, SAM attenuated OLZ-induced weight gain and fat accretion following 28-days of repeatdaily dosing.5 .The biology of the strong association between many atypical antipsychotics and adverse weight gain and metabolic dysfunctionhas not been fully elucidated. The same could be said for the high rate of co-occurrence between schizophrenia and substance abuse. As aconsequence, complexities of these associations present significant obstacles in the treatment and management of many patients withschizophrenia by limiting patient adherence and adversely impacting treatment outcomes.1,2 However, the role of the opioid system,specifically mu antagonism, for the treatment of substance abuse has been well established.3 As such, an antipsychotic designed to addressthese complexities through appropriate engagement of the opioid system and reward circuitry would present a substantive advancement in thetreatment of schizophrenia.Olanzapine (OLZ) is regarded as one of the most effective treatments for schizophrenia, but concerns with weight gain and adverse metaboliceffects prevent its use as part of a first line treatment paradigm, which is of particular importance for the treatment of early psychotic episodes.1Samidorphan (SAM), a novel opioid modulator, acts as an antagonist at mu opioid receptors. Nonclinical studies suggested that SAM may beuseful in mitigating or preventing OLZ-induced weight gain. Using a standard rodent model, it was demonstrated that co-administration ofSAM mitigated OLZ-induced weight gain, whereas naltrexone did not.4 In a subsequent study using non-human primates to investigate OLZ-induced changes in weight gain and metabolic effects, SAM attenuated OLZ-induced weight gain and fat accretion following 28-days of repeatdaily dosing.5 . Additionally, by virtue of its pharmacology, SAM may present additional benefits to patients with schizophrenia who have comorbid substanceuse disorder. Nonclinical studies have demonstrated that SAM, at doses that result in exposure similar to therapeutically relevant doses inhumans, blocked mu-opioid agonist effects and reduced ethanol self-administration in rodents. In an early clinical study, it was found thatSAM significantly reduced the event rate of heavy drinking compared to placebo in non-schizophrenic subjects.ALKS 3831, a novel drug candidate, is a fixed-dose combination of OLZ and SAM currently under development for the treatment ofschizophrenia. This formulation is intended to confer a more favorable safety profile compared to OLZ alone. To investigate the safety andeffect on weight of ALKS 3831 in comparison to OLZ, a Phase I study in healthy, normal weight (BMI 18-25) male volunteers was conducted.This was a double-blind, parallel group design with daily dosing for 21 days. Subjects were randomized (n=106) to OLZ, ALKS 3831, SAMor placebo in a 2:2:1:1 ratio. Efficacy was determined by the mean change from baseline to last treatment period assessment in body weight(kg) for OLZ vs. ALKS 3831. After 21 days of daily dosing, the mean±SD change in body weight for OLZ and ALKS 3831 was +3.4±1.8and +2.5±1.4, respectively. The weight gain observed in the ALKS 3831 group was significantly less than that of the OLZ group (p=0.014).Overall safety and tolerability of ALKS 3831 was similar to OLZ alone.In a subsequent Phase 2 OLZ-controlled dose-ranging study, the safety, tolerability, and efficacy of ALKS 3831 was evaluated in adults withstable schizophrenia. Subjects were randomized in a 1:1:1:1 ratio to receive daily OLZ + placebo or 3 different ALKS 3831 treatment options(OLZ + 5, 10, or 20 mg SAM) in a double-blind paradigm following a 1-wk OLZ lead-in period. The primary efficacy endpoint was changein Positive and Negative Syndrome Scale (PANSS) total score from baseline to Week 12 to test equivalence of antipsychotic efficacy of the3 pooled ALKS 3831 groups vs. OLZ. The analysis was performed for the full analysis set (FAS1) that included all randomized subjects whoreceived ≥1 dose of study drug and had ≥1 post-baseline PANSS assessment. The pre-specified secondary endpoint, percent change in weightfrom baseline to Week 12 was evaluated in FAS1 (n=300) and the subset of subjects with observed weight gain during the 1-wk OLZ lead inperiod (FAS2, n=195). Safety and tolerability of ALKS 3831 relative to OLZ was also assessed. The change from baseline in PANSS totalscore with ALKS 3831 was equivalent to OLZ (LS mean difference±SE: 0.6±0.9; 95% CI: -1.2, 2.5). At Week 12, treatment with ALKS3831 demonstrated a 37% lower mean weight gain vs. OLZ alone in FAS1 (p=0.006) and a 51% lower mean weight gain vs. OLZ in FAS2(p<0.001). The risk of weight gain of ≥10% of baseline weight with OLZ was 2.7 times that of ALKS 3831 (95% CI: 1.1, 6.7; p=0.023) inFAS1 and 4.1 times that of ALKS 3831 (95% CI: 1.4, 12.3; p=0.008) in FAS2. The most common adverse events (≥5%) in the pooled ALKS3831 subjects relative to OLZ subjects were somnolence, sedation, and dizziness. In this study, ALKS 3831 demonstrated efficacy equivalentto OLZ over the course of the 12-wk treatment. ALKS 3831 was associated with a clinically meaningful and statistically significant lowerweight gain compared to OLZ alone. ALKS 3831 was well-tolerated with a safety profile similar to OLZ, with the exception of lower weightgain.Evidence to date suggests that ALKS 3831 may represent a new advancement in the treatment of schizophrenia through maintaining benefitsof the highly effective antipsychotic OLZ with an enhanced safety profile that addresses weight and metabolic liabilities. The potential utilityof ALKS 3831 to treat patients with schizophrenia and co-occurring alcohol use disorder is the focus of an ongoing Phase 2 study.References:  Lieberman J, et al. N Eng J Med. 2005;353:1209-23.  Gastfriend DR. Ann NY Acad Sci. 2014;1327:112-30.  De Hert M, et al. World Psychiatry. 2011;10:52–77.  Todtenkopf MS, et al. Neuropsychopharmacol. 2010:81.  Todtenkopf MS, et al. Neuropsychopharmacol. 2011:206. BREMELANOTIDE FOR HYPOACTIVE SEXUAL DESIRE DISORDER: ANALYSES FROM APHASE 2B DOSE-RANGING STUDYAnita Clayton, Carl Spana, Robert JordanUniversity of Virginia, Palatin Technologies, Inc. Abstract Introduction: Bremelanotide (BMT) is a novel heptapeptide melanocortin-receptor-4 agonist. This study examined its subcutaneousself-administration by premenopausal patients with hypoactive sexual desire disorder (HSDD), female sexual arousal disorder (FSAD), orboth, and included exploratory analyses specifically in subjects with HSDD.Introduction: Bremelanotide (BMT) is a novel heptapeptide melanocortin-receptor-4 agonist. This study examined its subcutaneousself-administration by premenopausal patients with hypoactive sexual desire disorder (HSDD), female sexual arousal disorder (FSAD), orboth, and included exploratory analyses specifically in subjects with HSDD. Methods: Premenopausal women with HSDD and/or FSAD underwent a no-treatment diagnosis-confirmation month, followed by 4 weeks of single-blind, at-home placebo self-dosing (baseline). Subjects were then randomized to double-blind placebo or BMT 0.75, 1.25, or 1.75 mgself-administered for 12 weeks. Outcomes included changes from baseline to end of study in the number of satisfying sexual events (SSEs),Female Sexual Function Index (FSFI) scores, and Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) scores.Results: Of 327 at-home study-drug users, 281 either had mixed HSDD/FSAD with a primary diagnosis of HSDD (n=206) or had solelyHSDD (n=75). Among all 281 women, mean SSE change (per 4 weeks) was +0.2 for placebo, versus +0.8 for 0.75 mg, +0.7 for 1.25 mg, and+0.7 for 1.75 mg. Mean FSFI change was +1.55 versus +1.45, +3.11, and +4.24 for total score, and +0.37 versus +0.33, +0.58, and +0.97respectively for desire subscore. Mean FSDS-DAO change was –6.6 versus –8.0, –9.6, and –12.7 for total score and –0.6 versus –0.5, –0.7,and –1.0 for Question 13 (“bothered by low desire”). On all outcomes, BMT benefit was statistically significant (p < 0.05, Van Elteren test)with the 1.75 mg dose.Conclusions: In premenopausal HSDD, subcutaneous BMT yielded improvements across all key HSDD measures, with robust dose-dependence attaining statistical significance at the 1.75 mg dose.Funding: Palatin Technologies, Inc. 4:15 p.m. – 5:30 p.m.