- Email: [email protected]
690. Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone
Biological Psychiatry
Saturday Abstracts
Intraoperative real-time MRI was used to selectively infect the Ce with an AAV5 vector over expressing the CRH gene. Results: Results demonstrated that over expression of CRH in the Ce resulted in increased measures of anxiety including increases in anxious temperament. In addition, FDG-PET scanning revealed that over expression of CRH resulted in increased metabolism in the neural circuit that underlies anxiety including the dorsal amygdala and the posterior orbital frontal cortex. Chronic over expression of CRH also led to other functional and structural brain changes. Conclusions: These studies are highly relevant as there are important differences in the regional expression of CRH receptor subtypes between rodent and primate species. These are the first data manipulating the CRH gene in primates to demonstrate a potential role of this system in mediating pathological anxiety. These studies suggest the importance of the CRH system in the central nucleus of the amygdala in mediating human stressrelated psychopathology. Supported By: NIH Keywords: Anxiety, monkey, CRH, imaging, amygdala
688. The CRH-1 Receptor Antagonist Saga in Mood and Anxiety Disorders: The Good, the Bad and the Ugly Charles Nemeroff1 and Boadie Dunlop2 1
University of Miami Health System, 2Emory University
Background: This presentation will review the considerable evidence that corticotropin-releasing hormone (CRH) plays a major role in the mammalian stress response and in the pathophysiology of depression and PTSD. These data include both preclinical and clinical studies, the former demonstrating the antidepressant and anxiolytic properties of CRH R1 antagonists and the latter a multitude of pathophysiological studies in drug free patients. In spite of this foundation presaging the efficacy of CRH R1 antagonists, the resultant clinical trial data has been very disappointing. Failed studies in PTSD, depression and GAD have been reported. This presentation will discuss the apparent discrepancy between the evidence of an involvement of CRF circuits in the pathogenesis of these disorders and their lack of efficacy in clinical trials. Methods: Summary of the preclinical, clinical pathophysiological and clinical trial data related to CRH R1 antagonists will be reviewed in detail. All available data, both published and as yet unpublished, will be included. Results: The complete analysis of all of the studies in which CSF CRH concentrations were measured in depressed patients and in PTSD patients will be presented. Each of the CRH R1 antagonist clinical trials will be presented. Conclusions: Whether a subgroup of carefully defined patients with MDD or PTSD, either by history of child abuse and neglect, or by genetic polymorphisms of the CRH R1 would yield a population of responders to this treatment is of great interest. The pharmacological properties of the individual CRH R1 antagonists differ and such differences likely also contribute to the clinical trial results. Supported By: NIMH Keywords: CRH, Depression, PTSD - Posttraumatic Stress Disorder, CRH-R1, Clinical Trials
689. Mifepristone Plasma Levels, Receptor Blockade and Clinical Response in Patients with Psychotic Depression Joseph Belanoff Corcept Therapeutics Background: Psychotic Depression (PD) is a severe form of depression characterized by hypothalamic-pituitary-adrenal (HPA) axis overactivity and high morbidity and mortality. No treatment for it has been approved by the FDA. Because it modulates cortisol’s activity, mifepristone has been studied in over 1,400 patients with PD to test its ability to rapidly reduce psychotic symptoms. Receiver Operator Curve (ROC) analyses have been performed on mifepristone trough plasma level data in these studies to identify optimal values discriminating responders from non-responders. We present data on relationships among plasma drug, degree of cortisol modulation (as illustrated by changes in cortisol and ACTH levels) and clinical response. Methods: Data were collected across 5 phase II/III PD studies (1400 patients) treated for 7 days with mifepristone (3001,200mg per day) or placebo, followed for an additional 7 weeks. Morning cortisol levels were assessed before and after 7 days of treatment. Trough drug plasma levels were drawn prior to the final dose of study drug. Response was defined as a 50% reduction in psychotic symptoms from baseline to study day 7 sustained to day 56. Results: Patients with high mifepristone plasma level patients demonstrated significantly higher response rates than patients with low mifepristone plasma level or patients who received placebo. In addition, patients with high plasma drug levels demonstrated significantly greater increases in ACTH and cortisol levels than did the other two groups. Conclusions: Mifepristone at higher drug plasma levels has significant antipsychotic and biological effects in PD patients. Administration of mifepristone was safe and well tolerated. Supported By: Corcept Therapeutics Keywords: Mifepristone, Psychotic Depression
690. Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone Julia Golier1, Julia Golier2, Robin Hurley3, Rachel Yehuda2, Dewleen Baker4, Xue Li5, Brendan W. Bechard6, Lisa Robin5, Janine Flory2, Timothy Kimbrell7, Marcel Bizien8, and Domenic Reda5 Mt. Sinai School of Medicine, 2Mount Sinai School of Medicine, James J. Peters VAMC, 3Wake Forest School of Medicine, MIRECC, VAMC, 4San Diego Veterans Affairs, 5VA Cooperative Studies Program Coordinating Center, 6James J. Peters VAMC, 7Central Arkansas Veterans Healthcare System, University of Arkansas, 8VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center 1
Background: PTSD is a debilitating illness for which few effective pharmacological treatments exist. Given ample evidence of dysregulation of the hypothalamic pituitary
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal
S279
Biological Psychiatry
Saturday Abstracts
adrenal (HPA) axis in PTSD, including enhanced glucocorticoid receptor sensitivity, we assessed the efficacy and safety of mifepristone, a type II glucocorticoid receptor antagonist, in the treatment of PTSD. Methods: A multi-center phase IIa, double-blind, randomized clinical trial of mifepristone versus placebo was conducted through the Department of Veterans Affairs. Eighty-one male veterans were randomized to treatment with either mifepristone (600 mg/day) or placebo for seven days followed by periodic assessments over three months. Statistical selection theory will be used to determine if there is a signal for the efficacy of mifepristone on clinical response, based on reduction in the total score of the Clinician Administered PTSD Scale (CAPS). Results: Preliminary results will be presented to show the proportion of clinical responders (defined as a 30% or greater reduction in CAPS total score from baseline) at one month posttreatment on mifepristone vs. placebo. Information will also be provided about the sustainability of response and adverse events. Conclusions: This study will inform us as to whether there is a sufficient signal to warrant a larger scale trial of mifepristone in PTSD. If short-term mifepristone treatment is found to be effective and safe it would represent a novel approach to pharmacological treatment that is very different from chronic psychotropic medication usage and open up additional avenues for therapeutic manipulation of neuroendocrine activity in PTSD. Supported By: Department of Veterans Affairs, Cooperative Clinical Trial Award Program (#0004). Keywords: Glucocorticoids, PTSD - Posttraumatic Stress Disorder, Clinical Trials, Hydrocortisone, Mifespristone
SYMPOSIUM Regulation of Gene Networks in the Brain: New Insights from High-Throughput Sequencing Saturday, May 20, 2017 - 12:30 PM - 2:30 PM Sapphire EF Chair: Francis McMahon Co-Chair: Barbara Lipska 691. RNA-sequencing of the Subgenual Anterior Cingulate Cortex in Adult Major Psychiatric Disorders Nirmala Akula1, Robin Kramer2, Qing Xu1, Kory Johnson2, Stefano Marenco1, Jose Apud1, Harker Rhodes1, Brent Harris1, Barbara Lipska3, and Francis McMahon1 1
National Institute of Mental Health, 2NINDS, 3NIH/NIMH
Background: The subgenual anterior cingulate cortex (ACSg) has been implicated in both mood disorders and schizophrenia, but gene expression in this brain region has been little studied. Here we report the first large-scale study of the ACSg transcriptome in major psychiatric disorders. Methods: A total of 200 ACSg samples (39 bipolar disorder (BD), 54 major depression (MDD), 46 schizophrenia, 61 controls) were dissected from brains collected at the NIMHHBCC. Stranded, paired-end sequencing of high quality RNA (RIN 6) was performed on the Illumina HiSeq 2500. The
S280
resulting 125bp reads were mapped to the reference genome (hg38) using Tophat v2.1.1. Gene-level analyses were performed using HTSeq and DESeq2 was used for quality control, normalization, and differential gene expression, with correction for known covariates. Results: Of the 21 billion total reads obtained, 98M reads mapped to the reference genome and 70M reads were properly paired, per sample. A total of 38 genes, 68 genes and 141 genes were differentially expressed (FDR,10%) in BD, MDD and schizophrenia, respectively. The overlap of differentially expressed genes across disorders was highly significant (hypergeometric p-value,1.9E-05). Two genes, NR4A1(NUR77) and NR4A2(NURR1), were differentially expressed in all 3 disorders. Pathway enrichment analysis implicated the MHC class II. Conclusions: To our knowledge this is the largest study of the ACSg transcriptome in postmortem brain. The crossdisorder overlap in gene expression recapitulates genomewide association study results and highlights the shared genetic architecture among major psychiatric disorders. Future analyses will examine transcript-level expression and gene co-expression networks. Supported By: 1-ZIC-MH002903-09 Keywords: Anterior cingulate cortex, RNA sequencing, Bipolar disorder, Schizophrenia, Major depression
692. From Nucleosome to Nucleus: 3D Genome Mappings in Mouse Models of Psychiatric Disease, and in Human Postmortem Brain Schahram Akbarian, Prashanth Rajaran, and Kristen Brennand Icahn School of Medicine at Mount Sinai Background: Non-random chromosomal conformations, including promoter-enhancer loopings bypassing kilo- or megabases of linear genome, provide a critical layer of transcriptional regulation, and mobilize vast amounts of noncoding sequence into physical proximity of genes important for neurodevelopment, cognition and behavior. Loop-bound intergenic and intronic non-coding sequences have been implicated in psychiatric and adult-onset neurodegenerative disease, but insight into the developmental and diseaseassociated changes in the regulation of the neuronal and non-neuronal '3D genome', including its inter-relation with histone modification landscapes and other layers of epigenetic regulation, has been limited. Methods: Genome-scale restriction digest-religation assays in intact nuclei from human and mouse brain and neural cultures derived from pluripotent stem cells (in situ Hi-C). Chromatin immunoprecipitation followed by next generation sequencing from specific subtypes of neurons and glia, and RNA-seq transcriptome sequencing. Results: A significant subset of chromosomal loop formations and chromosomal interaction domains are differentially regulated in neural precursors compared to differentiated neurons and glia. A subset of risk haplotypes (Psychiatric Genomics Consortium) locate to such types of
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal
Saturday Abstracts
Intraoperative real-time MRI was used to selectively infect the Ce with an AAV5 vector over expressing the CRH gene. Results: Results demonstrated that over expression of CRH in the Ce resulted in increased measures of anxiety including increases in anxious temperament. In addition, FDG-PET scanning revealed that over expression of CRH resulted in increased metabolism in the neural circuit that underlies anxiety including the dorsal amygdala and the posterior orbital frontal cortex. Chronic over expression of CRH also led to other functional and structural brain changes. Conclusions: These studies are highly relevant as there are important differences in the regional expression of CRH receptor subtypes between rodent and primate species. These are the first data manipulating the CRH gene in primates to demonstrate a potential role of this system in mediating pathological anxiety. These studies suggest the importance of the CRH system in the central nucleus of the amygdala in mediating human stressrelated psychopathology. Supported By: NIH Keywords: Anxiety, monkey, CRH, imaging, amygdala
688. The CRH-1 Receptor Antagonist Saga in Mood and Anxiety Disorders: The Good, the Bad and the Ugly Charles Nemeroff1 and Boadie Dunlop2 1
University of Miami Health System, 2Emory University
Background: This presentation will review the considerable evidence that corticotropin-releasing hormone (CRH) plays a major role in the mammalian stress response and in the pathophysiology of depression and PTSD. These data include both preclinical and clinical studies, the former demonstrating the antidepressant and anxiolytic properties of CRH R1 antagonists and the latter a multitude of pathophysiological studies in drug free patients. In spite of this foundation presaging the efficacy of CRH R1 antagonists, the resultant clinical trial data has been very disappointing. Failed studies in PTSD, depression and GAD have been reported. This presentation will discuss the apparent discrepancy between the evidence of an involvement of CRF circuits in the pathogenesis of these disorders and their lack of efficacy in clinical trials. Methods: Summary of the preclinical, clinical pathophysiological and clinical trial data related to CRH R1 antagonists will be reviewed in detail. All available data, both published and as yet unpublished, will be included. Results: The complete analysis of all of the studies in which CSF CRH concentrations were measured in depressed patients and in PTSD patients will be presented. Each of the CRH R1 antagonist clinical trials will be presented. Conclusions: Whether a subgroup of carefully defined patients with MDD or PTSD, either by history of child abuse and neglect, or by genetic polymorphisms of the CRH R1 would yield a population of responders to this treatment is of great interest. The pharmacological properties of the individual CRH R1 antagonists differ and such differences likely also contribute to the clinical trial results. Supported By: NIMH Keywords: CRH, Depression, PTSD - Posttraumatic Stress Disorder, CRH-R1, Clinical Trials
689. Mifepristone Plasma Levels, Receptor Blockade and Clinical Response in Patients with Psychotic Depression Joseph Belanoff Corcept Therapeutics Background: Psychotic Depression (PD) is a severe form of depression characterized by hypothalamic-pituitary-adrenal (HPA) axis overactivity and high morbidity and mortality. No treatment for it has been approved by the FDA. Because it modulates cortisol’s activity, mifepristone has been studied in over 1,400 patients with PD to test its ability to rapidly reduce psychotic symptoms. Receiver Operator Curve (ROC) analyses have been performed on mifepristone trough plasma level data in these studies to identify optimal values discriminating responders from non-responders. We present data on relationships among plasma drug, degree of cortisol modulation (as illustrated by changes in cortisol and ACTH levels) and clinical response. Methods: Data were collected across 5 phase II/III PD studies (1400 patients) treated for 7 days with mifepristone (3001,200mg per day) or placebo, followed for an additional 7 weeks. Morning cortisol levels were assessed before and after 7 days of treatment. Trough drug plasma levels were drawn prior to the final dose of study drug. Response was defined as a 50% reduction in psychotic symptoms from baseline to study day 7 sustained to day 56. Results: Patients with high mifepristone plasma level patients demonstrated significantly higher response rates than patients with low mifepristone plasma level or patients who received placebo. In addition, patients with high plasma drug levels demonstrated significantly greater increases in ACTH and cortisol levels than did the other two groups. Conclusions: Mifepristone at higher drug plasma levels has significant antipsychotic and biological effects in PD patients. Administration of mifepristone was safe and well tolerated. Supported By: Corcept Therapeutics Keywords: Mifepristone, Psychotic Depression
690. Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone Julia Golier1, Julia Golier2, Robin Hurley3, Rachel Yehuda2, Dewleen Baker4, Xue Li5, Brendan W. Bechard6, Lisa Robin5, Janine Flory2, Timothy Kimbrell7, Marcel Bizien8, and Domenic Reda5 Mt. Sinai School of Medicine, 2Mount Sinai School of Medicine, James J. Peters VAMC, 3Wake Forest School of Medicine, MIRECC, VAMC, 4San Diego Veterans Affairs, 5VA Cooperative Studies Program Coordinating Center, 6James J. Peters VAMC, 7Central Arkansas Veterans Healthcare System, University of Arkansas, 8VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center 1
Background: PTSD is a debilitating illness for which few effective pharmacological treatments exist. Given ample evidence of dysregulation of the hypothalamic pituitary
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal
S279
Biological Psychiatry
Saturday Abstracts
adrenal (HPA) axis in PTSD, including enhanced glucocorticoid receptor sensitivity, we assessed the efficacy and safety of mifepristone, a type II glucocorticoid receptor antagonist, in the treatment of PTSD. Methods: A multi-center phase IIa, double-blind, randomized clinical trial of mifepristone versus placebo was conducted through the Department of Veterans Affairs. Eighty-one male veterans were randomized to treatment with either mifepristone (600 mg/day) or placebo for seven days followed by periodic assessments over three months. Statistical selection theory will be used to determine if there is a signal for the efficacy of mifepristone on clinical response, based on reduction in the total score of the Clinician Administered PTSD Scale (CAPS). Results: Preliminary results will be presented to show the proportion of clinical responders (defined as a 30% or greater reduction in CAPS total score from baseline) at one month posttreatment on mifepristone vs. placebo. Information will also be provided about the sustainability of response and adverse events. Conclusions: This study will inform us as to whether there is a sufficient signal to warrant a larger scale trial of mifepristone in PTSD. If short-term mifepristone treatment is found to be effective and safe it would represent a novel approach to pharmacological treatment that is very different from chronic psychotropic medication usage and open up additional avenues for therapeutic manipulation of neuroendocrine activity in PTSD. Supported By: Department of Veterans Affairs, Cooperative Clinical Trial Award Program (#0004). Keywords: Glucocorticoids, PTSD - Posttraumatic Stress Disorder, Clinical Trials, Hydrocortisone, Mifespristone
SYMPOSIUM Regulation of Gene Networks in the Brain: New Insights from High-Throughput Sequencing Saturday, May 20, 2017 - 12:30 PM - 2:30 PM Sapphire EF Chair: Francis McMahon Co-Chair: Barbara Lipska 691. RNA-sequencing of the Subgenual Anterior Cingulate Cortex in Adult Major Psychiatric Disorders Nirmala Akula1, Robin Kramer2, Qing Xu1, Kory Johnson2, Stefano Marenco1, Jose Apud1, Harker Rhodes1, Brent Harris1, Barbara Lipska3, and Francis McMahon1 1
National Institute of Mental Health, 2NINDS, 3NIH/NIMH
Background: The subgenual anterior cingulate cortex (ACSg) has been implicated in both mood disorders and schizophrenia, but gene expression in this brain region has been little studied. Here we report the first large-scale study of the ACSg transcriptome in major psychiatric disorders. Methods: A total of 200 ACSg samples (39 bipolar disorder (BD), 54 major depression (MDD), 46 schizophrenia, 61 controls) were dissected from brains collected at the NIMHHBCC. Stranded, paired-end sequencing of high quality RNA (RIN 6) was performed on the Illumina HiSeq 2500. The
S280
resulting 125bp reads were mapped to the reference genome (hg38) using Tophat v2.1.1. Gene-level analyses were performed using HTSeq and DESeq2 was used for quality control, normalization, and differential gene expression, with correction for known covariates. Results: Of the 21 billion total reads obtained, 98M reads mapped to the reference genome and 70M reads were properly paired, per sample. A total of 38 genes, 68 genes and 141 genes were differentially expressed (FDR,10%) in BD, MDD and schizophrenia, respectively. The overlap of differentially expressed genes across disorders was highly significant (hypergeometric p-value,1.9E-05). Two genes, NR4A1(NUR77) and NR4A2(NURR1), were differentially expressed in all 3 disorders. Pathway enrichment analysis implicated the MHC class II. Conclusions: To our knowledge this is the largest study of the ACSg transcriptome in postmortem brain. The crossdisorder overlap in gene expression recapitulates genomewide association study results and highlights the shared genetic architecture among major psychiatric disorders. Future analyses will examine transcript-level expression and gene co-expression networks. Supported By: 1-ZIC-MH002903-09 Keywords: Anterior cingulate cortex, RNA sequencing, Bipolar disorder, Schizophrenia, Major depression
692. From Nucleosome to Nucleus: 3D Genome Mappings in Mouse Models of Psychiatric Disease, and in Human Postmortem Brain Schahram Akbarian, Prashanth Rajaran, and Kristen Brennand Icahn School of Medicine at Mount Sinai Background: Non-random chromosomal conformations, including promoter-enhancer loopings bypassing kilo- or megabases of linear genome, provide a critical layer of transcriptional regulation, and mobilize vast amounts of noncoding sequence into physical proximity of genes important for neurodevelopment, cognition and behavior. Loop-bound intergenic and intronic non-coding sequences have been implicated in psychiatric and adult-onset neurodegenerative disease, but insight into the developmental and diseaseassociated changes in the regulation of the neuronal and non-neuronal '3D genome', including its inter-relation with histone modification landscapes and other layers of epigenetic regulation, has been limited. Methods: Genome-scale restriction digest-religation assays in intact nuclei from human and mouse brain and neural cultures derived from pluripotent stem cells (in situ Hi-C). Chromatin immunoprecipitation followed by next generation sequencing from specific subtypes of neurons and glia, and RNA-seq transcriptome sequencing. Results: A significant subset of chromosomal loop formations and chromosomal interaction domains are differentially regulated in neural precursors compared to differentiated neurons and glia. A subset of risk haplotypes (Psychiatric Genomics Consortium) locate to such types of
Biological Psychiatry May 15, 2017; 81:S277–S413 www.sobp.org/journal