Eric Hollander - US grants

Obsessive-compulsive disorder (OCD) is a common and disabling disorder that was until recently relatively unstudied, but is currently the focus of considerable research into the treatment and pathophysiology. Broad training is proposed in three phases. The first involves core studies of the pathophysiology of OCD, including pharmacological challenges, neuropsychiatric studies, electrophysiology, peripheral and CSF markers, and diagnostic assessment. These core studies will be performed at baseline and again during treatment with serotonin reuptake inhibitors. The second phase involves development of new studies in OCD, such as imaging (RCBF, SPECT), additional biological challenges to clarify issues raided in phase I, evoked potentials pre- and post challenges, and epidemiologic, pedigree and DNA marker studies of OCD. The third phase involves comparison of the core findings in OCD with related disorders. These include comparison with normal controls, other anxiety controls, such as social phobia and panic disorder, high risk relatives, patients with concurrent OCD and major depression (a common occurrence), childhood onset OCD, and genetically linked disorders such as Tourette's syndrome. Clinical issues such as the prediction of relapse, and the prediction of development in high risk relatives, will be addressed. In the course of these studies, broad training with recognized experts will be received in several areas, including pharmacological challenges, neurochemistry, neuropsychology, imaging, epidemiology, electrophysiology, Tourette's syndrome, childhood onset OCD, psychopharmacology, and statistics and research design. This training will develop further expertise, and permit further studies of the pathophysiology of related disorders.

This study will determine whether abnormalities exist in the functining of the endogenous opioid systems (EOS), noradrenergic system, and hypothalamic-pituitary-adrenal (HPA) axis of patients with a diagnosis of borderline personality disorder (BPD) who engage in self-injurious behavior (SIB), such as superficial wrist cutting or burning.

The main goal of this project is to understand the role of 5-HT in compulsive behavior and social deficits present in autism and Asperger's Syndrome via the behavioral/neuroendocrine response to m-CPP, FEN and sumatriptan challenge procedures.

DESCRIPTION: (Applicant's Abstract) Studies of the etiology of addiction have been limited in part by difficulty in obtaining homogeneous addiction populations, reinforcing the need to develop new pathophysiological models of addiction. Pathological gambling (PG) is a chronic, disabling, and understudied impulse control disorder which affects 1-3% of the population. PG is often viewed as an addiction, consisting of tolerance, dependence, and withdrawal. Up to half of pathological gamblers have substance use problems. Prior studies have suggested serotonergic and noradrenergic abnormalities in PG. Our pharmacological treatment studies with the serotonin reuptake blocker fluvoxamine revealed a reduction in actual pathological gambling behavior. In pilot pharmacological challenge studies, the partial 5-HT agonist m-CPP induced a "high" behavioral response and an augmented prolactin response in PG patients compared to normal controls. The alpha-2 agonist clonidine induced an augmented growth hormone response in PG. This pattern of response, not seen before in other impulsive, compulsive, and depressive conditions, may reflect behavioral initiation/ disinhibition and behavioral readiness, respectively, key features of PG relevant to addiction. To examine serotonergic and noradrenergic responsiveness in PG, this proposal will compare 70 PG patients (35 males, 35 females) and 40 normal controls (20 males, 20 females) of comparable marginal distribution of age, sex, SES, and ethnicity on behavioral (high) and neuroendocrine (prolactin, GH) response to m-CPP and clonidine, controlling for pulsatile neuroendocrine factors. Specificity of noradrenergic and serotonergic systems with regard to behavioral readiness vs. behavioral initiation/disinhibition, respectively, will be examined. Severity of impulsivity and depression will be correlated with these serotonergic and noradrenergic measures. Understanding the etiology of PG will facilitate the development of pathophysiological models of addiction.

This study proposes to investigate the treatment response of body dysmorphic disorder (BDD) in adolescents. Body dysmorphic disorder, a preoccupation with an imagined or slight defect in appearance, is a distressing and impairing disorder that is more common than is generally recognized. BDD usually begin during childhood or adolescence, but its treatment in adolescents has not been investigated. Such investigation is important because BDD appears to often be chronic and to cause considerable morbidity. It is associated with high rates of social and academic/occupational impairment, being housebound, psychiatric hospitalization, suicidal ideation, and suicide attempts. Preliminary data from adults and adolescents suggest that BDD and its delusional variant (a type of delusional disorder, somatic type) may respond to serotonin-re-uptake inhibitors. Furthermore, similarities between BDD and obsessive compulsive disorder (OCD) make these medications promising for adolescent BDD. The primary specific aim of this study is to assess the efficacy and safety of fluoxetine versus placebo in BDD and its delusional disorder variant in 100 adolescents age 12-17. The proposed study will be a 12-week double-blind parallel- group trial that will occur at three sites: Butler Hospital/Brown University, Mount Sinai School of Medicine, and The University of Cincinnati School of Medicine. A secondary specific aim is to explore the predictors of treatment response. The hypothesis to be tested is that delusionality (insight), comorbid major depression or OCD, and illness severity will not predict fluoxetine response. The proposed study will provide needed data on BDD's treatment in adolescents. It will be the first controlled treatment trial of BDD in an adolescent age group. Such investigation is needed because this under-recognized, often-secret disorder usually begins during adolescence and can cause significant distress and impairment in functioning. When untreated, adolescent-onset BDD appears to often interfere with the developmental tasks of adolescence, to persist, and to cause substantial morbidity through out the life span.

Borderline personality disorder (BPD) is a well-characterized psychiatric disorder with an estimated prevalence of 1-2 percent of the U.S. population, and high levels of impairment and mortality. BPD accounts for approximately 10 percent of all psychiatric outpatients and 20 percent of acute inpatient hospitalizations. Core symptoms of BPD include mood instability, anger, depression, psychoticism/paranoid ideation, aggression and anxiety. In an open label study, we treated 11 BPD patients with the mood stabilizer divalproex sodium (DS). Of the 8 patients who completed treatment, 50 percent showed significant improvement. There was a significant decrease in the SCL-90 total score from 99.1 (q68.4) to 56.6 (q59.5)(t=2.8, p=.03). Global subjective irritability showed significant decreases as well from 3.4(q0.55) to 1.7(q1.4)(t=3.0, p=.02). Improvement was also seen on clinical measures of irritability, anger, anxiety and rejection sensitivity. In a pilot double-blind placebo controlled trial of DS in 16 BPD patients, endpoint CGI improvement scores were 2.0 (much improved) for DS and 5.0 (minimally worse) for placebo. There was significant improvement on global functioning by GAS score (F=5.4, df=1,12, p=.04), aggression by OAS-M (F=19.1, df=1,18, p=.005) and improvement on depression by BDI from 15.5 to 6.9 on DS vs 14.7 to 12 on placebo. This and other preliminary studies suggest potential efficacy of mood stabilizers such as DS in BPD, which would complement existing nonpharmacologic treatment modalities. To further assess the efficacy of DS in BPD in the proposed small grant, 25 outpatients will be randomized to 10 week double-blind treatment with DS vs placebo, preceded by a two-week placebo run in to establish baseline levels on assessment measures. Clinical assessment of symptoms and behaviors by a treating psychiatrist will occur on a weekly basis for the first two weeks following initiation of treatment, then on an every-other week basis for the following 8 weeks. An independent evaluator, blind to dosage and side effects, will conduct assessments every 2 weeks for global severity, psychoticism/paranoid ideation, anger, anxiety and depression. Plasma valproate levels will be monitored, and DS raised to a target value of 70-120 mug/ml. This small grant (R03) will provide systematic information on the efficacy of DS in the treatment of outpatients with BPD, as well as provide information on feasibility, power, response rates, and reliability of outcome measures which will form the basis of a larger RO1 proposal.

The purpose of this NIH study is to examine serotonergic and noradrenergic abnormalities in pathological gamblers compared to controls utilizing m-chlorophenylpiperazine(m-CPP), clonidine, and placebo challenges, as well as behavioral responses.

DESCRIPTION (provided by applicant): Autism is a pervasive developmental disorder affecting social, communicative, and repetitive behavior domains and cognitive function, and has dramatic impact on quality of life. It is also frequently accompanied by aggression, self-injury, impulsivity, and mood instability, as well as EEG abnormalities and seizure disorders. While large scale studies of childhood autism are currently underway with SSRI's and atypical neuroleptics, little controlled data is available with other agents that might target these core and associated symptoms of autism. This application aims to determine whether there is scientific evidence to support the practice of prescribing divalproex sodium (DS)(valproate) to child/adolescent autistic patients. When a medication is used extensively prior to scientific substantiation in controlled clinical trials, the consequences can sometimes be problematic. Neither the side effects nor efficacy of valproate in treating child/adolescent autistic disorders has been definitively established. Of theoretical interest, valproate has possible neuroprotective effects mediated by signal transduction pathways (i.e., protein kinase-c inhibition and bcl-2 activation) which may potentially be beneficial for a neurodevelopmental disorder such as autism. This study is the first double-blind placebo-controlled medication trial of valproate for children and adolescents with autism, and utilizes a 12-week double-blind placebo-controlled parallel design. The study is unique in examining the treatment effects of valproate (DS) versus placebo on global autism severity; aggression, self-injury and impulsivity; affective instability; repetitive behaviors and social deficits; and functional ability. While our pilot open data evaluating the use of DS for autistic subjects has been encouraging so far (71 percent of autistic subjects were global treatment responders on open DS), a double blind placebo controlled trial with larger sample size and more precise methodology is needed to provide a scientifically sound conclusion about the efficacy, side effects, and effects on functional living skills of this medication in children with autism. This will definitively either support or contradict its widespread use in this understudied and neglected population, and provide a benchmark by which new treatments could be compared. It will also assess the relationship between dose and blood levels and response, potentially identify subgroups particularly responsive to this treatment, and identify which components and associated symptoms are most responsive to change.

gamblings; norepinephrine; serotonin; behavior disorders; piperazines; high risk behavior /lifestyle; clonidine; behavioral /social science research tag; clinical research; human subject; placebos;

The Greater New York Autism Research Center of Excellence, a collaborative effort of the Mount Sinai School of Medicine, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, University of Toronto, State University of New York at Stony Brook, and North Shore-Long-Island Jewish Health System, will aim to better understand the functions of the serotonin system in autism, specifically in its relation to repetitive behaviors, by combining methodologies from genetics, functional imaging and neuropsychopharmacology. By investigating core symptom domains of autism and linking this information to etiological factors, the multidisciplinary center's basic science and clinical research will facilitate development of novel or improved strategies for diagnosis, early detection and treatment of autism spectrum disorders. In achieving these goals, the center will be comprised of four integrated cores that will facilitate three interrelated research projects as well as multi-center collaborative endeavors. Project I: Identification of Autism Susceptibility Genes; Project II: Imaging Serotonin Function in Asperger's Disorder; Project Ill: Fluoxetine versus Placebo in Child/Adolescent Autistic Disorder. Core B: Clinical Core; Core C: Data Management and Statistics Core; Core D: Information Transfer Core.

While fluoxetine is frequently prescribed to autistic patients in clinical practice, its efficacy, side effects, maintenance and discontinuation effects have not been definitively established. Mixed results of efficacy, particularly between pre- and post-pubertal patients, and a lack of well-controlled trials leave many gaps in our knowledge about SSRIs, such as fluoxetine, in autism. Furthermore, it is important to determine whether specific subtypes of individuals (those with increased repetitive behaviors), or those with specific genetic variants or polymorphisms of the serotonin system respond differentially to fluoxetine. Little controlled data is available with medications that target the repetitive behavior domain of autism, which contributes to substantial functional impairment. This study will compare liquid fluoxetine vs. placebo in treating child/adolescent autistic patients and assess the relationship between dose, blood levels and response to treatment. The relationship between candidate genes of the serotonin system, symptom improvement, and side effects will be examined. The study will consist of three treatment phases: Phase 1 - a 12-week doubleblind placebo-controlled parallel acute treatment phase, Phase 2 - a 12-week treatment extension phase, and Phase 3 - a 12-week double-blind placebo-controlled discontinuation phase. We aim to evaluate a targeted treatment of a core symptom domain in a stratified sample of autistic children with repetitive behavior, and explore the relationship between genetic variation of the 5-HT system and fluoxetine treatment response and side effects.

[unreadable] DESCRIPTION (provided by applicant): This research training grant is designed to train psychiatrists and psychologists for careers in psychopharmacology and outcomes research. The research facilities and faculty of the Department of Psychiatry at the Mount Sinai School of Medicine and its major research affiliate will serve as the site and resources for this training program. The program consists of three primary components: (1) mentored research, (2) didactic curriculum, and (3) basic science and clinical research selectives. As part of the mentored research component, each trainee will work with a preceptor who is an established researcher with a track record of scientific productivity and funding. The fellow joins the preceptor's research group and takes part in ongoing research projects in addition to developing and completing a research project of his or her own. Mentored research will also involve working with a statistics tutor. The preceptorship and statistics training offers an intensive and immediate emphasis on learning the skills of data analysis and the oral and written presentation of research results, as well as how to develop and execute research protocols. The second major component is the didactic curriculum, which includes introductory and advanced courses in statistics, courses in research design, seminars on ethics in research and seminars on modern research techniques. The third component is the basic science and clinical research selectives. In the basic science selectives, trainees will learn the principles and application of specified laboratory techniques through collaboration with laboratory-based researchers (e.g., neuroimaging, molecular neuropharmacology, neurobehavioral genetics). In the clinical research selectives, trainees will participate in ongoing research protocols to better understand psychopharmacology and outcomes research in such areas as autism, schizophrenia and mood disorders. These selectives will also include training in outcomes assessment and cognitive/neuropsychological assessment. Stipends are requested to support the entry of two fellows per year for the initial two years and then three fellows per year for up to three years of training. [unreadable] [unreadable]

The primary objective of the Clinical Core (Core B) will be to provide a well-characterized cohort of subjects with autism and autism spectrum disorders and non-autistic control subjects for enrollment in GNYARCE research projects and collaborative endeavors. Core B will acquire comprehensive clinical and laboratory data through diagnostic evaluation and assessment of comorbidity, cognitive, developmental, and adaptive assessment, medical history and screening, and genetic sample collection from autistic and autism spectrum subjects as well as family members and control/comparison subjects, as appropriate. It will collect a common set of assessment data and measure target core symptom domains and associated features and comorbid conditions to better define the cohort. The Core will provide baseline evaluation to assess diagnostic eligibility and cognitive ability, perform a functional analysis, and characterize core symptomatology for inclusion in Projects I, II, and III. To accomplish its goals, Core B will utilize three clinical research sites and a genetic research site: the Seaver Autism Research Center at the Mount Sinai School of Medicine, the Cody Center for Autism and Developmental Disabilities at the State University of New York at Stony Brook, the Center for Autism in the North Shore-Long Island Jewish Health System, and the Family Genetic Studies Program at Mount Sinai.

binge eating disorder; comorbidity; mental disorder chemotherapy; human therapy evaluation; drug screening /evaluation; serotonin inhibitor; child psychology; children; depression; impulsive behavior; adolescence (12-20); obesity; sign /symptom; anxiety; self concept; obsessive compulsive disorder; behavioral /social science research tag; clinical research; human subject;

borderline personality disorder; human therapy evaluation; mental disorder chemotherapy; slow release drug; valproate; drug screening /evaluation; angers; clinical trials; aggression; behavioral /social science research tag; behavior test; human subject; clinical research;

chemosensitizing agent; thiazoles; human therapy evaluation; obsessive compulsive disorder; piperazines; mental disorder chemotherapy; drug screening /evaluation; antipsychotic agents; combination chemotherapy; serotonin inhibitor; drug tolerance; drug resistance; drug interactions; dosage; clinical trials; drug adverse effect; clinical research; human subject;

human therapy evaluation; psychopharmacology; psychopharmacologic agent; autism; drug screening /evaluation; child mental disorders; mental disorder chemotherapy; children; aggression; adolescence (12-20); child behavior; attention deficit disorder; clinical trials; impulsive behavior; mood disorders; behavioral /social science research tag; human subject; placebos; clinical research;

autism; health science research support; biomedical facility; therapy design /development; mental health education; mental disorder diagnosis; information dissemination; mental disorder chemotherapy; clinical research;

human therapy evaluation; mental disorder chemotherapy; drug screening /evaluation; adult human (21+); serotonin inhibitor; autism; placebos; clinical trials; behavioral /social science research tag; clinical research; human subject;

citalopram; Internet; psychopharmacology; compulsive behavior; drug screening /evaluation; mental disorder chemotherapy; human therapy evaluation; functional ability; adult human (21+); locus of control; clinical trials; social problems; behavioral /social science research tag; clinical research; human subject;

human therapy evaluation; mental disorder chemotherapy; drug screening /evaluation; valproate; child mental disorders; autism; children; adolescence (12-20); clinical trials; clinical research; placebos; human subject;

Abstract Not Provided.

community; obsessive compulsive disorder

Project Summary/Abstract Prader-Willi Syndrome (PWS) has been designated as a rare disease by the National Institutes of Health and is categorized as such with the NIH Office of Rare Diseases Research. [1]. Inclusion on this list requires a prevalence of less than 200,000 people in the United States. According to the Prader-Willi Syndrome Association USA and a review of the literature, current estimates of the prevalence of PWS range from 1: 8,000 ? 1: 30,000 with the most likely prevalence falling around 1 : 15,000 individuals [2-8]. Based on current U.S. Census data there are 317,434,622 people living in the U.S. Using the above prevalence estimates, the prevalence of PWS ranges from 10,581 to 39,679, and the most likely prevalence is approximately 21,000 Americans [9]. Using the most current available data from the U.S. Census (2010), there are 74,181,467 people in the pediatric population in the US (age < 18 years) [10]. Assuming that the prevalence of PWS falls between 1: 8,000 and 1: 30,000, there are currently between 2,473 and 9,273 people under age 18 with PWS. PWS is a rare neurodevelopmental disorder caused by lack of expression of paternally derived imprinted material on chromosome 15q11-q13. PWS is characterized by mild to moderate intellectual disabilities, repetitive/ compulsive behaviors and rigidity, social cognition deficits and severe hypotonia at birth, followed by the onset of hyperphagia later in life. Obesity is responsible for the majority of the morbidity and mortality associated with PWS, and compulsive eating behaviors are most responsible for diminishing the quality of life for caregivers and family members. Oxytocin has been implicated in the pathophysiology of PWS and there have been small studies of intranasal oxytocin (IN-OXT) in this population. To date, however, studies have not been adequately powered to detect significance in target symptoms of hyperphagia and associated symptoms of individuals with PWS. The overall goal of this proposal is to study the safety and efficacy of IN-OXT on hyperphagia as measured by the Revised Dykens Hyperphagia Questionnaire from baseline to week 8. Currently, there are no effective treatments available to manage hyperphagia in patients with PWS. Objective: The overall objective of this Phase 2 trial is to compare the change from baseline to week 8 of the peptide IN-OXT on changes on the Revised Dykens Hyperphagia Questionnaire in children with PWS. We have obtained an IND for the use of IN-OXT for PWS (IND 121109). We have acquired the IN-OXT and matching placebo (Manufactured by Novartis as Syntocinon - see letter and COA in appendix). This Phase 2 study is designed to generate preliminary data for future Phase 3 trials, and targets symptoms in this population that currently have no effective treatments. By treating these symptoms earlier in life in a pediatric PWS population, we may maximize the treatment impact. This study supports the Orphan Product Divisions goal of identifying and promoting the development of treatments indicated for a rare disease or condition. We propose a 3 year parallel, double-blind, randomized 8 week trial of IN-OXT vs. placebo in 50 children (stratified by gender; 25 male and 25 female) enrolled with PWS. Patients will receive a dose of 16 IU/day IN- OXT or placebo for 8 weeks. To allow for optimization for adverse events or lack of response, we allow for one downward titration to 12 IU, and one upward titration to 24 IU at week 2, respectively. Specific Aims: Primary: To compare IN-OXT vs. placebo on changes on the Revised-Dykens Hyperphagia Questionnaire from baseline to week 8 in children with PWS. We hypothesize that IN-OXT will be significantly superior to placebo in improving hyperphagia. Secondary: To compare the change from baseline to week-8 of IN-OXT vs. placebo on: 1. Repetitive Behavior Scale-Revised (RBS-R). 2. Weight, BMI (z-score) and Body composition via bioelectrical impedance analysis 3. World Health Organization Quality of Life Questionnaire (WHOQOL) 4. Salivary Oxytocin Concentration 5. Safety Analyses Exploratory: 1. To compare IN-OXT vs. placebo on changes in dietary intake using the ASA 24: Automated, Self- Administered, 24 hour Recall diet diary system, as provided by the National Cancer Institute (NCI). 2. To examine the impact of medical co-morbidities on treatment outcome. 3. To examine the relationship between weight-based dosing and treatment response on hyperphagia. 4. To compare IN-OXT vs. placebo on changes in hormone levels at baseline and endpoint. Measured hormones will include ghrelin, pancreatic polypeptide, peptide YY, GLP-1, insulin, glucagon, testosterone and estrogen. We will also look at changes in HbA1C.