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Obsessive-Compulsive Disorder, Serotonin and Oxytocin

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Obsessive-Compulsive Disorder, Serotonin and Oxytocin Obsessive-compulsive disorder, serotonin and oxytocin To the memory of Börje Wistedt 1935 - 2014 my mentor in psychiatry always enthusiastic always generous and supportive The truth is rarely pure and never simple. Oscar Wilde 1854 - 1900 Örebro Studies in Medicine 148 MATS B. HUMBLE Obsessive-compulsive disorder, serotonin and oxytocin Treatment response and side effects Frontcover photo: Per Ölund: Tvångsmässiga tennisrörelser [Compulsive tennis movements], gouache (1988) Photo: Edith Humble Author portrait photo: Eva Henriks © Mats B. Humble, 2016 Title: Obsessive-compulsive disorder, serotonin and oxytocin: treatment response and side effects Publisher: Örebro University 2016 www.oru.se/publikationer-avhandlingar Print: Örebro University, Repro September/2016 ISSN 1652-4063 ISBN 978-91-7529-153-6 Abstract Mats B. Humble (2016): Obsessive-compulsive disorder, serotonin and oxytocin: treatment response and side effects. Örebro Studies in Medicine 148. Obsessive-compulsive disorder (OCD), with a prevalence of 1-2 %, fre- quently leads a chronic course. Persons with OCD are often reluctant to seek help and, if they do, their OCD is often missed. This is unfortunate, since active treatment may substantially improve social function and quality of life. Serotonin reuptake inhibitors (SRIs) have well- documented efficacy in OCD, but delayed response may be problematic. Methods to predict response have been lacking. Because SRIs are effec- tive, pathophysiological research on OCD has focussed on serotonin. However, no clear aberrations of serotonin have been found, thus other mechanisms ought to be involved. Our aims were to facilitate clinical detection and assessment of OCD, to search for biochemical correlates of response and side-effects in SRI treatment of OCD and to identify any possible involvement of oxytocin in the pathophysiology of OCD. In study I, we tested in 402 psychiatric out-patients the psychometric properties of a concise rating scale, “Brief Obsessive Compulsive Scale” (BOCS). BOCS was shown to be easy to use and have excellent discrimi- nant validity in relation to other common psychiatric diagnoses. Studies II-V were based on 36 OCD patients from a randomised con- trolled trial of paroxetine, clomipramine or placebo. In study II, contrary to expectation, we found that the change (decrease) of serotonin in whole blood was most pronounced in non-responders to SRI. This is likely to reflect inflammatory influence on platelet turnover rather than serotonergic processes within the central nervous system. In studies IV-V, we found relations between changes of oxytocin in plasma and the anti-obsessive response, and between oxytocin and the SRI related delay of orgasm, respectively. In both cases, the relation to central oxytocinergic mechanisms is unclear. In males, delayed orgasm predicted anti-obsessive response. Keywords: Adverse effects, Obsessive-compulsive disorder, Orgasm, Oxytocin, Randomised controlled trial, Rating scale, Response prediction, Serotonin, Serotonin uptake inhibitors, Sexual function. Mats B. Humble, Faculty of Medicine & Health, School of Medical Sciences, Örebro University, SE-701 82 Örebro, Sweden, e-mail: [email protected] Table of Contents LIST OF PAPERS ..................................................................................... 11 LIST OF ABBREVIATIONS .................................................................... 12 PREFACE................................................................................................. 14 1 INTRODUCTION ................................................................................ 18 1.1 Obsessive-compulsive disorder – a brief presentation ......................... 18 1.2 History of OCD concept .................................................................... 19 1.3 Diagnostic definition of OCD ............................................................ 20 1.3.1 Delineations of OCD versus other disorders ............................... 20 1.3.2 Diagnostic criteria and classification of OCD ............................. 21 1.4 Many approaches to subtyping OCD ................................................. 22 1.4.1 Obsessions versus compulsions ................................................... 22 1.4.2 With versus without tics .............................................................. 22 1.4.3 Poor insight, schizotypal, autistic dimension ............................... 23 1.4.4 Early versus late onset ................................................................. 23 1.4.5 OCD “Dimensions” .................................................................... 23 1.4.6 OCD due to inflammation .......................................................... 24 1.5 Aetiology and pathophysiology of OCD ............................................ 24 1.5.1 Genetic and environmental factors .............................................. 24 1.5.2 Brain imaging: morphology, circuits and function ...................... 25 1.5.3 Neurochemistry and psychopharmacology ................................. 25 1.5.3.1 The serotonin hypotheses ......................................................... 25 1.5.3.1.1 Clomipramine efficacy in OCD – unique at the time ........ 25 1.5.3.1.2 The SSRIs – heirs of clomipramine in OCD treatment ...... 27 1.5.3.1.3 Measurements of serotonin ............................................... 28 1.5.3.1.4 But is there a serotonin deficiency in OCD? ...................... 29 1.5.3.2 Glutamate ................................................................................ 31 1.5.3.3 Oxytocin and other peptides .................................................... 32 1.5.4 Neuro-inflammation: autoimmune reactions, infections ............. 33 1.6 Clinical management of OCD and its obstacles ................................. 33 1.6.1 Patient identification and recognition ......................................... 33 1.6.2 Rating scales for use in psychiatric disorders .............................. 35 1.6.3 Specific rating scales for OCD..................................................... 36 1.6.3.1 Early OCD scales .................................................................... 36 1.6.3.2 The Y-BOCS and its derivatives ............................................... 37 1.6.3.3 The need of alternative scales ................................................... 38 1.6.4 Psychological OCD treatment – cognitive behavioural therapy ... 38 1.6.5 Pharmacotherapy for OCD – present recommendations ............. 39 1.6.6 Other OCD treatments ................................................................ 40 1.6.7 Side effects and their possible utility ............................................ 40 1.6.7.1. Side effects versus adverse effects ............................................ 40 1.6.7.2 Potential pathophysiological significance of side effects ........... 41 1.6.8 Treatment response and treatment resistance .............................. 42 1.6.8.1 Treatment response definitions ................................................ 42 1.6.8.2 Non-response and treatment resistance .................................... 42 1.6.9 Problems in current management and understanding of OCD .... 43 1.6.9.1 Under-recognition of OCD in clinical practice......................... 43 1.6.9.2 Response prediction ................................................................. 43 1.6.9.3 Adverse effect burden ............................................................... 44 1.6.9.4 Biochemical targets of medications .......................................... 45 2 AIMS ..................................................................................................... 47 2.1 General aims ...................................................................................... 47 2.2 Development of a clinically useful rating instrument .......................... 47 2.3 Treatment response prediction with biochemical measures ................ 48 2.4 Clues to SRI mechanisms and OCD pathophysiology ........................ 49 3 METHODS ........................................................................................... 50 3.1 Patients ............................................................................................... 50 3.1.1 Subjects for paper I ..................................................................... 50 3.1.2 Common cohort for paper II-V ................................................... 51 3.2 Diagnostics and rating scales used ...................................................... 52 3.2.1 Diagnostic methods ..................................................................... 52 3.2.2 General functioning/severity measures ........................................ 53 3.2.3 OCD scales used ......................................................................... 53 3.2.3.1 Y-BOCS ................................................................................... 53 3.2.3.2 NIMH-GOCS .......................................................................... 53 3.2.4 Depression scale used .................................................................. 54 3.2.5 Scale for evaluation of autistic traits ........................................... 54 3.2.6 Sexual functions scales ................................................................ 54 3.2.6.1 The Limited symptom checklist and the Sexual symptom checklist (SSCL) ................................................................................... 54 3.2.6.2 Comparison of the SSCL with the ASEX scale ......................... 55 3.2.7 Definitions
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