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Grant, JE

Leppink, EW

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Copyright 2016 American Medical Association. All rights reserved.5. Mollon J, David AS, Morgan C, et al. Psychotic experiences andneuropsychological functioning in a population-based sample. JAMA Psychiatry.2016;73(2):129-138.6. Gur RC. Prospective community studies linking cognitive deficits tosubclinical symptoms and a step toward precisionmedicine. JAMA Psychiatry.2016;73(2):109-110.HowSimilar Are theDisorders IncludedUnder theUmbrella of Obsessive-Compulsive Disorder andRelatedDisorders?To the Editor In JAMA Psychiatry, Grant and colleagues1 dem-onstrated the efficacy of N-acetylcysteine (NAC) in thetreatment of excoriation disorder (ED). The same group hadpreviously reported the benefits of NAC for adults withtrichotillomania (TTM).2 In both studies, NAC was used inmonotherapy in otherwise treatment-free patients. In theDSM-5, ED and TTM were included under the umbrella ofobsessive-compulsive disorder (OCD) and related disordersbecause of similarities regarding phenotypic expressionand common putative neurobiological underpinningsbetween these disorders and OCD. When used fortreatment-resistant OCD, NAC was not more effective thanplacebo as a selective serotonin reuptake inhibitor (SSRI)augmentation strategy.3In striking contrast withwhat we know about OCD, SSRIshave not been proved to be superior to placebo in TTMtreatment.2 As for ED, the evidence regarding the efficacy ofSSRIs is still scarce.1 So far, there are noUSFood andDrugAd-ministration–approved treatments for ED and TTM. The di-vergent results of the trials testing either SSRIs orNAC for ED/TTM and OCD suggest that treatments may not be usedinterchangeably between OCD and related disorders. Despitethepossiblemethodological issues related to thedesignof spe-cific trials, do such heterogeneous results regarding treat-ment response relate to heterogeneous neurobiology be-tween OCD and related disorders?Pathological grooming behaviors in animals are widelyused in the literature as a common animal model of ED/TTMand OCD. However, findings derived from animal studies donot always confirm the associationbetweengroomingbehav-ior andOCD.For example, nodifferenceswereobserved in theresults of themarble-burying test of rats with different levelsof grooming behavior.4In addition, results from genetic studies also suggestthat the neurobiology of pathological grooming may not benecessarily related to OCD. It had been demonstrated thatSapap3 knockout mice groomed themselves excessively.However, using family-based association analyses, Bienv-enu et al5 found that variation within the human equivalentof the Sapap3 gene appeared associated with ED/TTM, butnot with OCD.The conflicting results regarding the efficacy of NAC forED/TTM and OCD, in addition to the findings of translationalstudies, suggest that the neural basis of repetitive behaviorsobserved in patients with these disorders might not be thesame. So far, similarities between ED/TTM and OCD do notseem to go beyond the characterization by repetitive behav-iors and some degree of familial aggregation.Daniel L. C. Costa, MDJuliana Belo Diniz, MD, PhDEurípedes Constantino Miguel, MD, PhDAuthor Affiliations:Department and Institute of Psychiatry, University of SaoPaulo Medical School, Sao Paulo, Brazil.Corresponding Author: Eurípedes ConstantinoMiguel, PhD, Department andInstitute of Psychiatry, University of Sao Paulo Medical School, R Dr Ovídio Piresde Campos, 785. 05403-010 SP, Brazil (ecmiguel@usp.br).Published Online: July 13, 2016. doi:10.1001/jamapsychiatry.2016.1342.Conflict of Interest Disclosures:None reported.1. Grant JE, Chamberlain SR, Redden SA, Leppink EW, Odlaug BL, Kim SW.N-acetylcysteine in the treatment of excoriation disorder: a randomized clinicaltrial. JAMA Psychiatry. 2016;73(5):490-496.2. Grant JE, Odlaug BL, Kim SW.N-acetylcysteine, a glutamatemodulator, inthe treatment of trichotillomania: a double-blind, placebo-controlled study.Arch Gen Psychiatry. 2009;66(7):756-763.3. Costa DLC, Diniz JB, JoaquimM, et al. Serotonin reuptake inhibitoraugmentation with N-acetylcysteine in treatment-resistant obsessive-compulsive disorder: a double-blind randomized controlled trial. Biol Psychiatry.2015;77(9):63S.4. Reimer AE, de Oliveira AR, Diniz JB, Hoexter MQ, Chiavegatto S, BrandãoML. Rats with differential self-grooming expression in the elevated plus-mazedo not differ in anxiety-related behaviors. Behav Brain Res. 2015;292:370-380.5. Bienvenu OJ, Wang Y, Shugart YY, et al. Sapap3 and pathological grooming inhumans: results from the OCD Collaborative Genetics Study. Am JMed Genet BNeuropsychiatr Genet. 2009;150B(5):710-720.In ReplyCosta and colleagues raise important issues regardinghowgroomingdisorders (GDs) shouldbeoptimally treatedandclassified.N-acetylcysteine (NAC) showed superiority over placeboasmonotherapy in excoriationdisorder,1 similar to findings intrichotillomania. However, NAC’s findings in obsessive-compulsive disorder (OCD) are mixed. Two clinical trials re-ported significant benefits of NAC augmentation over pla-cebo forOCD,2,3while a third studydidnot showbenefits overplacebo.4 As Costa and colleagues suggest, differential phar-macological response across disorders is an important factorwhen considering diagnostic classification. This is also com-plicated by differences in study designs, as results may varywhenusingNACasaugmentation toaselectiveserotonin reup-take inhibitor rather than a primary intervention.A common link between GD and OCD is an appealing no-tion based on overt symptoms: these conditions are charac-terized by repetitive acts that are difficult to suppress. Thereis evidence for familial and comorbid overlap as well, butwhether this overlap is stronger than between GD and otherdisorders (eg, alcoholismorattention-deficit/hyperactivitydis-order) is less clear. Neuropsychological deficits in OCD span abroader range of domains than those identified in GD. Evenwithout these differences, the neurobiological underpin-nings may differ between disorders. Also, cognitive dysfunc-tion is heterogeneous evenwithin a given disorder: while pa-tient groups may manifest general cognitive deficits relativetocontrol groups, theseproblemsmaynotalwayspersistwhenassessed on an individual basis. The logical question then iswhether cognitive, imaging, or other markers could be usedto individualize treatment based on unique clinical features,possibly transdiagnostically.Lettersjamapsychiatry.com (Reprinted) JAMAPsychiatry August 2016 Volume 73, Number 8 877Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/935555/ by a CAMBRIDGE UNIVERSITY LIBRARY User  on 02/23/2017Copyright 2016 American Medical Association. All rights reserved.We agreewith the caveats by Costa et al regarding animalmodels of GD and OCD. In our experience, some animalmodels of OCD are in fact measuring excessive grooming,while other models of excessive grooming bear little facevalidity with human disorders, such as animals who exces-sively groom cage-mates, as opposed to themselves. Whilethese modalities may be beneficial in assessing widertrends, their utility in optimizing treatment based on indi-vidual traits may be more limited.We suggest that current diagnostic classification of GDis arbitrary but pragmatic given available evidence. Classify-ing GD with OCD in the DSM-5 encourages clinicians toscreen for relevant comorbidities and encourages researchto support or refute this conceptualization. Whether theInternational Statistical Classification of Diseases andRelated Health Problems, Eleventh Revision will adopt asimilar classification remains unclear because GDs are cur-rently listed in a separate category to OCD in the Interna-tional Statistical Classification of Diseases and Related HealthProblems, Tenth Revision. Despite possible neurobiologicalor cognitive distinctions, it may be beneficial to classify GDand OCD under a common heading based on similar symp-toms, given that not all clinicians have experience with GDand may conflate symptoms with OCD unless distinctguidelines are provided, as is often the case with disordersfalling under a common classification.Also of relevance here is the concept of behavioral addic-tion. In an animal model, NAC dampened the effects of co-caineonglutamate transporters in thenucleusaccumbensanddorsal striatum.5 Perhaps the beneficial effects of NAC in GDoccurat leastpartlyviaasimilarmechanism,an issuethatcouldbe explored further.Eric W. Leppink, BASamuel R. Chamberlain, MD, PhDJon E. Grant, JD, MD, MPHAuthor Affiliations:Department of Psychiatry and Behavioral Neuroscience,Pritzker School of Medicine, University of Chicago, Chicago, Illinois (Leppink,Grant); Department of Psychiatry, University of Cambridge, Cambridge, England(Chamberlain); Cambridge and Peterborough NHS Foundation Trust,Cambridge, England (Chamberlain).Corresponding Author: Jon E. Grant, JD, MD, MPH, Department of Psychiatryand Behavioral Neuroscience, Pritzker School of Medicine, University ofChicago, 5841 S Maryland Ave, MC 3077, Chicago, IL 60637 (jongrant@uchicago.edu).Published Online: July 13, 2016. doi:10.1001/jamapsychiatry.2016.1452.Conflict of Interest Disclosures:Dr Chamberlain reported being a paidconsultant for Cambridge Cognition, and his involvement was facilitated by agrant from the Academy of Medical Sciences. Dr Grant reported receiving grantU01MH076179 from the National Institute of Mental Health and research grantsfrom the National Center for Responsible Gaming, Forest Pharmaceuticals, andRoche Pharmaceuticals; yearly compensation from Springer Publishing foracting as editor in chief of the Journal of Gambling Studies; and royalties fromOxford University Press, American Psychiatric Publishing Inc, Norton Press, andMcGraw Hill. No other disclosures were reported.1. Grant JE, Chamberlain SR, Redden SA, Leppink EW, Odlaug BL, Kim SW.N-acetylcysteine in the treatment of excoriation disorder: a randomized clinicaltrial. JAMA Psychiatry. 2016;73(5):490-496.2. Afshar H, Roohafza H, Mohammad-Beigi H, et al. N-acetylcysteine add-ontreatment in refractory obsessive-compulsive disorder: a randomized,double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2012;32(6):797-803.3. Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S,Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind,placebo-controlled trial. J Clin Pharm Ther. 2016;41(2):214-219.4. Sarris J, Oliver G, Camfield DA, et al. N-acetyl cysteine (NAC) in the treatmentof obsessive-compulsive disorder: a 16-week, double-blind, randomised,placebo-controlled study. CNS Drugs. 2015;29(9):801-809.5. Ducret E, PuaudM, Lacoste J, et al. N-acetylcysteine facilitates self-imposedabstinence after escalation of cocaine intake [published online October 8,2015]. Biol Psychiatry. doi:10.1016/j.biopsych.2015.09.019.CORRECTIONOmittedStatisticalAnalysisDescriptionandErrors inFigure: In theOriginal In-vestigation titled “Whole-BodyHyperthermia for theTreatment ofMajorDepres-sive Disorder: A Randomized Clinical Trial,”1 published online May 12, 2016, therewas an omission in the Methods section and errors in Figure 2. The sentence de-scribing theCohend calculation in the Statistical Analysis subsectionof theMeth-ods section should have read as follows: “Cohen dwas calculated to assess effectsizes for between-group differences at all posttreatment points based onmeansandSDsderived from themixed-effectmodel.” Therewere also data errors in Fig-ure 2, which have been corrected, and the accompanying figure caption shouldhave read as follows: “The error bars indicate SEs. Means and SEs were derivedfrom the raw data provided in Table 2.” This article was corrected online.1. Janssen CW, Lowry CA, Mehl MR, et al. Whole-body hyperthermia for thetreatment of major depressive disorder: a randomized clinical trial [publishedonline May 12, 2016]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2016.1031.Letters878 JAMAPsychiatry August 2016 Volume 73, Number 8 (Reprinted) jamapsychiatry.comDownloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/935555/ by a CAMBRIDGE UNIVERSITY LIBRARY User  on 02/23/2017

How Similar Are the Disorders Included Under the Umbrella of Obsessive-Compulsive Disorder and Related Disorders?-Reply

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Comment and reply on Costa DLC, Diniz JB, Miguel EC. How Similar Are the Disorders Included Under the Umbrella of Obsessive-Compulsive Disorder and Related Disorders? JAMA Psychiatry. 2016;73(8):877., https://doi.org/10.1001/jamapsychiatry.2016.134

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