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Dimensional predictors of response to sri pharmacotherapy in obsessive–compulsive disorder

Journal of Affective Disorders 121 (2010) 175–179 Contents lists available at Journal of Affective Disorders Dimensional predictors of response to SRI pharmacotherapy inobsessive–compulsive disorder Angeli Landeros-Weisenberger , Michael H. Bloch ,Ben Kelmendi Ryan Wegner Jake Nudel Philip Dombrowski Christopher Pittenger , John H. Krystal , Wayne K. Goodman ,James F. Leckman , Vladimir Coric a Yale Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, United Statesb Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, United Statesc Department of Psychiatry, University of Florida, 100 South Newell Drive, Suite L4-100, Gainesville, FL 32611, United States Background: Obsessive–compulsive disorder (OCD) is clinically heterogeneous. Previous Received 16 April 2008 studies have reported different patterns of treatment response to serotonin reuptake Received in revised form 8 June 2009 inhibitors (SRI) based on symptom dimension. Our objective was to replicate these results in Accepted 8 June 2009 OCD patients who participated in one of four randomized, placebo-controlled, clinical trials Available online 3 July 2009 (RCT).
Methods: A total of 165 adult OCD subjects participated in one or more eight-week RCT with clomipramine, fluvoxamine, or fluoxetine. All subjects were classified as having major or minor symptoms in four specific OC symptom dimensions that were derived in a previous factor Symptom dimensions analytic study involving many of these same patients. Ordinal logistic regression was used to Serotonin reuptake inhibitors test the association between OC symptom dimensions and SRI response.
Results: We found a significant association between the symptom dimension involving sexual,religious and harm-related obsessions as well as checking compulsions (AGG/SR) andimproved SRI response. This increased rate of SRI response was experienced primarily byindividuals with harm-related obsessions. Over 60% of patients with AGG/SR OCD symptomswere rated as very much improved after SRI treatment.
Limitations: As some of the RCTs included were conducted prior to the development of the Yale–Brown Obsessive–Compulsive Scale (Y–BOCS), improvement in OCD severity was assessedusing the Clinical Global Improvement (CGI) Scale. Data from the double-blind and open-labelcontinuation phases of these trials was collapsed together to increase statistical power.
Conclusions: Patients with OCD vary in their response to SRIs. The presence of AGG/SRsymptoms is associated with an initial positive response to SRIs. These data add to the growingbody of work linking central serotonin systems with aggressive behavior.
2009 Published by Elsevier B.V.
unwanted obsession thoughts). Since it was recognized as apsychiatric disorder, there have been many attempts to split Obsessive–compulsive disorder (OCD) is a neuropsychia- the heterogeneous symptomatology of OCD into more tric disorder characterized by obsessions (unwanted, recur- homogenous subtypes. For example in 1869, Falret made rent and distressing thoughts) and compulsions (repetitive the distinction between "Folie du doute" (madness of doubt) and ritual-like behaviors typically done in response to and "Delire du toucher" (delusions of touch) ). Despite these earlier efforts, mainstreamdiagnostic systems, such as DSM and ICD, have persisted in ⁎ Corresponding author. Tel.: +1 203 785 7683; fax: +1 203 785 6293.
describing OCD as a unitary category characterized by heterogeneous clinical manifestations ().
0165-0327/$ – see front matter 2009 Published by Elsevier B.V.
A. Landeros-Weisenberger et al. / Journal of Affective Disorders 121 (2010) 175–179 Planning for DSM-V in 2012 has led to the desire to study. Data from each of these trials was collected with incorporate a more dimensional approach to diagnostic permission from the Yale IRB.
entities. These dimensions should be consistent and replic-able. They should have validity and utility in predicting 2.2. Clinical measures treatment responses and outcome. These dimensions mayalso serve as more precise phenotypic markers for genetic and Subjects were assessed using the Clinical Global Improve- brain imaging studies. This approach may be particularly ment Scale (CGI) ), the Yale–Brown Obsessive useful in studying OCD, where over a dozen factor analytic Compulsive Scale (Y–BOCS) and the Hamilton Depression studies have identified four to five fairly consistent symptom Rating Scale.
dimensions of the disorder 2.3. Data analysis Each subject was asked to describe their major and minor OC symptoms based on the 15 categories that came to be the dimensions in OCD that have been consistently replicated headings of the Y–BOCS Symptom Checklist. Based on these across studies include: aggressive obsessions and checking answers, subjects were rated in the four previously described behavior (AGG), sexual/religious obsessions and compulsions OC symptom dimensions as having (SR), contamination obsessions and related washing obses- either no symptoms present in a particular dimension (coded sions (CW), obsessions with symmetry and exactness and as a 0), any symptoms present in a particular dimension ordering compulsions (SYM), and hoarding obsessions and (coded as 1) or predominant symptoms in a particular di- compulsions (HRD). The main disagreement between studies mension (the most impairing of the 4 dimensions, coded involving four and five factor solutions for OCD symptom as 2). In post-hoc analysis the AGG/SR dimension was divided dimensions is whether aggressive obsessions and checking into individuals with either harm-related or sexual/religious behavior (AGG) and sexual/religious obsessions and com- obsessions. The subjects who were much or very much pulsions (SR) should be combined into a single dimension improved after the medication trial (CGI = 1–2) were (AGG/SR) or two separate dimensions. We used a four factor classified as responders (coded as 2), subjects who were solution involving a combined AGG/SR dimensions as this minimally improved (CGI = 3) were considered partial factor analytic solution was derived from data involving responders (coded as 1), and subjects who showed no im- many of the same subjects included in this present sample provement or were worse (CGI = 4–7) were considered non- responders (coded as 0). Medication response was evaluated OCD symptom dimensions are temporally stable and have during the period where an individual got active medication been associated with distinct patterns of comorbidity ( in RCT, i.e. randomized placebo controlled period, patients ). Preliminary data suggest that where assigned to active medication or in open trial of med- these quantitative traits may be useful phenotypic markers ication following placebo assignment.
for genetic, neuroimaging, and treatment-outcome studies Association between SRI response and presenting OC . Specifically, HRD symptom dimensions was assessed using ordinal logistic symptoms also have been reported to be associated with regression. The subject's response to SRI medication was the poor Serotonin Reuptake Inhibitor (SRI) response in most dependent variable and each symptom dimension was entered into separate logistic regression models as the in- ) but not all studies ). In contrast, dependent variable.
AGG/SR symptoms have been associated with improved long- In exploratory analyses we examined the association be- term outcome (and with improved SSRI tween OC symptom dimensions or the presence of lifetime response at trend levels (on the other psychiatric conditions [Major Depression, Anxiety Disorders, hand, when parsing out the SR dimension Alonso et al. found Substance Abuse, Eating Disorders, and Tic Disorders] and a worse ). In this study we sought gender using forward stepwise binomial regression analysis to clarify the association between OCD these two symptom with the disorders as the dependent variable and the OC dimensions and response to SRI pharmacotherapy.
dimensions as the independent variables. We analyzed theassociation between age of onset of OCD symptoms and symptom dimensions using a stepwise linear regressionanalysis with age of onset as the dependent variable and OC symptoms as the independent variable. For all exploratorystepwise models a two-tailed significance level of 0.05 was Subjects were originally seen at the Yale OCD Clinic from set as the threshold for entry of terms and 0.10 for exclusion of 1982 to 1996 and diagnosed with OCD by an expert clinician.
Each subject received a trial of at least 1 of 3 SRI medications(fluoxetine, fluvoxamine, clomipramine) for at least 8 weeks at the maximum tolerated dose as part of 4 RCTs ). Since somepatients participated in more than one of these trials, only There were 165 subjects eligible for analysis that com- data from their initial SRI clinical trial was included in this pleted the trials. Sixty-two subjects were on clomipramine, 79

A. Landeros-Weisenberger et al. / Journal of Affective Disorders 121 (2010) 175–179 insufficient number of patients with prominent HRD symptoms Baseline demographics of 165 subjects who were treated with 1 of 3 Serotonin to assess this dimension statistically, although the highest Reuptake Inhibitors medications during double-blind clinical trials or open- percentage of SRI non-responders occurred in those with primary label extension period of those studies at the Yale Obsessive Compulsive symptoms in the HRD dimension (40% non-responders). There Disorder Clinic.
was a modest negative association between OC symptoms in the Baseline demographical and clinical characteristics SYM dimension (PE=−0.40±0.20, Wald=4.1, df=1, p=.04).
Clomipramine Fluvoxamine Fluoxetine The association between SYM symptoms and poor medication response was most suggestive in subjects receiving clomipramine (PE=−0.64±0.33, Wald=3.7, df=1, p=.06) but not SSRI medication (PE = −0.28±0.25, Wald=1.3, df =1, p=.26).
Neither CW (PE=0.01±0.170, Wald=0, df =1, p=.98) nor Comorbid diagnosisTics MISC (PE=−0.06±0.20, Wald=0.09, df=1, p=.76) symp- Major depression 67 (34%) toms were associated with a differential response to SRIs Anxiety disorders 3.3. Dimensional association with subject demographics We found that male gender was associated with having increased OC symptoms in the AGG/SR dimension (β=0.38± 0.18, Wald=4.3, df =1, p=0.039). When AGG/SR dimension was divided into two separate dimensions, only SR symptoms (β=0.97±0.28, Wald=12.2, df=1, pb0.001) and not AGG symptoms (β=−0.02±0.20, Wald=0.1, df=1, p=.91) wereassociated with male gender. Later age of onset of OCD symptoms Prominent OC symptom dimensionsCW was associated with CW symptoms (β=1.48±0.54, t=2.8, df =1, p=.007).
3.4. Dimensional associations with comorbid psychiatric illness When analyzing the association between lifetime history of psychiatric disorders and OC symptom dimensions, no associa- Y–BOCS: Yale–Brown Obsessive Compulsive Scale, HAM-D: Hamilton DepressionRating Scale, OCD symptom dimensions: CW: cleaning/contamination; AGG/ tions were found with Major Depression, Anxiety Disorders, SR=fear of harm, sexual and religious obsessions and checking compulsions (this Eating Disorders and Substance Abuse. However, the presence dimension is subdivided into AGG: fear of harm obsessions and checking of a comorbid Tic Disorder was associated with increased compulsions and SR: sexual and religious obsessions and compulsions in post- symptoms in the SYM (β=0.61±0.31, Wald=3.9, df =1, hoc analysis); HRD: hoarding and SYM: ordering, symmetry and arranging obsessions and compulsions.
on fluvoxamine and 24 on fluoxetine. Baseline demographicsof the sample are presented in 3.2. Dimensional predictors of SRI response The proportion of responders to SRI medication stratified by symptom dimension is depicted in The presence of AGG/SROC symptoms was associated with a good response to SRIs(parameter estimate [PE] = 0.42 ± 0.18, Wald = 5.6, df = 1,p=.018). When the result was stratified by particular pharma-cological agent utilized (clomipramine vs. a Selective SerotoninReuptake Inhibitor), there was a significant association of goodresponse for subjects with AGG/SR OC symptoms receiving SSRIpharmacotherapy (PE = 0.70 ±0.23, Wald = 9.6, df = 1,p=.002) but not clomipramine (PE=0.04±0.30, Wald=0.01,df =1, p=.91). When the results in this dimension were split intoindividuals with harm-related obsession and checking compul-sions (AGG) and those with sexual and religious obsession andcompulsions (SR), only AGG OC symptoms were associated withgood SRI response (parameter estimate [PE] = 0.68 ± 0.21, Fig. 1. Proportion of response to SRI based on CGI score and divided accordingto symptom dimension. OCD symptom dimensions: CW: cleaning/contam- Wald=10.1, df =1, p=.001). There was no evidence SR OC ination; AGG/SR = fear of harm, sexual and religious obsessions and checking symptoms were associated with SRI treatment response SR compulsions; HRD: hoarding and SYM: ordering, symmetry and arranging (PE=0.14±0.24, Wald=0.3, df =1, p=. 56). There was an obsessions and compulsions.
A. Landeros-Weisenberger et al. / Journal of Affective Disorders 121 (2010) 175–179 extension period) active treatment as part of this study toincrease our statistical power. Lastly, we used CGI scores to We found that OC symptoms in the AGG/SR symptom measure clinical outcome rather than Y–BOCS Scale.
dimension were associated with good response to SRIs in In our exploratory analyses, the SYM OCD symptoms were accordance to our a priori hypothesis. Sixty percent of OCD associated with a poor response to SRI treatment. Symptoms patients with predominant symptoms in the AGG/SR dimen- in the ordering/symmetry dimension were also associated sion were very much improved in response to SRI treatment.
with the presence of a comorbid tic disorder. This result is not Although no previous studies have demonstrated a significant surprising as several previous studies have demonstrated that association between AGG/SR OC symptoms and response to tic disorders are associated with ordering and symmetry OCD pharmacotherapy, there has been some evidence suggesting that this might be the case. A recent factor analysis study in The presence of a tic disorders has been associated with poor the OCD Consortium group showed there was a trend-level response to SRI pharmacotherapy in previous studies( association between good response to SRI pharmacotherapy and symptoms in the AGG/SR dimension ( The development of OCD severity scales specific to these AGG OC symptoms have also been associated with symptom dimensions should facilitate these efforts good long-term outcome in the Brown Longitudinal OCD ). Further studies are needed to extend study ). It should be noted that our results genetic, neuroanatomical understanding of these quantitative differed from which used similar phenotypes so that a better understanding of the hetero- methodology, but failed to show an association between SRI geneous symptoms of OCD. Understanding further the dif- response and symptoms in either the AGG or SR symptom ferences in treatment response in OCD patients presenting dimensions When stratifying by with different symptoms may help us to provide better treat- type of pharmacological agent, we found a significant as- ments and more accurate prognostic information to them.
sociation between the AGG/SR OC symptom dimension and agood pharmacological response in patients treated with SSRIs Role of funding source (fluoxetine and fluvoxamine), but not clomipramine. There No funding conflicts.
are two possible explanations for this finding — (1) there is abetter response to SSRIs within the AGG/SR OC symptom Conflict of interest dimension or (2) this finding is due to type I error.
The authors have no conflict of interests to report.
There exists significant basic science and clinical evidence to suggest that the former explanation may be correct. Studiesmeasuring serotonin metabolite levels (5-HIAA) in psychia- tric patients have associated low serotonergic brain activitywith hostile mood and aggressive behavior We wish to acknowledge the support and mentorship ). When SRI's are given to individuals without psychiatric from the APA/NIMH Psychiatry Minority Research Training illness they have been demonstrated to decrease negative Program (ALW). We also wish to acknowledge the support of affect and hostile tendencies ). Patients the National Institute of Mental Health support of the Yale with post-traumatic stress disorder (PTSD) not only have Child Study Center Research Training Program (MHB), the flashbacks and aggressive behavior, but they have a heigh- National Institutes of Health Loan Repayment Program (MHB, tened sense of threat, similar to what may be seen in OCD VC), the support of the Tourette's Syndrome Association Inc.
patients with symptoms in the AGG dimension. SSRIs are (MHB), the support of the Obsessive Compulsive Foundation currently the first-line pharmacological intervention for PTSD (VC), the National Alliance for Research on Schizophrenia and Depression Young Investigator Award 2005 (VC), and the logical to hypothesize that SSRI medications may be particu- support of the APA/Janssen Research Scholars Program larly effective in reducing the symptoms of OCD patients with (MHB), and the AACAP Pilot Research Award (MHB).
AGG/SR symptoms because they are additionally effective inreducing hostile tendencies and threat perception.
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CEU DO MONTREAL VISITOR'S GUIDELINES PREPARATION FOR A SANTO DAIME WORK . 2 CEU DO MONTREAL MISSION STATEMENT . 4 CODE OF ETHICS . 5 THE TENETS OF THE FAITH . 7 MEDICATION INFORMATION . 10 DIETARY INFORMATION . 14 VISITOR FORMS / GENERAL INFORMATION . 17 CÉU DO MONTRÉAL PREPARATION FOR A SANTO DAIME WORK Welcome. You are about to participate in what, for us, is the most sacred and profound experience that we can share with you. Enclosed are a few pages of practical suggestions to make your Work most comfortable. First, we would like to share with you something of the spiritual nature of this Work. The Daime offers an opportunity to align with the divine. Your bodies (physical, emotional, mental and spiritual) become open allowing access to and communion with spiritual energies, guides, healers, and teachers. It opens your consciousness, giving you the opportunity to experience love and truth at depths you may never have imagined. Within this space you will see and feel many things. Some will be very beautiful and some may be painful. The Daime opens you to what is highest and lowest in yourself. The purpose is to use the highest in you to transform the low. To a certain extent, each is not complete without the other. Know that whatever happens is for the highest good; we cannot transform and heal what we don't recognize as part of ourselves. Also know that, whatever you experience, you are not alone. There will be "guardians" (specially trained members of the Centre) to help you, and whether or not you can see them, spiritual guides and healers. 1. PRACTICAL GUIDELINES TO PREPARE FOR THE SPIRITUAL WORK FOOD: Most people prefer not to eat for several hours before a Work. What you choose to do will depend on your constitution. Eat lightly if you choose to eat; choose simple, fresh wholesome foods. For reasons of safety, certain foods and medications must be avoided or discontinued for prescribed time periods before and after ingesting the sacrament. (See drugs and foods to avoid in the sections MEDICATION INFORMATION and DIETARY INFORMATION). VISITOR'S ATTIRE: White clothes – women should wear a blouse or sweater with sleeves and skirt or dress, below knee-length. Men wear white pants and a long-sleeved shirt or sweater. Hair – wear your hair loose (no ponytails, braids, etc.) with the exception of barrettes. Shoes – again, white or light colored are ideal. Please don't wear red ones. For dancing Works, shoes should be comfortable and offer good support – you will be on your feet for many hours. For sitting Works, light shoes, slippers or socks work well. CLEANSING: It is helpful to cleanse on the physical, mental and emotional levels, in order to be more open on the spiritual level. This can be done through bathing, yoga, walking, praying, meditating, or whatever helps to center, ground and relax you. Part of the Centre's tradition is to be mindful of activities and habits for three days before a work and for three days following a work. Healthy self-care is important; please abstain from alcohol and drugs for several days before and after the Work.


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