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.
Given the small number of subjects reporting HRD
symptoms we were unable to replicate previous studies that
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Source: http://ocd.yale.edu/research/Landeros-Weisenberger%20et%20al%20(2010)%20Dimensional%20predictors%20of%20response%20to%20SRI%20pharmocotherapy%20in%20OCD_tcm329-114505_tcm329-284-32.pdf
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.
Research Children's Health Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure Shanna H. Swan,1 Katharina M. Main,2 Fan Liu,3 Sara L. Stewart,3 Robin L. Kruse,3 Antonia M. Calafat,4Catherine S. Mao,5 J. Bruce Redmon,6 Christine L. Ternand,7 Shannon Sullivan,8 J. Lynn Teague,9 and the Study for Future Families Research Team*