Journal of Affective Disorders 94 (2006) 199 – 209
www.elsevier.com/locate/jad
Research report
Clinical features associated to refractory
obsessive–compulsive disorder
Ygor A. Ferrão a,b,c,⁎, Roseli G. Shavitt a,b,c , Nádia R. Bedin c,d ,
Maria Eugênia de Mathis b,c , Antônio Carlos Lopes a,b,c , Leonardo F. Fontenelle c,e ,
Albina R. Torres c,f , Eurípedes C. Miguel a,b,c
a
Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil
Psychiatric Institute Obsessive-Compulsive Spectrum Program (PROTOC), São Paulo, Brazil
c
Brazilian Consortium on Obsessive-Compulsive Spectrum Research (CTOC), Brazil
d
Psychiatric Service, Presidente Vargas Hospital, Porto Alegre, Brazil
e
Institute of Psychiatry of the Federal University of Rio de Janeiro, Brazil
Department of Neurology and Psychiatry, Botucatu Faculty of Medicine-UNESP, São Paulo State University, Brazil
b
f
Received 5 December 2005; received in revised form 4 April 2006; accepted 10 April 2006
Available online 9 June 2006
Abstract
Some patients with obsessive–compulsive disorder (OCD) exhibit an unsatisfactory reduction in symptom severity despite
being treated with all the available therapeutic alternatives. The clinical variables associated with treatment-refractoriness in OCD
are inconsistently described in the literature.
Methods: To investigate factors associated with treatment-refractoriness of patients with OCD, we conducted a case-control study,
comparing 23 patients with treatment-refractory OCD to 26 patients with treatment-responding OCD.
Results: The factors associated with refractoriness of OCD were higher severity of symptoms since the onset of OCD (p < 0.001),
chronic course (p = 0.003), lack of a partner (p = 0.037), unemployment (p = 0.025), low economic status (p = 0.015), presence of
obsessive–compulsive symptoms of sexual/religious content (p = 0.043), and higher scores on family accommodation (p < 0.001).
Only the three latter variables remained significantly associated with treatment-refractoriness after regression analyses. Limitations:
small sample size, the biases and drawbacks inherent to a case-control study, and the inclusion criteria used to define the study
groups may have limited the generalisation of the results.
Conclusion: A major strength of this study is the systematic and structured evaluation of a vast array of variables related to the
clinical expression of OCD, including epigenetic factors and ratings derived from instruments evaluating family accommodation.
The presence of sexual/religious symptoms, low economic status and high modification on family function due to OCD were
independently associated with treatment-refractoriness. Future longitudinal studies are warranted to verify if these variables
represent predictive factors of treatment non-response.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Obsessive–compulsive disorder; Treatment response; Predictive factors
1. Introduction
⁎ Corresponding author.
E-mail address: ygoraf@terra.com.br (Y.A. Ferrão).
0165-0327/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2006.04.019
Despite the proven effectiveness of cognitive-behavioural therapy (CBT) and selective serotonin reuptake
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Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
inhibitors (SSRIs) in the treatment of obsessive–
compulsive disorder (OCD), trials employing these
two treatment strategies have demonstrated, respectively, inadequate responses in approximately 20% (Piacentini et al., 2002; The Pediatric OCD Treatment Study
(POTS) Team, 2004) and 40% (DeVaugh-Geiss et al.,
1990; Jenike and Rauch, 1994; Pallanti et al., 2002) of
OCD patients. Factors that have been associated with
poor response to treatment in OCD include sexual/
religious obsessions (Alonso et al., 2001; Mataix-Cols et
al., 2002a,b), hoarding (Black et al., 1998; Saxena et al.,
2002), psychiatric comorbidity (Minichello et al., 1987;
McDougle et al., 1990; Baer, 1994; Mundo et al., 1995;
Shavitt et al., in press), poor insight (Neziroglu et al.,
1999; Erzegovesi et al., 2001), early onset and chronic
course of obsessive–compulsive (OC) symptoms (Ackerman et al., 1994; Ravizza et al., 1995; Skoog and
Skoog, 1999; Rosario-Campos et al., 2001; Erzegovesi
et al., 2001; Fontenelle et al., 2003), absence of sensory
phenomena and greater symptom severity (Hollander et
al., 2002; Shavitt et al., in press), lack of family history
(Erzegovesi et al., 2001), and family involvement in the
OC symptoms (Guedes, 1997; Steketee et al., 1999;
Steketee and VanNoppen, 2003). This study aimed to
identify intrinsic clinical characteristics to the phenotypic expression of OCD (such as content and formal
aspects of OC symptoms, as well as OCD course and
patterns of co-morbidity) and other factors regarding
demography, epigenetic factors and family history, as
well as aspects of family functioning, that could be
associated with OCD patient refractoriness to treatment.
2. Methods
Patients with OCD according to DSM-IV criteria
(American Psychiatric Association, 1994) were consecutively recruited from three Brazilian treatment reference centres (1) the Obsessive–Compulsive Spectrum
Disorders Clinic of the Hospital Presidente Vargas
(n = 36), (2) the Anxiety Disorders Clinic of the
Universidade Federal do Rio Grande do Sul Hospital
das Clínicas (n = 6); and (3) the OCD clinic of the
Universidade de São Paulo Hospital das Clinicas
Institute of Psychiatry (n = 7). The first two centres are
located in the city of Porto Alegre, and the third is in the
city of São Paulo. The distribution of the patients in each
group did not differ in terms of the recruitment site
(χ2 = 4.23; df = 1, p = 0.12). Inclusion criteria were (1)
age between 18 and 65 years, (2) OCD as the most
significant current psychiatric diagnosis, (3) absence of
general medical or neurological diseases. Prior to being
enrolled in the study, which was carried out in
accordance with the latest version of the Declaration
of Helsinki, all patients gave written informed consent,
which was approved by the local ethics committees.
Jenike and Rauch (1994) used the terms “treatmentresistant” to describe individuals with OCD who do not
respond satisfactorily to any first-line therapy and
“treatment-refractory” to refer to those patients with
OCD who, despite being treated with all available
therapeutic alternatives, do not present a satisfactory
reduction in symptom severity. To study possible factors
associated with treatment-refractory OCD, two welldefined and operational sub-groups were compared: one
composed of OCD patients who were refractory to
conventional treatments and the other of patients with
OCD who had been shown to be treatment responders.
In this case-control study, patients with treatmentrefractory OCD (refractory group) were defined by the
following criteria: (1) a decrease of less than 25% in the
initial Yale-Brown Obsessive Compulsive Scale
(YBOCS) score or a less than minimal improvement
on the Clinical Global Impressions (CGI) scale after
treatment with first-line drugs for at least 16 weeks each.
First-line drugs, according to March et al. (1997), are
clomipramine (maximum recommended dose [MRD] of
300mg/day), fluoxetine (MRD of 80mg/day), fluvoxamine (MRD of 300 mg/day), sertraline (MRD of
250mg/day), paroxetine (MRD of 60mg/day), citalopram (MRD of 60mg/day); (2) at least three therapeutic
trials with first-line drugs (necessarily including clomipramine), at maximum recommended or tolerated doses,
for 16 weeks each; (3) at least two pharmacological
augmentation strategies (including other SSRIs or
neuroleptics); and (4) at least 20 h of Cognitive and
Behaviour Therapy (CBT) (exposure and response
prevention). Subjects were considered treatment-responsive OCD patients (responder group) if, after
treatment with any conventional therapy (not necessarily the first trial with a SRI or CBT), they presented at
least a 35% decrease in the initial YBOCS score, were
rated “better” or “much better” on the CGI scale, and
had maintained improvement for at least 1 year. The
refractory group consisted of 23 patients, and the
responder group consisted of 26.
2.1. Assessment
The instruments were administered by two experienced psychiatrics, one of whom was always present at
either sites (YAF and NRB in Porto Alegre and YAF and
MEM or ACL in São Paulo). Whenever possible the
raters were blinded as to the treatment response status
(with the exception of three patients who had to be
Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
interviewed at home because of the severity of their
symptoms).
To investigate the intrinsic clinical characteristics to
the phenotypic expression of OCD, the following
structured instruments were employed: (1) the YBOCS
and its Symptom Checklist for the assessment of
severity and content of obsessions and compulsions
(Goodman et al., 1989a,b). (2) The Dimensional
YBOCS (DYBOCS). This instrument measures the
severity for each of six symptom dimensions (contamination/cleaning, hoarding, symmetry, aggressive, sexual/religious, and miscellaneous). Innovative features
include the joint consideration of obsessions and
compulsions in assessing the severity of each domain,
separation of specific forms of checking, division of
repetition and mental rituals into discrete dimensions,
and inclusion of avoidance in measurements of severity.
This instrument has recently been validated (RosarioCampos et al., 2006). (3) The 14-item Hamilton Anxiety
scale (HAM-A) and the 21-item Hamilton Depression
scale (HAM-D) (Hamilton, 1959; Hamilton, 1967). (4)
The Medical Outcomes Study 36-Item Short-Form
Health Survey (MOS SF-36), a self-report instrument
with 36 questions, divided into eight dimensions
reflecting quality of life (Ware and Gandek, 1998). (5)
The Structured Clinical Interview for DSM-IV Axis I
Disorders (First et al., 1997), including a section on
Impulse Control Disorders not classified elsewhere. (6)
The Structured Interview for DSM-IV Personality
Disorders (Pfohl et al., 1997), applied by at least two
interviewers, who later reach a consensus. (7) The Yale
Global Tic Severity Scale (YGTSS), for the assessment
of vocal and motor tics (Leckman et al., 1989). (8) The
Brown Assessment of Beliefs Scale (BABS), which
measures patient conviction and insight about the
obsessions (Eisen et al., 1998). (9) A self-report
instrument that consists of five visual analogical scales
with possible OCD course types (under request). Two of
them express intermittent (symptoms waxing-and-waning) course and other 3, chronic course of obsessive–
compulsive symptoms. It is part of The Structured
Interview for Socio-demographic data, developed at the
(PROTOC-USP) OCD Clinic (available upon request).
(10) The Psychiatric State Rating (PSR), which
measures the severity of OC symptoms during four
disease states (sub-clinical OC symptoms, clinical OC
symptoms, the worse episode of OC symptoms and the
current episode of OC symptoms). It also collects
information about onset of OC symptoms (abrupt or
insidious) (Keller et al., 1987). (11) The USP-Harvard
Repetitive Behavior Interview (Miguel et al., 1997). To
study other features related to demographic and
201
epigenetic factors, as well as to family history and
functioning (extrinsic variables), the following instruments were also used. (12) The Structured Interview for
Socio-demographic data, developed at the (PROTOCUSP) OCD Clinic. This instrument was designed to
gather information about marital, educational, occupational and socio-economic status (the socio-economic
classification in Brazil is based upon the consideration
of economic characteristics of products and services as
well as social standing (such as profession and
education) ranging from class A, which includes the
higher managerial and professional occupations, to class
E, which includes nonworkers and routine occupations);
family history; epigenetic factors; medical history and
previous psychiatric treatments (details available upon
request). (13) The Family Accommodation Scale (FAS)
(Calvocoresi et al., 1995), which assesses family
accommodation of the OCD patient symptoms, family
distress and patient reactions to family member
resistance to accommodation. A family member was
interviewed for this and also for family history and
epigenetic factors checking.
2.2. Statistical analysis
The Student's t-test or the Mann–Whitney test was
used to compare continuous variables, which were
tested for homogeneity of variance. The chi-square test
with Yates' correction or Fisher's exact test was used to
compare categorical variables. Two stepwise logistic
regressions were employed to identify factors independently associated with refractoriness, controlling for
possible confounding factors. Variables with a p value of
0.10 or less in the univariate analysis were incorporated
into the models. The first model included aspects
directly related to the phenotypic expression of OCD
(intrinsic variables), and the second included aspects not
directly related to such expression (extrinsic variables)
but deemed relevant for clinical practice. The level of
statistical significance adopted was 5%. The Statistical
Package for Social Sciences for Windows, version 10.0
(SPSS 10.0) was employed.
3. Results
3.1. General clinical variables
General demographic data of the patients with OCD
are shown in Table 1. Patients from the refractory group
were more frequently single, more often unemployed,
and tended to be of lower educational and socioeconomic status.
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Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
Table 1
Comparison of demographic variables between refractory and respondent Obsessive–Compulsive Disorder (OCD) groups
Male
Caucasian
Marital status (no spouse)
Occupation (unemployed)
Socio-economic classification
Class A
Class B
Class C
Class D
Current age
Education level
Refractory (n = 23)
n (%)
Responder (n = 26)
n (%)
12 (52.2)
21 (91.3)
18 (78.3)
14 (60.9)
Analysis
χ2 Yates
P
10 (38.5)
24 (92.3)
5 (19.2)
6 (23.1)
0.46
⁎
6.62
5.04
0.499
1.00
0.037
0.025
1 (4.3)
5 (21.7)
14 (60.9)
3 (13.0)
2 (7.7)
13 (50.0)
11 (42.3)
0 (0.0)
⁎⁎
0.015
Mean (S.D.)
Mean (S.D.)
t
P
35.22 (10.74)
Median (25% and 75% quartile)
4 (2;6)
41.35 (11.45)
Median (25% and 75% quartile)
6 (4;7)
1.918
U
204.5
0.061
P
0.054
⁎Fisher's exact test; ⁎⁎Mann–Whitney U = 189,50; S.D., standard deviation.
3.2. Previous psychiatric treatments
As expected from the selection criteria, more patients
in the refractory group had received CBT (100% versus
73% in the responder group; Fisher's exact test,
p = 0.011), had been hospitalised (65% versus 23% in
the responder group; χ2 = 7.21, df = 1, p = 0.007), and
had been submitted to electroconvulsive therapy (17%
versus 3.8% in the responder group; Fisher's exact test,
p = 0.17), although it is not recommended for OCD,
unless a refractory and severe major depression appears
in comorbidity with it.
All patients had at least one trial with a serotonergic
antidepressant. Twenty-two (96%) individuals in the
refractory group and 12 (46%) in the responder group
had used antipsychotics (Fisher's exact test, p < 0.001),
17 (74%) in the refractory group and 8 (31%) in the
responder group had used mood stabilizers (χ2 = 9.09,
df = 1, p = 0.004), 14 (61%) in the refractory group and 7
(27%) in the responder group had used tricyclics
antidepressants (χ2 = 5.74, df = 1, p = 0.022).
3.3. Symptom severity
The mean and standard deviation (S.D.) were
calculated for each YBOCS score. The mean total
YBOCS score for the refractory group was 27.82 (S.D.,
6.09), compared with 17.42 (S.D., 7.74) for the
responder group (t = 5.03, p < 0.001). The mean
YBOCS obsession subscale score was 13.64 (S.D.,
2.98) for the refractory group and 8.67 (S.D., 4.47) for
the responders (t = 4.39, p < 0.001). The mean YBOCS
compulsions subscale score was 14.18 (S.D., 4.00) for
the refractory group and 8.75 (S.D., 4.29) for the
responder group (t = 4.43, p < 0.001). The mean
DYBOCS total score for the refractory group was
21.65 (S.D., 4.26) and for the responder group it was
14.69 (S.D., 4.42) (t = 5.60, p < 0.001). Mean anxiety and
depression symptom scores were also higher for the
refractory group: HAM-A = 13.7 (S.D., 5.37) versus 7.54
(S.D., 4.72) for the responder group (t = 4.27, p < 0.001),
and HAM-D = 13.3 (S.D., 5.21) versus 6.89 (S.D., 3.77)
for the responder group (t = z4.98, p < 0.001).
3.4. Quality of life
Mean quality of life scores, as assessed by the MOS
SF-36, were lower for the refractory group than for the
responder group in three dimensions: vitality = 36.91 (S.
D., 21.99) versus 54.61 (S.D., 18.27) (t = 3.02,
p = 0.004); social aspects = 37.50 (S.D., 24.04) versus
68.85 (S.D., 21.26) (t = 4.74, p < 0.001); and mental
health = 33.91 (S.D., 16.13) versus 57.54 (S.D., 16.08)
(t = 5.00, p < 0.001).
The findings described above, in addition to further
validating the entry criteria used for the refractory group,
reflect the general severity of OCD and accompanying
features, as well as their impact on the patients' lives.
3.5. Clinical variables directly related to OCD
phenotypic expression (intrinsic variables)
Content and formal aspects of OC symptoms,
patterns of co-morbidity, insight, age at onset of OC
symptoms, course of OC symptoms, and duration of
OCD are shown in Tables 2–4. A comparison of the
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Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
Table 2
Obsessive–compulsive symptoms sub-types according to the YaleBrown Obsessive–Compulsive Scale (YBOCS) and Dimensional
Yale-Brown Obsessive–Compulsive Scale (DYBOCS)
YBOCS–Obsessions of
Aggression
Contamination
Sexual content
Hoarding
Religiosity
Symmetry
Somatic content
Other contents
Refractory
n (%)
Responders
n (%)
Analysis
χ2 Yates
P
20 (95.2)
16 (76.2)
8 (38.1)
5 (23.8)
11 (52.4)
15 (71.9)
9 (42.9)
21 (100.0)
19 (76.0)
17 (68.0)
9 (36.0)
9 (36.0)
15 (60.0)
14 (56.0)
11 (44.0)
21 (84.0)
⁎
0.08
0.03
0.33
0.05
0.60
0.05
⁎
0.11
0.775
0.87
0.566
0.825
0.44
0.825
0.11
17 (68.0)
23 (92.0)
18 (72.0)
7 (28.0)
13 (52.0)
9 (36.0)
21 (84.0)
0.43
⁎
⁎
0.55
0.10
0.33
⁎
0.51
0.22
0.31
0.457
0.747
0.566
0.36
18 (81.8)
15 (57.7)
1.27
0.26
16 (72.7)
10 (38.5)
4.11
0.043
18 (81.8)
19 (73.1)
0.00
1.00
19 (86.4)
16 (61.5)
⁎
0.202
5 (22.7)
10 (38.5)
0.34
0.559
20 (90.9)
20 (76.9)
⁎
0.472
a
YBOCS–Compulsions of a
Cleaning/washing
17 (80.9)
Checking
16 (76.2)
Repeating
18 (85.7)
Counting
9 (42.9)
Ordering/arranging
9 (42.9)
Hoarding
5 (23.8)
Other contents
20 (95.2)
DYBOCS b
Aggression
dimension
Sexual/religious
dimension
Symmetry/order
dimension
Contamination/
cleaning dimension
Hoarding
dimension
Other contents
dimension
⁎Fisher Test.
a
Refractory group (n = 21) and Respondent group (n = 25).
b
Refractory group (n = 22) and Respondent group (n = 26).
content of OC symptoms is presented in Table 2. We
found a statistically significant difference between the
two groups only for sexual/religious content of OC
symptoms, which, according to the DYBOCS symptom
checklist, was exhibited more frequently in the refractory group (p = 0.043). As can be seen in Table 3, there
were no differences between the two groups regarding
psychiatric co-morbidities (Axis I or Axis II) or the
mean number of Axis I co-morbidities.
After the period of time between the age of
obsessive–compulsive symptoms onset and the first
adequate OCD treatment, all the patients were continuously treated. In spite of the adequate treatment they
have received, Table 4 shows a higher frequency of
chronic course for the refractory group, in opposition of
an episodic course for responding group. The patients of
responding group, after the adequate OCD treatment,
continued to show residual symptoms, but with a much
lower severity and level of morbidity. Table 4 also
shows an earlier age at first OCD treatment for the
refractory group. The time interval between the age at
OC symptoms onset and the initial treatment tended to
be shorter in the refractory group.
According to the PSR assessment, when the OC
symptoms were sub-clinical (no interference or distress), there was only a trend for a higher symptom
severity among refractory patients (t = 1.75, p = 0.086).
When OC symptoms were discomfiting and interfered
Table 3
DSM-IV Axis I and II diagnoses in the refractory and responder OCD
groups
Refractory
(n = 23)
Responder
(n = 26)
Analysis
n (%)
n (%)
χ2 Yates P
4 (15.4)
0 (0.0)
1 (3.8)
17 (65.4)
12 (46.2)
4 (15.4)
5 (19.2)
4 (15.4)
2 (7.7)
1 (3.8)
⁎
⁎
⁎
0.11
0.04
⁎
⁎
⁎
⁎
⁎
0.716
0.215
1.00
0.737
0.836
1.00
0.194
0.67
0.655
0.594
0 (0.0)
4 (15.4)
⁎
⁎
0.096
1.00
1 (3.8)
⁎
1.00
1 (3.8)
3 (11.5)
8 (30.8)
4 (15.3)
3 (11.5)
1 (3.8)
1 (3.8)
0 (0.0)
1 (3.8)
8 (30.8)
3 (11.5)
1 (3.8)
4 (15.4)
⁎
⁎
0.08
⁎
⁎
⁎
⁎
⁎
⁎
0.39
⁎
⁎
⁎
0.173
0.608
0.775
1.00
0.612
0.594
1.00
0.469
1.00
0.533
0.692
0.33
1.00
14 (53.8)
1.93
0.165
Mean
(S.D.)
t
P
Substance abuse
5 (21.7)
Schizophrenia
2 (8.7)
Bipolar disorder
0 (0.0)
Major depression
17 (73.9)
Anxiety disorders
9 (39.1)
Social phobia
3 (13.0)
Simple phobia
1 (4.3)
Panic/agoraphobia
2 (8.7)
Generalised anxiety
3 (13.0)
Post-traumatic stress
2 (8.7)
disorder
Eating disorders
3 (13.0)
Tricothilomania/skin
4 (17.4)
picking
Attention deficit/
0 (0.0)
hyperactivity disorder
Tourette syndrome
4 (17.4)
Other tics disorder
1 (4.3)
Personality disorders
7 (31.8)
Cluster A
3 (13.05)
Paranoid
1 (4.35)
Schizoid
2 (8.70)
Cluster B
1 (4.35)
Histrionic
1 (4.35)
Narcissistic
0 (0.0)
Cluster C
10 (43.5)
Avoidant
4 (17.4)
Dependent
3 (13.04)
Obsessive–
3 (13.04)
compulsive
Any psychiatric
17 (77.3)
comorbidity
Mean
(S.D.)
Number of axis I
comorbidities
2.41 (1.26) 1.92 (1.20) 1.372
⁎Fisher Test; S.D., standard deviation.
0.177
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Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
Table 4
Comparison of insight, course, age at onset and duration of illness
between refractory and respondent obsessive–compulsive patients
Chronic course
a
which included pregnancy-related events, emotional
problems, excessive caffeine consumption, smoking,
use of alcohol or illicit drugs during pregnancy,
childbirth site (in a hospital or not), childbirth type
(caesarean operation or not), forceps use, premature
birth, birth weight, and medical occurrences during or
after childbirth.
Refractory
(n = 22)
Responder
(n = 26)
Analysis
n (%)
n (%)
χ2 Yates P
10 (47.6)
1 (4.2)
⁎
0.0027
Mean
(S.D.)
Mean
(S.D.)
t
P
3.7. Family functioning
0.55
1.52
0.92
0.587
0.135
0.361
3.32
0.002
1.76
0.085
In the FAS evaluation, the refractory group presented
the following: a higher family accommodation index
(FAI) rate, with a median of 20 versus 6.5 for the
responder group (U = 64.5, p < 0.001); a higher family
distress index (FDI) rate, with a mean of 3.29 (S.D.,
2.83) versus 1.27 (S.D., 0.92) for the responder group
(t = 3.42, p < 0.001); and higher scores for patient
consequences (anxiety, aggressiveness, and slowness)
if family members did not participate in the OC
symptoms, with a mean of 5.24 (S.D., 3.00) versus
3.31 (S.D., 2.62) for the responder group (t = 2.36,
p = 0.023). There was a positive correlation between FAI
and YBOCS severity scores (r = 0.71, p < 0.001) and
between FDI and YBOCS scores (r = 0.50, p < 0.001).
The correlation between the FAI (r = − 0.0013, p = 0.931)
and the FDI (r = − 0.223, p = 0.14) with the duration of
OCD was less than significant.
In our sample, although the relatives of patients in the
responder group were more likely to present limited
family accommodation, those of refractory patients
displayed significantly higher levels of serious accommodation (U = 64.5, p < 0.001). Most (76.9%) of the
families of patients with treatment-responsive OCD
were at the no/limited accommodation level versus only
14.3% of those of patients with treatment-refractory
OCD. Whereas 52.4% of the families of refractory
patients were at the serious/extreme level, only 3.8% of
those of responders were at that level.
BABS b
7.45 (4.44)
6.67 (5.24)
Age at onset (years) 13.5 (6.46)
17.0 (8.82)
OCD duration
22.27 (10.55) 25.46 (12.63)
(years)
Age starting
23.95 (7.04) 32.17 (9.42)
treatment (years)
Period of time to
10.32 (7.88) 15.17 (10.45)
start treatment
(years)
⁎Fisher's exact test; S.D., standard deviation; OCD, obsessive–
compulsive disorder; BABS, Brown Assessment of Beliefs Scale.
a
Refractory group (n = 21) and Respondent group (n = 24).
b
Refractory group (n = 21) and Respondent group (n = 26).
with functioning, refractory patients presented greater
disease severity (t = 3.88, p < 0.001). During the worse
OC symptoms state, there were no differences between
the groups (t = 1.53, p = 0.133). As expected, current
severity of OC symptoms was higher for refractory
patients (t = 8.67, p < 0.001).
Using the USP-Harvard Repetitive Behaviour
Interview to analyse the presence of at least one
sensory phenomenon preceding the compulsions, we
found that 20 (86.9%) of the patients in the refractory
group and 22 (88.0%) of those in the responsive group
presented this condition, a less than significant difference (Fisher's exact test, p = 0.57). We also found no
differences in the following specific sensory phenomena: mental sensations, body sensations, “just right”
sensations (the need for repeating an act until reaching
a sensation that it was done in the “right manner,”
“perfectly”), energy, premonitory “urges,” and feelings
of incompleteness.
3.6. Variables indirectly related to OCD phenotypic
expression (demographic, epigenetic, family history
and family functioning factors—extrinsic variables)
No statistically significant differences were found
between the two groups regarding family history of
psychiatric disorders (Fisher's exact test, p = 0.58), OCD
(χ2 Yates = 0.05, p = 0.82, df = 1) or tics (χ2 Yates = 0.01,
p = 0.93, df = 1), or any of the epigenetic factors studied,
3.8. Logistic regression analysis
To verify the independent associations of the
variables most significantly (p = 0.10) identified with
refractoriness in the univariate analysis (dependent
variables), we performed two stepwise logistic regression analyses (enter probability of 0.05 and exit
probability of 0.10). For the first model, we entered the
following intrinsic factors: severity of OC symptoms
according to the YBOCS, interval between the onset of
OCD and the beginning of treatment, course of the
illness, and presence of sexual/religious dimension
according to the DYBOCS checklist. For the second
Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
Table 5
Variables independently associated with obsessive–compulsive disorder
(OCD) refractoriness to treatment after the logistic regression analyses
Variable
OCD intrinsic factors
Sexual/religious
dimension
Coefficient
(S.E.)
P
1.50 (0.66) 0.024
Odds
ratio
95%
confidence
interval
0.22 (0.06–0.82)
OCD extrinsic factors a
Lower socio-economic 3.03 (1.37) 0.027 20.72 (1.42–303.32)
status
Higher family
0.42 (0.16) 0.009 1.53 (1.11–2.10)
accommodation
index
S.E.–standard error.
a
Variable entered in step 1: family accommodation index; variable
entered in step 2: socio-economic status.
model, we entered the following extrinsic factors:
marital status, educational level, occupation, socioeconomic status and FAI. Other variables were not
included because of their co-linearity with OC symptom
severity or with FAI. Table 5 presents the results of the
final logistic regression analysis. As shown, the presence
of sexual/religious symptoms, lower socio-economic
level and higher FAI scores were the only factors
independently associated with OCD refractoriness.
4. Discussion
The criteria we used for refractoriness (less than
25% decrease of the initial YBOCS scores; less than a
minimal improvement on CGI; at least three adequate
therapeutic trials with first-line drugs; at least two
pharmacological augmentation strategies; and at least
20 h of exposure and response prevention) were stricter
than those previously adopted by other authors. This
strategy allowed a clear-cut comparison between the
two groups and was partially justified by the findings
of greater OC symptom severity, more symptoms of
depression and anxiety, and lower quality of life in the
refractory group. Likewise, our responder group
included only patients with at least 1year of proven
consistent treatment-related improvement. However,
these defining criteria are arbitrary, may limit the
generalisation of our findings, and cannot preclude the
possibility that current responders may become
refractory in the future. A major strength of this
study is the systematic and structured evaluation of a
vast array of variables related to the clinical expression
of OCD, including scores derived from a new
instrument (the DYBOCS, especially designed to
205
describe the OCD phenotype), epigenetic factors and
ratings derived from instruments evaluating family
accommodation, the latter not having been previously
employed.
4.1. Content and formal aspects of OC symptoms
The DYBOCS sexual/religious dimension, more
frequently found in the refractory group, has also been
associated with poor treatment response in previous
studies (Alonso et al., 2001; Mataix-Cols et al., 2002a,b).
Using a different instrument than the present study,
Mataix-Cols et al., (2002a,b), found that higher scores on
the “sexual/religious obsessions” factor were also related
to less favourable outcomes of behavioural therapy.
Although Tek and Ulug (2001) found that the
expression of the religious obsessive–compulsive
symptoms seems not to be related exclusively to cultural
influences, this topic needs more descriptive and
analytical studies, since it could be a key aspect when
establishing differences between sexual and religious
obsessive–compulsive symptoms and normal sexuality
and religiosity. It could also explain how social and
cultural aspects influence obsessive–compulsive symptoms. One aspect that makes this task quite difficult is
that the social concepts and ensuing traditions regarding
mental illness vary considerably in different cultures.
These concepts are determined by religious and
superstitious beliefs, moral codes, cultural values, and
economic factors. Some cultures still accept attitudes
and behaviors that are rejected elsewhere. We could
speculate, for example, that, since some sexual and
religious contents are particularly unacceptable and, at
the beginning of the disease the patient has no idea that
he/she has OCD, patients may believe that the
obsessional thoughts are really expressions of their
own moral values. This could bring serious guilt and
sinful feelings, enhancing depressive symptoms and
worsening OCD.
Yaryura-Tobias and Neziroglu (1997) suggest that
scrupulosity's obsessional content closely relates to
morality, sexuality and religiosity. Some scrupulous
patients might be religious individuals and when this
occurs, OCD, morality and religiosity may blend,
worsening the disorder (Yaryura-Tobias and Neziroglu,
1997). Moll et al. (2005), reviewing functional neuroimaging studies of moral cognition, describe consistent
involvement mainly of the anterior prefrontal cortex, but
also of the temporal sulcus, anterior temporal lobes and
limbic structures in moral judgment in normal individuals, postulating a theory that posits mutually competitive roles of cognition and emotion in moral judgement.
206
Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
They also affirm that prefrontal cortex has a central role
in the internalization of moral values and norms through
the integration of cultural and contextual information
during development (Moll et al., 2005). Neuroimaging
studies of OCD patients also reveal some dysfunction of
prefrontal cortex, showing hyperfunction of the orbitofrontal areas (Alexander and Crutcher, 1990; Saxena et
al., 1998; Saxena and Rauch, 2000), what could lead to a
moral “hypertrophy” that could be expressed by
religious and sexual dimension on OCD patients.
Recent neuro-imaging studies have provided additional evidence, suggesting different patterns of activation according to different OC symptom dimensions
(Rauch et al., 1998; Mataix-Cols et al., 2003). One could
speculate that the expression of sexual/religious OC
symptoms involves neuro-anatomical regions previously associated with poor treatment response (Rauch et al.,
1998; Saxena et al., 1998; Saxena and Rauch, 2000),
and that its circuit may overlap with social, cultural and
moral neurocircuits.
through the Young Mania Rating Scale. In our study,
the refractory patients have been more often treated with
mood stabilizers and antipsychotics, although it must be
stressed that this may only be due to their refractoriness.
It could also be argued, for example, that if these
patients with OCD were more often cyclothymic in
temperament, the intense use of antidepressant, perhaps
especially clomipramine at high doses, could worsen
their clinical picture towards a more mixed (and
refractory) state. As the Structured Clinical Interview
for DSM-IV Axis I Disorders is conservative in
detecting bipolar disorder type II (Akiskal and Benazzi,
2005), this may have been a limitation of our study.
Shavitt et al. (in press) found that a higher number of
co-morbid psychiatric disorders, although unrelated to
OCD severity, were related to a poor response to
clomipramine. In our study, the presence and number of
co-morbid conditions were not related to refractoriness.
However, it is likely that the sample size was too small
to evince the expected differences between groups (type
II error).
4.2. Psychiatric co-morbidity
4.3. Sensory phenomena
In our sample, 42 patients (85.4%), 21 refractory
(90.9%) and 21 responsive (80.8%), presented at least
one lifetime psychiatric co-morbidity. These findings
are comparable to those found in the literature, where
the most prevalent lifetime psychiatric co-morbidities
are major depression, simple phobia, social phobia and
tics (Rasmussen and Eisen, 1997; Vallejo, 1998).
Although bipolar disorder was mostly absent in our
sample, the frequency of bipolar disorders among
patients with OCD are said to range from 2% to 3%
for Bipolar I and from 8% to 13.6% for Bipolar II
Disorders (American Psychiatric Association, 1994;
Perugi et al., 1997). It must be noted, however, that “soft
bipolarity” (when hypomania and cyclothymia are
included) may occur more frequently than previously
known in OCD patients according to Cyclothymic
Temperament Questionnaire (Hantouche et al., 2003;
Akiskal et al., 2003). In fact, it has been shown that
“cyclothymic OCD” patients exhibit several features
that could lead to treatment resistance or refractoriness,
such as more severe obsessive–compulsive symptoms,
elevated risk of suicide, greater comorbidity with mania
or hypomania and major depression, earlier emotional
problems, greater social and conjugal problems, and
greater frequency of learning difficulties. Issler et al.
(2005), studying the expression of OCD in women with
bipolar disorder, found that there was a positive
correlation between the score in the YBOCS and the
intensity of hipomanic/manic symptoms measured
Leckman et al. (1994) suggest that basal ganglia are
composed of pathways that contribute to the multiple
parallel cortical–striatal–thalamo–cortical circuits that
concurrently subserve a wide variety of sensoriomotor,
motor, oculomotor, cognitive, and limbic “processes.”
They also suggest that Tourette Syndrome and etiologically related forms of OCD are associated with a failure
to inhibit subsets of the cortical–striatal–thalamo–
cortical minicircuits. Therefore, as we speculated that
sensory phenomena could be related to a dopaminergic
subtype of OCD (similar to Tourette Syndrome), we
expected that it could be more frequent in refractory
patients, but there were no differences between groups.
Kane (1994) proposed that pre-tic sensory experiences
result from a specific attentional deficit. Based on his
own introspective case study, the author argues that the
premonitory urges that precede tics are not unique
sensory events, but rather manifestations of somatosensory hyperawareness, which serves as an aversive
stimulus toward which tics are purposively directed.
4.4. Course of OC symptoms
In the refractory patients we studied, the illness was
more likely to have a chronic course, whereas an
intermittent course was more common among the
responders. Similar results were reported by Hollander
et al. (2002), who found that the disease presented a
Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
chronic course in approximately 90% of refractory OCD
patients (versus 70% of responders). Our PSR results
showed that refractory patients, in addition to displaying
a more chronic course, had more severe symptoms from
the onset, even before meeting OCD criteria. This
probably leads to more interference in emotional, social
and professional functioning, which may in turn
contribute to a less favourable treatment response.
4.5. Age at onset and duration of OCD
In our sample, the mean age at which treatment began
was lower among refractory patients than among
responders (p = 0.002); the latter tended to go untreated
for an average of 5 years longer (p = 0.08). As opposed to
what we expected, no differences were found between
groups regarding age at OCD onset and first treatment.
Therefore, refractory patients may seek treatment
earlier, either because their OCD is more severe from
the onset or because of secondary depressive and
anxiety symptoms.
4.6. Socio-demographic aspects
There was a trend toward a statistically significant
difference between groups regarding educational level
(p = 0.054). Refractory patients were more likely than
responders to be of lower social-economic status
(p = 0.015) and to be single (p = 0.037). Steketee et al.
(1999) found that the chance of presenting partial
symptom remission within a 5-year period was two
times greater for OCD patients who were married than
for those who were single. These findings are in
accordance with another study conducted by our
group, in which we showed that having a spouse was
associated with a greater degree of improvement
(Shavitt et al., in press). Thus, it seems that refractory
patients with OCD present reduced productivity, resulting in lower wages and probably imposing a considerable economic burden on their families, on their
employers, and on society. Our results are in line with
those of Stein et al. (1996), suggesting that OCD
(especially refractory cases) leads to considerable
distress and interferes with social, academic and
occupational functioning. Therefore, lower socio-economic status and higher numbers of unmarried patients
(as well as lower educational level and higher
unemployment) are possibly consequences of the
severity of the disorder, although the design of this
study does not allow us to draw conclusions about the
direction of causality. The burden associated with
refractory OCD should be investigated further.
207
4.7. Family functioning
Our sample evinced significant differences for all
scores on the FAS. The participation of relatives in
patient rituals and the modification of family functioning due to OC symptoms compose what Calvocoresi et
al. (1995) called the family accommodation index (FAI).
When the relative performs a ritual together with the
patient, the symptom is reinforced. The family distress
index (FDI) refers to the direct distress that OCD causes
to the family member. The way in which patients react
when relatives do not participate in their compulsions
contributes to family accommodation. This study found
significantly higher FAI, FDI and patient reactions in the
refractory group. Guedes (1997), evaluating 26 OCD
patients, found that all of the families presented some
degree of family accommodation and found a positive
correlation between FAI and higher YBOCS scores
(r = 0.41, p = 0.003). This correlation was also found in
the present study (r = 0.71, p < 0.001).
The higher FAIs may lead to a less favourable patient
response to CBT techniques (Steketee and VanNoppen,
2003) as some family members, rather than responding
adaptively by engaging in problem solving with the
patient, become over-involved, frustrated, angry, or
rejecting. Maladaptive reactions increase patient stress,
possibly leading to symptom aggravation and relapse.
There is some evidence that hostility and emotional
over-involvement, as well as any statements perceived
by the patient as criticism, have a negative effect on
CBT outcome. As previously mentioned, family accommodation is predictive of poorer family functioning
and more severe OC symptoms after behavioural
treatment (Steketee and VanNoppen, 2003). Conversely,
the phenomenon of accommodation could be also
secondary to case severity or complexity. Prospective
studies are needed to better understand the causal
direction of this and other associations—to investigate,
for example, whether family accommodation and low
socio-economic status are risk factors or consequences
of refractoriness.
The clinical implications of this study include that
sexual/religious obsessions in OCD patients and greater
symptom severity from the onset may constitute
warning signs for clinicians to establish a more
comprehensive protocol for initial treatment in order
to prevent future refractoriness. Also, we found that high
impact on family function is associated with a less
favourable response to treatment. In dealing with patient
symptoms, it is also important to target the maladaptive
behaviours of family members. Our findings corroborate
the importance of early treatment interventions, together
208
Y.A. Ferrão et al. / Journal of Affective Disorders 94 (2006) 199–209
with social and family approaches, in order to minimise
the negative impact of OCD on the social, educational
and occupational functioning of the individual.
Other clinical and neurobiological studies, with
larger samples, adequate instruments of assessment
and prospective research designs, should investigate
further how symptoms of sexual and religious content
may contribute to refractoriness of OCD patients.
Therapeutic interventions on family functioning are
warranted when OCD patients are not responding to
conventional treatment approaches. As our findings are
clinically relevant, they should be replicated by other
research centres, in order to determine predictive factors
of treatment non-response in OCD.
Acknowledgements
This study was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP) and from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ), Brazil
(grant #521369/96-7) to Dr. Miguel. The authors thank
Paulo Rogério Aguiar for his help in data collection, and
Mariana Curi for the statistical assistance.
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