Professional Documents
Culture Documents
Daniëlle C. Cath d, j, k
a Overwaal Center for Anxiety Disorders, OCD, and PTSD, Pro Persona Institute for Integrated Mental Health Care,
Nijmegen, The Netherlands; b Behavioral Science Institute, Radboud University, Nijmegen, The Netherlands;
c Altrecht Eating Disorders Rintveld, Zeist, The Netherlands; d Department of Clinical Psychology, Utrecht University,
Utrecht, The Netherlands; e Rivierduinen Eating Disorders Ursula, Leiden, The Netherlands; f Institute of Psychology,
Leiden University, Leiden, The Netherlands; g Department of Methodology and Statistics, Utrecht University,
Utrecht, The Netherlands; h Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands;
i Radboud University Medical Center, Department of Psychiatry, Radboud University, Nijmegen, The Netherlands;
j Altrecht Academic Anxiety Center, Utrecht, The Netherlands; k GGz Drenthe, Department of Specialist Training,
Rijksuniversiteit Groningen and University Medical Center Groningen, Department of Psychiatry, Groningen,
The Netherlands
tention therapy (SAT), as add-ons to treatment as usual (TAU). AN merits future efforts at replication. © 2020 S. Karger AG, Basel
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b.van.passel @ propersona.nl
Introduction younger patients, and dietary management [32]. Longitu-
dinal studies have shown that <50% of patients recover
Obsessive-compulsive disorder (OCD), which is char- fully, while 20–30% experience residual symptoms, 10–
acterized by intrusive thoughts, images, or urges (i.e., ob- 20% remain significantly ill, and 5–10% die from their
sessions) and repetitive behaviors performed to relieve illness [33].
obsessional distress (i.e., compulsions) [1], affects 1–3% Clearly, current treatment strategies for OCD and AN
of the population worldwide [2, 3]. The eating disorder warrant optimization, but this poses a real challenge to
anorexia nervosa (AN) affects up to 4% of the population clinicians worldwide. Potentially, therapy results can be
(predominantly women) [4]; it is characterized by a se- improved in both populations if the underlying ineffi-
vere restriction of energy intake leading to a significantly ciencies in neurocognitive functioning are tackled before
low body weight, associated with an intense fear to be- targeting the core symptoms of the disorders.
come fat, and inadequate cognitions about body shape Cognitive remediation therapy (CRT) specifically
[1]. Of all mental disorders, AN is among those with the aims at modifying cognitive inflexibility and organiza-
highest mortality rates [5]. Both OCD and AN are associ- tional inefficiencies [34]. The intervention was originally
ated with impaired quality of life (QoL) [6–8]. designed to treat patients with schizophrenia [35, 36] but
Interestingly, OCD and AN share several phenotypic, has since been adapted to treat individuals suffering from
epidemiological, and neuropsychological features [9]. eating disorders [37]. CRT uses cognitive exercises to
Both patient populations show excessive habit formation, moderate people’s adaptive thought processes about their
cognitive rigidity, and repetitive and ritualistic behaviors daily routines and to promote a more flexible behavioral
[10]. Moreover, several studies have demonstrated an in- repertoire (by expediting a shift from habitual to more
creased risk of co-occurrence of the two disorders [9, 11], goal-directed behaviors) and a more global rather than a
with rates of AN varying between 11–13% in clinical detail-focused style of processing information. Case se-
OCD populations and rates of OCD between 9.5 and 62% ries and randomized trials looking at CRT for AN found
in patients with a primary diagnosis of AN. Patients with that the intervention improved the participants’ cognitive
OCD and AN also share specific inefficiencies in execu- flexibility [38, 39], QoL [40], motivation to change [41],
tive functioning, most commonly in set-shifting/cogni- and AN-specific pathology [40]. However, to date, no
tive flexibility, visuospatial abilities, processing speed, studies in eating disorders have compared the effect of
motor inhibition, and working memory [12–19]. These CRT on treatment outcome using an active control con-
inefficiencies have been associated with frontostriatal ab- dition. Since the randomized controlled trials compared
normalities in functional neuroimaging studies [20–22]; the treatment under investigation with waiting-list con-
they are assumed to be central to the development and ditions, a design which is known for its risk of overesti-
maintenance of obsessive thoughts and compulsive be- mating treatment effects [42, 43], a logical next step would
haviors in both OCD and AN [23, 24] and thought to in- be to compare CRT to an active control condition.
terfere with a patient’s ability to acquire and use concepts Although to date CRT has, as such, not been evaluated
trained in psychotherapy, most particularly cognitive in randomized designs with an active control arm, two
therapies [25], where the traits negatively affect treatment studies, both from 2006, did compare cognitive remedia-
motivation and outcomes. tion-like approaches to OCD with a control condition. In
The first-line treatment for OCD is cognitive-behav- one randomized controlled trial [44], 35 adults with OCD
ioral therapy in combination with pharmacotherapy, es- who received a single-session training designed to help
pecially selective serotonin reuptake inhibitors. In case of them augment their organizational skills in terms of
nonresponse, specialized intensive interventions are ad- memorizing and replicating complex visuospatial infor-
vised, including residential treatments [26–29], but de- mation improved more than 36 unaffected controls who
spite efficient treatment regimens the rates of incomplete did not receive this training. The second randomized
recovery and treatment resistance remain relatively high controlled trial [45] likewise found that the 15 patients
[30]. While two-thirds of patients receiving (cognitive-) with OCD who received nine 60-min training sessions
behavioral therapy and/or pharmacotherapy respond to focused on enhancing visual-organizational and prob-
these therapies, only about 50% of individuals diagnosed lem-solving strategies in everyday life improved more in
with OCD achieve complete remission [31]. both areas as well as in OCD symptoms than 15 peers who
The first-choice treatment for adult AN is a combina- did not receive the treatment modality. Based on these
Imperial College, School of Medicine, Wellcome Libr.
tion of psychotherapy, including family therapy for preliminary results, we thought it worthwhile to evaluate
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lowed provided that dosages were kept constant during the ex- range of cognitive exercises to modify cognitive inflexibility and
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Enrolment
OCD: n = 211
AN: n = 227
Assessed (n = 132)
Altrecht Academic Anxiety Center (n = 36)
Overwaal Center for Anxiety Disorders (n = 35)
Randomization
End CRT, start TAU (n = 59) End SAT, start TAU (n = 48)
Dropout reasons: Dropout reasons:
Could not be reached (n = 3) Could not be reached (n = 5)
Withdrawal from study (n = 4) Withdrawal from study (n = 7)
Withdrawal from treatment (n = 2) Withdrawal from treatment (n = 4)
Fig. 1. Patient flowchart. AN, anorexia nervosa; CRT, cognitive remediation therapy; OCD, obsessive-compulsive
disorder; SAT, specialized attention therapy; TAU, treatment as usual.
overdetailed information processing. The exercises encourage pa- helping them focus on positive experiences by means of “exercis-
tients to reflect on the nature of their thinking styles. To help them es.” Addressing the same principles as the CRT modalities, the ex-
recognize the effect of these thinking styles on their daily lives, pa- ercises comprised board games tapping into motor, visual, and
tients are given home assignments comprising real-life cognitive- verbal skills, luck games, collaborative games, including e.g. Djen-
behavioral tasks in addition to the ten twice-weekly 45-min ses- ga, Mikado, Game of the Goose, Ludo, and Snakes and Ladders,
sions. and reading poems (for an overview, see van Passel et al. [46]).
SAT. SAT was specifically developed for this trial [61]. The de- TAU. TAU contained all the essential elements as recommend-
sign was similar to that of CRT with respect to its structure, dura- ed in the Dutch OCD and AN guidelines [62–64], which closely
tion (ten twice-weekly 45-min sessions), and inclusion of home- follow the international guidelines [65, 66]. TAU for the patients
work assignments, but cognitive flexibility, central coherence, per- with OCD comprised cognitive-behavioral therapy delivered in
fectionism, and awareness training of thinking styles were not weekly or twice-weekly 45- to 90-min sessions in which exposure
Imperial College, School of Medicine, Wellcome Libr.
addressed expressly. Patients were told that SAT was aimed at with response prevention forms a key element. In line with the lit-
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dicted means from the three-way LMM. To facilitate overall out- the 132 patients included in the study, 9% (n = 12; CRT:
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Characteristics OCD subgroup Statistics AN subgroup Statistics OCD+AN CRT vs. SAT
Sex χ2(1) = 0.24, p = 0.62 χ2(1) = 1.14, p = 0.29 χ2(1) = 0.70, p = 0.40
Female 27 (73%) 23 (68%) 30 (97%) 27 (90%)
Male 10 (27%) 11 (32%) 1 (3%) 3 (10%)
Years of education 8.35 (2.01) 8.35 (2.23) t(41) = 0.00, p = 1.00 8.77 (1.83) 9.23 (1.45) t(54) = –1.04, p = 0.25 t(97) = –0.69, p = 0.49
Psychological treatments χ2(4) = 2.10, p = 0.72 χ2(3) = 2.68, p = 0.44 χ2(4) = 0.52, p = 0.97
0 7 (21%) 9 (21%) 13 (42%) 8 (27%)
1–5 13 (38%) 8 (24%) 10 (32%) 13 (42%)
6–10 2 (6%) 1 (3%) 2 (7%) 4 (13%)
>10 9 (26%) 11 (33%) 5 (16%) 3 (10%)
Unknown 3 (9%) 4 (12%) 0 (0%) 0 (0%)
Age at onset, years 28.48 (10.95) 23.66 (8.78) t(58) = 1.88, p = 0.07 20.10 (7.11) 19.76 (7.40) t(58) = 0.18, p = 0.86 t(118) = 1.53, p = 0.13
Age, years 34.78 (10.57) 33.09 (11.39) t(69) = 0.65, p = 0.52 25.19 (7.66) 24.60 (6.98) t(59) = 0.32, p = 0.75 t(130) = 0.72, p = 0.48
Duration of illness, years 7.52 (8.95) 9.79 (12.93) t(58) = –0.80, p = 0.43 5.10 (7.50) 4.66 (4.35) t(58) = 0.28, p = 0.78 t(118) = –0.55, p = 0.58
Current BMI 25.01 (4.62) 23.33 (4.27) t(62) = 1.51, p = 0.14 15.87 (1.64) 16.26 (1.99) t(58) = –0.83, p = 0.41 t(122) = 0.70, p = 0.49
Concurrent medication 8 (25%) 6 (20%) χ2(1) = 0.29, p = 0.59 22 (59%) 18 (53%) χ2(1) = 0.31, p = 0.58 χ2(1) = 0.60, p = 0.44
EDE-Q – total 1.42 (1.62) 1.20 (1.24) t(50) = 0.56, p = 0.58 4.00 (1.31) 4.12 (1.23) t(52) = –0.34, p = 0.74 t(104) = 0.54, p = 0.59
Y-BOCS – total 23.81 (7.15) 24.41 (5.68) t(66) = –0.38, p = 0.71 5.60 (9.39) 5.80 (9.98) t(58) = –0.08, p = 0.94 t(126) = –0.06, p = 0.95
EDQOL or OCDQOL – 2.62 (0.65) 2.57 (0.59) t(65) = 0.31, p = 0.76 2.86 (0.54) 2.93 (0.68) t(52) = –0.46, p = 0.65 t(98.9) = –1.50, p = 0.13
total
DFlex – rigidity 45.20 (13.51) 41.78 (12.06) t(65) = 1.09, p = 0.28 42.52 (11.84) 46.96 (10.08) t(51) = –1.45, p = 0.15 t(118) = –0.01, p = 0.99
DFlex – attention 40.69 (13.10) 41.38 (12.78) t(65) = 0.21, p = 0.83 38.86 (11.88) 38.75 (12.02) t(51) = 0.034, p = 0.97 t(118) = 0.17, p = 0.87
Values are presented as n (%) or mean (standard deviation). AN, anorexia nervosa; BMI, body mass index; CRT, cognitive remediation therapy; DFlex, self-report Detail and Flexibility question-
naire; EDE-Q, Eating Disorder Examination Questionnaire; EDQOL, Eating Disorders Quality of Life questionnaire; OCD, obsessive-compulsive disorder; OCDQOL, Obsessive-Compulsive Disor-
der Quality of Life self-report questionnaire; SAT, specialized attention therapy; Y-BOCS, Yale-Brown Obsessive Compulsive Scale.
n = 5; SAT: n = 7) never started CRT/SAT therapy, while found that during the experimental phase 4 patients (2
11% (n = 14; CRT: n = 4; SAT: n = 10) terminated CRT/ OCD in CRT and 2 OCD in SAT) showed a reliable dete-
SAT prematurely (Fig. 1). The treatment completers and rioration, 82 no change, and 14 a reliable improvement.
dropouts did not differ regarding all but one of their base- Table 2 shows the total number of patients with reliable
line variables (i.e., age, number of previous treatments, deterioration, no change, or reliable improvement.
baseline Y-BOCS score or baseline EDE-Q score, age at on- Dropout at 6 and 12 Months. Of the 120 patients hav-
set, QoL scores, and psychotropic drug use), with illness ing started CRT or SAT, 23% (n = 28) did not complete
duration being significantly longer in the patients dropping the follow-up assessment at 6 months. There were no dif-
out (mean illness duration: 6.2 years for completers vs. 9.9 ferences in the number of patients dropping out from the
years for dropouts; t[122.17] = 2.972, p < 0.01). There was CRT and SAT condition at this first follow-up (χ2[1, n =
no difference in the number of patients dropping out from 120] = 0.54, p = 0.46). Finally, 49% (n = 59) never com-
CRT and SAT (χ2[1, n = 132] = 3.30, p = 0.07). All com- pleted the second follow-up assessment (12 months),
pleters of both interventions participated in the first follow- with no differences for the two treatment arms (χ2[1, n =
up assessment. As mentioned, the data of the dropouts re- 120] = 0.47, p = 0.52). Moreover, the last available z-scores
mained included in the analyses if they concerned more of the primary outcome measure from patients who
than one assessment. No adverse events were reported for dropped out during TAU were not significantly higher or
either intervention. Applying the Jacobson and Truax [70] lower than the z-scores of patients who stayed in the study
Imperial College, School of Medicine, Wellcome Libr.
method for the calculation of reliable change indices, we until 52 weeks (t[12.20] = –1.54, p = 0.15).
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AN, anorexia nervosa; CRT, cognitive remediation therapy; EDE-Q, Eating Disorder Examination Question-
naire; OCD, obsessive-compulsive disorder; SAT, specialized attention therapy; T0, baseline; T1, after 6 weeks;
T2, after 6 months; T3, after 12 months; Y-BOCS, Yale-Brown Obsessive Compulsive Scale.
T0 T1 T2 T3
z-score, OCDQOL
and EDQOL 0.35 (54) 0.75 0.38 (44) 0.87 0.38 (55) 1.03 –0.09 (46) 0.95 –0.22 (39) 0.93 –0.21 (34) 0.98 –0.17 (28) 1.15 –0.43 (23) 1.03
OCDQOL 2.63 (30) 0.62 2.54 (26) 0.61 1.90 (30) 0.80 2.03 (26) 0.70 2.21 (20) 0.77 2.29 (17) 0.73 2.45 (16) 0.77 1.92 (12) 0.75
EDQOL 2.77 (24) 0.48 2.88 (18) 0.67 2.41 (25) 0.68 2.73 (20) 0.64 2.33 (19) 0.57 2.28 (17) 0.67 2.09 (12) 0.80 2.31 (11) 0.77
DFlex total score 83.16 (55) 23.97 84.24 (45) 21.99 77.00 (54) 21.75 77.66 (47) 24.22 79.03 (39) 21.26 79.66 (35) 25.20 83.42 (28) 27.22 79.46 (24) 22.93
OCD subgroup 85.16 (30) 25.90 84.69 (26) 23.34 75.31 (29) 23.05 73.23 (26) 25.94 77.80 (20) 25.87 81.76 (17) 26.73 90.13 (16) 28.05 77.58 (12) 23.32
AN subgroup 80.76 (25) 21.71 83.63 (19) 20.62 78.96 (25) 20.43 83.14 (21) 21.25 80.32 (19) 15.64 77.67 (18) 24.28 74.50 (12) 24.35 81.33 (12) 23.42
Values are presented as mean (n) followed by standard deviation. AN, anorexia nervosa; CRT, cognitive remediation therapy; DFlex, self-report Detail and Flexibility questionnaire; EDE-Q, Eating Disorder
Examination Questionnaire; EDQOL, Eating Disorders Quality of Life questionnaire; OCD, obsessive-compulsive disorder; OCDQOL, Obsessive-Compulsive Disorder Quality of Life self-report questionnaire; SAT,
specialized attention therapy; T0, baseline; T1, after 6 weeks; T2, after 6 months; T3, after 12 months; Y-BOCS, Yale-Brown Obsessive Compulsive Scale.
CRT+TAU versus SAT+TAU across Diagnostic kept in the model (t[251.61] = 2.74, p = 0.01). Next, hav-
Groups ing added the covariates age, illness duration, and educa-
Table 3 shows the time course for the primary and sec- tion years to the model followed by condition, we found
ondary outcome measures comparing the combined no significant group effect on condition, which means
CRT+TAU group with the combined SAT+TAU group there was no difference in the baseline primary outcome
from baseline to follow-up. scores between the two treatment groups. To test for
baseline differences between CRT and SAT for the OCD
Primary Outcome Measures and AN groups, we subsequently added the diagnosis ×
Mixed model analyses revealed a significant effect of condition interaction to the model, which was nonsig-
time (t[257.63] = –11.01, p < 0.01) for the total group. A nificant (t[70.34] = –0.04, p = 0.97). As can be seen in
Imperial College, School of Medicine, Wellcome Libr.
quadratic relation over time was significant and therefore Table 4, when the two-way interactions time × diagnosis
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Condition T0 T1 T2 T3
Predicted mean scores Predicted mean scores Predicted mean scores Predicted mean scores
OCD (Y-BOCS)1 CRT 23.46 21.92 17.84 15.02
SAT 24.81 22.82 17.25 12.48
AN (EDE-Q)2 CRT 4.37 4.21 3.84 3.78
SAT 4.60 4.36 3.74 3.35
Predicted mean z-scores Predicted mean z-scores Predicted mean z-scores Predicted mean z-scores
Total group3 CRT 0.31 0.19 –0.12 –0.30
SAT 0.40 0.24 –0.19 –0.52
Within-group ES CRT reference 0.23 0.88 1.38
Y-BOCS SAT reference 0.26 1.02 1.67
Within-group ES CRT reference 0.20 0.73 1.08
EDE-Q SAT reference 0.23 0.87 1.36
Between-group effects z-scores CRT vs. SAT z-scores CRT vs. SAT z-scores CRT vs. SAT z-scores CRT vs. SAT
estimate reference 0.44 –0.06 –0.21
95% CI –0.15, 0.24 –0.26, 0.13 –0.45, 0.04
p value 0.65 0.51 0.10
ES 0.4 –0.1 –0.2
1 Time × condition: t(70.0) = –2.97, p < 0.01. 2 Time × condition: t(101.7) = –0.82, p = 0.42. 3 Time × condition: t(174.18) = –2.37, p = 0.02; time × diagnosis:
t(173.48) = –2.90, p < 0.01. AN, anorexia nervosa; CRT, cognitive remediation therapy; EDE-Q, Eating Disorder Examination Questionnaire; ES, effect size;
LMM, linear mixed-effects modeling; OCD, obsessive-compulsive disorder; SAT, specialized attention therapy; T0, baseline; T1, after 6 weeks; T2, after
6 months; T3, after 12 months; Y-BOCS, Yale-Brown Obsessive Compulsive Scale.
and time × condition were added to the model, both in- hen’s d = 0.73 for CRT and 0.87 for SAT) and at 52 weeks
teractions were significant (t[173.48] = –2.901, p < 0.01, (Cohen’s d = 1.08 for CRT and 1.36 for SAT).
and t[174.18] = –2.37, p = 0.02, respectively), implying
that the main outcome variable z-scores of the patients in Secondary Outcome Measures
the SAT condition had declined more over time than QoL. The mixed-model analyses of QoL revealed a
those of the patients receiving CRT prior to TAU and that significant effect over time (t[235.40] = –4.44, p < 0.01)
the main outcome variable z-scores of the patients with for the total group. A quadratic relation over time was
OCD had declined more than those of the patients with significant and kept in the model (t[226.84] = 3.64, p =
AN. Finally, the three-way time × diagnosis × condition 0.00). The covariates age, illness duration, and education
interaction was nonsignificant: t(205.45) = –1.16, p = years were added to the model, with interactions proving
–0.12, i.e., there were no between-group differences over nonsignificant, meaning there were no baseline differ-
time for CRT and SAT. Therefore, the two-way interac- ences between the two treatment conditions. Addition of
tion model (time × diagnosis and time × treatment) was diagnosis revealed that this predictor was also nonsig-
the best-fitting model and is presented in Table 4 and in nificant, showing there were no significant (t[63.81] =
Figure 2. –1.00, p = 0.32) baseline differences in QoL scores be-
The upper part of Table 4 demonstrates the time tween the OCD and AN groups. Since the interaction
course of the Y-BOCS and EDE-Q scores and their com- with treatment condition, which was added next, also
bined z-scores comparing CRT+TAU with SAT+TAU was nonsignificant (t[64.10] = –0.30, p = 0.98), there
between baseline and follow-up. We found time effects were no significant differences in baseline QoL between
for the patients treated for OCD for both conditions, CRT and SAT. The time × condition interaction was also
with large effect sizes at 26 and 52 weeks (Cohen’s d = nonsignificant, indicating that the treatment effect on
0.88 for CRT+TAU and 1.02 for SAT+TAU at 26 weeks QoL did not differ between groups over time (t[169.40]
and 1.38 and 1.67 at 52 weeks, respectively). The time ef- = –1.85, p = 0.07). However, the time × diagnosis interac-
fects for the patients with AN showed medium to large tion was significant (t[166.87] = 2.88, p = 0.04), indicat-
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effect sizes for both conditions, both at 26 weeks (Co- ing that QoL had improved more over time for the pa-
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0.2
z-score
0
–0.2
–0.4
–0.6
0 10 20 30 40 50 60
a Time, weeks
0.8
AN-CRT
0.6 AN-SAT
0.4 OCD-CRT
OCD-SAT
0.2
0
–0.2
z-score
–0.4
–0.6
–0.8
Fig. 2. Change over time of symptom sever-
ity. a CRT vs. SAT. b Two-way interaction –1.0
model. AN, anorexia nervosa; CRT, cogni- –1.2
tive remediation therapy; OCD, obsessive- 0 10 20 30 40 50 60
compulsive disorder; SAT, specialized at- b Time, weeks
tention therapy.
tients with AN than it had for the patients with OCD. the OCD and AN patients, it was subsequently left out of
Finally, the three-way time × condition × diagnosis in- the model. The two-way interactions time × diagnosis
teraction was nonsignificant (t[217.43] = –1.24, p = and time × condition were both nonsignificant (t[167.38]
0.218); therefore, the previous model was the determina- = –1.37, p = 0.17, and t[167.97] = –1.64, p = 0.10, respec-
tive model. tively), signifying there was no significant difference in
Cognitive Rigidity and Attention to Detail (DFlex). the main DFlex outcome scores of the patients in the SAT
This model was constructed in the same way as the and those in the CRT condition. As the final three-way
two previous models. First, a significant effect of time time × diagnosis × condition interaction was also nonsig-
(t[231.12] = –2.01, p < 0.05) was found for the total group. nificant (t[195.34] = –1.10, p = 0.27), denoting there were
A quadratic relation over time was significant and there- no between-group differences in the time course for the
fore kept in the model (t[226.74] = 2.01, p < 0.05). Having two treatment conditions, the two-way interaction mod-
added the covariates age, illness duration, and education el (time × diagnosis and time × treatment) proved the
years to the model followed by treatment condition re- best-fitting model.
vealed no significant group effect for condition (t[70.42] Psychotropic Medication. There were no differences
= –0.20, p = 0.85), implying there was no difference in the in the proportion of patients using psychopharmaceuti-
baseline primary outcomes between the two treatment cals between the CRT+TAU and the SAT+TAU groups
groups. As the diagnosis × condition interaction was at each time point, except for the number of patients us-
nonsignificant (t[70.57] = –0.65, p = 0.51), indicating the ing benzodiazepine at time point 1 (6 weeks), which was
Imperial College, School of Medicine, Wellcome Libr.
absence of baseline differences between CRT and SAT for significantly higher in the CRT+TAU group. Further-
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active control condition. This study enabled us to spe- treatment effects for CRT+TAU in the previous studies
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The trial design was approved by the Medical Ethics Com This study was funded by a ZonMw grant (project number
mittee of the University Medical Center Utrecht (METC No. 837001004).
NL43751.041.13 v0.3). The trial was registered in The Netherlands
Trial Register (www.trialregister.nl, identifier: 3865) prior to the
start of data collection (registered February 20, 2013). All patients
gave their written informed consent before enrolment after receiv- Author Contributions
ing oral and written information about the study.
All authors were involved in the conception and design of the
study and/or in the analysis and interpretation of the data reported
in this paper. All authors contributed to the original draft of the
Disclosure Statement manuscript and/or added important intellectual content during
the revision process.
The authors have no conflict of interest to declare.
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