Are the symptom dimensions a predictor of short-term response to pharmacotherapy in pediatric obsessive-compulsive disorder? A retrospective cohort study.

Background: Obsessive-compulsive disorder (OCD) symptom dimensions respond differently to behavioral and pharmacological interventions, and some dimensions are reported to be more resistant to treatment. Aim: We aimed to investigate the responses of three symptom dimensions (harm/sexual, symmetry/hoarding, and contamination/cleaning) to serotonin reuptake inhibitor (SRI) therapy in pediatric OCD.
Methods: Children who were between 6 and 17 years old, diagnosed with OCD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, followed up at our clinic for at least 3 months, and received SRI treatment were included in our study. Response to treatment was assessed using the Clinical Global Impressions scale. Predictors of treatment response were analyzed using regression models.
Results: Of the 102 children with a mean age of 11.84 ± 2.87 years, 57.8% were male and the mean follow-up period was 12.39 ± 9.55 months. The overall response rate to pharmacotherapy was 66.7%. Patients with symmetry/hoarding symptoms [relative risk (RR) = 0.66, 95% confidence interval (CI) (0.12-0.79), P = 0.015] did not respond as well to SRIs. Besides, adolescent age (RR = 0.65, 95% CI (0.10-0.73), P = 0.01) was associated with a less favorable SRI response.
Conclusion: This study shows that symptom dimensions are one of the factors predicting response to pharmacotherapy in pediatric OCD. It is hypothesized that considering the dimensions is important to plan more appropriate treatment and provide more accurate prognostic information when assessing children with OCD. Copyright:

INTRODUCTION

Obsessive-compulsive disorder (OCD) is a chronic, debilitating, and time-consuming neuropsychiatric disorder associated with substantial global disability. OCD usually begins in childhood or adolescence and the lifetime prevalence varies between 0.5 and 4% worldwide.[123] Seventeen different symptom categories have been defined in the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS).[4] The diversity of symptoms has led to the need for a more homogeneous definition of OCD subgroups, and thus a dimensional approach.[5] The OCD symptoms were first examined in three dimensions by Baer (1994),[6] and then defined in four dimensions as symmetry/counting/ordering, sexual/religious/aggression/checking, contamination/cleaning, and hoarding in a meta-analytic study.[7]

Owing to its wide clinical spectrum, various options are used in the treatment of OCD, particularly serotonin reuptake inhibitors (SRIs) and cognitive behavioral therapy (CBT). However, a significant number of patients with OCD do not benefit from treatment and the response rates vary between 30 and 65%.[289] As some dimensions have been reported to be more treatment-resistant, symptom dimensions are becoming increasingly important in OCD treatment. While Stein et al. (2007, 2008)[1011] associated symmetry/ordering symptoms with poorer treatment response, a meta-analysis reported that the hoarding symptoms are more resistant to conventional treatments than other OCD dimensions.[12] There are also differences in response to pharmacotherapy between age groups. In a study conducted with adults, it was stated that the harm/sexual/religious dimension responded better to SRI,[13] while it was found that the contamination/cleaning dimension was found to be more responsive to pharmacotherapy in children.[14]

While many studies examined the relationship between symptom dimension and treatment response in adult OCD patients, the number of studies with children and adolescents is limited.[15] It was also observed that most studies conducted in the pediatric age group examined treatment response using four symptom dimensions, with hoarding as a separate dimension. However, because hoarding symptoms are milder in childhood, and their severity increases with age, children are diagnosed less frequently than adults.[16] In addition, hoarding symptoms in children have been reported to often occur together with symmetry/order/counting symptoms rather than alone.[17] Therefore, in this study, we examined OCD symptoms in three dimensions based on a single factor analysis conducted according to the pediatric age group: harm/sexual, symmetry/hoarding, and contamination/cleaning.[18]

This study aims to reveal the relationship between three symptom dimensions and the response to SRI treatment in pediatric OCD.

MATERIALS AND METHODS

Study design and population

This retrospective cohort study was carried out in Marmara University School of Medicine, Department of Child and Adolescent Psychiatry, a tertiary care center located in the largest city of Turkey, Istanbul, whose catchment area includes suburban districts with middle to low-income population. The universe of the study was formed by the children diagnosed with OCD between 2014 and 2018. Children were included in the study if they were between 6 and 17 years of age at initial presentation to the clinic, met diagnostic criteria for OCD for the first time between 2014 and 2018, had been followed up in our clinic for at least 3 months, had started treatment at SRI, attended at least three appointments, and had disease severity and response to treatment assessed by clinicians during follow-up. The study did not include patients diagnosed with mental retardation or autism spectrum disorder who were expected to have difficulty adhering to treatment. In our outpatient clinics, only basic supportive psychotherapy was provided in addition to pharmacotherapy and no structured CBT was applied; therefore, our study group was designated as a “CBT-free group.”

The study protocol was designed according to the principles of The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, carried out following the Declaration of Helsinki ethical guidelines, and approved by Marmara University Ethics Committee for Clinical Research (Protocol number: 09.2020.973, Date: 04.09.2020).

Data collection and variables

In our study, we obtained the data by examining the records of the outpatient clinics and collected them using the Patient Follow-up Form. We identified the factors affecting known treatment responses to account for potential confounders. The confounders we considered were age, sex, the sociocultural status of the family (educational level and employment status), stressful life events, psychiatric family history, comorbid physical and mental disorders, and OCD symptoms. Because age of onset of symptoms is prone to recall bias, we based our statistical analysis on age at first presentation. Furthermore, as we assumed that the mean age for the onset of puberty in Turkish children is 12 years, we divided the sample into two subgroups: Children (age < 12) and Adolescents (age ≥ 12).[19]

OCD diagnosis of the children was made according to the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria.[1] Obsession and compulsion symptoms were evaluated based on CY-BOCS in the first interview[4] and grouped according to a three-factor dimensional approach.[18]

Comorbid psychiatric disorders were examined in three subgroups recommended for pediatric OCD[20]: Class 1 disorders included neurodevelopmental (articulation/phonation disorder, specific learning disorder, and tic disorder) and disruptive behavior disorders (attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder), whereas depressive and anxiety disorders (generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, specific phobias, and panic disorder) were included in Class 2. Class 3 included children who had no psychiatric diagnosis other than OCD.

Clinicians examined disease severity and treatment response during the interview using the 7-item Clinical Global Impression (CGI) scale, which assesses disease severity (CGI-S) and global improvement (CGI-I).[21] CGI-S score evaluates the severity of the global symptomatology between 1 (“normal, not at all ill”) and 7 (“among the most extremely ill patients”). CGI-I score evaluates the patient’s improvement from 1 (“very much improved”) to 7 (“very much worsened”), recorded at the last post-treatment interview. In our study, in accordance with previous studies,[1322] the children whose CGI-I score was 1 (“very much improved”) or 2 (“much improved”) were considered responders to SRI pharmacotherapy.

Statistical analysis

Data were analyzed with the Statistical Package for the Social Sciences (SPSS) 20.0 for Windows (Armonk, NY, USA; 2011).[23] Categorical variables were reported as frequency and percentage. Continuous variables were analyzed for normality distribution with the Kolmogorov-Smirnov test and expressed as mean and standard deviation (SD). Univariate analysis of the differences between treatment responder and non-responder groups was performed with Pearson’s Chi-square and Fisher’s exact test.

OCD is a polysymptomatic disorder and the most patients endorse multiple obsessions and compulsions.[24] Some children are included in more than one-dimensional subgroup in our study group. Because of violations of the assumption of group independence, we did not perform omnibus tests between groups. Therefore; sex, age group, comorbid diseases, and treatment responses were evaluated separately within each symptom dimension (e.g., children with symmetry/hoarding symptoms vs children without symmetry/hoarding symptoms) by stepwise bivariate logistic regression analysis and the relative risk (RR) and confidence interval (CI) was calculated. CGI-S (baseline and post-treatment) and duration of medication use were analyzed by the Mann–Whitney U test for each symptom dimension. Differences between response rates for each symptom dimension were assessed by Chi-square, and potential predictors of treatment response (sex, age, presence of parental psychiatric history, CGI-S score at baseline, and presence of symmetry/hoarding symptoms) were analyzed using the multivariate logistic regression model. The statistical significance level was accepted as P < 0.05 for all tests.

RESULTS

Between 2014 and 2018, 642 children and adolescents with an OCD diagnosis according to International Classification of Diseases-10 (ICD-10) were recorded in the database of our clinic. The records of 153 children could not be accessed due to archival issues at the clinic, so the records of 489 children were examined. Of the files scanned, 101 did not fully meet the DSM-5 OCD diagnostic criteria, 13 were under 6 years old, and 119 had insufficient data for the study (including CGI scores). Additionally, 75 children were followed for less than 3 months and 79 patients did not receive SRI. Those who were considered ineligible for treatment were not included in the study. In total, 102 children and adolescents met the inclusion criteria.

Fifty-nine children (57.8%) were male and the mean age at first presentation was 11.84 ± 2.87. The mean follow-up period was 12.39 ± 9.55 months (median = 10, max = 40), while the mean duration of medication use was 8.10 ± 6.28 months (median = 6, max = 35). The proportion of children who had experienced a stressful life event in the year prior to admission was 29.4%. (13.7%: illness or death of a family member, 8.8%: financial loss, 5.9%: relocation, 3.9%: accident or attack, respectively). A total of 32.4% of the children had a chronic disease, including 18.6% allergic (respiratory or dermatological), 5.9% neurological, 2% rheumatological, 2% gastrointestinal, 2% skeletal deformity, 2% congenital heart disease, and 1% endocrine disorder.

Of the children, 98% (n = 100) were using a selective SRI, 65 of them were on fluoxetine (20.0% of them were taking 10 mg, 59.1% 20 mg, 9.2% 30 mg, 16.2% 40 mg, and 1.6% 60 mg), 37 on sertraline (17.2% of them took 25 mg, 62.9% 50 mg, 5.7% 75 mg and 14.3% 100 mg), 2 on escitalopram (5–10 mg), and one was using paroxetin (10 mg), while two patients were on clomipramine (75–100 mg). Five children were using the SRI combination. In addition, 24 patients were on augmentation with atypical antipsychotics, 14 of them with risperidone (0.25–2 mg), 6 with aripiprazole (2.5–5 mg), and 4 with quetiapine (25–200 mg). Antipsychotic augmentation was more common in adolescents (29.8%) compared to children (15.6%); however, that was not statistically significant (P = 0.092). According to the CGI-I score, the proportion of responders to pharmacotherapy was 66.7% (n = 68). The sociodemographic and clinical characteristics of the responder and non-responder subgroups are given in Table 1. While treatment response was worse in adolescents (response rate: 56.1%) than in children (response rate: 80.0%) (RR = 0.68, 95% CI 0.13–0.77, P = 0.013), it was found to be better in children with a positive psychiatric family history (RR = 1.17, 95% CI 1.01–6.47, P = 0.046).

Table 1

Sociodemographic and clinical characteristics of responder and non-responder subgroups

Sociodemographic and clinical characteristics	Responders (n=68) n (%)	Non-responders (n=34) n (%)	Total (n=102)	χ² or z	P
Sex (female)	41 (60.3)	18 (52.9)	59 (57.8)	0.478	0.503
Age (median (IQR))	11.66 (4.7)	13.08 (0.0)	12.7 (4.1)	−1.958	0.049a*
Age group (adolescents)	32 (47.1)	25 (73.5)	57 (55.9)	6.442	0.011*
The educational level of the mother
Secondary school and lower	40 (60.6)	21 (61.8)	61 (59.8)	0.013	0.910
High school and above	26 (39.4)	13 (38.2)
Mother’s employment status	12 (17.9)	7 (20.6)	19 (18.8)	0.106	0.745
The educational level of the father
Secondary school and lower	36 (55.4)	17 (53.1)	53 (52.0)	0.044	0.834
High school and above	29 (44.6)	15 (46.9)
The employment status of the father	61 (92.4)	28 (84.8)	89 (87.3)	1.390	0.238
Stressful life event	21 (30.9)	9 (26.5)	30 (29.4)	0.213	0.645
Death or serious illness of one of the close family members	10 (14.7)	4 (11.8)	14 (13.7)	0.166	0.684
Financial loss	4 (5.9)	5 (14.7)	9 (8.8)	2.194	0.139
Presence of chronic disease	20 (29.4)	13 (38.2)	33 (32.4)	0.806	0.369
History of mental disorder in first-degree relatives	30 (44.1)	8 (23.5)	38 (37.3)	4.110	0.043*
OCD in first-degree relatives	8 (11.8)	1 (2.9)	9 (8.8)		0.131b
Comorbid psychopathologies
Class I disordersc	35 (48.5)	18 (52.9)	53 (52.0)	0.020	0.889
Class II disordersd	25 (36.8)	13 (38.2)	38 (37.3)	0.021	0.885
Class III disorderse	21 (37.3)	6 (17.6)	27 (26.5)	2.040	0.153
Augmentation with atypical antipsychotics	14 (20.6)	10 (29.4)	24 (23.5)	0.981	0.322
CGI-S/baseline (median (IQR))	4.00 (0.0)	4.00 (0.0)	4.00 (0.0)	−0.219	0.826a
CGI-S/post-treatment (median (IQR))	1.00 (1.0)	3.00 (1.0)	2.00 (2.0)	−7.030	<0.001a**
CGI-I (median (IQR))	1.00 (1.0)	3.00 (1.0)	2.00 (2.0)	−8.570	<0.001a**

IQR=Interquartile range, CGI-S=Clinical Global Impression Severity score, CGI-I=Clinical Global Impression score. a Mann-Whitney U test, b Fisher’s exact test, cNeurodevelopmental and disruptive behavioral disorders, dAnxiety and major depressive disorder, eNo comorbid psychiatric disorder, *P<0.05, **P<0.001

The most common symptom dimension was contamination/cleaning (n = 63, 61.8%), followed by harm/sexual at 59.8% (n = 61) and symmetry/hoarding at 47.5% (n = 48). Bivariate analyses between OCD symptom dimensions and sociodemographic characteristics, comorbidity, and treatment responses are given in Table 2. CGI-S scores and response rates of symptom dimensions are shown in Table 3. Treatment response rates were lower in children with symmetry/hoarding symptoms (54.2%) than in children without symptoms (77.8%) (χ² = 6.375, P = 0.012), although duration of medication use was similar (z = −1.471, P = 0.116).

Table 2

Bivariate association of clinical features and symptom dimensions

Parameters	Harm/sexual			Symmetry/hoarding			Contamination/cleaning
	RR	CI	P	RR	CI	P	RR	CI	P
Sex (female)	1.12	0.60-2.97	0.487	1.20	0.64-3.13	0.380	1.10	0.56-2.90	0.552
Age group (adolescents)	1.36	0.93-4.66	0.072	0.98	0.43-2.10	0.916	0.98	0.43-2.16	0.933
Class I disordersa	0.81	0.27-0.60	0.202	0.84	0.50-2.39	0.818	0.84	0.28-1.42	0.266
Class II disordersb	1.48	1.17-6.70	0.021*	0.96	0.41-2.05	0.834	0.78	0.24-1.23	0.146
Class III disordersc	1.01	0.42-2.51	0.957	0.85	0.31-1.82	0.517	1.20	0.65-4.30	0.286
History of mental disorder in first-degree relatives	0.66	0.17-0.90	0.028*	0.87	0.34-1.74	0.535	1.26	0.81-4.50	0.140
Response to pharmacotherapy	1.25	0.36-1.92	0.321	0.68	0.14-0.79	0.013*	1.08	0.51-2.84	0.708

RR=Relative risk, CI=Confidence interval (95%). aNeurodevelopmental and disruptive behavioral disorders, bAnxiety and major depressive disorder, cNo comorbid psychiatric disorder, *P<0.05

Table 3

CGI Severity (baseline and post-treatment) scores and treatment response rates of the symptom dimensions

Subgroups	CGI-S (mean±SD)		Response rate
	Baseline	Post-treatment	%	χ² (P)
Harm/sexual	4.11±0.68	2.39±1.18	68.9	0.326 (0.568)
Symmetry/hoarding	4.12±0.64	2.58±1.31	54.2	6.375 (0.012)*
Contamination/cleaning	4.01±0.58	2.23±1.16	65.1	0.187 (0.666)
Overall	4.09±0.65	2.37±1.25	66.7

CGI-S=Clinical Global Impression Severity score, SD=Standard deviation, *P<0.05

To assess variables that might influence treatment response in children, sex, age group, presence of parental psychiatric history, baseline CGI-S score, and presence of symmetry/hoarding symptoms were examined using multinominal logistic regression analysis. It was determined that symmetry/hoarding dimension [β = −1.14, standard error (S.E.) = 0.47, Wald = 5.96, RR = 0.66, 95% CI (0.12–0.79), P = 0.015] and the adolescent age [β = −1.28, S.E. = 0.49, Wald = 6.68, RR = 0.65, 95% CI (0.10–0.73), P = 0.01] were associated with poorer response to SRIs (P = 0.011).

DISCUSSION

A limited number of studies have examined the relationship between OCD symptom dimensions and pharmacotherapy response in children and adolescents, and the present study makes an important contribution to the literature on this topic. Moreover, it is the first study to examine the SRI responses to pediatric OCD symptoms in three dimensions (harm/sexual, symmetry/hoarding, and contamination/cleaning), to the best of our knowledge.

In our study, one-third of the children proved to be non-responders to drug treatment, and in terms of sex, sociocultural status, and stressful life events, the subgroups of responders and non-responders were similar. Although fluoxetine was most commonly prescribed SRI, which is consistent with clinical practice in other countries,[25] there was no difference in drug treatments between the two subgroups.

In the light of our findings, the presence of symmetry/hoarding symptoms was associated with a less favorable treatment response. In adults, symmetry/hoarding symptoms were associated with worse SRI response when symmetry and hoarding were considered as a single dimension[1011] or symmetry/hoarding separately as two different dimensions.[132627] However, there is also evidence that symmetry symptoms do not differ from other subtypes in terms of response to treatment.[2829] In children, Masi et al. (2009)[14] associated hoarding symptoms with poor response to pharmacotherapy but found no difference in symmetry/ordering symptoms. Furthermore, there are conflicting results regarding the response to CBT of symmetry/hoarding symptoms.[163031] Højgaard et al. (2018),[20] using the same symptom dimensioning as in our study, revealed that the symmetry/hoarding dimension had a better CBT response. The hypothesis is that this difference in outcomes is due to the treatment modalities and the methodological differences used.

In examining the causal relationship between OCD dimensions and treatment response, it has been suggested that the symmetry/hoarding dimension is related to the dopaminergic system, including the thalamus and dorsolateral prefrontal cortex,[102832] and pathologies and activation changes in these regions may cause poor response to OCD treatment.[33] On the other hand, sexual, religious, and aggressive obsessions are more often associated with limbic system pathologies[3435] and respond better to longitudinal antidepressant treatment.[36] These psychoneurobiological evidences may be the reason why symmetry/hoarding symptoms responded worse to SRI treatment in our study.

Apart from symptom dimensions, one of the factors influencing pharmacotherapy response is age, and early presentation age has been found to be a predictor of better SRI response. The literature highlights the influence of earlier clinical presentation and pharmacological interventions on treatment response.[143738] Additionally, our study found that children with a family psychiatric disease history had a better response to treatment, although positive family history and genotypic variances such as serotonin-receptor gene polymorphisms were associated with poorer response to SRI therapy.[3940] This is thought to be due to the higher awareness of families about medication use, treatment compliance, and the follow-up process.

Many researchers worldwide have associated the presence of comorbid psychopathologies with unfavorable treatment responses.[404142] In this study, although comorbidity rates were higher in the non-responder group, the difference was not statistically significant. Furthermore, in terms of symptom dimensions, it was observed that children with harm/sexual symptoms had more depression and anxiety disorders, which is also consistent with the findings of other studies conducted with adults and children.[204344]

Several limitations should be considered when interpreting our results. First, because our study was a retrospective cohort study, not all children were followed over the same time period and researchers were unable to control for confounding factors, unlike prospective studies. Second, due to the fact that data were taken from the hospital database, insufficient data could be obtained from some children, insufficient data could be obtained from some children. Also, since some clinical features such as the age of onset were unclear in some cases, we did not include this variable in our statistical analysis. Third, this study’s generalizability is limited because it was a single-center study with a relatively small sample size, and caution should be used when interpreting the results to larger groups. Conducting multicenter and community-based studies in the future may help to clarify this issue. Fourth, disease severity and treatment response were assessed using CGI rather than CY-BOCS, unlike many other studies. This may lead to differences in our results, although the outcomes of both scales are generally correlated.[45] Finally, there was overlap among symptom dimensions, and most patients display multiple symptoms. Because the dimensions were not completely independent of each other, we were unable to examine the differences between them.

CONCLUSION

It was determined that symptom dimension and age at clinical presentation are factors that may influence pharmacotherapy response in pediatric OCD. When assessing children presenting to the clinic with OCD symptoms, consideration of these aspects is crucial to plan more appropriate treatment and provide more accurate prognostic information.

Future researchers are advised to demonstrate the relationship between symptom dimensions and SRI therapy in children through randomized controlled studies and to investigate the neurobiological and genetic basis of this relationship.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.