Participants and treatment
The randomised clinical trial is described in [11]. In brief, children and adolescents (N = 102, age 9–17 years) were referred to the Department of Children and Adolescent Psychiatry, Aarhus University hospital, Denmark (described in the included flowchart). Children and adolescents were assessed using a modified version of the Schedule for affective disorders and schizophrenia for school-age children–present and lifetime version (K-SADS-PL) ([20]) administered to the parents and child/adolescent separately. The K-SADS-PL information was used to confirm a primary diagnosis of chronic tic disorder, to diagnose any comorbidities such as obsessive compulsive disorder, affective disorder, psychosis, anorexia, anxiety disorders, planning difficulties (ICD-10 code: DF83.9), and to ensure that none of the exclusion criteria were met [11]. The inclusion and exclusion criteria were chosen as to ensure that the study would be representative of clinical practice. Exclusion criteria included disorders that required immediate treatment: psychotic disorder, primary severe depression, suicidal ideation or attempts, primary severe anorexia nervosa. Furthermore, children and adolescents were excluded if their IQ was below 70, they had a life-time diagnosis of pervasive developmental disorder, or if they had been treated with HRT or ERP during the last 6 months.
The children and adolescents (N = 59, age 9–17 years) with a primary diagnosis of either Tourette syndrome or chronic motor or vocal tic disorder as described in the WHO ICD-10 diagnostic criteria and the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, Text Revision, and of moderate or greater severity corresponding to a total score on the Yale Global Tic Severity Scale (YGTSS) [18] higher than 13 (higher than nine if only motor or vocal tics were described) [6], and who did not meet the exclusion criteria were offered manualised treatment constituted by a combination of habit reversal training (HRT) and exposure response prevention (ERP) either as an individualized treatment or in a group setting [11]. The therapeutic treatment was based on the newly developed manual adapted by the individual treatment manuals by Woods et al. [21] and Verdellen et al. [22]. The manual described a nine-session therapy for either individual or group treatment. In both settings, participants trained in HRT for 2 sessions, and ERP for two sessions. In the following sessions, the participants trained in both treatment modalities depending on the presented tic symptom. There were 2 weeks between the first six sessions. Hereafter, there were 3 weeks between the next three sessions, and between session 8 and the delayed booster session 9, there were 8 weeks. The parents participated in the last 15 min of each individual session, or in the end of the second, fourth, eighth and ninth session in the group setting. The total number of the participants who completed all sessions was 54. They were all contacted 6 and 12 months after the 8th session. Completers of follow-up were defined as participants who were assessed at 12 months follow-up.
The study was approved by the National Ethical Committee (1-10-72-216-15) and the Danish Data Protection Agency (1-16-02-490-15), registered 12 October 2015. Oral and written information was given to parents and patients, and written consents from patients over 15 years of age and parents were received.
Evaluations and assessments
Evaluations were conducted at the 8th session (acute outcome), after the 9th session (8 weeks delayed booster session), and 6 and 12 months after the 8th session. The main outcome measures were TTS (motor score + vocal score) and FI as evaluated by YGTSS, and a positive therapeutic improvement, defined as a more than 25% reduction in severity scores [23]. Evaluations of treatment response were made by an independent evaluator who was not blinded to the treatment allocation, yet not involved in the treatment of the patient, and blinded to any previous evaluations.
The YGTSS is a clinician-administered semi-structured interview including a checklist of all tics present in the past week. It covers five dimensions divided into ten items including the number, frequency, intensity, complexity and interference of motor and vocal tics. Furthermore, it includes a separate evaluation of the functional impairment. The scores are summed to yield separate motor and vocal tic scores (0–25) and a combined total tic score (0–50). The functional impairment scale (range 0–50) rates the tic-related disability over the past week [18, 23].
The parents and the children/adolescents were furthermore asked to complete Screen for Child Anxiety Related Emotional Disorders (SCARED) [24], the Mood and Feelings Questionnaire (MFQ) [25], the Premonitory Urge Scale (PUTS) [26] and Beliefs About Tics Scale (BATS) [27]. Furthermore the parents completed SCARED, the MFQ, Child Behaviour Checklist (CBCL) [28], and Sensory Profile [29].
SCARED [24] includes separate versions for parents and the child/adolescent. Using 41 items rated on a three-point scale, the questionnaire assesses the occurrence of anxiety symptoms based on DSM-IV. Scores range from zero to 82.
MFQ assesses the occurrence of depressive symptoms, using 13 items rated on a three-point scale [25]. Scores range between 0 and 26, where high scores indicate a severe functional impairment.
PUTS is a short self-reporting scale with nine items [26]. It measures the tic-related premonitory urge. The scale was developed by D. Woods and colleagues, US. For this project, the scale was translated into Danish by the principal investigator (J. Nissen). After a re-translation into English, the scale was approved by D. Woods, US.
BATS is a self-reporting scale with 20 items developed to assess the different beliefs children and adolescent experience in relation to tic symptoms and to suppressing their tic symptoms [27]. The scale was developed by T. Steinberg, A. Apter and colleagues, Israel. For the present study, the scale was translated into Danish by the principal investigator (J. Nissen). After a re-translation to English, the scale was approved by Dr. Steinberg, Schneider Children`s Medical Center, Israel.
CBCL is a parent questionnaire evaluating behavioral and emotional problems in children and adolescents [28]. The questionnaire is used in the age range 6–18 years. CBCL has 113 items rated on a three-point scale. The results are depicted both in a total problem scale and several subscales.
The Dunn Sensory Profile 2 was used to access any sensory challenges. It is a collection of questionnaires for different age groups [29]. The aim of the questionnaires is to assess children's responses to commonly occurring sensory events and to evaluate the ability to process the sensorimotor impressions. The questions are grouped into three main areas: sensory processing, sensory modulation and behavior, and emotional response.
Statistics
Two-sample t-tests were used to compare outcome scores at baseline and after 8 weeks of treatment of completers and non-completers of follow-up, between individual and group setting at 6 and 12 months, and between therapeutic improvers and non-therapeutic improvers at 12 months. A positive therapeutic improvement was defined as a more than 25% reduction in severity scores [24]. The association between group setting and TTS and FI over time was assessed using mixed linear regressions models with a random intercept to account for the repeated measurements within subject. The association between TTS and BATS, PUTS, SCARED and MFQ over time were assessed using the latter approach.
Response trajectories based on TTS score at all time points were estimated using a semi-parametric group-based trajectory model (GBTM) for repeated measurements [30, 31]. The GBTM was fitted using the Stata Plugin TRAJ for estimating group-based trajectory models. TTS score were modelled using the censored normal distribution [31, 32].
The models were tested with one to four trajectory groups to identify the optimal number of groups to fit the data. In the initial model, trajectory group orders were examined as quadratic models. Each participant was assigned exclusively to the trajectory group for which s/he had the highest posterior probability of group membership. The best fitting model was selected on the basis of the following criteria: (1) a group size of at least 5% of the analysed population, (2) the highest possible Bayesian Information Criterion (BIC) and Akaike Information Criterion (AIC), (3) a minimum average posterior probability (AvePP) of 0.7 for group membership, (4) an odds of correct classification (OCC) above 5, and (5) agreement between the estimated probability of group membership and the proportion assigned to each group according to the maximum posterior probability assignment rule.
When criterion 1 (group size) was fulfilled, the best fitting model was identified on the basis of a simultaneous evaluation of the remaining criteria. Once the best fitting model was chosen, the shape of the trajectory of each group was investigated and it was found that a cubic shape resulted in the best fitting model. GBTM uses the maximum likelihood method to estimate model parameters. This will generate asymptotically unbiased parameter estimates assuming the data are missing at random (MAR) [32].
Odds ratios (ORs) and 95% CIs were determined for the association between age, gender, group setting, ADHD, planning difficulties, hypersensitivity, having OCD, Anxiety, PUTS, BATS and CBCL and response trajectory group using logistic regression models. The lesser responder trajectory group was used as reference in the analyses.
The association between BATS and PUTS and trajectory group over time was assessed using mixed linear regressions models with a random intercept to account for the repeated measurements within subject. The between trajectory group differences at all time points were assessed using chi square statistics. All analyses were undertaken using Stata 16.1 (StataCorp, Texas, USA).
