Pharmacological studies

Other

Treatment

Psychological interventions

Behaviour therapy (BT) is recommended as the first-line intervention for TS/CTD in treatment guidelines published by the American Academy of Neurology (AAN)\cite{Pringsheim_2019} and the European Society for the Study of Tourette Syndrome (ESSTS).\cite{M_ller_Vahl_2021} Two types of BT are recommended, of which Habit Reversal Training (HRT) and its extended package Comprehensive Behavioral Intervention for Tics (CBIT) has the strongest evidence base. The second recommended BT-intervention, Exposure and Response Prevention (ERP), has comparatively less support to date, but is especially popular among clinicians and researchers in Europe.\cite{Andrén2022} 
Remote delivery of BT has become increasingly popular within the last years as a way to make BT more accessible to healthcare seeking individuals with TS/CTD. Several new studies on remote delivery of BT were published in 2022. The by far largest study was conducted in Sweden by Andrén et al.,\cite{Andrén2022a} where 221 young individuals were randomized to therapist-supported, internet-delivered ERP or therapist-supported, internet-delivered psychoeducation (comparator). The results showed that both groups improved on the primary outcome (tic severity as measured by the Yale Global Tic Severity Scale - Total Tic Severity Score [YGTSS-TTS]) from baseline to the primary endpoint (3 months post-treatment). YGTSS-TTS reductions were 6.1 points (27%) in the ERP group and 5.3 points (23%) in the comparator. Contrary to the similar ORBIT study conducted in the UK,\cite{Hollis2021} there was no significant interaction of group and time on the primary outcome. However, treatment response rates at the 3-month follow-up were identical in both studies, with significantly more treatment responders in ERP (47%) than in the comparator (29%). The authors concluded that both internet-delivered interventions may be efficacious for young individuals with TS/CTD. Long-term follow-up data will be published in a future publication.
Internet-delivered BT has also recently been evaluated in Israel. Originally published in 2020, Rachamim et al. compared internet-delivered CBIT to waitlist in a randomized controlled trial (RCT) of 41 youth with TS/CTD.\cite{Rachamim2022} The results showed that internet-delivered CBIT was feasible to implement and superior to waitlist. In a new analysis of the same data published in 2022,\cite{Rachamim2021} the authors focused on 27 treatment completers with comorbid attention deficit hyperactivity disorder (ADHD; n=16) or comorbid obsessive-compulsive disorder (OCD; n=11). This new analysis showed that, like the complete sample, tic severity (YGTSS-TTS) improved in both the ADHD and the OCD groups, although the OCD group improved significantly less than participants without comorbid OCD.
Another way of delivering BT remotely is through videoconferencing, a format which increased in popularity worldwide during the COVID-19 pandemic. In an Italian RCT conducted by Prato et al.,\cite{Prato2022} 40 youth with TS were randomized to BT (HRT or ERP) delivered face-to-face at a clinic or remotely via videoconference. Participants improved on the YGTSS-TTS in both groups, in line with previous studies.\cite{Himle2012}\cite{Ricketts2016} This did however not, contrary to the authors’ claim, indicate that the two interventions were to be considered as equally efficacious, since the study lacked a pre-defined non-inferiority aim. The videoconference format was also partly used in a naturalistic study of ERP conducted at a TS/CTD specialist clinic in Denmark. In this study by Sørensen et al., \cite{Soerensen2023}\cite{Soerensen2023a} 116 youth received ERP (either face-to-face [n=72] or via videoconference [n=44]) and were followed up one-year post-treatment. The study showed significant short- and long-term tic severity reductions (YGTSS-TTS) in both groups, with no significant between-group differences. Participants who completed the planned ERP sessions or discontinued early due to a satisfactory tic reduction, improved significantly more than participants who dropped out due to lack of motivation. Firm conclusions are limited by the open design, but the study overall provides support for both face-to-face and videoconference delivery of ERP.
Another way to make BT more accessible is the group format, where the simultaneous treatment of several individuals by one therapist may save therapist resources. Based in the Republic of Korea, Kang et al. \cite{Kang2022} conducted a non-randomized controlled study (N=30) comparing group-CBIT (n=18) to a supportive psychotherapy and psychoeducational control condition (n=12). Overall, the baseline TS/CTD severity of the sample was mild. The CBIT group showed modest improvements, with the clearest result being superiority over the comparator in reducing tic-related impairment. The study provided some preliminary support to the feasibility of providing CBIT in a group format in this Korean context. Also published in 2022, Inoue et al. \cite{Inoue2022} evaluated group-CBIT in a case series (N=3) in Japan. In this study, group-CBIT was delivered via videoconference software, to further increase accessibility of BT to individuals in the region. The results showed an average tic severity reduction (YGTSS-TTS) of 7 points from baseline to post-treatment. Overall, the treatment was concluded feasible, acceptable, and promising for further evaluation.
A few studies on face-to-face CBIT were also conducted in 2022. In a US study, Greenberg et al.\cite{Greenberg2023} evaluated a modified CBIT intervention, which also included the treatment of comorbid ADHD and associated psychosocial impairment (from both TS/CTD and ADHD). Seventeen young participants with both TS/CTD and ADHD were randomized to modified CBIT (n=9) or a traditional CBIT comparator (n=8). The results showed significant improvements in tic severity, tic-related impairment, and ADHD severity for both groups, but the study was likely underpowered to detect between-group differences. Overall, the results indicated feasibility and acceptability for this modified treatment for youth with TS/CTD and ADHD. In a Chinese RCT, Xu et al. \cite{Xu2022} recruited 37 youth with TS/CTD to compare face-to-face CBIT (n=12), face-to-face CBIT combined with pharmacotherapy (n=10), and pharmacotherapy alone (n=15). Tic severity (YGTSS-TTS) improved for all three groups between baseline and post-treatment. Although the approach of comparing BT and pharmacotherapy is relatively novel for the TS/CTD field, the study lacked sufficient power for between-group comparisons.
Lastly, interest in investigating the underlying working mechanisms of BT has increased in later years. In a study of 80 adults with TS, Ramsey et al. \cite{Ramsey2022} concluded that higher levels of premonitory urge intolerance predicted greater levels of tic severity and tic-related impairment. This result highlights a potential clinical implication of targeting the concept of urge intolerance, rather than for instance urge severity, in BT. In an RCT including 53 youth, McGuire et al. \cite{McGuire2022} investigated the relationship between several pre-selected cognitive control processes and face-to-face CBIT outcomes. The results showed that only one of the investigated processes – baseline inhibition/switching (as measured by the D-KEFS Color Word Interference Test) – predicted post-treatment tic severity. Morand-Beaulieu et al. \cite{Morand-Beaulieu2022} conducted a similar RCT (N=32), although instead focusing on underlying brain mechanisms – particularly EEG coherence. Face-to-face CBIT was superior to the treatment as usual comparator, but EEG coherence during a Go/NoGo task was not associated with the tic severity outcome. In a small open study by Eapen et al. (N=17), \cite{Eapen2022} tic severity significantly improved following face-to-face CBIT. Further, the study showed preliminary support for neurophysiologic changes in cortical inhibition as a potential underlying working mechanism. To summarize, considering that CBIT is a package of numerous behavioral exercises, several underlying mechanisms may be part of explaining how and why the treatment works.