Pharmacological studies
To date, no compound has been specifically marketed for the treatment of tics. Ecopipam, a selective D1 receptor antagonist, might be one of the first drugs to be commercialized for this purpose. After two first proof of principle studies \citep{Gilbert2014,Gilbert2018}, Gilbert and colleagues have now published the results of a phase 2b trial (D1AMOND study) in individuals with TS \citep{36628546a}. Seventy six patients were randomized to ecopipam and 77 to placebo. Total tic scores as assessed by the YGTSS were significantly reduced (by around 30%) in the ecopipam group, as well as secondary outcome measures. Importantly, no metabolic side effects were reported. A phase 3 trial is now underway (NCT06021522).
The results of the CANNA-TICS study appeared in early 2023 \citep{36878177}. The authors performed a randomized, controlled trial of nabiximols in 97 adults with TS or chronic motor or verbal tic disorder. Befitting the study investigators' a priori view of the literature, people were randomized to drug or placebo in a 2:1 ratio. The primary, predefined efficacy endpoint was a tic reduction of at least 25% on the YGTSS total tic score after 13 weeks of treatment, a magnitude of change recognized as clinically meaningful improvement by an expert panel. The study did not show significant improvement by this measure. However, there were some indications of improvement, including a higher response rate (22% vs 9%) in the nabiximols group, a significantly greater reduction in self-reported tic severity on the Adult Tic Questionnaire, a numerically greater improvement of tics on a standardized video rating scale, and trends for improvement in quality of life and in impairment due to tics. There were no serious safety issues, with side effects of similar severity in 95% of those in the active drug group versus 79% of those in the placebo group (p=.03). Patients with ADHD or with worse general health were most likely to improve. Thirteen percent of patients at the site that enrolled over half the participants reported intentional or accidental unblinding on an end-of-study interview. Of course, other participants likely suspected their drug assignment; a forced-choice blindedness assessment is not reported. In sum, a reasonably large RCT showed hints of superiority for nabiximols over placebo, but the study did not meet the pre-specified treatment target. The authors are to be commended for timely publishing a technically negative study, but one with important clinical implications. In contrast, a small cross-over RCT (N=22) showed significantly more improvement in tics with a THC + CBD combination than with placebo, YGTSS decrease being 8.9 (±7.6) in the active group and 2.5 (±8.5) in the placebo group \citep{Mosley2023}. The main side effects were cognitive / sedative in nature.
A 2-year naturalistic study with 1,410 participants (1,147 with ADHD, the rest without ADHD) provided important information relevant to the safety of methylphenidate (MPH) in tic patients \citep{36958362}. Their main goal was to see if the stimulant, which suppresses appetite, suppressed growth. There was no significant difference in growth among children in or out of the MPH group. Blood pressure and pulse were significantly higher in the MPH group, but only trivially (about 1 mm Hg and 1 beat per minute after correcting for baseline differences). Tic prevalence decreased significantly in all 3 groups, more in the ADHD groups. There was slightly less tic improvement at 12 months in the group taking MPH (< 2 points on the YGTSS) but no significant difference at 6 months. Note that randomized, placebo-controlled studies show that tics actually improve, on average, on MPH \citep*{Black_2024}. In summary, MPH is relatively safe in ADHD.
Neurosurgery
Several notable papers were published this year about deep brain stimulation (DBS) in TS. Rusheen and colleagues investigated the effect of centromedian (CM) thalamic DBS on modulating dopamine activity in the dorsomedial striatum, using a comprehensive approach combining electrophysiology, electrochemistry, optogenetics and behavioural measurements \citep{Rusheen_2023}. They found that CM DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons, while inactivation of D2 receptors reduced clinical response. This pivotal study suggests that tic improvement with thalamic DBS is mediated by D2 receptor activation, providing further evidence of the involvement of dopamine dysfunction as a crucial factor for motor tics in TS.
There is ongoing debate around the most relevant target for DBS in TS, the commonly accepted view being that different structures within a common basal ganglia-thalamo-cortical network may serve as potential targets. In a retrospective study using MRI tractography in 21 patients, Avecillas and colleagues investigated the basal ganglia-thalamo-cortical networks associated with tics and obsessive compulsive behaviors (OCB) improvement in patients treated with either anteromedial globus pallidus (amGPi) or thalamic ventral-oralis complex / centromedian (Vo/CM) DBS \citep{Avecillas_Chasin_2023}. The networks associated with clinical improvement of tics consisted of a limbic pallidothalamic network for the amGPi target, and the premotor thalamocortical network for the thalamic target, both of which being part of a larger “limbic-motor interface network”. Notably, analysis of the volume of tissue activated by DBS in non-responders showed that the stimulation missed the tracts associated with this specific network. This study reinforces the idea that stimulating this network either at its origin (amGPi), or terminal fields (Vo) can lead to substantial tic improvement. Improvement in OCB was related to the connectivity between the dorso-medial prefrontal cortex (dmPFC)/dorsal anterior cingulate (dACC) and CM. The fact that tics and OCB improvement may be linked to the stimulation of distinct networks questions the relevance of targeting more than one structure.
Najera and colleagues reported on two patients with severe GTS and OCD who underwent dual-targeting DBS in both the ventral capsule / ventral striatum (VC/VS) for OCD, and posteroventral GPi for tics \citep{Najera_2023}. Both patients experienced sustained improvement in both tics and OCB.