Alternative Treatment of the Resistant-to-Treatment Tourette Syndrome-A Systematic Review

Background: Tourette syndrome (TS) is a chronic neurodevelopmental disorder with a significant rate of patients remaining refractory to standard treatments. Refractory TS is defined as the persistence of clinically significant tics causing functional impairment despite adequate trials of both behavioral therapy and at least two generally accepted pharmacological treatments from different classes, administered at appropriate doses and durations. This systematic review synthesizes the current evidence on alternative pharmacological and non-pharmacological interventions for treatment-resistant TS. Methods: The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, Embase, and Scopus were searched for studies published from 2010 onward. Eligible publications included randomized and non-randomized clinical studies, and case reports evaluating alternative interventions in refractory TS, excluding deep brain stimulation. The primary outcome measures included validated scales assessing tic severity and functional impairment, with available data demonstrating reductions in tic severity, including clinically meaningful improvements reported in several studies. Thirteen studies met the inclusion criteria, comprising five clinical studies (including three randomized trials) and eight case reports. Heterogeneity across studies was primarily driven by differences in study design, patient populations, and variability in intervention types, protocols, and outcome assessments. Results: Investigated interventions included cannabinoids, valproic acid, deep transcranial magnetic stimulation, neurofeedback, biofeedback, electroconvulsive therapy, and ablative neurosurgical procedures. Cannabinoid-based treatments showed potential reductions in tic severity; however, results were inconsistent and often not statistically significant, with evidence largely derived from small or uncontrolled studies. Evidence for non-pharmacological approaches was limited and largely derived from individual cases, with some modalities showing potential benefit in specific subgroups, such as patients with comorbid obsessive-compulsive disorder. Conclusions: Overall, alternative interventions may offer therapeutic value for selected individuals with treatment-resistant TS, with the greatest data regarding cannabinoid use; however, the current evidence base remains heterogeneous and methodologically constrained. Deep transcranial magnetic stimulation might be beneficial in a specific patient population. Larger, well-controlled studies are required to clarify efficacy, safety, and treatment response.