Increasing knowledge about the neurochemical and neurophysiological abnormalities underlying tics has suggested rational, potentially beneficial new pharmacologic approaches. Dopamine agonists pergolide and ropinirole have been reported to improve tic severity in reported trials.67,68
Benefit from low doses of dopamine agonists has been presumed to be mediated by presynaptic receptors in the striatum.69
However, recent data from functional MRI studies suggest that dopamine can restore faulty inhibitory function in the frontal cortex of individuals with TS.70,71
A placebo-controlled trial of the dopamine agonist pramipexole is in progress. Calcium channel antagonists may have activity at dopamine receptors, either through direct blockade or by reducing depolarization of midbrain dopamine neurons.72
Nifedipine, verapamil, and flunarizine have had individual reports of benefit, which have not been confirmed in a research trial.73–75
Antipsychotic drugs have varying effects on glutamate receptor trafficking,76
and a study of postmortem putamenal tissue suggested that a subtype of glutamate metabotropic receptor may be abnormally expressed in TS.77
Dopamine receptors in the frontal cortex, modulated by acetylcholine and glutamate, may have important inhibitory functions that oppose the prokinetic function of striatal dopamine receptors.71,78,79
Therefore, drugs which modify cholinergic neurotransmission at CNS nicotinic receptors or glutamatergic activity at N-methyl D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors may be rational for study. Drugs of interest with activity at glutamate receptors include D-serine, D-cycloserine, sarcosine, modafanil, riluzole, memantine, and talampanel.
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter released by the globus pallidus internus through its connections with the thalamus. Increased activity would be expected to reduce motor output and thus might reduce involuntary movements such as tics. Unfortunately, to date the studies of GABA-A and GABA-B receptor modulators (benzodiazepines, baclofen) have not produced good results. One randomized trial reported that the GABA-B agonist baclofen had benefit over placebo for TS, although most of the improvement was for perceived impairment from tics, rather than severity of the tics themselves.80
Levetiracetam is a medication of interest given its activity at GABA receptors. Although promising in open-label fashion,81
it has shown conflicting results in two randomized trials.82,83
Other drugs known to enhance GABA activity include topiramate, tiagabine, vigabatrin, zonisamide, zolpidem, pagaclone, and ganaxolone.
Cortical 5HT-2A receptor density may be increased in TS.84
It is possible that some of the benefit for tics from the atypical antipsychotics risperidone50
is mediated, in part, by their respective 5HT-2 and 5HT-3 receptor blockade. There has been one open-label study report of benefit for tics from the 5HT-2 antagonist ketanserin,85
and one small placebo-controlled report of benefit for the 5HT-3 antagonist ondansetron.86
Similar to the study of baclofen, the latter showed more benefit for the global quality of life ratings than for tics.
Anecdotal reports from TS patients that marijuana use ameliorates their tics may have scientific relevance given evidence that basal ganglia cannabinoid receptors modulate dopamine, glutamate, and GABA activity governing motoric output.87
Delta-9-tetrahydrocannabinol has shown promise for efficacy88
in a small placebo-controlled crossover study. Further studies using drugs acting on cannabinoid receptors, such as dronabinol or nabilone, may be rational.
Given the 4:1 male to female predominance in TS89
and the typical peak of symptoms around puberty,90
a role for androgens has been proposed.91,92
Mild tic reduction was reported for the androgen blocker flutamide in a placebo-controlled crossover trial. Finasteride had dramatic benefit reported for one case of neuroleptic-refractory TS with comorbid self-injurious tics and compulsions.93