Abstract
To The Editor:
T
Regarding pharmacotherapy for TS, as pointed out by the two recent guidelines from Europe (Roessner et al. 2011) and Canada (Pringsheim et al. 2012), evidence for recommending specific medication was relatively weak, because rigorous experimental studies were scarce. Based mostly on open trials, case series, case reports, and expert opinions, these guidelines suggested α-adrenergic agonists and antipsychotics as two of the main treatment options because of their α2 agonism and dopamine D2 blockade, respectively. The two α2-adrenergic agonists frequently used to treat TS are clonidine and guanfacine. However, controversies exist regarding the efficacy of specific antipsychotics. This clearly reflects the complex pathophysiology of TS as well as the difficulty in its clinical management. We herein report a 15-year-old boy with severe TS and ADHD, whose tics were finally controlled by antipsychotic combination treatment with quetiapine and clozapine.
Case Report
A 15-year-old boy was diagnosed with TS and ADHD at age 9, according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria (American Psychiatric Association 2000). His tic symptoms included motor tics of eye blinking, neck twitching, shoulder shrugging, blowing air, touching earlobe, hopping, and throat clearing.
Initial treatment with clonidine 37.5 μg/day and osmotic controlled release oral delivery system (OROS)-methylphenidate 36 mg/day were prescribed. The patient was sensitive to clonidine's side effect of drowsiness; therefore, it was difficult to increase the dosage further. Clonidine was subsequently kept at 37.5 μg/day. The other α2-adrenergic agonist, guanfacine, which may cause less sedation, was unavailable in Taiwan, and could not be tried in our case. An antipsychotic with risperidone 1.5mg/day was then added 2 weeks later, and this regimen led to fair response in controlling both tics and ADHD symptoms. Risperidone had been further increased to 2.5 mg/day when the patient was 10 years of age, and to 3 mg/day when he was 11, because of worsening of tics, with subsequent control of tics.
Unfortunately, at 12 years of age, his tics worsened significantly in both severity and frequency, and caused substantial distress in daily life. He chose to wear a cap, a facemask, and even a neck collar to conceal his motor tics in public. In an attempt to alleviate his tics, OROS-methylphenidate was discontinued and replaced by atomoxetine 50 mg/day. However, the patient could not tolerate atomoxetine because of the side effects of shortness of breath and palpitations. Therefore, OROS-methylphenidate was resumed at a lower dose of 18 mg/day with the addition of clonazepam 0.5 mg/day, but the response was still unsatisfactory. OROS-methylphenidate was then discontinued because of the patient's persistent severe motor tics, and antipsychotic adjustments became the focus of pharmacological intervention.
Risperidone was first increased to 4 mg/day with substantial improvement of tics observed the next month, but the patient's tics were once again exacerbated 3 months later. Olanzapine 10 mg/day then replaced risperidone, and a marked improvement of tics was noted within 1 month; however, the patient could not tolerate the daytime sedation effect and olanzapine was discontinued 3 months later. Risperidone 4 mg/day was tried for a second time, with the patient's tics noticeably improved initially, but gradually worsened during the following 3 month period. In addition to risperidone 4 mg/day, clozapine 25 mg/day was added and gradually increased to 100 mg/day, with concurrent tapering down and final discontinuation of risperidone within a 6 month period. The patient's tics improved continuously after the medication adjustment and remained under control for another 4 months.
At age 14, the patient's motor tics became exacerbated yet again and vocal tics of coprolalia also developed. Haloperidol 3 mg/day was added while clozapine 100 mg/day was continued. Both the patient's motor and vocal tics markedly improved within 1 month but then gradually worsened in the following 3 months. We then replaced haloperidol with amisulpride 200 mg/day combined with clozapine, but no treatment response was observed. Antipsychotic combination therapy with quetiapine and clozapine was tried, with subsequent dosage adjustments. Finally, the patient's tics were well controlled by the combination of clozapine 50 mg/day and quetiapine 200 mg/day for >1 year up to the present; the patient no longer wears a facemask or neck collar in public.
Discussion
Our case report depicted a difficult clinical scenario in treating patients with Tourette's syndrome. Further examining this patient's clinical course, the repetitive exacerbations of tics was prominent in spite of continuous pharmacotherapy. The natural course of TS is usually onset at childhood, with subsequent worsening and peak at early adolescence, and then gradual decline during the second decade of life (Hassan and Cavanna 2012). Therefore, some episodes of exacerbation of this patient's tics may have been a manifestation of the natural course of his disease. During different developmental stages, there may be changes in dopamine receptor sensitivity (McDougall et al. 2014) and this may alter the response of TS to an antipsychotic agent at different ages.
A specific phenomenon noted in our case is worth discussing in detail. Loss of initial treatment response of tics was repeatedly observed with some of the antipsychotics we prescribed. We had observed obvious improvement of tics within the 1st month after switching to a new antipsychotic, but subsequent worsening after ∼ 3 months of use. This phenomenon was noted twice with risperidone 4 mg/day and again with haloperidol 3 mg/day, and a similar transient response was also noted in another case report (Piccinni et al. 2013). However, the underlying mechanism has not been elaborated, and we suspect that the loss of initial treatment response may have been the result of dopamine supersensitivity. Dopamine supersensitivity is caused by presynaptic elevation of basal dopamine release as well as postsynaptic increase in dopamine D2 receptor number and sensitivity with ongoing antipsychotic use (Samaha et al. 2007). In clinical psychiatry, dopamine supersensitivity is most often associated with “breakthrough psychosis” in schizophrenia (Seeman 2011). We believe that dopamine supersensitivity may be the cause of antipsychotic treatment failure in TS patients despite a tinitial good response.
Combination treatment with quetiapine and clozapine finally controlled the tics effectively in our case, which may be attributed to several factors. There have been conflicting reports on the effects of quetiapine (Parraga and Woodward 2001; Schaller and Behar 2002; Mukaddes and Abali 2003; Chen et al. 2014) and clozapine (Schmider and Hoff 1998; Alhamad 2003; Begum 2005; Bastiampillai et al. 2008) on tics, with good response in some patients whereas others experienced exacerbations or even new-onset tics. It is of note that reports of antipsychotic-induced tics were mainly from patients with an established diagnosis of schizophrenia or bipolar disorder. The underlying pathophysiology may be different between these patients and those with TS, and may cause a different response to the antipsychotic agent. Clozapine and quetiapine might possess additional therapeutic effects for tics because of dopamine D4 receptor (DRD4) blockade and serotonin 5-HT6 antagonism (Parraga and Woodward 2001).
A genetic study had demonstrated the association between DRD4 gene variation and the severity of tics and comorbid symptoms in children with tic disorder (Bos-Veneman et al. 2010). Impaired cholinergic neurotransmission was reported in TS patients (Kataoka et al. 2010) and antagonism at the 5-HT6 receptor increased the cholinergic output (Riemer et al. 2003), which may further improve tics. Because of different and not overlapping pharmacological profiles, combining two different antipsychotics may be a good treatment strategy for TS, with an effect superior to that of monotherapy (Piccinni et al. 2013). Finally, atypical antipsychotics may have a lower potential to cause dopamine supersensitivity than that of typical antipsychotics (Bedard et al. 2013), especially those with fast dissociation from D2 receptors, such as quetiapine and clozapine (Seeman 2011).
In conclusion, TS may progress to its peak during the second decade of life, and warrants antipsychotic treatment at least for several years. Dopamine supersensitivity may cause the loss of initial treatment response. Therefore, prescribing antipsychotics with a lower potential for causing dopamine supersensitivity, or switching antipsychotics periodically, may be effective strategies for successful long-term treatment for TS.
Disclosures
No competing financial interests exist.