Tourette's Syndrome - Treatment

First of all, the doctor must decide whether treatment of Tourette syndrome is indicated for the given severity of symptoms. Drug trials for Tourette syndrome are complicated by the wave-like course with exacerbations and remissions, which do not necessarily occur under the influence of drugs. Short-term fluctuations in the severity of symptoms do not necessarily require immediate changes in the treatment of Tourette syndrome. The general goal of treatment is to partially alleviate symptoms: complete drug suppression of tics is unlikely and is associated with the occurrence of side effects.

Special educational programs are needed for the patient, his family, and school personnel to promote understanding of the disease and development of tolerance to symptoms. Comorbid disorders may be the main cause of discomfort and impaired social adaptation. Adequate treatment of comorbid ADHD, OCD, anxiety, and depression sometimes reduces the severity of tics, probably due to improvement of the psychological state of the patient and stress relief.

Neuroleptics and other antidopaminergic agents

For nearly three decades, dopamine D2 receptor antagonists such as haloperidol and pimozide have been the mainstay of treatment for Tourette syndrome. In about 70% of patients, these drugs initially produce clinically significant tic suppression. However, long-term follow-up shows that only a minority maintain sustained improvement. For many years, haloperidol was the treatment of choice for Tourette syndrome, partly because it was the drug that had proven successful in Tourette syndrome and also because it was considered safer than pimozide.

Tourette's syndrome is also treated with other effective antidopaminergic agents, including fluphenazine and sulpiride, risperidone, and tetrabenazine. Encouraging results have been obtained in open studies with fluphenazine, a phenothiazine neuroleptic. Sulytiride, a selective dopamine D2 receptor antagonist structurally related to metoclopramide, has also been reported to be effective in tics. However, side effects associated with increased prolactin production may become a significant problem when using the drug. Ambiguous results have been obtained in treating children and adolescents with Tourette's syndrome with tiapride, which is structurally related to sulpiride. Tetrabenazine, which depletes presynaptic monoamine stores, was moderately effective in Tourette's syndrome in an open study. However, significant side effects have been noted with its use: Parkinsonism in 28.5% of cases and depression in 15% of cases.

Recently, a new generation of neuroleptics has been introduced into the practice of treating mental illnesses. This group includes clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. Treatment of Tourette syndrome with clozapine has proven ineffective, but encouraging results have been obtained in several open studies with risperidone. The affinity of risperidone for dopamine D2 receptors is approximately 50 times higher than that of clozapine. The incidence of extrapyramidal side effects and tardive dyskinesia with risperidone is lower than with typical neuroleptics. However, a comparative study of the effectiveness of risperidone and other neuroleptics has not been conducted. Thus, at present, the main advantage of risperidone is its better tolerability and greater safety.

A double-blind, placebo-controlled study showed the efficacy of olanzapine isiprasidone in Tourette syndrome. There are currently no studies on the efficacy of quetiapine in Tourette syndrome, although some physicians have reported success with it. However, the overall role of these atypical antipsychotics in the treatment of Tourette syndrome remains unclear.

Mechanism of action

Although antipsychotics have complex effects on many types of receptors belonging to different neurotransmitter systems, their primary mechanism of action in Tourette syndrome is probably related to the blockade of dopamine D2 receptors in the brain. This ability is inherent in all antipsychotics that suppress tics. Pimozide and fluphenazine also block calcium channels - this may be the reason for the ECG changes observed with treatment with these drugs. Risperidone has a two-fold lower affinity for dopamine D2 receptors, but is 500 times more potent at blocking serotonin 5-HT2 receptors than haloperidol. Tetrabenazine reduces dopamine stores in presynaptic vesicles.

Side effects

Side effects often limit the therapeutic potential of neuroleptics and are the reason for low patient compliance and treatment discontinuation. Side effects such as fatigue, intellectual dullness, and memory loss may be the cause of low performance and poor school performance. Weight gain increases the patient's dissatisfaction with their appearance (in addition to the problems caused by the disease itself). Liver dysfunction has recently been reported in young men taking risperidone, which developed following the onset of excess weight. Ultrasound examination revealed signs of fatty liver. Extrapyramidal side effects are apparently related to blockade of dopamine D2 receptors in the caudate nucleus and substantia nigra and include akathiea, parkinsonism, and muscular dystonia. In studies in adults, extrapyramidal side effects were observed relatively rarely, while an increased risk of dystopia was found in children. Prolactin secretion is under the inhibitory tonic control of the dopaminergic system and is enhanced by taking dopamine receptor blockers. Increased prolactin levels can cause breast swelling, galactorrhea, amenorrhea, and sexual dysfunction. Prolactin levels can be a useful guide to pimozide therapy: they allow timely limitation of the drug dose and prevention of extrapyramidal side effects. When taking neuroleptics for more than 1 year, tardive dyskinesia develops in 10-20% of patients. Its risk is higher in children, elderly women, African Americans, and patients with affective disorders. Tardive dyskinesia can be difficult to recognize against the background of tics. Cases of school phobia in children after the start of neuroleptic therapy have been described. Dysphoria is a common side effect of neuroleptics, but true depression is a significant problem only when taking tetrabenazine. When taking pimozide, ECG changes (prolongation of the QTc interval) have been noted. This has led experts to recommend regular ECG monitoring and limiting the daily dose of the drug to no more than 10 mg. In addition, when taking pimozide at a dose exceeding 20 mg/day, the risk of epileptic seizures increases.

Contraindications

Neuroleptics are contraindicated in Parkinson's disease, CNS depression and hypersensitivity to drugs. It is not recommended to use neuroleptics during pregnancy and breastfeeding - in these circumstances, the drugs can be used only for very severe tics, when the benefit of their suppression may outweigh the risk to the child. Pimozide and, possibly, fluphenazine can cause cardiovascular dysfunction due to calcium channel blockade. Pimozide is contraindicated in congenital long QT syndrome, cardiac arrhythmias. It cannot be combined with macrolide antibiotics (clarithromycin, erythromycin, azithromycin, dirithromycin) or other drugs that prolong the QT interval

Toxic effect

Overdosage of neuroleptics may result in epileptic seizures, cardiac arrhythmias, and other life-threatening conditions. Malignant neuroleptic syndrome is rare, but it is serious and may develop even with normal therapeutic doses of drugs. A drop in blood pressure, sedation, and severe extrapyramidal complications such as acute dystonia and rigidity are also possible. Cases of sudden death in patients with schizophrenia have been reported when taking pimoeide in high doses (80 mg/day).

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Alpha2-adrenergic receptor agonists

Clonidine and guanfacine are used primarily as antihypertensives. However, clonidine has been used for a number of years to treat tics and ADHD. Many clinicians consider clonidine to be the drug of first choice because it does not cause severe neurological complications such as early extrapyramidal syndromes or tardive dyskinesia. However, placebo-controlled studies have shown that it is ineffective or only partially effective in some patients. Clonidine has the greatest effect on motor tics. The effect of clonidine is often delayed and does not become apparent until 3-6 weeks later. However, the main benefit of clonidine is the improvement of associated behavioral disorders such as hyperactivity, increased vulnerability, sleep disturbances, and aggression, which are common in patients with Tourette syndrome and ADHD. However, many patients cannot tolerate clonidine because of its sedative effect and orthostatic hypotension. Of particular concern is the potential for severe symptoms to develop if the drug is suddenly discontinued (eg, due to poor patient compliance) and recent reports of sudden death in children taking clonidine.

Recently, it has been shown that treatment of Tourette syndrome and ADHD with guanfacine may be more effective and cause fewer side effects than clonidine. The ability of guanfacine to reduce associated behavioral disorders has been proven not only in open but also in placebo-controlled studies.

Mechanism of action

At low doses, clonidine has a stimulating effect on presynaptic alpha2-adrenoreceptors, which function as autoreceptors. At higher doses, it also stimulates postsynaptic receptors. The mechanism of action of the drug is associated with the ability to inhibit the release of norepinephrine. In addition to the effect on the noradrenergic system, it probably has an indirect effect on the activity of dopaminergic systems, as evidenced by studies of the level of homovanillic acid - HMA.

Side effects

The main adverse effects of clonidine are drowsiness, dizziness, bradycardia, constipation, dry mouth, and weight gain. Irritability and dysphoria sometimes develop in children soon after starting treatment. Cases of depression appearing or worsening have been reported. Abrupt discontinuation of clonidine may cause a rebound increase in blood pressure, tachycardia, psychomotor agitation, muscle pain, increased sweating, salivation, and possibly a manic-like state. Cases have been described of a sharp increase in tics upon discontinuation of clonidine, which persisted for a long time despite reintroduction of clonidine. A few cases of sudden death in children have been reported during or after clonidine use. However, in most of these cases, other factors may have contributed to the death, and the role of clonidine remains unclear.

Contraindications

Clonidine should be avoided in patients with myocardial or valvular disease (especially with left ventricular output restriction), syncope, and bradycardia. Renal disease (due to increased risk of cardiovascular disease) is a relative contraindication. Careful examination for cardiovascular disorders is necessary before treatment, and regular monitoring of pulse, blood pressure, and ECG is recommended during treatment.

Toxic effect

Serious side effects may occur with sudden withdrawal or overdose of clonidine. Children may be particularly at risk in these situations. Withdrawal syndrome often occurs when parents do not understand the importance of strictly following the doctor's instructions and the child misses several doses of the drug. Overdose may occur when clonidine tablets are confused with tablets of another drug, such as methylphenidate, resulting in the child taking three tablets instead of one. Even minimal doses of clonidine (eg, 0.1 mg) can have a toxic effect in children. Symptoms of overdose include bradycardia, CNS depression, hypertension alternating with hypotension, respiratory depression, and hypothermia.

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Treatment of Tourette syndrome with other drugs

Although tricyclic antidepressants only slightly reduce tics, they are useful in the treatment of patients with mild tics who also suffer from VHD, depression, or anxiety. Tricyclic antidepressants are also recommended when tics are accompanied by nocturnal enuresis or sleep disturbances. Their use may cause tachycardia and ECG changes (increased QRS, PR, QTc intervals) with a potential risk of cardiotoxicity. Therefore, regular monitoring of ECG, plasma drug levels, and vital signs is required. The possibility of interactions between tricyclic antidepressants and other drugs should also be taken into account. Seven cases of sudden death, possibly associated with the use of desipramine and imipramine, have been reported. Selegiline may also be useful in the combination of tics and VHD.

Open studies have shown that nicotine can potentiate the effect of neuroleptics on motor and vocal tics in Tourette syndrome. Scientists noted a significant reduction in the severity of tics after 24 hours of using a nicotine patch. The improvement lasted an average of 11 days (if the treatment of Tourette syndrome was not disrupted). In other open studies, similar results were obtained using a nicotine patch as monotherapy for Tourette syndrome. Nicotine is known to affect many neurotransmitter systems. By stimulating nicotinic acetylcholine receptors, it increases the release of beta-endorphin, dopamine, serotonin, norepinephrine, acetylcholine, and corticosteroids. However, the mechanism by which nicotine potentiates the effect of neuroleptics in Tourette syndrome remains unclear. The potentiating effect of nicotine can be blocked by the nicotinic receptor antagonist mecamylamine.

Treatment of Tourette syndrome with benzodiazepine drugs is most effective when using clonazepam. Clonazepam can be used:

1. as monotherapy to suppress tics, especially motor ones;
2. for the treatment of concomitant anxiety disorders, including panic attacks;
3. as a means of enhancing the effect of neuroleptics.

Several other drugs have also been shown to have beneficial effects in Tourette syndrome in open studies: naloxone, antiandrogens, calcium antagonists, lithium, and carbamazepine. Baclofen and the dopamine receptor agonist pergolide have been shown to be moderately effective in double-blind, placebo-controlled studies. Botulinum toxin injections have been used to treat a few cases of severe coprolalia.