Tourette's Syndrome: Treatment

First of all, the doctor must decide whether treatment of Tourette's syndrome is indicated for a given severity of symptoms. Tests of drugs with Tourette's syndrome are complicated by a wave-like course with exacerbations and remissions that do not necessarily occur under the influence of drugs. For short-term fluctuations in the severity of the symptoms, it is not necessary to immediately react to the treatment of Tourette's syndrome. The overall goal of treatment is to partially relieve the 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, contributing to an understanding of the characteristics of the disease and the development of tolerance for symptoms. Comorbid disorders can be the main cause of discomfort and impaired social adaptation. Adequate treatment of comorbid DVG, OCD, anxiety and depression sometimes reduces the severity of tics, probably by improving the patient's psychological state and easing stress.

Neuroleptics and other antidopaminergic agents

For almost three decades, dopamine D2-receptor antagonists, such as haloperidol and pimozide, are the main treatment for Tourette's syndrome. Approximately in 70% of patients, these drugs initially lead to clinically significant suppression of tics. However, lengthy observations show that only a minority of them have a persistent improvement. For years, haloperidol was the drug of choice for Tourette's syndrome - in part because it was a drug that was successful in Tourette's syndrome, and also because it was considered safer than pimozide.

Treatment of Tourette's syndrome is also performed by other effective antidopaminergic agents, including fluphenazine and sulpiride, risperidone and tetrabenazine. With the use of fluphenazine - an antipsychotic phenothiazine series - encouraging results have been obtained in open-label studies. There was also reported efficacy in ticks of sul- tiride, a selective antagonist of dopamine D2 receptors, which has a structural similarity to metoclopramide. However, with the use of the drug, side effects associated with an increase in prolactin production may become a significant problem. Ambiguous results were obtained in the treatment of children and adolescents with Tourette's syndrome tiaprid, close in structure to sulpiride. Tetrabenazine, which drains the presynaptic stocks of monoamines, has been moderately effective in Tourette's syndrome in an open study. However, when applied, significant side effects were noted: 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, ziprasidone. Treatment of Tourette's syndrome with clozapine proved ineffective, but with risperidone in several open studies, encouraging results have been obtained. The affinity of risperidone for dopamine D2-receptors is approximately 50 times higher than that of clozapine. The frequency of extrapyramidal side effects and tardive dyskinesia with risperidone is lower than in typical antipsychotics. However, a comparative study of the efficacy of risperidone and other antipsychotics has not been conducted. Thus, at present, the main advantage of risperidone is its better tolerability and greater safety.

In a double-blind, placebo-controlled study, efficacy was shown for Tourette's syndrome of olanzapine, ipiprasidone. To date, no quetiapine efficacy studies have been performed in Tourette's syndrome, although some doctors have reported successful use of it. However, in general, the role of these atypical antipsychotics in the treatment of Tourette's syndrome remains unclear.

Mechanism of action

Although neuroleptics have a complex effect on many types of receptors related to different neurotransmitter systems, their primary mechanism of action in Tourette's syndrome is probably associated with blockade of dopamine D2-peuerrropostrong in the brain. This ability is characteristic of all neuroleptics, overwhelming tics. Pimozide and fluphenazine, in addition, block calcium channels - this may be the cause of ECG changes observed in the treatment with these drugs. Risperidone has a twofold lower affinity for dopamine D2 receptors, but 500 times more blocks serotonin 5-HT2 receptors than haloperidol. Tetrabenazin reduces the supply of dopamine in presynaptic vesicles.

Side effects

Side effects often limit the therapeutic potential of neuroleptics and are the cause of low patient compliance and discontinuation of treatment. Such side effects as fatigue, intellectual dullness, memory loss can be the cause of poor performance and a decline in school performance. Weight gain enhances the patient's dissatisfaction with his appearance (in addition to the problems that the disease itself engenders). A recent report of a violation of liver function in young men taking risperidone, which developed after the appearance of excess weight. At ultrasound examination, signs of fatty liver infiltration were found. Extrapyramidal side effects appear to be associated with the blockade of dopamine D2 receptors in the caudate nucleus and the black substance and include acathia, parkinsonism and muscular dystonia. In studies in adult patients, extrapyramidal side effects were relatively rare, while children showed an increased risk of dystopia. Prolactin secretion is under the tonic dopaminergic control of the dopaminergic system and is enhanced by the reception of dopamine receptor blockers. An increased level of prolactin is the cause of swelling of the mammary glands, galactorrhea, amenorrhea, sexual dysfunction. The level of prolactin can be a useful guide in the treatment with pimozide: it allows you to timely limit the dose of the drug and prevent extrapyramidal side effects. When taking antipsychotics for more than 1 year, 10-20% of patients develop late disneaemia. Her risk is higher in children, elderly women, African Americans, patients with affective disorders. Late diskineia can be difficult to recognize against a background of tics. The cases of development of school phobia in children after the beginning of neuroleptic therapy are described. A common side effect of neuroleptics is dysphoria, but true depression is a significant problem only with tetrabenazine. When taking pimozide, changes in the ECG (prolongation of the QTc interval) were noted. This led experts to recommend regular ECG monitoring and limit the daily dose of the drug, which should not exceed 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. Apply antipsychotic drugs during pregnancy and during breastfeeding is not recommended - in these circumstances, drugs can be used only in very severe tics, when the benefits of suppressing them can outweigh the risk to the child. Pimozide and, possibly, fluphenazine can cause impaired cardiovascular function due to blockade of calcium channels. Pimozide is contraindicated in the congenital syndrome of QT prolongation, heart rhythm disturbances. It can not be combined with antibiotic-macrolides (clarithromycin, erythromycin, azithromycin, dirithromycin) or other drugs that extend the QT interval

Toxic effect

With an overdose of antipsychotic, epileptic seizures, heart rhythm disturbances and other life-threatening conditions are possible. Malignant neuroleptic syndrome is rare, but it is a serious danger and can develop even when taking conventional therapeutic doses of drugs. There may also be a drop in blood pressure, sedation and severe extrapyramidal complications such as acute dystonia and stiffness. Cases of sudden death of patients with schizophrenia were reported when taking pimoide in a high dose (80 mg / day).

[1], [2]

Α2-adrenergic receptor agonists

Clonidine and guanfacine are used mainly as antihypertensive agents. However, clonidine has been used for a number of years to treat tics and DVG. In many clinicians, clonidine is considered as a first choice since it does not cause severe neurological complications, such as early extrapyramidal syndromes or tardive dyskinesia. Nevertheless, as placebo-controlled studies have shown, in some patients it is ineffective or has only a partial effect. The greatest influence clonidine has on motor tics. The effect of clonidine is often delayed and manifests itself only after 3-6 weeks. But the main benefit of using clonidine is to improve the attendant behavioral disorders, such as hyperactivity, increased vulnerability, sleep disorders, aggressiveness, which are often found in patients with Tourette's syndrome and DVG. However, many patients can not tolerate clonidine because of sedation and orthostatic hypotension. Of particular concern is the possibility of developing severe symptoms with a sudden discontinuation of the drug (for example, due to poor patient compliance) and also recent reports of sudden deaths of children taking clonidine.

Recently, it has been proven that treatment with Tourette's syndrome and DVG with guanfacin can be more effective, and causes fewer side effects than clonidine. The ability of guanfacin to reduce and accompanying behavioral disorders was proved not only in open, but also in placebo-controlled studies.

Mechanism of action

In a low dose, clonidine has a stimulating effect on presynaptic alpha2-adrenergic receptors, which serve as autoreceptors. In a higher dose, 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 influencing the noradrenergic system, it probably has an indirect effect on the activity of dopaminergic systems, as evidenced by studies of the level of homonyl acid - GMC.

Side effects

The main side effects of clonidine are drowsiness, dizziness, bradycardia, constipation, dry mouth and weight gain. Sometimes shortly after the start of treatment, children develop irritability and dysphoria. There have been cases of the appearance or aggravation of depression. With a sudden discontinuation of clonidine, ricochet arterial hypertension, tachycardia, psychomotor agitation, muscle pain, increased sweating, drooling, and possibly manic-like conditions may occur. Cases of sharp strengthening of tics with the abolition of clonidine, which persisted for a long time, despite the repeated administration of clonidine, are described. There were reported several cases of sudden death in children with or without clonidine. However, in most of these cases, other factors could have contributed to the death, while the role of clonidine remained unclear.

Contraindications

Clonidine administration should be avoided in patients with myocardial or cardiac disease (especially with limited left ventricular ejection), syncopal conditions, and bradycardia. Relative contraindication is a kidney disease (due to the increased risk of cardiovascular diseases). Before the treatment, a thorough examination is necessary to identify cardiovascular disorders, and during treatment, regular monitoring of the pulse, blood pressure and ECG is recommended.

Toxic effect

Serious side effects can occur with sudden withdrawal or overdose of clonidine. In children, especially severe complications are possible in these situations. The withdrawal syndrome often occurs when parents do not understand the importance of strict adherence to the doctor's recommendations, and the child misses several of the medications. Overdosing can occur because the clonidine tablets are confused with tablets of another drug, for example, methylphenidate, as a result the child takes three tablets instead of one. Toxic effect in children can even have a minimum dose of clonidine (for example, 0.1 mg). Symptoms of overdose include bradycardia, CNS depression, hypertension, alternating with hypotension, respiratory depression and hypothermia.

[3], [4]

Treatment of Tourette's syndrome with other medications

Although tricyclic antidepressants only slightly weaken tics, they are useful in treating patients with mild tics that also suffer from DVG, depression, or anxiety. Tricyclic antidepressants are also recommended in cases where tics are accompanied by nocturnal enuresis or sleep disturbances. When they are used, it is possible to develop tachycardia and ECG changes (increase in QRS, PR, QTc intervals) with a potential risk of cardiotoxic effect. Therefore, regular monitoring of the ECG, the level of the drug in the plasma, vital indicators is required. It is necessary to take into account the possibility of interaction of tricyclic antidepressants with other drugs. There were reported seven cases of sudden death, possibly associated with the use of desipramine and imipramine. Selegiline can also be useful in combining tics and DVG.

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

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

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

In open studies, a positive effect on Tourette's syndrome is noted in several other drugs: naloxone, antiandrogenic agents, calcium, lithium and carbamazepine antagonists. In double-blind, placebo-controlled studies, moderate efficacy of baclofen and a pergolide dopamine receptor agonist was noted. Botulinum toxin injections were used to treat several cases of severe coprolathy.