Attention Deficit Hyperactivity Disorder: Treatment

Non-drug treatment of attention deficit hyperactivity disorder

The choice of treatment is affected by the severity of the symptoms, the opinions of parents, educators, school workers and the children themselves. It also depends on how much the environment can mitigate the manifestations of the disease, as well as the effectiveness of previous treatment. Currently, preference is given to an integrated ("multimodal") approach, combining medical therapy and psychosocial correction methods. Medication and psychosocial effects are mutually complementary. For example, psychosocial correction can improve a patient's condition at a time when the effect of medication is reduced.

Various non-drug methods have been developed, including those that provide for behavior correction and are used in home or school settings. Methods have been created for training parents and teaching them, for example, how to respond in unforeseen situations. Great importance can be the maintenance of a daily diary reflecting behavior in school and at home, as well as a special symbolic system for assessing behavior. According to Cantwell (1996), the training of parents strengthens their self-confidence, helps to weaken the manifestations of destructive behavior at home, reduces tension in the family. Cantwell also mentions such techniques as psychological counseling for parents, correction of the atmosphere in school, group therapy aimed at developing social skills, individual counseling or psychotherapy aimed at increasing self-esteem, reducing depression, anxiety, strengthening control over impulses, improving social skills. An important component of a favorable school atmosphere is a well-equipped classroom.

Psychopharmacology of Attention Deficit Hyperactivity Disorder

A child with attention deficit hyperactivity should sit in close proximity to the teacher, in order to less distracted and concentrate more on the performance of tasks. Behavior of children with attention deficit hyperactivity improves in a situation where it is clearly regulated by the rules known to them. Encouraging, remarks, breaks in classes should be used both in school and at home. School attendance is very important, but it can take many forms: training in a regular classroom, sometimes supplemented with individual lessons, training in special programs, in a specialized class or in a specialized school. Clinicians play an important role in deciding on the conditions of the child's education and the need for special programs.

A number of summer programs have been developed, the task of which is not to "pull up" children in some subjects, but to correct their behavior and improve their communication skills. In the US there are support groups for patients with attention deficit hyperactivity disorder and their families. Positive influence on patients can be rendered by their older brothers and sisters. A popular literature for parents, teachers and children is published, which contains information on attention deficit hyperactivity, outlined in an accessible language. Evaluation and correction of psychopathological features of parents, disharmonious family relationships enhance the effectiveness of treatment.

Psychostimulants in the treatment of attention deficit hyperactivity disorder

Psychostimulants are the main class of drugs used for attention deficit hyperactivity disorder. Of the psychostimulants most commonly used are methylphenidate (ritalin), dextramphetamine (dexedrine) and ipemolin (cilert). In addition to dextramphetamine, a mixed amphetamine salt is produced under the name of adderal, it contains a combination of racemic amphetamine and dextramphetamine. The popularity of methyl-phenidate and dextramphetamine is explained by their rapid dramatic effect and low cost. These are relatively safe drugs with a wide therapeutic window. They have a positive effect mainly on anxiety, hyperactivity, impulsiveness, destructive and aggressive behavior.

Psychostimulants reduce excessive activity in the situation of organized activities, for example, in school; they reduce negativity and aggressiveness, increasing manageability, academic performance and productivity. Outside the organized activities, their effect is less constant. Drugs improve the relationships of children with parents, brothers and sisters, peers, teachers, as well as family relationships in general. Thanks to the preparations, it becomes possible for the child to participate more actively in some forms of active leisure, for example, in sports competitions or games.

Comorbidity

In children with attention deficit hyperactivity with high frequency, comorbid conditions are revealed, which casts doubt on the legitimacy of the allocation of attention deficit hyperactivity to a separate nosological form. In particular, British doctors are more strict in the diagnosis of attention deficit hyperactivity, even if they use the same diagnostic criteria. Moreover, many British psychiatrists doubt that this condition can be regarded as an independent nosological unit. Comorbid states can have a significant effect on the effectiveness of therapy. For example, in the presence of comorbid anxiety disorder, psychostimulants are less effective and often cause side effects. Although in general, psychostimulants are probably more effective than behavioral therapy, and seem to be as effective as the combination of psychostimulants with behavioral therapy, these results largely depend on comorbid conditions.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Choice of preparation

Methylphenidate is usually considered the first choice drug with attention deficit hyperactivity, however, dextramphetamine is no less effective and has an equally beneficial effect on hyperactivity, impaired attention, impulsivity. Although both drugs seem to be equally effective, there is a factor of individual sensitivity: about a quarter of patients react only to one or only to another drug, but not both. Nevertheless, methylphenidate seems to be somewhat more preferable, since it reduces the motor activity to a greater extent. In general, psychostimulants are much more effective than placebo, which causes improvement in only 18% of children with attention deficit hyperactivity disorder. The effectiveness of psychostimulants in preschool children and adults is more variable.

Pemolin is probably less effective than the two psychostimulants described above. Until recently, it was considered a third-line drug and was prescribed with ineffectiveness of methylphenidate and dextramphetamine. However, after recent reports of cases of severe toxic liver damage with the development of hepatic insufficiency, it was used much less often. One of the candidates for the role of the third-line drug is bupropion (wellbutrin), which, despite the known risk of reducing the threshold of epileptic seizures, has a positive effect with attention deficit hyperactivity.

The next alternative are tricyclic antidepressants, primarily those that are less likely to cause cardiac side effects (nortriptyline or imipramine) or alpha-adrenergic agonists. The latter can be a drug of choice in children who have tics or an indication of tics or Turetg's syndrome in a family history. Currently, two agonists of alpha-adrenoreceptors are used: clonidine (available in the form of tablets and as a skin patch) and guanfacin (available only in tablet form). Guanfacin is less sedative than clonidine. Following this, the question of the appointment of normotimic agents - valproic acid, lithium salts, carbamazepine may be considered. They are especially indicated in the presence of comorbid affective disorders or indications of similar conditions in the family history. In the absence of cardiac pathology (according to anamnesis and ECG), the use of desipramine is possible. However, it should be administered with caution, since there are reports of four sudden deaths associated with its use. And in three cases, he was appointed for attention deficit hyperactivity. It should be noted that the usefulness of special diets and vitamins is not proved, moreover, sometimes they are capable of causing harm.

[10], [11], [12]

The mechanism of action of psychostimulants

Psychostimulants are sympathomimetic amines not related to catecholamines. They act as indirect aminergic agonists and increase the level of dopamine and norepinephrine in the synaptic cleft by blocking the presynaptic reuptake. Dextramphetamine (dextrin) promotes the release of cytoplasmic dopamine and blocks the re-uptake of dopamine, norepinephrine and serotonin. Methylphenidate (Ritalin) in structure and pharmacological properties is similar to amphetamine, but its mechanism of action is somewhat different. Methylphenidate does not contribute to the release of dopamine and to a greater extent blocks the re-uptake of dopamine than noradrenaline. Psychostimulants are well absorbed in the intestines and easily penetrate the blood-brain barrier. Simultaneous food intake improves their absorption. In children the plasma concentration reaches a peak in 2-3 hours, the half-elimination period is 4-6 hours, although there are significant individual variations. Subjectively, the maximum clinical effect occurs 1-3 hours after taking the drug - that is, before the concentration in the plasma reaches the peak. When taking methylphenidate, the plasma concentration reaches a peak in 1-2 hours (faster than in the case of dextramphetamine), the clinical effect is manifested after 30 minutes, and the half-elimination period is 2.5 hours. Several studies have confirmed that the effect usually occurs already in the absorption phase . Pemolin, structurally different from other psychostimulants, also blocks the reuptake of dopamine, although it has a minimal sympathetic effect. In children, it begins to act as quickly as other psychostimulants, its plasma concentration reaches a peak in 2-4 hours, and the half-elimination period is 12 hours, which allows it to be taken once a day.

Dextramphetamine and methylphenidate improve the performance of neuropsychological tests for attention, activity, reaction time, short-term memory, visual and verbal perception. This can be explained by an improvement in the state of the regulatory functions and an increase in the signal-to-noise ratio; thanks to this, children concentrate better and are less distracted by extraneous stimuli. This effect is typical not only for patients with attention deficit hyperactivity disorder, in healthy children and adults, psychostimulants cause similar changes in cognitive and behavioral functions. Despite the obvious improvement of neuropsychological indicators, against the background of long-term use of psychostimulants, there is no significant increase in overall academic performance or significant success in other areas. In addition, it has not been possible to show that psychostimulants improve social adaptation in the long term, contributing to the subsequent life success, for example, gaining a more prestigious profession.

It is shown that there is a discrepancy between the dose-effect curves for various indicators-an improvement in one of the indicators (for example, reflecting hyperactivity) may be accompanied by deterioration in another (for example, reflecting attention). This phenomenon is known as the Sprague effect. It can be explained by the fact that doses that provide the maximum behavioral effect can limit cognitive possibilities, reducing the flexibility of cognitive processes. In these cases, the dose of the stimulant should be reduced. Negative influence on cognitive functions is especially unfavorable in children with developmental delay, already having a tendency to get stuck and perseverate.

Physiological and psychophysiological effects of psychostimulants

Psychostimulants have an exciting effect on the respiratory center in the medulla oblongata, but do not have any significant effect on the respiratory rate. They also stimulate the reticular activating system, which sometimes leads to insomnia, but, at the same time, can partly explain their positive impact on attention and ability to perform tests. Due to direct action on the cardiovascular system, a slight increase in systolic and diastolic pressure is possible, which, however, is rarely clinically significant. Psychostimulants relax the smooth muscles of the bronchi, cause a reduction in the sphincter of the bladder, sometimes - unforeseen gastrointestinal disorders. It was reported on the ability of dextramphetamine to suppress night secretion of prolactin.

Side effects of psychostimulants

The most frequent short-term side effects of psychostimulants are: insomnia, anorexia and weight loss. Suppression of appetite is probably explained by the influence on the lateral departments of the hypothalamus, which mediate the sense of satiety. Sometimes this leads to a ricochet increase in hunger in the evening.

Although growth retardation with stimulant therapy is believed to be temporary, there are reports of statistically significant growth retardation and weight gain in long-term treatment with dextramphetamine and methylphenidate. This circumstance is especially important to take into account when the patient may find it difficult to reconcile with the possible restriction of growth. Since dextrose-mpetamine has a longer half-elimination period and is able to inhibit the secretion of prolactin, its effect on height and weight may be more significant. Less common side effects such as dizziness, headache, nausea, abdominal pain, sweating - they are usually short-lived and rarely require withdrawal of the drug. Pain in the stomach, nausea, loss of appetite can be reduced by lowering the dose, taking the drug while eating, switching to a drug with delayed release or the appointment of antacids. As a rule, side effects rarely occur if the dose of methylphenidate does not exceed 1 mg / kg, and the dose of dextramphetamine is 0.5 mg / kg.

A particular problem with the use of psychostimulants is their ability to provoke, "unmask" tics and Tourette's syndrome or cause their exacerbation. Although there are cases when psychostimulants reduced not only manifestations of DVG, but also tics. Other undesirable effects of psychostimulants - dysphoria, "blunting" affect, irritability, especially often occurring in children with developmental delay. An important problem is the possibility of a ricochet strengthening of behavioral symptoms against the background of the termination of the next dose or the withdrawal of the drug. In these cases, the symptomatology can become more pronounced than it was before the treatment. After 5-15 hours after receiving the last dose, speech excitement, irritability, disobedience, insomnia develop, which can persist for half an hour or more. Ricochet intensification of behavioral disorders is especially frequent in preschool children. This manifestation can be weakened by prescribing a sustained-release preparation or adding a small dose of methylphenidate in the daytime.

To the rare side effects of psychostimulants are: leukocytosis, toxic psychosis with tactile and visual hallucinations, mania, paranoia, choreoathetosis (with the use of pemolin), cardiac rhythm disturbances (especially rarely with pemoline), hypersensitivity, angina. It is suggested that methylphenidate may reduce the threshold of epileptic seizures, whereas dextramphetamine has the opposite effect. However, when taken in therapeutic doses, psychostimulants have no significant effect on epileptic activity, especially if epileptic seizures in a patient are well controlled by anticonvulsants.

But the main concern is the danger of dependence on psychostimulants. Although the euphoria that occurs in healthy adults using psychostimulants does not appear in healthy or hyperactive children at the pre-pubertal age. Although the risk of dependence development does exist, it is realized primarily in adults with a propensity to develop drug addiction and antisocial personality disorder, and they usually inject methylphenidate and dextramphetamine intravenously. Nevertheless, recently there have been reports that dependence on psychostimulants can still develop in children and adolescents. As a result, methylphenidate and destramfet-mines were assigned to the second class of DEA - that is, to drugs that require strict prescription accounting. At the same time, pemoline belongs to the IV class of drugs that do not require strict accountability. Public concern was caused by cases when psychostimulants were not used strictly according to the testimony - in particular, they were prescribed to children only because they behaved poorly in school. This led to the emergence of public skepticism in relation to psychostimulants.

Contraindications to the use of psychostimulants

Contraindications to the appointment of psychostimulants are few and include psychotic disorders, as well as tics and Tourette's syndrome (relative contraindication). It is necessary to distinguish between Tourette's syndrome and lung transient tics, which are common in children. As recent studies have shown, in most children, tics disappear, despite continued therapy with psychostimulants. If this does not occur, then an additional agent is prescribed to correct the tics: clonidine, guanfacin, haloperidol or pimozide. Other contraindications are somatic diseases that prevent the reception of sympathomimetics, or the presence of substance abuse in family members of a child with attention deficit hyperactivity disorder or an adult treated for attention deficit hyperactivity disorder. In the latter case, pemoline (which is less likely to cause euphorogenesis than other psychostimulants), bupropion or a tricyclic antidepressant may be used. Borderline personality disorder is another relative contraindication to the appointment of psychostimulants, because they can enhance affective lability.

[13], [14], [15], [16], [17], [18], [19]

Assessment of the effectiveness of attention deficit management with hyperactivity

When conducting drug therapy, several phases can be identified: the preparation phase, the phase of the dose titration, the phase of maintenance therapy. In the preparation phase, it is necessary to measure height, weight, blood pressure, heart rate, and make a clinical blood test. For the quantitative assessment of the main and concomitant symptoms, the Connors Teachers Rating Scale (CTRS, Connors Rating Scale - CPRS) rating scales are widely used. To create a scale of hyperactivity, a Standardized CTRS assessment technique can be used.

A criterion for a satisfactory treatment effect is a 25% reduction in the overall teacher assessment of hyperactivity in the Connors Teacher Questionnaire (CTQ) questionnaire. Also, the effect can be assessed using a computerized Continuous Performance Test (CPT), which makes it possible to assess impulsivity (by the number of unnecessary reactions, or impulsive errors) or inattention (in terms of the number of missed reactions or inert errors). To assess the effect of treatment is widely used and Abbreviated Rating Scale-ARS, which can fill parents or teachers. The scale includes 10 points; it is simple and does not require much time, but it is reliable enough. The maximum score on the scale is 30 points.

[20], [21], [22], [23], [24], [25], [26],

Laboratory research

The risk of hepatitis and liver failure in the use of pemoline requires the study of liver function before starting therapy, and then regularly every 6 months. As for the other psychostimulants, sometimes a clinical blood test and a biochemical test are performed prior to their appointment, but if there are no abnormalities, it is usually not necessary to repeat these studies during the titration phase and maintenance therapy.

Dose selection

Patients who never took stimulants are given methylphenidate or dextramphetamine, as they are rarely ineffective in untreated patients. Several variants of dose selection for these drugs have been developed.

The first is the stepwise titration method. In preschool children, treatment with methylphenidate begins with a dose of 2.5-5 mg (which the patient should take at 7.30 or at 8.00 am after breakfast). Depending on the duration and severity of the effect, the dose is sequentially increased by 2.5-5 mg until the desired effect is achieved. If necessary, the second dose of the drug is administered, usually 30 minutes before the beginning of the morning dose reduction. Due to the second method, the effect becomes longer and the probability of rebounding of the symptoms is reduced. The second dose begins to titrate from a value corresponding to half the maximum value of the morning dose. Increase the dose at intervals of 3-7 days until the desired effect is achieved or a side effect occurs. In general, the dose can be increased to a maximum of 10-15 mg 2 times a day. Sometimes the third dose of the drug (2.5-10 mg) is administered 30 minutes before the end of the previous daily dose or before starting the homework. In school-age children, treatment starts with a dose of 5 mg.

The second option involves determining the dose in accordance with the patient's weight at the rate of 0.3-1.2 mg / kg (preferably 0.3-0.6 mg / kg). The maximum daily dose is 60 mg.

According to the third option, the treatment starts with an empirical starting dose, in the case of the use of dextramphetamine and methylphenidate - 5 mg 2 times a day (in children over 6 years old), with the use of pemolin - 18.75 mg (later his dose is increased by 18, 75 mg until the clinical effect is reached, maximum - up to 75 mg / day). The maximum dose of methylphenidate, according to the manufacturer's recommendations, is 112.5 mg / day. Pemoline, which has a long semi-elimination period, can be prescribed once a day, which eliminates the need to take medicine at school. Thus, the label of the patient does not "stick" to the child at school and there is no conflict with school employees who sometimes object to taking the drug. Patients who have never taken psychostimulants may receive half the usual starting dose. In recent years, a new mixed salt of amphetamine (adderal) is increasingly being used because of the longer duration of action. It is prescribed 1-2 times a day in the same doses as dextramphetamine. If after two weeks of taking the maximum dose of dextramphetamine or methylphenidate or five weeks of taking pemoline there is no improvement, you should cancel the drug and reassess the patient's condition.

Because psychostimulants cause anorexia and discomfort in the abdomen, they are recommended to be taken with food or immediately after it. In addition, in this case, the absorption of the drug is improved. Depending on the purpose of treatment, different doses may be prescribed. For example, low doses are preferred to improve cognitive function, while higher doses are required to normalize behavior. As the child grows, the dose may increase according to weight gain, with the onset of puberty, the dose is sometimes reduced. When prescribing the drug, the patient and his parents should be informed about possible side effects and benefits that the drug can bring, as well as plans for further therapy in case it turns out to be ineffective. In the patient's card, you need to make an appropriate entry. It is necessary to obtain informed consent from the parents, as well as the consent of the patient himself, which must also be reflected in the map.

It is also necessary to provide a detailed instruction that contains the scheme of taking the drug, a copy of which must remain in the patient's chart. The map should contain a separate sheet, which includes information on newly prescribed drugs, changes in their dose, cancellation: this helps to track the progress of treatment (including insurance companies), and plan further activities. In the phase of maintenance therapy, the schedule of visits to the doctor, conducting examinations and medical holidays should be clearly established. If possible, the estimated duration of treatment should be determined in order to dispel fears of parents and caregivers. Treatment is convenient to plan according to the schedule of the school year, and it is better to spend possible medical holidays during those periods of the school year, which are less stressful. Sometimes after the initial treatment period, the dose may be somewhat reduced.

During regular visits, the patient is examined, the effectiveness of the treatment is evaluated, in particular, they determine how the progress or relationships with others have changed, and identify undesirable effects. At the same time, psychological counseling and educational conversations are conducted. It is important to assess whether the patient is taking the drug on a regular basis. For this, parents or educators are asked to bring the used bottles with the drug and count the number of tablets left in them. Monthly, it is necessary to measure weight, height (the results are recommended to be represented graphically on special growth charts), blood pressure, heart rate. Annually recommend to conduct a full physical examination, a clinical blood test, a study of liver function (when taking pemoline this test is carried out 2 times a year).

Psychostimulants can be abolished at once, but there are usually no complications. It remains unclear whether tolerance develops to the action of drugs. More often there is a so-called "pseudo-tolerance", which is caused by an independent discontinuation of the drug (Greenhill, 1995), although it can not be ruled out that in these cases depletion of the placebo effect or low efficiency of generics takes place. In the phase of maintenance therapy, it is important to maintain a written or verbal contact with the teacher or school principal - in addition to being usually asked to regularly complete assessment scales such as CTPS or ARS. Evaluation of these scales is recommended to be carried out at least 1 time in 4 months (more often in the period of drug replacement, titration dose or increased symptomatology). Methylphenidate is allowed for use in children not younger than 6 years, but many doctors use it as a first choice and in preschool children. There is limited experience with the use of methylphenidate in adults, the dose in this case is approximately 1 mg / kg or higher, but not more than 60 mg / day.

[27], [28], [29], [30], [31], [32], [33], [34], [35]

Medicinal holidays

In the past, medicinal vacations were recommended to be performed in order to compensate for the possible slowdown in the use of psychostimulants. It has now become apparent that the child's education takes place not only in school, but also outside the school, and that psychostimulants are able to improve the relationship of patients with peers and parents. In this regard, medicinal vacations are not recommended as a standard procedure, and the decision to conduct them is taken individually. For example, some parents prefer not to give the drug to children on weekends, if they are relatively manageable. In many respects this decision is dictated by the widespread opinion in society about the danger of psychostimulants, especially associated with the risk of drug dependence. However, once a year the drug can be canceled - in order to assess the need for further therapy.

Medicinal Combinations

With psychostimulants, especially with methylphenidate, clonidine was often combined. This combination was particularly widely used for sleep disorders, primarily associated with attention deficit hyperactivity disorder or caused by stimulants. But in recent years, the security of such a combination has been questioned. Four cases of sudden death of children taking methylphenidate and clonidine simultaneously were reported. Nevertheless, it remains unclear whether the lethal outcome is associated with taking a particular drug. From a pragmatic point of view, one should refrain from concomitant administration of these drugs, especially in children with cardiovascular pathology (sometimes it is only possible to administer clonidine overnight to get a sedative effect). An open study shows the effectiveness of a combination of tricyclic antidepressants and adrenoreceptor agonist in children and adolescents with attention deficit hyperactivity combined with tics. In tics, a combination of methylphenidate and clonazepam is also successfully used. It is also possible to add a tricyclic antidepressant to the psychostimulant. Selective serotonin reuptake inhibitors (eg, fluoxetine or sertraline) are also combined with psychostimulants, especially when there is a comorbid affective disorder. However, such a combination can enhance excitement.

Interaction with other drugs

The combined use of MAO inhibitors and stimulants is contraindicated because of the risk of a severe hypertensive crisis that can lead to death. In patients with concomitant bronchial asthma, the intravenous theophylline can cause palpitations, dizziness, excitation, so in this case, preference should be given to inhaled bronchodilators or steroids. Dextramphetamine blocks the action of propranolol and slows the absorption of phenytoin and phenobarbital. Methylphenidate can increase the concentration in the blood of tricyclic antidepressants, coumarin anticoagulants and phenylbutazone.

Dosage forms of psychostimulants. Methylphenidate is available in conventional tablet form (5 and 10 mg each) and in the form of a slow-release preparation (20 mg tablets). Both forms are effective, but one tablet of methylphenidate with a slow release containing 20 mg does not seem to be equivalent in effectiveness to two standard 10 mg tablets. Therefore, the drug with slow release is prescribed relatively rarely, despite the convenience of use. With his appointment, the daily dose usually has to be increased by 30-50%.

Dextramphetamine is available in tablets of 5 mg and in a special form with a slow release ("spinsula") containing 5, 10 or 15 mg. When switching from a standard dextramphetamine drug to a sustained-release preparation, there is no need to increase its dose. Pemolin is available in tablets at 18.75, 37.5 and 75 mg, as well as in the form of chewable tablets of 37.5 mg. The drug mixed amphetamine salt (adderal) is available in tablets of 10 and 20 mg. In children aged 3 to 5 years, treatment with this drug is recommended to start with a dose of 2.5 mg once a day, in children 6 years and older - 5 mg once or twice a day.

Non-psychostimulating agents used for attention deficit hyperactivity disorder

Approximately in 25-30% of patients with attention deficit hyperactivity psychostimulants are not effective enough. These patients can be successful with other drugs that are prescribed as monotherapy or added to psychostimulants to enhance their effect. At present, there is insufficient data to separate individual attention deficit hyperactivity variants with different etiologies and respond differently to treatment with psychostimulating, non-psychostimulating agents or a combination thereof. Non-psychostimulating agents used in attention deficit hyperactivity disorder include atypical antidepressant bupropion, adrenoreceptor agonists clonidine and guanfacine, tricyclic antidepressants (eg, nortriptyline), normotimes (eg, valproic acid), and new generation neuroleptics (eg risperidone).

According to the experts of the American Medical Association, the use of non-psychostimulating drugs for indications not officially approved is possible if "this application is based on rational scientific theory, expert judgment or controlled clinical trials." And further it is said that, "experience shows that official confirmation of testimony lags behind new scientific knowledge and publications". Green (1995) believes that "the appointment of non-psychostimulating agents is justified if the stimulant is ineffective or if there is scientifically confirmed data on the preference of a non-psychostimulating drug."

Bupropion is an antidepressant belonging to the class of aminoketones. According to some reports, bupropion is effective in children and adolescents with attention deficit hyperactivity disorder. One study found that it also improves cognitive function in these patients. It has been shown that bupropion is particularly effective in cases when attention deficit hyperactivity is accompanied by marked manifestations of behavioral disorder. To the relatively frequent side effects of bupropion should be attributed to an allergic rash, swelling, agitation, dry mouth, insomnia, headache, nausea, vomiting, constipation and tremor. Less often, the drug causes a hypomanic condition.

But the most serious side effect of bupropion is epileptic seizures. They occur in 0.4% of adult patients taking the drug at a dose of up to 450 mg / day. As the dose increases, their probability increases. The risk of seizures is higher in patients with comorbid eating disorders. To reduce the likelihood of developing seizures, it is recommended to take a daily dose in several doses. Perhaps, the risk of seizures is higher for children with developmental delay, but this assumption is not confirmed by the data of the studies. It has been shown that bupropion strengthens tics in children with attention deficit hyperactivity and Tourette syndrome and, therefore, is relatively contraindicated in this condition. Bupropion is prescribed 2-3 times a day. The initial dose is 37.5-50 mg twice a day, then gradually increase for at least 2 weeks to a maximum of 250 mg / day; in adolescents - up to 300-400 mg / day.

Tricyclic antidepressants

A large experience has been accumulated in the use of tricyclic antidepressants (TCAs) with attention deficit hyperactivity disorder. According to some reports, the effectiveness of desipramine in attention deficit hyperactivity disorder reaches 70%. Until recently, antidepressants were most often seen as second-line drugs for the treatment of attention deficit hyperactivity disorder. But in recent years, many doctors have become less likely to prescribe antidepressants - after a series of reports about the possible cardiotoxic effect of drugs (especially in pre-pubertal age) and complications associated with overdose. Many TCAs are able to reduce hyperactivity, impulsivity and improve mood in patients with attention deficit hyperactivity disorder. With comorbid anxiety disorder or depression, the efficacy of TCAs is higher than in psychostimulants. However, the impact of these funds on attention concentration and training is less studied. In addition, they often cause a pronounced sedative effect.

As a rule, TCA has a relatively long half-elimination period, which eliminates the need to take the drug at school. Behavior after school and in the evening against the backdrop of treatment with TCAs is usually improved to a greater extent than with the use of stimulants. The effect of TCAs with attention deficit hyperactivity is apparently not related to their antidepressant effect. In this regard, the optimal dose of TCAs with attention deficit hyperactivity is lower, and the effect occurs faster than in the treatment of depression. It is shown that in a patient resistant to one of the TCAs, another drug of this group can be effective.

Cardiotoxicity of tricyclic antidepressants

Pharmacokinetics in children has its own characteristics. Because of the lower ratio of the ratio of fat and muscle tissue, the volume of distribution in children is smaller, and the fat stores are less effective in protecting against overdose, as in adults. In addition, the metabolism of these drugs in children occurs faster than in adolescents and adults, which leads to more significant fluctuations in their concentration in the blood. Because TCAs reduce the threshold for epileptic seizures, they should be used with caution in patients with epilepsy.

In children, the plasma concentration after receiving the same dose of TCAs is subject to significant individual variations. In 3-10% of the population, the genetically determined decrease in cytochrome P450 2D6 activity is detected in the population, therefore they metabolize TCAs more slowly, which creates the conditions for reaching the toxic concentration of the drug, even if its dose does not exceed 5 mg / kg. The toxic effect can be manifested by dysfunction of the cardiovascular and central nervous systems and can be mistaken for intensifying the symptoms of the disease. Since, on the one hand, there is no clear connection between the dose of TCA and its serum concentration, and, on the other hand, the probability of potentially dangerous adverse events depends on the serum concentration, the control of the blood content of the drug and its metabolites in the treatment of attention deficit with hyperactivity is considered mandatory. To minimize the undesirable effects that occur at the peak serum concentration of the drug, children are advised to prescribe TCA 2-3 times per day (if the daily dose exceeds 1 mg / kg). For the same reason, it is undesirable to prescribe long-acting drugs, for example, capsules of imipramine pamoate.

The toxic effects of TCAs can appear at any age, but they are especially dangerous in children and adolescents. Of particular concern is the possibility of slowing cardiac conduction, which is manifested in increasing PR hQRS intervals on the ECG, development of tachycardia and other cardiac arrhythmias, and atrioventricular blockade. At least 5 cases of sudden death in children under 12 years of age taking desipramine have been reported. The lethal outcome was presumably associated with "pirouette" tachyarrhythmia (torsade de pointes). In three cases, death occurred after physical exertion. Four of the deceased children were aged 9 years and younger, and five - at the age of 12 years. In this regard, before the appointment of the drug, during the titration dose and when receiving a maintenance dose, ECG with QT interval measurement is recommended. Official recommendations on the use of TCAs with attention deficit hyperactivity require an ECG before the start of treatment, with a dose of 3 mg / kg / day, and after reaching the final dose, which should not exceed 5 mg / kg / day. The following guidelines are recommended: the PR interval should be 210 ms, the QRS interval should not exceed the original value by more than 30%, the QT interval should be shorter than 450 ms, the heart rate should not exceed 130 beats per minute, the maximum systolic pressure should be is equal to 130 mm Hg. And the maximum diastolic pressure is 85 mm Hg. Art. After reaching a stable level of the drug in the blood.

The ECG should be performed every six months. One study showed that 10% of children and adolescents with attention deficit hyperactivity taking desipramine show incomplete blockade of the right leg of the bundle 1aa (which is considered a variant of the norm in children under 10 years old), an increase in the QRS interval to 120 ms and more, and 18% of patients had sinus tachycardia up to 100 beats per minute and more. However, it is not known whether these changes increase the risk of complications caused by desipramine.

Daily monitoring of the ECG showed that in children taking desipramine for a long time, the incidence of single and paired premature atrial contractions and attacks of supraventricular tachycardia is significantly higher. In addition, they have a decrease in the frequency of sinus pauses and nodal rhythm. Nevertheless, the level of desipramine in the blood correlated only with paired premature contractions of the ventricles. Since parasympathetic impulses following to the heart decrease significantly with age, and desipramine is able to increase the activity ratio of the sympathetic and parasympathetic system mainly in young patients, a decrease in heart rate variability may be associated with an increased risk of serious arrhythmias.

In 1992, the American Academy of Child and Adolescent Psychiatry reported that the risk of sudden death in children 5-14 years of age taking desipramine at therapeutic doses is approximately equivalent to that in children of the same age in the general population, 1.5-4.2 million population per year. Thus, the question remains open. Some experts suggest strictly limiting the use of desipramine, while others find it unnecessary and believe that the causal relationship between deaths and desipramine intake has remained unproven. Green (1995) believes that since the number of cases of sudden death is small, their immediate cause is unknown, and because there are no specific changes in cardiac activity that would have predictive value, it is necessary to monitor the ECG, the blood content of the drug and its metabolites , ensuring that they are maintained within the recommended parameters, whichever TCA is registered. Until more accurate data are obtained, it is recommended that these pragmatic recommendations be followed and, in the treatment of pre-pubertal children, preference should be given to nortriptyline and imipramine among other TCAs. In addition, indications in the family history of heart disease should be considered a relative contraindication to the appointment of TCAs as a whole.

[36], [37], [38], [39]

Tricyclic antidepressants, most commonly used in attention deficit hyperactivity disorder

Given the risk of cardiotoxicity described earlier, TCAs are currently less commonly used to treat attention deficit hyperactivity disorder. Thus advantage by many doctors is given nortriptiline. Wilens (1993), who collected data on 58 patients with attention deficit hyperactivity-resistant, found that nortriptyline at an average daily dose of 73.6 mg had a mild positive effect in 48% of patients, regardless of the presence of concomitant conditions. In most cases of "marked improvement," the concentration of nortriptyline in the blood ranged from 50 to 150 ng / ml. Side effects in these patients were mild, and no significant changes in conduction of the heart were detected. It is noted that nortriptyline can be effective in combining attention deficit with hyperactivity with Tourette's syndrome or another version of tics.

Desipramine and imipramine are the most well-studied drugs, which until recently were more often used by other TCAs to treat attention deficit hyperactivity disorder. Currently, desipramine is still widely used. It is shown that in a dose of less than 3 mg / kg / day it is quite effective, and the probability of a cardiotoxic effect is minimized. Imipramine is TCA, which, apparently, is most widely used in children, as it is often prescribed for nocturnal enuresis. According to a number of studies, imipramine is effective both in the attention deficit with hyperactivity and in Tourette's syndrome, but there is a high incidence of undesirable effects and low tolerability. Amitriptyline in controlled trials was effective in some children, positively affecting hyperactivity and aggressiveness both at home and in school, but the frequent undesirable effects, especially sedation, make it difficult to take the drug at the required dose. Children and adolescents use another TCA, clomipramine. Its side effects are drowsiness, dry mouth, oppression of hemopoiesis, increased risk of epileptic seizures.

Other medicines used for attention deficit hyperactivity disorder

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, are now prescribed more often than TCAs. Because they are much safer. They have minimal effect on the cardiovascular system and are not so dangerous in case of an overdose.

Overall, the use of these drugs is small, but there are reports of positive effects of fluoxetine treatment in children and adolescents with attention deficit hyperactivity with or without comorbid disorders. More research is needed to compare the effectiveness of SSRIs with the efficacy of TCAs and bupropion in attention deficit hyperactivity disorder. In the treatment of SSRIs, side effects such as anxiety, hyperactivity, behavioral activation, insomnia, impulsivity, suicidal ideology are possible.

Α2-adrenoreceptor alpha agonists

Α2-adrenoreceptor agonists clonidine and guanfacin are often used to treat attention deficit hyperactivity disorder. Their effectiveness as a monotherapy has not been sufficiently studied, but in combination with psychostimulants, they are reported to reduce hyperactivity, agitation and can be useful in children with tics.

Clonidine is an antihypertensive drug, the effect of which is due to the stimulation of presynaptic alpha 2-adrenergic receptors and inhibition of the release of noradrenaline. In children with attention deficit hyperactivity disorder, clonidine improves frustration tolerance, orientation in tasks, and reduces hyperexcitability. Especially good effect is observed in those cases when symptoms appear at an early age: there are such manifestations as hyperexcitability, hyperactivity, impulsivity, disinhibition accompanied by violation of recognized norms of behavior and negativism. At the same time, clonidine has little effect on attention disturbances and is not so useful in the attention deficit with hyperactivity without hyperactivity. The dose of clonidine is recommended to increase gradually, starting from 0.05 mg / day and increasing it by the same amount every 3 days until it reaches 3-5 μg / kg / day. The daily dose of clonidine is prescribed in 3-4 divided doses.

Clonidine is also available in the form of patches for dermal application. In one study, it was shown that when switching from oral administration to a transdermal daily dose, clonidine should be increased by one-third. Approximately half of patients have a lower effectiveness after 5 days of wearing. This is probably associated with a lower half-elimination period in children (4-6 hours) and adolescents (8-12 hours); in adults, it is 12-16 hours. Significant clinical improvement with clonidine comes not earlier than a month. Clonidine in children with attention deficit hyperactivity disorder can remain effective for 5 years. When cessation of treatment with clonidine, its dose should be reduced gradually within 2-4 days to avoid hypertensive crisis and withdrawal symptoms - irritability, agitation, headache.

The most common side effect of clonidine is drowsiness. Usually it occurs 1 hour after taking the drug and persists for 30-60 minutes. Typically, after 3 weeks of treatment, tolerance to sedation develops. When these doses are applied, the mean arterial blood pressure is reduced by about 10%. Approximately 5% of children and adolescents with symptoms of depression. This complication is more common when there are cases of affective disorders in the family history, therefore it is not recommended to prescribe this drug in this category of patients. Deficiency of attention with hyperactivity is detected in approximately 50% of patients with Tourette's syndrome, and in 20-50% of them the reception of stimulants leads to an increase in tics. In this situation, as well as in all cases where patients do not tolerate stimulants due to side effects, clonidine may be the drug of choice.

Hunt et al. (1990) reported the use of a combination of clonidine and methylphenidate in children with attention deficit hyperactivity combined with behavioral disorder and Oppositional Deficiency Disorder (OVP), which had a violation of accepted norms of behavior, negativity, pronounced hyperexcitability and distraction. Adding clonidine reduces the dose of methylphenidate. This is especially useful when methylphenidate causes severe side effects (eg, ricochet insomnia, significant growth retardation, or weight loss).

Guangfincin is also used in the treatment of children and adolescents with attention deficit hyperactivity, especially when combined with tics. Like clonidine, guanfacin stimulates alpha2-adrenoreceptors and causes an antihypertensive effect, but differs from it by a more selective action. Unlike clonidine, guanfacine acts more not on presynaptic, but on postsynaptic alpha2-adrenergic receptors in the prefrontal cortex. In an open study in 10 patients with attention deficit hyperactivity and Tourette's syndrome, the effective dose of guanfacin ranged from 0.75 to 3 mg / day, with the optimum daily dose for most patients being 1.5 mg. Although there was no significant reduction in attention deficit hyperactivity symptoms in the group as a whole, three patients showed moderate improvement, and 1 had significant improvement. The severity of tics in the whole group significantly decreased. The most common side effects were drowsiness, headache, insomnia, dizziness, but all of them regressed within 3-4 days. Guanfacin can be especially useful in children and adolescents who are simultaneously deficient in attention with hyperactivity and chronic tics.

Neuroleptics

Most studies comparing the efficacy of antipsychotics and psychostimulants in the treatment of attention deficit hyperactivity have been performed more than 20 years ago. And mainly during these studies, psychostimulants were more effective than neuroleptics. Although neuroleptics have a certain effect, most doctors refrain from their use because of the risk of irreversible tardive dyskinesia, neuroleptic malignant syndrome, adverse effects on cognitive function and learning ability due to sedation. But at the present time it is believed that neuroleptics with attention deficit hyperactivity have minimal effect on cognitive functions, if they are prescribed in adequate doses. Moreover, according to some information, thioridazine may be more effective than psychostimulants with attention deficit hyperactivity disorder in children with developmental delay.

Nevertheless, the risk of tardive dyskinesia inhibits the use of traditional antipsychotics with attention deficit hyperactivity disorder. However, new-generation drugs, such as risperidone, which are characterized by a relatively low risk of developing parkinsonism and tardive dyskinesia, can be used in severe behavioral manifestations of attention deficit hyperactivity disorder. A new atypical antipsychotic olanzapine may be less likely to cause extrapyramidal complications than risperidone, but its effectiveness in attention deficit hyperactivity should be confirmed in clinical trials.

Monoamine Oxidase Inhibitors

Non-selective monoamine oxidase inhibitors phenelzine and tranylcypromine are used mainly as antidepressants. They can cause serious side effects, especially hypertensive crises, require a restriction in the diet of tyramine-containing products, and also make it impossible to use a large number of drugs. Because of this, none of these drugs are not recommended for use in children and adolescents, although there are reports of the efficacy of tranylcypromine in attention deficit hyperactivity disorder. Since selegiline (deprenyl) selectively blocks MAO-B, it is safer and causes hypertensive crises only when used in a large dose. The drug is most often used when a combination of attention deficit with hyperactivity and Tourette syndrome. Selegiline is available in tablets of 5 mg. Its maximum daily dose is 15 mg. The drug is prescribed in 2 divided doses (morning and afternoon).

Drugs of other groups used for attention deficit hyperactivity disorder

Normotimic drugs (lithium, carbamazepine and valproic acid) do not appear to have a positive effect on the main attention deficit symptoms with hyperactivity, but can be useful in attacks of uncontrolled behavior or cyclical affective disorders. With idiopathic attention deficit with hyperactivity not accompanied by other disorders, benzodiazepines and mianserin are also ineffective.

[40], [41], [42], [43], [44],