Attention Deficit Hyperactivity Disorder - Treatment

Non-drug treatment of attention deficit hyperactivity disorder

The choice of treatment is influenced by the severity of symptoms, the opinion of parents, educators, school staff and the children themselves. It also depends on the ability of the environment to alleviate the manifestations of the disease, as well as the effectiveness of previous treatment. Currently, preference is given to a comprehensive ("multimodal") approach combining drug therapy and psychosocial correction methods. Drug and psychosocial effects complement each other. For example, psychosocial correction can improve the patient's condition during the period when the effect of drug therapy is reduced.

Various non-drug methods have been developed, including those that involve behavioral correction and are used at home or at school. Methods have been developed to train parents and teach them, for example, how to react in unexpected situations. Keeping a daily diary reflecting behavior at school and at home, as well as a special symbolic system for assessing behavior, can be of great importance. According to Cantwell (1996), parental training strengthens their self-confidence, helps to reduce manifestations of destructive behavior at home, and reduces tension in the family. Cantwell also mentions such methods as psychological counseling of parents, correction of the atmosphere at school, group therapy aimed at developing social skills, individual counseling or psychotherapy aimed at increasing self-esteem, reducing depression, anxiety, strengthening control over impulses, and 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 ADHD should sit in close proximity to the teacher to reduce distractions and to concentrate more on tasks. The behavior of children with ADHD improves when it is clearly regulated by rules that they know. Rewards, comments, and breaks in activities should be used both at school and at home. School attendance is very important, but it can take many forms: regular classroom instruction, sometimes supplemented by individual instruction, special programs, a specialized class, or a specialized school. Clinicians play an important role in deciding the child's educational environment and the need for special programs.

A number of summer programs have been developed whose goal is not to “pull up” children in some subjects, but to correct their behavior and improve their communication skills. In the USA, there are support groups for patients with attention deficit hyperactivity disorder and their family members. Older brothers and sisters can have a positive influence on patients. Popular literature is published for parents, teachers, and the children themselves, which contains information about attention deficit hyperactivity disorder, presented in accessible language. Evaluation and correction of psychopathological traits of parents, disharmonious family relationships increase the effectiveness of treatment.

Psychostimulants in the treatment of attention deficit hyperactivity disorder

Psychostimulants are the main class of drugs used in attention deficit hyperactivity disorder. The most widely used psychostimulants are methylphenidate (Ritalin), dextramphetamine (Dexedrine), and ipemoline (Zilert). In addition to dextramphetamine, a mixed amphetamine salt called Adderall is produced; it contains a combination of racemic amphetamine and dextramphetamine. The popularity of methylphenidate and dextramphetamine is explained by their rapid dramatic effect and low cost. They are relatively safe drugs with a wide therapeutic window. They have a positive effect mainly on anxiety, hyperactivity, impulsivity, destructive and aggressive behavior.

Psychostimulants reduce overactivity in organized activities, such as school; they reduce negativity and aggression, increasing controllability, academic performance, and productivity. Outside of organized activities, their effect is less consistent. The drugs improve children's relationships with parents, siblings, peers, teachers, and family relationships in general. The drugs make it possible for a child to participate more productively in some forms of active leisure, such as sports competitions or games.

Comorbidity

Children with attention deficit hyperactivity disorder often have comorbid conditions, which calls into question the validity of isolating attention deficit hyperactivity disorder as a separate nosological entity. In particular, British doctors are more strict in diagnosing attention deficit hyperactivity disorder, even if they use the same diagnostic criteria. Moreover, many British psychiatrists doubt that this condition can be considered as an independent nosological entity. Comorbid conditions can have a significant impact on the effectiveness of therapy. For example, in the presence of comorbid anxiety disorder, psychostimulants are less effective and more often cause side effects. Although psychostimulants are probably more effective than behavioral therapy methods in general, and are apparently not inferior in effectiveness to a combination of psychostimulants with behavioral therapy, these results largely depend on comorbid conditions.

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Choice of drug

Methylphenidate is generally considered the drug of first choice for attention deficit hyperactivity disorder, but dextroamphetamine is equally effective and has similar beneficial effects on hyperactivity, attention deficit disorder, and impulsivity. Although both drugs appear to be equally effective, there is a sensitivity factor: about a quarter of patients respond to only one or the other drug, but not both. However, methylphenidate appears to be slightly more effective because it reduces motor activity to a greater extent. Overall, psychostimulants are much more effective than placebo, which produces improvement in only 18% of children with attention deficit hyperactivity disorder. The effectiveness of psychostimulants in preschool-aged children and adults is more variable.

Pemoline is probably less effective than the two stimulants described above. Until recently, it was considered a third-line drug and was prescribed when methylphenidate and dextroamphetamine were ineffective. However, after recent reports of cases of severe toxic liver injury with the development of liver failure, its use has been significantly reduced. One of the contenders for the role of a third-line drug is bupropion (Wellbutrin), which, despite the known risk of lowering the threshold for epileptic seizures, has a positive effect on attention deficit hyperactivity disorder.

The next alternatives are tricyclic antidepressants, primarily those that cause fewer cardiac side effects (nortriptyline or imipramine) or alpha-adrenergic agonists. The latter may be the drug of choice in children with tics or a family history of tics or Tourette's syndrome. Two alpha-adrenergic agonists are currently used: clonidine (available as tablets and as a skin patch) and guanfacine (available only in tablet form). Guanfacine causes less sedation than clonidine. Following this, the question of prescribing mood stabilizers - valproic acid, lithium salts, carbamazepine - may be considered. They are especially indicated in the presence of comorbid affective disorders or a family history of such conditions. In the absence of cardiac pathology (according to anamnesis and ECG), desipramine may be used. However, it should be prescribed with caution, since there are reports of four cases of sudden death associated with its use. Moreover, in three cases it was prescribed for attention deficit hyperactivity disorder. It should be noted that the usefulness of special diets and vitamins has not been proven, moreover, sometimes they can cause harm.

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Mechanism of action of psychostimulants

Psychostimulants are sympathomimetic amines that are not catecholamines. They act as indirect aminergic agonists and increase the level of dopamine and norepinephrine in the synaptic cleft by blocking presynaptic reuptake. Dextramphetamine (dextrin) promotes the release of cytoplasmic dopamine and blocks the reuptake of dopamine, norepinephrine, and serotonin. Methylphenidate (Ritalin) is similar to amphetamine in structure and pharmacological properties, but its mechanism of action is somewhat different. Methylphenidate does not promote the release of dopamine and blocks the reuptake of dopamine to a greater extent than norepinephrine. Psychostimulants are well absorbed in the intestine and easily penetrate the blood-brain barrier. Simultaneous food intake improves their absorption. In children, plasma concentrations peak at 2–3 h and the half-life is 4–6 h, although there is considerable individual variation. Subjectively, the maximum clinical effect occurs 1–3 h after dosing, i.e., before the peak plasma concentration. With methylphenidate, plasma concentrations peak at 1–2 h (faster than with dextramphetamine), the clinical effect occurs within 30 min, and the half-life is 2.5 h. Several studies have confirmed that the effect usually occurs during the absorption phase. Pemoline, which is structurally different from other psychostimulants, also blocks dopamine reuptake, although it has minimal sympathomimetic effects. In children, it has a rapid onset of action like other psychostimulants, with peak plasma concentrations at 2–4 h and a half-life of 12 h, allowing once-daily dosing.

Dextroamphetamine and methylphenidate improve performance on neuropsychological tests of attention, activity, reaction time, short-term memory, and visual and verbal perception. This may be due to improvements in executive functions and an increase in the signal-to-noise ratio; as a result, children are better able to concentrate and are less distracted by extraneous stimuli. This effect is not limited to patients with attention deficit hyperactivity disorder; psychostimulants produce similar changes in cognitive and behavioral functions in healthy children and adults. Despite the apparent improvement in neuropsychological parameters, long-term use of psychostimulants does not result in significant increases in overall academic performance or significant gains in other areas. In addition, psychostimulants have not been shown to improve long-term social adaptation, contributing to subsequent life success, such as obtaining a more prestigious profession.

It has been shown that there is a divergence of the dose-response curves for different parameters - an improvement in one parameter (for example, reflecting hyperactivity) may be accompanied by a 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 capabilities, reducing the flexibility of cognitive processes. In these cases, the dose of the psychostimulant should be reduced. The negative effect on cognitive functions is especially unfavorable in children with developmental delays who already have a tendency to get stuck and perseverate.

Physiological and psychophysiological effects of psychostimulants

Psychostimulants have an excitatory 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 may partly explain their positive effect on attention and the ability to perform tests. Due to the direct effect 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 contraction of the sphincter of the bladder, and sometimes - unexpected gastrointestinal disorders. The ability of dextramphetamine to suppress nocturnal secretion of prolactin has been reported.

Side effects of psychostimulants

The most common short-term side effects of psychostimulants include insomnia, anorexia, and weight loss. Appetite suppression is likely due to effects on the lateral hypothalamus, which mediates satiety. This sometimes leads to a rebound increase in hunger in the evening.

Although growth retardation associated with psychostimulants is generally considered temporary, statistically significant growth retardation and weight gain have been reported with long-term treatment with dextramphetamine and methylphenidate. This is especially important to consider in cases where the patient may have difficulty accepting the potential for growth restriction. Since dextramphetamine has a longer half-life and is capable of inhibiting prolactin secretion, its effect on growth and weight may be greater. Less common side effects include dizziness, headache, nausea, abdominal pain, and sweating; these are usually short-lived and rarely require discontinuation of the drug. Stomach pain, nausea, and decreased appetite may be managed by reducing the dose, taking the drug with food, switching to a slow-release drug, or prescribing antacids. In general, side effects are rare when the methylphenidate dose does not exceed 1 mg/kg and the dextroamphetamine dose does not exceed 0.5 mg/kg.

A special problem associated with the use of psychostimulants is their ability to provoke, "unmask" tics and Tourette's syndrome or cause their exacerbation. Although there are cases described where psychostimulants reduced not only the manifestations of ADHD, but also tics. Other undesirable effects of psychostimulants are dysphoria, "blunting" of affect, irritability, which are especially common in children with developmental delays. An important problem is the possibility of a rebound increase in behavioral symptoms against the background of the cessation of the effect of the next dose or withdrawal of the drug. In these cases, the symptoms may become more pronounced than they were before treatment. Speech agitation, irritability, disobedience, insomnia develop 5-15 hours after taking the last dose, which can persist for half an hour or more. Rebound increase in behavioral disorders is especially often observed in preschool children. This effect can be reduced by prescribing a slow-release preparation or adding a small dose of methylphenidate during the day.

Rare side effects of psychostimulants include: leukocytosis, toxic psychosis with tactile and visual hallucinations, mania, paranoia, choreoathetosis (with pemoline), cardiac arrhythmia (especially rare with pemoline), hypersensitivity, angina. It is believed that methylphenidate can lower the threshold for the occurrence of epileptic seizures, while dextroamphetamine has the opposite effect. However, when taken in therapeutic doses, psychostimulants do not have a significant effect on epileptic activity, especially if the patient's epileptic seizures are well controlled by anticonvulsants.

But the main concern is the risk of addiction to psychostimulants. Although the euphoria that occurs in healthy adults using psychostimulants does not appear to occur in healthy or hyperactive prepubertal children. Although the risk of addiction does exist, it occurs primarily in adults with a history of drug abuse and antisocial personality disorder, who typically inject methylphenidate and dextramphetamine intravenously. However, recent reports have suggested that addiction to psychostimulants may indeed develop in children and adolescents. As a result, methylphenidate and dextramphetamine have been classified as DEA Class II drugs, requiring strict prescription control. Pemoline, on the other hand, is a Class IV drug that does not require strict control. Public concern has been raised by cases where stimulants were not being used strictly according to indications - in particular, they were prescribed to children simply because they were behaving badly at school. This has led to public skepticism about stimulants.

Contraindications to the use of psychostimulants

Contraindications to the use of psychostimulants are few and include psychotic disorders, as well as tics and Tourette's syndrome (relative contraindication). A distinction should be made between Tourette's syndrome and mild transient tics, which are common in children. Recent studies have shown that tics disappear in most children despite continued therapy with psychostimulants. If this does not happen, an additional agent is prescribed to correct the tics: clonidine, guanfacine, haloperidol or pimozide. Other contraindications include somatic diseases that prevent the use of sympathomimetics, or the presence of substance abuse in the family of a child with attention deficit hyperactivity disorder or in an adult being treated for attention deficit hyperactivity disorder. In the latter case, pemoline (which causes a lesser euphoric effect than other psychostimulants), bupropion or a tricyclic antidepressant can be used. Borderline personality disorder is another relative contraindication to the use of psychostimulants, as they may increase affective lability.

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Evaluation of the effectiveness of treatment for attention deficit hyperactivity disorder

When conducting drug therapy, several phases can be distinguished: the preparation phase, the dose titration phase, the maintenance therapy phase. In the preparation phase, it is necessary to measure height, weight, blood pressure, heart rate, and perform a clinical blood test. For a quantitative assessment of the main and accompanying symptoms, the Connors Teachers Rating Scale (CTRS), Connors Parents Rating Scale (CPRS) are widely used. The Standardized Method of CTRS Assessment can be used to create a hyperactivity scale.

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

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Laboratory research

The risk of hepatitis and liver failure with pemoline requires liver function tests before starting therapy and then regularly every 6 months. As for other psychostimulants, a complete blood count and biochemistry are sometimes performed before their use, but if no abnormalities are found, there is usually no need to repeat these tests in the titration and maintenance phase.

Dose selection

Patients who have never taken psychostimulants are prescribed methylphenidate or dextroamphetamine, since they are rarely ineffective in untreated patients. Several options for selecting the dose of these drugs have been developed.

The first is the step titration method. In preschool-aged children, treatment with methylphenidate begins with a dose of 2.5-5 mg (which the patient should take at 7.30 or 8.00 a.m. after breakfast). Depending on the duration and severity of the effect, the dose is successively increased by 2.5-5 mg until the desired effect is achieved. If necessary, a second dose of the drug is administered - usually 30 minutes before the effect of the morning dose begins to decrease. Thanks to the second dose, the effect becomes longer lasting and the likelihood of a rebound increase in symptoms is reduced. The second dose is titrated from a value corresponding to half the maximum value of the morning dose. The dose is increased at intervals of 3-7 days until the desired effect is achieved or side effects occur. In general, the dose can be increased to a maximum of 10-15 mg 2 times a day. Sometimes a third dose of the drug (2.5-10 mg) is administered - 30 minutes before the end of the previous daily dose or before starting homework. In school-age children, treatment begins with a dose of 5 mg.

The second option involves determining the dose in accordance with the patient's weight at a 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, treatment is started with an empirical starting dose, in the case of dextramphetamine and methylphenidate - 5 mg 2 times a day (in children over 6 years old), in the case of pemoline - 18.75 mg (subsequently its dose is increased weekly by 18.75 mg until the clinical effect is achieved, up to a maximum of 75 mg/day). The maximum dose of methylphenidate, according to the manufacturer's recommendations, is 112.5 mg/day. Pemoline, which has a long half-elimination period, can be prescribed once a day, which eliminates the need to take the drug at school. Thus, the child is not labeled as a patient at school and there is no conflict with school staff, who sometimes object to taking the drug. Patients who have never taken psychostimulants can be prescribed half the usual starting dose. In recent years, a new mixed amphetamine salt (Adderall) has been increasingly used due to its longer duration of action. It is given 1-2 times daily in the same doses as dextroamphetamine. If there is no improvement after two weeks of maximum dose of dextroamphetamine or methylphenidate or five weeks of pemoline, the drug should be discontinued and the patient's condition re-evaluated.

Since psychostimulants cause anorexia and abdominal discomfort, it is recommended to take them during or immediately after meals. In addition, this improves the absorption of the drug. Depending on the purpose of treatment, different doses may be prescribed. For example, low doses are preferable to improve cognitive functions, while higher doses are required to normalize behavior. As the child grows, the dose may increase in accordance with weight gain; with the onset of puberty, the dose is sometimes reduced. When prescribing a drug, the patient and his parents must be informed of possible side effects and the benefits that the drug may bring, as well as plans for further therapy in case it proves ineffective. A corresponding entry must be made in the patient's chart. Informed consent from the parents must be obtained, as well as the consent of the patient himself, which must also be reflected in the chart.

It is also necessary to provide detailed instructions containing the regimen for taking the drug, a copy of which should remain in the patient's chart. The chart should have a separate sheet where information on newly prescribed drugs, changes in their dose, and cancellation is recorded: this helps to track the progress of treatment (including for insurance companies) and plan subsequent activities. In the maintenance therapy phase, a schedule of visits to the doctor, examinations, and drug holidays should be clearly established. If possible, an approximate duration of treatment should be determined to allay the concerns of parents and caregivers. Treatment is conveniently planned taking into account the school year schedule, while possible drug holidays are best spent during those periods of the school year that are least stressful. Sometimes, after the initial period of treatment, the dose can be slightly reduced.

During regular visits, the patient is examined, the effectiveness of the treatment is assessed, in particular, how academic performance or relationships with others have changed, and undesirable effects are identified. At the same time, psychological counseling and educational talks are conducted. It is important to assess whether the patient takes the drug regularly. For this, parents or caregivers are asked to bring used vials of the drug and the number of tablets remaining in them is counted. Weight, height (the results are recommended to be presented graphically on special growth charts), blood pressure, and heart rate must be measured monthly. A complete physical examination, clinical blood test, and liver function test are recommended annually (when taking pemoline, this test is performed twice a year).

Psychostimulants can be discontinued immediately, with no complications usually occurring. It remains unclear whether tolerance to the effects of the drugs develops. More commonly, so-called "pseudo-tolerance" is observed, which is caused by spontaneous discontinuation of the drug (Greenhill, 1995), although it cannot be ruled out that in these cases the placebo effect is exhausted or the generics are of low efficacy. In the maintenance phase, it is important to maintain written or verbal contact with the teacher or school principal - in addition to the fact that they are usually asked to regularly complete rating scales such as the CTPS or ARS. It is recommended that these scales be assessed at least once every 4 months (more often during the period of drug substitution, dose titration, or exacerbation of symptoms). Methylphenidate is approved for use in children aged 6 years and older, but many doctors also use it as a first-line drug in preschoolers. There is limited experience with the use of methylphenidate in adults, with doses in this case being approximately 1 mg/kg or higher, but not exceeding 60 mg/day.

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Medicinal holidays

In the past, drug holidays were recommended to compensate for the possible growth retardation associated with taking psychostimulants. It has now become clear that a child's education takes place not only at school but also outside of school, and that psychostimulants can improve the patient's relationships with peers and parents. In this regard, drug holidays are not recommended as a standard procedure, and the decision to conduct them is made on an individual basis. For example, some parents prefer not to give the drug to their children on weekends if they are relatively manageable. In many ways, this decision is dictated by the widespread public opinion about the dangers of psychostimulants, especially related to the risk of developing drug dependence. However, the drug can be discontinued once a year in order to assess the need for further therapy.

Drug combinations

Clonidine has often been combined with psychostimulants, especially methylphenidate. This combination has been particularly widely used for sleep disorders primarily associated with attention deficit hyperactivity disorder or stimulant-induced sleep disorders. However, the safety of this combination has been questioned in recent years. Four cases of sudden death in children taking methylphenidate and clonidine simultaneously have been reported. However, it remains unclear whether the deaths were related to either drug. From a pragmatic point of view, the simultaneous administration of these drugs should be avoided, especially in children with cardiovascular disease (sometimes only clonidine is allowed at night to achieve a sedative effect). An open study showed the effectiveness of a combination of tricyclic antidepressants and an adrenergic agonist in children and adolescents with attention deficit hyperactivity disorder associated with tics. A combination of methylphenidate and clonazepam has also been used successfully for tics. It is also possible to add a tricyclic antidepressant to a psychostimulant. Selective serotonin reuptake inhibitors (eg, fluoxetine or sertraline) are also combined with psychostimulants, especially in the presence of a comorbid affective disorder. However, such a combination may increase agitation.

Interaction with other drugs

The combined use of MAO inhibitors and stimulants is contraindicated due to the risk of severe hypertensive crisis, which can be fatal. In patients with concomitant bronchial asthma, orally administered theophylline may cause palpitations, dizziness, and agitation, 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 may increase the blood concentration of tricyclic antidepressants, coumarin anticoagulants, and phenylbutazone.

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

Dextramphetamine is available as 5 mg tablets and in a special slow-release form ("spansula") containing 5, 10, or 15 mg. There is no need to increase the dose when switching from the standard dextramphetamine preparation to the slow-release preparation. Pemoline is available in 18.75, 37.5, and 75 mg tablets and as a 37.5 mg chewable tablet. The mixed amphetamine salt preparation (Adderall) is available in 10 and 20 mg tablets. In children aged 3 to 5 years, treatment with this drug is recommended to begin with a dose of 2.5 mg once a day, and in children aged 6 years and older - 5 mg once or twice a day.

Non-psychostimulant drugs used in attention deficit hyperactivity disorder

In approximately 25-30% of patients with attention deficit hyperactivity disorder, psychostimulants are insufficiently effective. In these patients, success may be achieved with other agents, which are prescribed as monotherapy or added to psychostimulants to enhance their effect. At present, there are insufficient data to distinguish individual variants of attention deficit hyperactivity disorder, which have different etiologies and respond differently to treatment with psychostimulants, nonpsychostimulants, or a combination of both. Nonpsychostimulants used in attention deficit hyperactivity disorder include the atypical antidepressant bupropion, the adrenergic agonists clonidine and guanfacine, tricyclic antidepressants (eg, nortriptyline), mood stabilizers (eg, valproic acid), and new-generation neuroleptics (eg, risperidone).

According to the American Medical Association, the use of non-psychostimulants for indications not officially approved is possible in the case "if this use is based on sound scientific theory, expert opinion, or data from controlled clinical trials." And it goes on to say that, "as experience shows, official confirmation of indications lags behind new scientific knowledge and publications." Green (1995) believes that "the prescription of non-psychostimulants is justified when psychostimulants are ineffective or when there is scientifically confirmed data on the preference of a non-psychostimulant drug."

Bupropion is an antidepressant that belongs to the class of aminoketones. According to some data, bupropion is effective in children and adolescents with attention deficit hyperactivity disorder. One study found that it also improves cognitive functions in these patients. Bupropion has been shown to be especially effective in cases where attention deficit hyperactivity disorder is accompanied by severe manifestations of behavioral disorder. Relatively common side effects of bupropion include allergic rash, edema, agitation, dry mouth, insomnia, headache, nausea, vomiting, constipation, and tremor. Less often, the drug causes a hypomanic state.

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. Their likelihood increases with an increase in the dose. The risk of seizures is higher in patients with comorbid eating disorders. To reduce the likelihood of seizures, it is recommended to take the daily dose in several doses. Perhaps, the risk of seizures is also higher in children with developmental delays, but this assumption is not supported by research data. It has been shown that bupropion increases tics in children with attention deficit hyperactivity disorder 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 2 times a day, then gradually increased over at least 2 weeks to a maximum of 250 mg / day; in adolescents - up to 300-400 mg / day.

Tricyclic antidepressants

There is extensive experience in using tricyclic antidepressants (TCAs) in attention deficit hyperactivity disorder. According to some data, the effectiveness of desipramine in attention deficit hyperactivity disorder reaches 70%. Until recently, antidepressants were most often considered second-line drugs for the treatment of attention deficit hyperactivity disorder. However, in recent years, many doctors have begun to prescribe antidepressants less often - after a series of reports on the possible cardiotoxic effect of the drugs (especially common in prepubertal age) and complications associated with overdose. Many TCAs are able to reduce hyperactivity, impulsivity and improve mood in patients with attention deficit hyperactivity disorder. In comorbid anxiety disorder or depression, the effectiveness of TCAs is higher than that of psychostimulants. However, the effect of these drugs on concentration and learning has been less studied. In addition, they often cause a pronounced sedative effect.

TCAs generally have a relatively long half-life, eliminating the need to take the drug at school. After-school and evening behavior usually improves to a greater extent with TCA treatment than with psychostimulants. The effect of TCAs in ADHD is apparently not related to their antidepressant effect. Therefore, the optimal dose of TCAs in ADHD is lower and the effect occurs more quickly than in the treatment of depression. It has been shown that in a patient resistant to one of the TCAs, another drug in this group may be effective.

Cardiotoxicity of tricyclic antidepressants

Pharmacokinetics in children has its own peculiarities. Due to the lower ratio of fat and muscle tissue, the volume of distribution in children is smaller, and fat depots do not protect against overdose as effectively as in adults. In addition, the metabolism of these drugs in children occurs faster than in adolescents and adults, which leads to greater fluctuations in their concentration in the blood. Since TCAs lower the threshold for the development of epileptic seizures, they should be used with caution in patients with epilepsy.

In children, plasma concentrations after administration of the same dose of TCAs are subject to significant individual variations. Genetically determined decrease in cytochrome P450 2D6 activity is detected in 3-10% of individuals in the population, so they metabolize TCAs more slowly, which creates conditions for reaching toxic concentrations of the drug even if its dose does not exceed 5 mg/kg. The toxic effect can manifest itself as dysfunction of the cardiovascular and central nervous systems and can be mistaken for an increase in disease symptoms. Since, on the one hand, there is no clear relationship between the dose of TCA and its concentration in serum, and, on the other hand, the likelihood of potentially dangerous adverse effects depends on the serum concentration, monitoring the blood content of the drug itself and its metabolites in the treatment of attention deficit hyperactivity disorder is considered mandatory. To minimize adverse effects that occur at peak serum drug concentrations, it is recommended that children receive TCAs 2-3 times daily (if the daily dose exceeds 1 mg/kg). For the same reason, it is not advisable to prescribe long-acting drugs, such as imipramine pamoate capsules.

The toxic effects of TCAs can occur at any age, but they are especially dangerous in children and adolescents. Of particular concern is the possibility of slowing of cardiac conduction, which is expressed as an increase in PR hQRS intervals on the ECG, the development of tachycardia and other cardiac rhythm disturbances, and atrioventricular block. At least 5 cases of sudden death have been reported in children under 12 years of age taking desipramine. The fatal outcome was presumably associated with "pirouette" tachyarrhythmia (torsade de pointes). In three cases, death occurred after physical exertion. Four of the deceased children were 9 years of age and younger, and five were 12 years of age. In this regard, before prescribing the drug, during the titration period and during the maintenance dose, it is recommended to perform an ECG with measurement of the QT interval. Official guidelines for the use of TCAs in attention deficit hyperactivity disorder require an ECG before starting treatment, at a dose of 3 mg/kg/day, and after reaching the final dose, which should not exceed 5 mg/kg/day. The following standards are recommended: PR interval should be equal to 210 ms, QRS interval width should not exceed the initial value by more than 30%, QT interval should be shorter than 450 ms, heart rate should not exceed 130 beats per minute, maximum systolic pressure should be equal to 130 mmHg, and maximum diastolic pressure - 85 mmHg. After achieving a stable drug level in the blood.

An ECG should be performed every six months. One study showed that 10% of children and adolescents with ADHD taking desipramine had incomplete right bundle branch block (which is considered a normal variant in children under 10 years of age), an increase in the QRS interval to 120 ms or more, and 18% of patients had sinus tachycardia of 100 beats per minute or more. However, it is unknown whether these changes increase the risk of complications caused by desipramine.

Daily ECG monitoring showed that children taking desipramine for a long time had a significantly higher frequency of single and paired premature atrial contractions and attacks of supraventricular tachycardia. In addition, they had a decrease in the frequency of sinus pauses and a nodal rhythm. However, the level of desipramine in the blood correlated only with paired premature ventricular contractions. Since parasympathetic impulses to the heart decrease significantly with age, and desipramine is able to increase the ratio of sympathetic and parasympathetic activity 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 aged 5-14 years taking desipramine at therapeutic doses is approximately the same as that in children of the same age in the general population - 1.5-4.2 cases per million population per year. Thus, the question remains open. Some experts suggest strictly limiting the use of desipramine, while others consider this unnecessary and believe that a causal relationship between deaths and desipramine remains unproven. Green (1995) believes that since the number of cases of sudden death is small, their immediate cause is unknown, and also because there are no specific changes in cardiac activity that would have prognostic value, it is necessary to monitor the ECG, blood levels of the drug and its metabolites, ensuring that they are maintained within the recommended parameters, no matter which TCA is prescribed. Until more definitive data are available, it is recommended to follow these pragmatic recommendations and to prefer nortriptyline and imipramine over other TCAs in prepubertal children. In addition, a family history of cardiac disease should be considered a relative contraindication to the use of TCAs in general.

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Tricyclic antidepressants, most commonly used for attention deficit hyperactivity disorder

Given the previously described risk of cardiotoxicity, TCAs are currently used less frequently for the treatment of attention deficit hyperactivity disorder. Many physicians prefer nortriptyline. Wilens (1993), who collected data on 58 patients with attention deficit hyperactivity disorder resistant to treatment, found that nortriptyline at an average daily dose of 73.6 mg had a moderate positive effect in 48% of patients, regardless of the presence of concomitant conditions. In most cases of “marked improvement,” the blood concentration of nortriptyline ranged from 50 to 150 ng/ml. Side effects in these patients were mild, and no significant changes in cardiac conduction were detected. It was noted that nortriptyline can be effective in the combination of attention deficit hyperactivity disorder with Tourette syndrome or another type of tic.

Desipramine and imipramine are the most well-studied drugs and, until recently, were the most commonly used TCAs for the treatment of attention deficit hyperactivity disorder. Desipramine is still widely used today. It has been shown to be quite effective at doses of less than 3 mg/kg/day, with minimal cardiotoxicity. Imipramine is the TCA that is probably most widely used in children, as it is often prescribed for nocturnal enuresis. According to a number of studies, imipramine is effective for both attention deficit hyperactivity disorder and Tourette syndrome, but it has a high incidence of adverse effects and low tolerability. Amitriptyline has been shown to be effective in some children in controlled trials, positively influencing hyperactivity and aggression both at home and at school, but frequent adverse effects, primarily sedation, make it difficult to take the drug in the required dose. Another TCA used in children and adolescents is clomipramine. Its side effects include drowsiness, dry mouth, suppression of hematopoiesis, and an increased risk of epileptic seizures.

Other medications used for attention deficit hyperactivity disorder

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs), which include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, are now prescribed more often than TCAs because they are significantly safer. They have minimal effects on the cardiovascular system and are not as dangerous in case of overdose.

Experience with these agents is generally limited, but there are reports of positive results with fluoxetine in children and adolescents with attention deficit hyperactivity disorder with or without comorbid disorders. Further studies are needed to compare the efficacy of SSRIs with that of TCAs and bupropion in attention deficit hyperactivity disorder. Side effects associated with SSRIs include anxiety, hyperactivity, behavioral activation, insomnia, impulsivity, and suicidal ideation.

Alpha 2-adrenergic receptor agonists

The alpha2-adrenergic agonists clonidine and guanfacine are often used to treat attention deficit hyperactivity disorder. Their effectiveness as monotherapy has not been well studied, but in combination with psychostimulants they have been shown to reduce hyperactivity, agitation, and may be useful in children with tics.

Clonidine is an antihypertensive drug whose action is due to stimulation of presynaptic alpha2-adrenoreceptors and inhibition of norepinephrine release. In children with attention deficit hyperactivity disorder, clonidine improves frustration tolerance, task orientation, and reduces hyperexcitability. A particularly good effect is noted in cases where symptoms appear at an early age: manifestations such as hyperexcitability, hyperactivity, impulsivity, disinhibition are observed, which are accompanied by a violation of recognized norms of behavior and negativism. At the same time, clonidine has little effect on attention disorders and is not so useful in attention deficit hyperactivity disorder without hyperactivity. It is recommended to increase the clonidine dose gradually, starting with 0.05 mg/day and increasing it by the same amount every 3 days until it reaches 3-5 mcg/kg/day. The daily dose of clonidine is prescribed in 3-4 doses.

Clonidine is also available in the form of patches for skin application. One study showed that when switching from oral to transdermal administration, the daily dose of clonidine should be increased by a third. In approximately half of the patients, the effectiveness of the patch decreases after 5 days of wearing it. This is probably due to a shorter half-life in children (4-6 hours) and adolescents (8-12 hours); in adults, it is 12-16 hours. Significant clinical improvement with clonidine occurs no earlier than after a month. Clonidine in children with attention deficit hyperactivity disorder can remain effective for 5 years. When clonidine treatment is discontinued, its dose should be gradually reduced over 2-4 days to avoid hypertensive crisis and withdrawal symptoms - irritability, agitation, headache.

The most common side effect of clonidine is drowsiness. It usually occurs 1 hour after taking the drug and lasts for 30-60 minutes. As a rule, tolerance to the sedative effect develops after 3 weeks of treatment. When using the indicated doses, mean arterial pressure decreases by about 10%. About 5% of children and adolescents experience symptoms of depression when taking the drug. This complication is more common in cases of affective disorders in the family history, so this category of patients is not recommended to prescribe this drug. Attention deficit hyperactivity disorder is detected in about 50% of patients with Tourette syndrome, and in 20-50% of them, taking psychostimulants leads to an increase in tics. In this situation, as well as in all cases where patients do not tolerate psychostimulants 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 disorder with conduct disorder and oppositional defiant disorder (ODD) who exhibited disruption of social norms, negativism, marked hyperexcitability, and distractibility. The addition of clonidine allowed a reduction in the methylphenidate dose. This is particularly useful when methylphenidate causes significant side effects (e.g., rebound insomnia, significant growth retardation, or weight loss).

Guanfacine is also used to treat children and adolescents with attention deficit hyperactivity disorder, especially when combined with tics. Like clonidine, guanfacine stimulates alpha2-adrenergic receptors and produces a hypotensive effect, but differs from it in having a more selective action. Unlike clonidine, guanfacine acts to a greater extent on postsynaptic rather than presynaptic alpha2-adrenergic receptors in the prefrontal cortex. In an open study in 10 patients with attention deficit hyperactivity disorder and Tourette syndrome, the effective dose of guanfacine ranged from 0.75 to 3 mg/day, with the optimal daily dose for most patients being 1.5 mg. Although no significant reduction in attention deficit hyperactivity disorder symptoms was noted in the group as a whole, moderate improvement was observed in three patients and significant improvement was observed in one. The severity of tics in the group as a whole decreased reliably. The most common side effects were drowsiness, headache, insomnia, dizziness, but all of them regressed within 3-4 days. Guanfacine may be especially useful in children and adolescents who simultaneously suffer from attention deficit hyperactivity disorder and chronic tics.

Neuroleptics

Most studies comparing the effectiveness of neuroleptics and psychostimulants in the treatment of attention deficit hyperactivity disorder were conducted more than 20 years ago. Moreover, in most of these studies, psychostimulants were more effective than neuroleptics. Although neuroleptics have some effect, most doctors refrain from using them because of the risk of irreversible tardive dyskinesia, neuroleptic malignant syndrome, adverse effects on cognitive functions and learning due to the sedative effect. However, it is currently believed that neuroleptics for attention deficit hyperactivity disorder have a minimal effect on cognitive functions if they are prescribed in adequate doses. Moreover, according to some data, thioridazine may be more effective than psychostimulants in attention deficit hyperactivity disorder in children with developmental delay.

However, the risk of tardive dyskinesia limits the use of traditional antipsychotics in ADHD. However, newer generation drugs such as risperidone, which have a relatively low risk of developing parkinsonism and tardive dyskinesia, may be used in severe behavioral manifestations of ADHD. The new atypical antipsychotic olanzapine may cause fewer extrapyramidal complications than risperidone, but its efficacy in ADHD needs to be confirmed in clinical trials.

Monoamine oxidase inhibitors

The non-selective monoamine oxidase inhibitors phenelzine and tranylcypromine are used primarily as antidepressants. They can cause serious side effects, especially hypertensive crises, require dietary restrictions on tyramine-containing foods, and make it impossible to use a large number of medications. For this reason, neither of these drugs is recommended for use in children and adolescents, although tranylcypromine has been reported to be effective in attention deficit hyperactivity disorder. Since selegiline (deprenyl) selectively blocks MAO-B, it is safer and causes hypertensive crises only when used in high doses. The drug is most often used for a combination of attention deficit hyperactivity disorder and Tourette syndrome. Selegiline is available in 5 mg tablets. Its maximum daily dose is 15 mg. The drug is prescribed in 2 doses (morning and afternoon).

Drugs of other groups used for attention deficit hyperactivity disorder

Mood stabilizers (lithium, carbamazepine, and valproic acid) do not appear to have a beneficial effect on the core symptoms of ADHD, but may be helpful for behavioral outbursts or repetitive affective disorders. Benzodiazepines and mianserin are also ineffective in idiopathic ADHD without other disorders.

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