Resumen

El trastorno por déficit de atención con hiperactividad se ubica en el CIE-10 dentro de los denominados trastornos hipercinéticos y en el DSM-IV como parte de los trastornos de inicio en la infancia y la adolescencia. La prevalencia de este trastorno se ha calculado entre 3 a 6% en la población general, y persiste en la adolescencia y la vida adulta en 60% de los pacientes. Este padecimiento constituye la principal causa de búsqueda de atención psiquiátrica en la población infantil de nuestro medio, lo cual señala la necesidad de crear protocolos de atención para su diagnóstico oportuno y tratamiento adecuado.

El tratamiento de este trastorno se basa en la administración de medicamentos. El tratamiento farmacológico más estudiado, y que ha demostrado mayor eficacia, es el uso de estimulantes, siendo el metilfenidato el único medicamento de este género disponible en México. Su presentación original como medicamento de liberación inmediata tiene una vida media corta, y requiere ser administrado dos o tres veces al día. Por lo anterior, se diseñó el sistema de liberación osmótica tras la administración vía oral (OROS), que permite mantener dosis plasmáticas terapéuticas tras una sola toma al día. Los estudios a largo plazo han mostrado que el metilfenidato no tiene potencial de abuso y que los pacientes con trastorno por déficit de atención que reciben tratamiento tienen menor riesgo de consumir sustancias que los pacientes no tratados.

Hasta 30% de los pacientes no responde adecuadamente al tratamiento con metilfenidato, por lo que se consideran otros medicamentos como segunda elección. Entre ellos se cuentan los antidepresivos tricíclicos, que han mostrado su utilidad en el manejo de los pacientes con trastorno por déficit de atención y conductas disruptivas. Entre las ventajas de su uso está su mayor vida media, que permite la administración de una a dos dosis por día. La mayor desventaja del uso de estos medicamentos son sus efectos colaterales, en particular la prolongación del intervalo Q-T del electrocardiograma. El bupropión es otro antidepresivo que ha mostrado utilidad en el tratamiento del trastorno por déficit de atención solo y comórbido con trastorno disocial, uso de sustancias y la depresión. Su presentación en forma de liberación prolongada favorece el apego al tratamiento al reducir la necesidad de varias tomas durante el día. Entre los efectos colaterales del bupropión se encuentran la reducción del umbral convulsivo, la erupción cutánea y la elevación leve de la tensión arterial.

Los estimulantes de la alerta constituyen una nueva generación de fármacos y otra opción para el tratamiento del trastorno por déficit de atención; de ellos, la atomoxetina ha mostrado efectividad terapéutica a corto y largo plazo. Entre las ventajas de este fármaco se cuentan la administración en una sola toma, su bajo potencial cardiotóxico y el hecho de que no afecta el crecimiento. Además, se ha reportado una reducción de los tics y de los síntomas ansioso-depresivos comórbidos del trastorno por déficit de atención. Los efectos colaterales reportados más frecuentemente con atomoxetina son la náusea y la disminución del apetito. El modafinil es otro estimulante de la alerta que ha mostrado efecto terapéutico en estudios abiertos y comparativos contra placebo. Sus efectos secundarios más frecuentes son la náusea, el vómito y el insomnio inicial.

Tomando en cuenta la información anterior, un grupo de clínicos se reunió en el Hospital Psiquiátrico Infantil “Dr. Juan N Navarro” y elaboró un consenso para la evaluación y el manejo del trastorno por déficit de atención, con el fin de actualizar la información y uniformar los criterios y los tiempos de tratamiento dentro de una institución. De este consenso derivaron cuatro algoritmos para el manejo en preescolares del trastorno sin comorbilidad, comórbido con trastornos internalizados y comórbido con trastornos externalizados.

Palabras Clave: trastorno por déficit de atención; tratamiento farmacológico; niños; adolescentes

Summary

The diagnostic criteria for the Attention Deficit Hyperactivity Disorder (ADHD) have been changing according to international classifications. It is currently included in the ICD-10 as an hyperkinetic disorder and in the DSM-IV as a disorder having its onset during childhood and adolescence. The reported prevalence for ADHD is between 3% and 6%; up to 60% of the patients remain symptomatic through adolescence and adulthood. Population-based surveys of physicians who treat children and adolescents reveal that the rate and the proportion of office visits associated with ADHD are high and have increased over the past decade. This fact points to the need of elaborating clinical guidelines for the treatment of this disorder.

Evidence from controlled clinical trials confirms the superiority of medication management for ADHD over behavioral therapy and the combination of medication and behavioral treatment. Stimulants are the most studied drugs for ADHD and constitute the first treatment of choice. Methylphenidate (MPH) is the only stimulant available in Mexico. Its mechanism of action is based on the blocking of the dopamine reuptake, which increases the availability of this neurotransmitter in the synaptic cleft. Based on the dopaminergic theories of ADHD, dopamine genes have been the initial candidates for molecular studies regarding response to MPH. Variations of the dopamine D4 receptor gene (DRD4) and the dopamine transporter gene (DAT1) have been related with the response to MPH. The short half life of this drug (less than three hours) supports the shift from once-a-day to twice-a-day or thrice-a-day dosing. The Osmotic Release Oral System (OROS) of MPH allows to maintain therapeutic plasmatic doses with once-a-day dose. Its efficacy and tolerability have been shown in clinical trials.

Regarding the long-term effects of MPH, this drug has demonstrated efficacy in a two-year follow-up controlled study. In addition, animal models have shown that the chronic exposure to MPH during developmental periods produces changes in the function of brain dopaminergic cells, as well as changes in behavior. The association between MPH and substance abuse has also been explored. The pharmacokinetic and pharmacodinamic differences between MPH and cocaine, which also acts by blocking the dopamine transporter, were examined: When administered intravenously, MPH, like cocaine, has a reinforcing effects at doses that exceed a 60% dopamine transporter blockade threshold. When administered orally at clinical doses, the pharmacological effects of MPH also exceed this threshold, but reinforcing effects rarely occur. So, the pharmacokinetic properties of MPH in brain differ for oral and intravenous routes of administration, suggesting that the oral administration of MPH mimics the tonic dopamine cell firing, which may be a critical factor associated with clinical effects. In addition, therapeutic doses of MPH do not act at the nucleus accumbens, a brain structure highly associated with reinforcing. These data suggest that oral administration of MPH does not lead to abuse. Follow-up studies have also shown that stimulant therapy is not associated with increased risk of substance abuse.

Since 30% of the patients do not respond to stimulant treatment, the efficacy and safety of other drugs have been evaluated. Among them, tricyclic antidepressants (TCAs) are considered a good choice for the management of ADHD and conduct disorders. Their half life is longer than that of MPH, which allows a once-a-day or twice-a-day dosing. It has also been described that TCAs are effective for the treatment of comorbid tics. The main disadvantage of these drugs is their effect on cardiac conduction, which has been associated with sudden death.

Bupropion is another antidepressant having an effect on dopamine activity. It has shown efficacy for the treatment of ADHD in children, adolescents, and adults, particularly in patients with nicotine dependence, patients with comorbid conduct disorder, or depression. Bupropion is available in a extended-release, once-daily formulation (XL). The main side effects of this antidepressant are the increased risk of seizure development, rash and mild elevation of blood pressure. This drug is not recommended for the treatment of patients with comorbid eating disorders.

Venlafaxine (a serotonin and norepinephrine reuptake inhibitor) and reboxetine (a norepinephrine reuptake inhibitor) are recently introduced antidepressants which have shown efficacy in open label trials on patients with and without comorbid depressive disorder.

Atomoxetine is another non-stimulant medication; its main mechanism of action is the inhibition or the reuptake of norepinephrine. Several clinical trials have shown its efficacy for the treatment of ADHD in children, adolescents and adults. This drug can also be administered in a single dose; in addition, it has a low potential for cardiotoxicity and a reduction of tic frequency and severity has been reported with its use. It is also recommended for the ADHD comorbid with anxiety or depression. Nausea and decreased appetite are the most common side effects of atomoxetine.

Modafinil is another non-stimulant drug which was initially described for the treatment of narcolepsy. This drug increases the dopamine and norepinephrine activity through its direct effect on glutamate and GABA, among other neuromodulators.

Some clinical trials have shown its superiority over placebo on ADHD symptoms. The main side effects of modafinil are gastrointestinal distress and insomnia.

Clonidine and risperidone are drugs considered as second treatment of choice or adjunctive treatments for patients with comorbidity.

Although medication is the first treatment of choice, patients often get benefits from psychosocial interventions, particularly parent training in contingency management methods and classroom applications of contingency management techniques. The value of these measurements lies in the temporary reduction of symptom levels and/or in the reduction of related behavioral and emotional difficulties, such as defiance and conduct problems, depression, low self-esteem, or academic underachievement.

Parents’ training focus on general contingency management tactics, such as contingent application of reinforcement or punishment following appropriate/inappropriate behaviors. Reinforcement procedures have typically relied on praise or tokens, while punishment methods have usually been the loss of tokens or time-out from reinforcement. The classroom management include a continuous communication with teachers, in order to maintain them informed about the illness and its treatment, as well as training on contingency management tactics.

The aforementioned information was used in the elaboration of clinical guidelines for the treatment of youngsters with ADHD, either alone or comorbid with internalizing or externalizing disorders. Another guideline for the management of preschool children with ADHD is included. Psychoeducation follows the assessment of the children in each case. The pharmacological treatment recommendations give priority to monotherapy. Stimulants are the first treatment of choice in each guideline. The use of non-stimulant medications as second choice will depend on the age and comorbidity of patients.

Key words: Attention deficit hyperactivity disorder; pharmacological treatment; children; adolescents