Pharmacotherapy for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder defined by impairing levels of inattention, disorganization, and/or hyperactivity-impulsivity. ADHD often persists into adulthood, with resultant impairments of social, academic and occupational functioning. ADHD is a very common disease during childhood and, the pooled overall prevalence of ADHD was found to be 5.29%. When screening for ADHD, clinicians should try to develop rapport with patients and their caregivers to increase the likelihood that they will follow the diagnostic process and treatment. The current drugs that have received Food and Drug Administration-approval for ADHD include stimulants (methylphenidate and dextroamphetamine) and non-stimulants (atomoxetine, guanfacine, and clonidine). Stimulants improve inattention, hyperactivity, and impulsivity in addition to decreasing disruptive behaviors and promoting academic achievement and the maintenance of appropriate friendships. In order to enhance drug compliance, the use of long-acting stimulants is increasing. Atomoxetine is a selective norepinephrine reuptake blocker, the effects of which may take 2 to 6 weeks to be noticeable. Furthermore, α2 agonists may help to improve behavioral side effects, tics, and sleep problems during stimulant or atomoxetine use. Common side effects of stimulants and atomoxetine include headache, stomachache, and loss of appetite. Routine electorcardiography before medication is not recommended unless there is a specific indication. Methylphenidate and atomoxetine are safe as first line therapies, and their side effects are well tolerated.

Tratamento farmacológico e intervencionista do sistema nervoso simpático / Pharmacological and interventional treatment of sympathetic system

o sistema nervoso autônomo contribui diretamente para uma série de atividades biológicas e está envolvido em inúmeras doenças. A hiperatividade simpática é um dos vários mecanismos envolvidos na patogênese da hipertensão arterial sistêmica (HAS) primária. A transmissão da informação nervosa através de sinapses é mediada por agentes químicos específicos conhecidos como neurotransmissores, representados pela acetilcolina e pelas catecolaminas. O bloqueio dos receptores pré e pós-sinapse permite que a ação de fárrnacos alcance sua plenitude no controle dos portadores de hiperati vidade simpática. Um percentual significativo de hipertensos são resistentes ao tratamento farrnacológico. A denervação simpática renal surgiu como estratégia terapêutica adjunta no controle de hipertensos resistentes ao tratamento clínico. Nos últimos cinco anos, diversos estudos demonstraram resultados consistentes na redução da pressão arterial. Diversas outras condições clínicas associam-se à hiperatividade do sistema adrenérgico, tais como a insuficiência cardíaca, o diabetes mellitus, a doença renal crônica, a síndrome da apneia e hipopneia obstrutiva do sono e as arritmias cardíacas. Nestes contextos, a redução da atividade simpática renal também mostrou-se ser benéfica em estudos clínicos iniciais. Uma variedade de dispositivos dedicados foram e estão sendo desenvolvidos com o objetivo de ampliar a segurança e a eficácia do método, além de facilitar o procedimento. Estudos multicêntricos, prospectivos, randomizados e controlados em andamento investigam desfechos como mortalidade cardiovascular, infarto agudo do miocárdio e acidente vascular cerebral em longo prazo.

The autonomic nervous system contributes directly to a number of biological activities and is involved in numerous diseases. Sympathetic hyperactivity is one of several mechanisms involved in the pathogenesis of primary hypertension. The transmission through the nerve synapses is mediated by specific chemical agents known as neurotransmitters represented by the acetylcholine and catecholarnine. Blockade of specific pre-and post-synapse receptors allows the treatment of patients with sympathetic hyperactivity. A large proportion of hypertensive patients are resistant to pharmacological treatment. Renal sympathetic denervation emerged as adjunctive therapeutic strategy in controlling hypertension resistant to medical treatrnent. ln the last five years, several studies have shown consistent results in lowering blood pressure. Several other clinica! conditions are associated with hyperactivity of the adrenergic system such as heart failure, diabetes mellitus, chronic kidney disease, obstructive sleep apnea, polycystic ovary syndrome and cardiac arrhythrnias. ln these contexts, the reduction in renal sympathetic activity also proved to be beneficial in initial clinical studies. A substantial variety of dedicated devices have been developed in order to reduce variability between operators, reduce renal artery manipulation, improve vessel contact, reduce radiation exposure and procedure time, and therefore improving safety and efficacy. Mu!ticenter, prospective, randomized, controlled trials are ongoing to investigate long term outcomes such as cardiovascular mortality, acute myocardial infarction and stroke.

The α(2A)-adrenoceptor agonist guanfacine improves spatial learning but not fear conditioning in rats / 生理学报

It is known that stimulation of the α(2A)-adrenoceptors (α(2A)-ARs) by the selective α(2A)-AR agonist guanfacine produces an important and beneficial influence on prefrontal cortical (PFC) cognitive functions such as spatial working memory and selective attention. However, it is unclear whether stimulation of the α(2A)-ARs has a similar effect on fear conditioning that involves the amygdala and hippocampus. Here, we show that systemically administered guanfacine significantly enhances spatial learning of rats in the Lashley maze: compared with controls, the rats treated with guanfacine required significantly fewer trials and made significantly fewer errors to reach learning criterion. However, guanfacine produced no effect on acquisition of contextual and auditory fear memories. The present study suggests that beneficial effect of α(2A)-AR stimulation is task-dependent: guanfacine improves spatial learning but not fear conditioning.

An open-label, prospective study of guanfacine in children with ADHD and tic disorders.

OBJECTIVES: To evaluate the efficacy and safety of guanfacine in children with attention-deficit hyperactivity disorder (ADHD) and tic disorders. MATERIAL AND METHOD: Twenty-five medication-free subjects (23 males and 2 females), aged 7-16 (mean = 10.6 +/- 2.0) years participated in an 8-week open-label guanfacine study. Subjects were recruited from a specialty clinic for children with tic disorders over a four-year period. Eligibility criteria included presence of ADHD (any type), a tic disorder (any type), and being medication free for two weeks. Outcome measures included the Hyperactivity Index of the Conners Parent Questionnaire, the teacher-rated ADHD Rating Scale, and the Yale Global Tic Severity Scale (YGTSS). RESULTS: All subjects met criteria for ADHD (combined type N = 22; predominantly inattentive type N = 3) and a tic disorder (Tourette's Disorder N = 20; chronic motor tic disorder N = 5). At an average dose of 2.0 +/- 0.6 mg/ day, guanfacine was associated with mean improvement of 27% on the Hyperactivity Index (N = 25; t = 4.61; p < 0.001), 32% on the total score of the teacher-rated ADHD Scale (N = 19; t = 5.27; p < 0.001), and 39% on the total tic severity scale (N = 19; t = 4.17; p < 0.001). Mild and statistically insignificant decreases in blood pressure and pulse were observed in the sample as a whole. Five subjects had endpoint systolic blood pressure below 1 SD from their age and gender norms. CONCLUSION: Results of this open-label study add to the growing data base on the safety and efficacy of guanfacine in children with ADHD and tic disorders.

Diagnosis and Treatment of Tic Disorders

Tics are brief, rapid and repetitive movement and sounds that are either simple or complex in presentation. Tics can be preceded by a premonitory urge (sensation) that decreases after tic is completed. The fourth edition of Diagnostic Statistical Manual of Mental Disorder (DSM- IV) includes diagnoses for Tourettes disorder, chronic motor or vocal tic disorder, transient tic disorder and tic disorder not otherwise specified (Table 1) according to the duration of tic symptoms and degree of complexity. The purposes of treatment of tic disorders must be set up based on the comprehensive evaluation of developmental profiles, strength, weakness, family situation, and school adaptation status. The family education must be included early in treatment process and psychosocial treatment including the cognitive behavioral therapy will be needed to develop and maintain the self-efficacy in controlling the tic symptoms. The most effective and efficient method for the reduction of tic symptoms, however, are drug treatment. The pharmacotherapy is usually one component of treatment for chronic tic disorder and Tourettes disorder. The gold standard for tic reduction is the dopaminergic receptor blocking agent (or antipsychotic agent, neuroleptics). The primary drugs are haloperidol, pimozide, and risperidone. Among theses, risperidone will be the primary choice because of its low side effect profiles, esp, neurologic side effects. In the near future, the studies on the efficacy of the olanzapine, quetiapine and ziprasidone will be more reported. As second line drugs, clionidine, guanfacine, nicotine related drugs can be considered.

Preliminary Findings of Guanfacine in Comorbid ADHD and Habit Disorder-Open Trial / 신경정신의학

OBJECTIVE: Attention Deficit/Hyperactivity Disorder(ADHD) and tic disorders are relatively common childhood onset neuropsychiatric disorders, and these two disorders frequently cooccur in some individual. Although the efficacy of psychostimulants is well established in ADHD, as many as 25% of children fail to respond to psychostimulant treatment due either to a lack of efficacy or to intolerable side effects including exacerbations of tics. Guanfacine, a selective alpha2A-adrenergic agonist, was recently introduced for the treatment of children with ADHD. This study is to evaluate the efficacy and safety of guanfacine in children with ADHD and comorbid habit disorders and to identify subgroups of children who may have a more favorable response to guanfacine. METHODS: Twenty five children who were 6 to 16 years old were enrolled in an open trial of guanfacine for two months. Primary outcome measures were DuPaul Parent and Teacher Rating Scales, Conners Parent and Teacher Rating Scales and Yale Global Tic Severity Scale. Paired t-test and multiple logistic regression were performed to evaluate symptom improvement and to examine predictor variables for positive drug response. RESULTS: Severity of ADHD symptoms and tics after guanfacine administration was significantly reduced at each follow-up point in the ratings completed by both parents and teachers and in clinical evaluation, compared to their pre-medication status. Children with moderate ADHD symptoms responded more favorably to guanfacine than children with mild or severe symptoms. CONCLUSION: These findings suggest that guanfacine may be a safe and an effective medication for ADHD children who cannot benefit from psychostimulants, but more definitive research strategies are needed for future investigation.

Effect of guanfacine on kidney, heart and GABA level in DOCA and salt hypertensive rats

Experimental hypertension, was induced in rats by intramuscular injection of desoxycorticosterone [DOCA] in a dose of 50 mg/kg body weight/week for six weeks, in addition to salt in drinking water. Guanfacine was given to normotensive and hypertensive rats intraperitoneally in a daily dose of 0.09 and 0.18 mg/kg body weight for 30 days. Induction. of hypertension resulted in significant reduction in the neurotransmitter gamma aminobutyric acid [GABA] concentration in the brain, hypertrophy of the cardiac muscle and nephrosclerosis with impaired renal function. However, these histophathological and biochemical changes were paradoxically decreased after giving guarifacine in a daily dose of 0.09 mg/kg body weight for 30 days, as a result of marked decrease of blood pressure. The hypertensive rats treated with 0.18 mg/kg body weight of guanfacine for 30 days showed marked increase in the incidence and severity of cardiac and renal histopathological changes, due to the combined toxic effect of guanfacine and hypertension. The increased GABA concentration in the brain and the reduction in blood pressure after giving the drug were more significant with the low dose. In normotensive groups, rats treated with guanfacine in a daily dose of 0.18mg/kg body weight for 30 days showed moderate renal toxicity, while no biochemical or histopathological changes were observed with 0.09 mg/kg body weight of guanfacine. The two doses of guanfacine induced insignificant changes in both blood pressure and GABA concentration in the brain as compared to control non-treatment rats. Thuse law dose of guanfacine is considered more effective and safe and so it is superior to high dose in the ambulatory treatment of hypertension

Effect of guanfacine and methyldopa on insulin secretion in diabetic rabbits

Two different alpha 2-adrenoceptor agonists, guanfacine and methyldopa, were used to evaluate the role of alpha 2-adrenoceptor stimulation on insulin release, serum glucose level and glucose tolerance in diabetic rabbits. Both drugs induced a remarkable inhibition of insulin release accompanied by an increase in serum glucose and impairment of glucose tolerance. Methyldopa showed weaker effects than guanfacine. It was concluded that, in diabetic fasting rabbits, stimulation of alpha 2-adrenoceptors depresses basal insulin secretion. It was also suggested that successive alpha 2-adrenergic stimulation by alpha 2-adrenoceptor agonists in diabetic persons might to be a harmful adjunct to diabetes mellitus

Effect of a single dose of clonidine and guanfacine on the content of norepinephrine and GABA in rat brain

This work aimed at studying the pattern of GABA and norepinephrine in Egyptian strain of male albino rats in normotensive and DOCA/ Salt hypertensive rats. Moreover, the effect of two centrally acting antihypertensive drugs namely clonidine and quanfacine upon the contents of neurotransmitters in whole brain as well as cerebral cortex, thalamus and hypothalamus, mid brain and hind brain was investigated. The data revealed that, the highest levels of norepinephrine and GABA were in hind brain of normotensive rats. Hypertensive rats showed significant increase in norepinephrine concentration in whole brain and specified areas.The concentration of GABA in hind brain of DOCA/Salt hypertensive rats was significantly raised. On the other hand, it was significantly decreased in other areas of brain. The agonistic effect of clonidine caused a significant rise in norepinephrine concentration in hind brain. Other brain areas showed significant decrease. The findings in the work showed that guanfacine is a weaker agonist than clonidine as it failed to raise norepinephrine concentration in hind brain. This may explain the lack of sedation after guanfacine treatment, while clonidine has a powerful sedative effect

Effect of clonidine and guanfacine on dopamine and serotonin level in rat brain

In the present work, the pattern of dopamine and 5-HT in whole and different areas of brain of Egyptian strain of male albino rats both in normotensive and DOCA and salt hypertensive rats has been determined. Moreover, the effects of two centrally acting antihypertensive drugs, namely clonidine [0.1 mg/kg] and guanfacine [1 mg/kg], have been analyzed using biochemical fluorescent techniques. The findings revealed that in normotensive rats the highest level of dopamine was in the cerebral cortex compared with the midbrain for serotonin. Hypertensive rats showed rise in dopamine level in whole and specified areas of brain. This may be due to increase in dopamine synthesis or inhibition of its release. Serotonin level was also elevated which can be due to enhancement in its synthesis secondary to its influence on other neurotransmitters as well as adaptation to stress. On the other hand, clonidine and guanfacine normalized the dopamine level in hypertensive rats to the values of controls. This may be attributed to increased dopamine release. On the other hand, clonidine and guanfacine increased serotonin level in hind brain possibly due to reduction in its release. This may explain the central hypertensive role of serotonin. The quantitative differences in the action of clonidine and guanfacine can be explained by their relative concentration and effectiveness in different areas of rat brain

Etude clinique de la guanfacine dans le traitement de l'hypertension arterielle

The antihypertensive efficacy of Guanfacine at a single dose was tested in 20 patients. Before Guanfacine treatment was begun systolic blood pressure was 189 +/- mmHg and diastolic blood presure was 108 +/- 8 mmHg. After a 3 months period of treatment, the values of blood pressure were 153/91 [ +/- 24/10] mmHg. 80% of patients received a daily dose of Guanfacine of 2 mg or less. The efficacy of the drug was satisfactory in 68% of the patients. Side effects common to all drugs which block sympathetic activity do not accur as frequently with Guanfacine except dry mouth that appears in nearly 50% of the patients

Guanfacine and hypertension: effect on blood pressure, electrocardiographic changes, heart rate and some biochemical values

This study was carried out on 18 dogs, using a new antihypertensive agent, Guanfacine. Experimental hypertension was performed by constriction of renal arterial blood supply and compression of the kidneys. Guanfacine was injected as acute intravenous single dose [0.02 mg/kg body weight] alone and combined with diuretic [furosemide] or B-blocker [pindolol]. No significant changes in serum electrolytes, glucose, FFA were reported with Guanfacine alone or combined with diuretic. While combination with [pindolol], resulted in significant decrease in arterial blood pressure with brady-cardia was observed after Guanfacine alone and not changed when combined with diuretic. Significant reduction in arterial blood pressure and heart rate was noted after combination with B-blocker