[Atomoxetine: a new treatment for Attention Deficit/Hyperactivity Disorder (ADHD) in children and adolescents]. / L'atomoxétine: un nouveau traitement du trouble déficitaire de l'attention/hyperactivité de l'enfant et de l'adolescent.

This paper provides a review of safety and efficacy data as well as of pharmacological characteristics of atomoxetine, a new drug treatment for the Attention Deficit/Hyperactivity Disorder (ADHD). To date, the only pharmacological treatment available in France for children and adolescents diagnosed with ADHD is methylphenidate, a psychostimulant drug. However, the clinical response to methylphenidate may be absent or insufficient in about 20-30% drug-treated children while the occurrence of adverse effects with methylphenidate (sleep disturbances, loss of appetite, tics increase...) may sometimes require a dose reduction or even the discontinuation of the treatment. Atomoxetine is an alternative candidate drug for the treatment of ADHD. The drug has been developed with respect to the actual standards of investigation of drugs intended to a -pediatric use. Atomoxetine has been recently licensed in the USA for the treatment of ADHD. Atomoxetine is a potent inhibitor of the norepinephrine transporter that shows only mini-mal affinity for other neurotransmitter systems. Although pharmacokinetics of atomoxetine is influenced by the polymorphism of the CYP2D6 metabolic pathway, safety and -tolerability data reported during clinical trials did not show any difference in poor versus extensive metabolizers. In addition, atomoxetine does not inhibit nor induce the CYP2D6 enzymatic function. The major metabolite of atomoxetine is 4-hydroxyatomoxetine, a pharmacologically active metabolic found in very low plasma concentrations in pediatric patients, suggesting that it plays only a minor role in the norepinephrine reuptake inhibition. Preliminary studies were aimed to assess the effective dose range of atomoxetine and to evaluate its safety and efficacy on the reduction of ADHD symptoms in adults and children diagnosed with ADHD. Main data on the child and adolescent population were obtained in four double-blind, randomized, placebo-controlled trials: two identical pivotal trials, a multiple dose study, a once-daily dose study. The first two pivotal trials were carried out in ADHD children aged 7-13 years, treated with atomoxetine vs placebo for a duration of 9 weeks. Patients presenting comorbidities (ie conduct disorder, -anxiety, depression) as well as a history of previous treatment with methylphenidate were also eligible to participate. The primary outcome was the reduction of the score on the ADHD rating scale, ADHD-RS ; secondary criteria included the responder's rate (patients with an ADHD-RS score reduction of 25% or above), the Clinical Global Impression Scale and the Conners Parent Rating Scale. With a mean dose of 1.5 mg/kg/day, atomoxetine showed a significant reduction of mean ADHD-RS scores at endpoint (ANOVA, p<0.001) (table II). Yet, the clinical significance of both studies is limited since efficacy was scored only in a social/familial setting and not in classroom conditions. In addition, intermediate results from baseline to endpoint were not presented in the publication. The multiple dose trial showed a significant reduction of the symptom score at the 1.2 and 1.8 mg/kg/day doses. The objective of the last study was to assess the efficacy of a single daily dose of atomoxetine versus placebo during a 6 week-treatment. Patients were evaluated by parents, investigators, as well as by teachers. The superiority of atomoxetine was demonstrated as compared to the placebo and the effect size of the daily dosing was similar to that reported with multiple doses. Preliminary data on ADHD patients presenting comorbidities showed that atomoxetine alone signi-ficantly reduced the symptom scores of anxiety and depression and similarly to atomoxetine associated with fluoxetine. In ADHD children with the oppositional defiant disorder, oppositional symptoms were reduced in the group receiving atomoxetine 1.8 mg/kg/day. Preliminary results in children with ADHD and chronic tics or Tourette syndrome showed a significant reduction of ADHD symptoms and a tendency to the decrease of tics. Tolerance and safety data pooled from the child and adolescent trials were acceptable. Study discontinuations due to adverse events in the four registration studies were only 2.8%. The most frequent adverse effects reported were gastrointestinal symptoms and decreased appetite. Weight loss reported early in clinical studies tended to stabilize during the open-label extension phases lasting up to 9 months. A retrospective comparison showed that the adverse event profile of poor metabolizers was similar to that of extensive metabolizers. In summary, data presented suggest that atomoxetine is a safe and effective drug for the treatment of ADHD in children and adolescents. Further studies are expected to accurately define the place of atomoxetine in the treatment strategy of ADHD, a chronic and invalidating disorder affecting 3 to 7% of school-aged children.

Idazoxan and 8-OH-DPAT modify the behavioral effects induced by either NA, or 5-HT, or dual NA/5-HT reuptake inhibition in the rat forced swimming test.

The rat forced swimming test (FST) predicts the efficacy of antidepressants, which decrease immobility duration in the test, and can distinguish selective serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors, which, respectively, increase swimming and climbing behaviors. However, dual 5-HT and NA reuptake-inhibition produces climbing behavior solely, thereby suggesting with other data that the NA-system mediates inhibiting interactions on 5-HT-induced swimming in the FST. Since alpha(2)-adrenoreceptors and 5-HT(1A)-receptors have important regulatory functions and are involved in 5-HT/NA interactions, we examined whether the alpha(2)-receptor-antagonist idazoxan and the 5-HT(1A)-receptor-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) would modify the behavioral pattern induced in the FST by either selective or non-selective antidepressant treatments. The rats were treated subacutely (3 injections IP over 48 h) with: (a) idazoxan (0.5-10 mg/kg) alone, and in combination with desipramine (10 mg/kg), or desipramine + fluoxetine (10/10 mg/kg), or the dual serotonin/noradrenaline reuptake-inhibitor milnacipran (20 mg/kg). (b) 8-OH-DPAT (0.25-1 mg/kg) alone, and in combination with either desipramine (10 mg/kg) or fluoxetine (10 mg/kg). The results indicated: (a) Idazoxan (0.5, 5, 10 mg/kg) produced no anti-immobility effects per se in the FST, antagonized the effects of the NA-reuptake-inhibitor desipramine, and allowed desipramine + fluoxetine, as well as milnacipran, to increase swimming behavior. (b) 8-OH-DPAT produced non-significant effects per se, potentiated desipramine-induced antidepressant-like effects on immobility and climbing, and both antagonized swimming and produced climbing behavior in combination with fluoxetine. Our data support clinical trials suggesting that alpha(2)-receptor-antagonists and 5-HT(1A)-receptor-agonists may be of interest in augmentation strategies for antidepressant treatments. The scoring of active behaviors in the FST appears to be an interesting tool for studying 5-HT/NA interactions induced by antidepressants, as well as for the testing of augmentation strategies.

Post-ECT agitation and plasma lactate concentrations.

This prospective study evaluated the hypothesis that emergence agitation after electroconvulsive therapy (ECT) could be caused by lactate-induced panic secondary to insufficient neuromuscular blockade. Plasma lactate levels were measured before and after 245 consecutive ECT sessions in 37 patients monitored for evidence of post-ECT agitation. ECT was administered using a brief-pulse, rectangular, constant-current device through bilaterally placed electrodes under general anesthesia and neuromuscular blockade. Agitation was observed in 7% of all ECT sessions. No significant difference could be found in pre-ECT lactate levels. However, mean post-ECT lactate levels in agitated sessions were significantly greater than those in nonagitated sessions (4.77 versus 2.54 mmol/l, p < 0.05). An increase (+27%) in the pre-ECT succinylcholine dose for those patients who previously had repeated post-ECT agitation resulted in cessation of post-ECT agitation and return of the formerly high post-ECT lactate levels to normal (1.61 versus 2.07 mmol/l). Although the number of patients who had post-ECT agitation was small, the data support the hypothesis that post-ECT agitation might be a manifestation of lactate-induced panic.

Total neurochemical lesion of noradrenergic neurons of the locus ceruleus does not alter either naloxone-precipitated or spontaneous opiate withdrawal nor does it influence ability of clonidine to reverse opiate withdrawal.

It has been suggested that an increase firing rate of noradrenergic neurons of the locus ceruleus is responsible for the opiate withdrawal syndrome. However, lesion studies have indicated that the noradrenergic neurons of the locus ceruleus are not essential for either the expression or suppression by clonidine of opiate withdrawal. The present study was designed to determine the effect of the almost complete 6-hydroxydopamine lesion of noradrenergic neurons (94%) of the locus ceruleus on various components of the opiate withdrawal syndrome and on its protection by clonidine. Morphine dependence was induced by s.c. implantation of morphine pellets (2 x 75 mg base). The following paradigms were used: 1) naloxone-induced conditioned place aversion, 2) naloxone-precipitated acute opiate withdrawal syndrome, 3) nycthemeral locomotor activity as a measure of spontaneous opiate withdrawal. The results showed that quasi-total lesion of noradrenergic neurons of the locus ceruleus did not modify opiate dependence as revealed by naloxone-induced conditioned place aversion and the expression of an acute morphine withdrawal syndrome. Moreover, clonidine prevented the opiate withdrawal syndrome in both lesioned and sham-operated rats, suggesting that the action of clonidine is certainly mediated through postsynaptic alpha(2)-adrenoceptor stimulation. Finally, the nycthemeral locomotor activity during spontaneous morphine withdrawal did not differ between the lesioned and the sham-operated rats.

[Atypical neuroleptics in the child and adolescent]. / Neuroleptiques atypiques chez l'enfant et l'adolescent.

The FDA approval for clozapine in 1990 under several hematologic surveillance conditions has reactualized the debate on the use of atypical neuroleptics for adults with schizophrenia. The use of conventional neuroleptics in children and adolescents has always been a subject of controversy due to their side effects and the absence of controlled studies. The pharmacological action of clozapine and risperidone is mainly on D2 and 5HT. Since 1992 several studies concerning children and adolescents show the efficiency and the tolerance of the clozapine and risperidone in various disorders, especially in very early onset schizophrenia (VEOS). Controlled trials are necessary to confirm the data obtained in open studies.

Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test.

Because of clinical interest in the effects of antidepressant drugs that exert their effects on multiple neurotransmitter systems, the behavioral effects produced by combined treatment with an SSRI (fluoxetine) with a selective norepinephrine (NE; desipramine) or dopamine (DA) reuptake inhibitor (buproprion) were examined in the forced swimming test (FST), a behavioral test in rodents that predicts the clinical activity of antidepressants. Three additional compounds with mixed activity as NE-5-HT reuptake inhibitors, milnacipran, duloxetine and venlafaxine, were also examined. Desipramine and fluoxetine both reduced immobility in the FST, but desipramine increased only climbing behavior, whereas fluoxetine increased only swimming behavior. The combination of fluoxetine with desipramine or bupropion increased both climbing and swimming behaviors at certain doses, but higher doses of desipramine when combined with fluoxetine replaced swimming behavior with climbing behavior. The mixed NE-5-HT reuptake inhibitors milnacipran and duloxetine reduced immobility and increased climbing behavior, but did not alter swimming. Venlafaxine reduced immobility and increased swimming behavior, except at the highest dose tested (80 mg/kg), which increased both swimming and climbing behaviors. Thus, combining certain doses of pharmacologically selective monoamine reuptake inhibitors, or the mixed reuptake inhibitor venlafaxine, produced a pattern of mixed active behaviors in the FST (climbing and swimming) that may reflect the activity of multiple neurotransmitters, especially the combination of enhanced 5-HT and DA activity. The combination of higher doses of desipramine with fluoxetine, or compounds with mixed activity at inhibiting NE and 5-HT reuptake, demonstrated effects similar to those of desipramine alone and may reflect inhibition of the expression of serotonergic antidepressant behavioral effects by selective NE reuptake inhibitors.