Drugs in children and adolescents

We recently surveyed pharmaceutical companies producing antidepressant medication or central nervous system (CNS) stimulants for the European market. Approval for use of such drugs in children and adolescents is limited worldwide. Sertraline, clomipramine, and flu-voxamine have been approved for use in children (for some drugs down to the age of 6 years) for OCD in some European countries (the most wide spread approval being for sertraline in Austria, France, Hungary, Italy, Latvia, Norway, Portugal, Romania, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom, and Denmark) and countries outside Europe. Methyl-phenidate has been approved for the treatment of children with ADHD in a number of European and non-European countries (Novartis Health care A/S, personal communication). 

The first information to come to light will be on the pharmacokinetics of newly approved drugs in children and adolescents simply because such studies are faster to complete than are clinical trials for efficacy, safety, and tolerability. Such pharmacokinetic data can aid the determination of the optimal dose and dosing schedule for the efficacy/safety trials (34, 35 and 36). 

Weight gain related to the use of atypical neuroleptic drugs in children and adolescents, in whom this adverse effect is of particular concern, has been reviewed (804). The published data suggest that clozapine and olanzapine... 

There are few controlled clinical trials of drugs in children and adolescents with GAD. CBT alone or in conjunction with antidepressants can have long-term benefits. Randomized controlled trials of sertraline and fluovoxamine, and open trials of alprazolam, clonazepam, and fluoxetine indicate short-term efficacy however, be-... 

Observational studies The use of antipsychotic drugs in children and adolescents is of particular concern. In a 24-week, multicenter, open study supported by Eli-Lilly, the marketing authorization holder, 96 adolescents with schizophrenic disorder (mean age 16 years 68% boys) were given olanzapine 10 mg/day [83 ]. BPRS scores fell from baseline to week 6 by a mean of 17. The most common adverse events were weight gain and increased prolactin. Weight... 

The long-term (more than several weeks) use of levofloxacin in children and adolescents has not be approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with tuberculosis caused by organisms resistant to both INH and RIF. The optimal dose is not known. 

Eissenberg T, Balster RL (2000) Initial tobacco use episodes in children and adolescents current knowledge, future directions. Drug Alcohol Depend 59(Suppl 1) S41-S60 Pant RV, Schuh KJ, Stitzer ML (1995) Response to smoking as a function of prior smoking amounts. Psychopharmacology 119 385-390... 

Murry DJ, Crom WR, Reddick WE, Bhargava R, Evans WE. Liver volume as a determinant of drug clearance in children and adolescents. Drug Metab Dispos 1995 23(10) 1110-6. 

Carrey NJ, Wiggins DM, Milin RP. Pharmacological treatment of psychiatric disorders in children and adolescents focus on guidelines for the primary care practitioner. Drugs 1996 51(5) 750-9. 

Although not relevant to geriatricpatients, this drug may produce suicidal ideation in children and adolescents. 

Although PK data in children and adolescents are limited, clinical observations suggest that children and adolescents require larger, weight-adjusted doses of most drugs than do adults to achieve comparable blood levels and therapeutic effects (Soldin and Steele, 2000). This appears to be mostly the result of increased rate of metabolism and elimination. 

Dahlstrom, M., Ahonen, A., Ebeling, H., Torniainen, P., Heikkila, J., and Moilanen, I. (2000) Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents. Mol Psychiatry 5 514—522. 

CLINICAL USE IN CHILDREN AND ADOLESCENTS Before Starting the Drug... 

Drugs that are marketed for the treatment of psychotic disorders in adults, the antipsychotics, are prescribed for a range of problems in children and adolescents. At present, 15 medications are marketed as antipsychotics in the United States. These agents come from several different classes of chemical compounds (Table 26.1). 

During the early twentieth century the barbiturates were used in children and adolescents for their sedative and hypnotic effects however, their safety profile and propensity to cause physical dependence led scientists in search of safer anxiolytics. The development of animal models of behavioral disorders facilitated the formulation of drugs with more specific central nervous system (CNS) effects. In 1959, chlordiazepoxide (Librium) was the first benzodiazepine (BZ) to receive a patent. It entered the market in 1960, followed by diazepam (Valium) in 1963. Today, over 35 BZs have been formulated and over 10 are available in the United States (Ballenger, 1995 Hobbs et ah, 1996). 

There is no empirical evidence available for clinical use in children and adolescents. Yet, Hypericum seems to be used for the treatment of mild to moderate depression in the young (Walter et ah, 2000). St. John s wort should be avoided in young patients with severe depression and bipolar disorder (given the lack of adult data about effectiveness and risk of manic induction, respectively) and in those who have significant suicide risk. Treatments of proven efficacy (e.g., SSRIs, mood stabilisers) should be preferred in these cases. However, St. John s wort may be considered in cases of unipolar depression where conventional treatments have failed and prior to the use of combinations of drugs that have an increased risk of side effects and whose efficacy has not been demonstrated. 

Despite the early encouraging results described above, the use of ECT in minors then diminished. A constellation of factors may be implicated, including concerns about possible harmful effects (such as how ECT might impair brain development), the advent of psychotropic drugs, the antipsychiatry movement, and negative media depictions of the treatment (Bauer, 1976 Perkins and Tanaka, 1979). ECT in children and adolescents became a controversial treatment of last resort in most countries. There have been attempts in England to prohibit ECT for this age group (Baker, 1994), while ECT has been outlawed for people below 16 years in several states in the United States. 

Childhood Anxiety Sensitivity Index (CASI) Private, via author W.K. Silverman, Ph.D., Department of Psychology, Florida International University, University Park, Miami, EL also in Werry, J.S. and Aman, M.G. eds.. Practitioner s Guide to Psychoactive Drugs for Children and Adolescents. New York Plenum. 

On the basis of these results and other clinical, pre-clinical and safety data, the RUPP Autism Network chose risperidone as the first drug to study in children and adolescents with autistic disorder (McDougle et al., 2000b). When completed, this investigation will be the largest drug study conducted to date in autistic disorder, with an anticipated sample size of 101 children and adolescents. 

In this chapter, we attempt to review the latest information on drug therapy for psychiatric conditions in children and adolescents with MR. Before doing this, however, it is appropriate to address special considerations in this clinical population that may impinge on the use of psychotropic medicines. 

Whereas some drug studies have been done in children with normal IQ who have conduct disorder, there are very few studies involving children with MR and disruptive behavior problems. We are not aware of any studies of psychostimulants primarily to manage conduct problems in children with MR. However, most studies of children with both MR and ADHD have observed improvements on subscales assessing conduct problems, especially as rated by teachers (Aman et al., 1991, Aman et al., 1993). Given the low toxicity and well-tolerated side effects of the stimulants, they should at least be considered for treating conduct disorder in children and adolescents with MR, especially if they have ADHD. 

Sovner et al. (1998) have done an excellent job summarizing the data on antidepressants in patients with developmental disabilities. There have been nine reports of antidepressant use in adults with depression and MR and three reports of antidepressant use in children and adolescents. Eight of nine reports in adults were positive. The drugs studied included nialimide (n = 27), fluoxetine (9), imipramine (6), amoxapine (2), and nortriptyline (1) (total n = 45). In addition, Sovner et al. identified four reports of antidepressant use in children. One involved successful treatment with fluoxetine in an adolescent, another indicated efficacy with imipramine and amitriptyline in 9 of 12 children (Do-sen, 1982), and a third showed successful management in 3 of 4 children treated with imipramine or tryptophan plus nicotinamide (Dosen, 1990). One study of fluoxetine in depressed children with autism and MR witnessed improvement in depression but not in compulsive symptoms (Ghaziuddin and Tsai, 1991). 

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