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Trends in the prescribing of psychotropic medications to preschoolers.
Zito JM, Safer DJ, dosReis S, Gardner JF, Boles M, Lynch F.
JAMA 2000 Feb 23;283(8):1025-30.

The results of this study indicate that between 1990 and 1995, the number of children aged 2 through 4 taking psychotropic drugs increased by 50%, from 100,000 to 150,000. In particular, prescriptions rates for stimulant drugs, for antidepressant drugs -particularly tricyclic antidepressants- and for clonidine, an alpha 2-agonist that suppresses central nervous system function and is used to treat insomnia- increased by 3-, 2-, and 28-folds, respectively. The article also reports that, according to data released by the FDA, in 1994 doctors wrote 3,000 prescriptions for Prozac in children younger than 1 year. The large increase in intake of drugs that interfere with the developing brain is worrisome, particularly when considering that no data exist on their safety and efficacy, and that these drugs are used off-label, i.e. their use has not been approved in children younger than 6.

Behavioral disorders are over diagnosed in US.
Roberts, J.
BMJ 1996;312:657 (16 March).

This article reports on the United Nations' and the US Drug Enforcement Administration' concerns about the widespread use of the amphetamine Ritalin to control children behavior. It is emphasized that the worldwide production of Ritalin almost trebled from 1990 to 1994, with 90% of the product being prescribed to American children, adolescents and adults. Statistics elaborated by the United Nations revealed that in 1995 more than 2 millions children and 10-12% of American boys (attention-deficit disorder is diagnosed 4 times more frequently in boys than in girls) where taking the drug. The concern is that children may be improperly diagnosed and treated as shown by research conducted in 1994 at the University of California-Riverside, indicating that 50% of children diagnosed with attention deficit disorder are prescribed the drug without undergoing psychological or educational testing.

US education board advises against drugs for behavioral problems. News.
Charatan F.
BMJ 1999;319:1456 ( 4 December ).

This article reports on a resolution passed by the Colorado Board of Education urging teachers to employ educational measures to control children's disruptive behavior rather than counseling parents to seek drug treatment for their children. Members of the Board were especially concerned about the finding that many violent crimes occurring in schools are committed by students who are taking anti-psychotic drugs (as an example, Eric Harris, one of the author of the massacre of Columbine High School in Littleton, Colorado, had been taking the antidepressant fluvoxamine). Dr. Peter Breggin, director of the International Centre for Study of Psychiatry and Psychology in Bethesda, Maryland, also believes that psychotropic drug use in children is linked to violence.  Currently in the U.S., approximately 2.5 million children are prescribed drugs for attention-deficit disorder.

Tardive dyskinesia and other clinical consequences of neuroleptic treatment in children and adolescents.
Gualtieri CT, et al.
Am J Psychiatry 1984 Jan;141(1):20-3.

The results of this study show that 18 of 41 children, adolescents, and young adults in whom discontinuation of chronic neuroleptic drug treatment was attempted, developed withdrawal symptoms such as tardive dyskinesia movement disorders and behavior deterioration. In only 12 individuals antipsychotic drug treatment had to be restarted, indicating that discontinuation of treatment should always be tried even in chronically medicated patients.

Neuroleptic use, parkinsonian symptoms, tardive dyskinesia, and associated factors in child and adolescent psychiatric patients.
Richardson MA, et al.
Am J Psychiatry 1991 Oct;148(10):1322-8.

This study evaluated the rate of occurrence of drug-induced parkinsonism and tardive dyskinesia in a cohort of 104 children and adolescents treated with antipsychotic drugs in a psychiatric hospital. Of the 104 children, 61 were found to have risk factors for the development of parkinsonism and 41 had risk factors for the development of tardive dyskinesia. Of the children with risk factors, 34% developed parkinsonism and 12% tardive dyskinesia. These data indicate a high rate of severe and disabling complications in neuroleptic-treated children and adolescents, indicating that these drugs should be given only when absolutely necessary and for the shortest period of time.

Adolescents on neuroleptic medication: is this population at risk for tardive dyskinesia?
McDermid SA, et al.
Can J Psychiatry 1998 Aug;43(6):629-31.

The results of this study, conducted on a cohort of 40 adolescents treated with antipsychotic drugs, show that over a two-year period, 5% of them developed full-blown tardive dyskinesia and an additional 12.5% developed symptoms of tardive dyskinesia, indicating that, contrary to common thinking, the risk of this severe and disabling complication is high in every age group.

Increased methylphenidate usage for attention deficit disorder in the 1990s.
Safer DJ, Zito JM, Fine EM.
Pediatrics 1996 Dec;98(6 Pt 1):1084-8.

The results of this study indicate that from 1990 to 1995, rates of prescription of the psycho stimulant drug Ritalin (methylphenidate ) for attention-deficit disorder increased by 2.5-folds, and in 1995, approximately 3% (or 1.5 million) of U.S. youths aged 5 to 18 years were taking the drug.

Antidepressant prescribing practices of outpatient psychiatrists.
Olfson M. et al.
Arch Gen Psychiatry 1998 Apr;55(4):310-6.

The results of this study show that, from 1985 to 1994, the proportion of outpatient psychiatric visits resulting in prescription of an antidepressant drug increased from 23% to 49%. Patients were 2.3 times more likely to receive a prescription in 1994 compared to 1985. Rates of prescribing increased particularly for children and young adolescents, and for individuals with less severe psychiatric disorders.

Psychotropic medication treatment patterns among school-aged children in foster care.
Zima BT, Bussing R, Crecelius GM, Kaufman A, Belin TR.
J Child Adolescent Psychopharmacology 1999;9(3):135-47.

The results of this study indicate that 16% of children who live in foster homes for at least 6 months receive psychotropic drugs.

Prevalence and patterns of psychotropic and anticonvulsant medication use in children and adolescents referred to residential treatment.
Connor DF. et al.
J Child Adolescent Psychopharmacology, 8(1):27-38 1998.

The results of this study, conducted on a cohort of 83 emotionally disturbed children and adolescents admitted to a residential treatment facility, show that 76% of them were started on psychotropic drugs. Antipsychotic drugs, sedative-hypnotics and antiepileptics were given to 35%, 26%, and 15% of individuals, respectively. Forty percent of youths received a minimum of two psychotropic drugs.

Short-term side effects of stimulant medication are increased in preschool children with attention-deficit/hyperactivity disorder
a double-blind placebo-controlled study.
Firestone P, Musten LM, Pisterman S, Mercer J, Bennett S.
J Child Adolescent Psychopharmacology 1998;8(1):13-25.

This double blind, placebo-controlled study was conducted on 32 preschool children with attention-deficit/hyperactivity disorder to determine the incidence of short-term adverse effects associated with use of Ritalin. Ten percent of children experienced severe side effects. In addition, children who took Ritalin experienced significantly more behavioral changes indicative of an adverse reaction, compared to those taking placebo. These data indicate that preschoolers are more susceptible to experience adverse reactions from use of Ritalin, compared to older children.

Risks and benefits of drugs used in the management of the hyperactive child.
Fox AM, Rieder MJ.
Drug Saf 1993 Jul;9(1):38-50.
This article emphasizes that although treatment with psychotropic drugs of children diagnosed with attention-deficit hyperactive disorder has been associated with short-term benefits in the majority of them, no data are available demonstrating long-term efficacy of these drugs. In addition, these drugs have been associated with severe and potentially fatal adverse effects, such as tics, suppression of growth, drug abuse, cardiac arrest and sudden death. Benefits and risks of treatment should be carefully weighted when considering initiation of drug treatment in these children.

Pediatric psychopharmacology and the interaction between drugs and the developing brain.
Vitiello B.
Can J Psychiatry 1998 Aug;43(6):582-4.

This article explains that while there are no data demonstrating that use of psychotropic drugs in children and adolescents is safe, research conducted on animals has shown that exposure of the developing brain to drugs that alter the balance of its neurotransmitter can result in permanent brain changes.

Efficacy of methylphenidate among preschool children with developmental disabilities and ADHD.
Handen BL, Feldman HM, Lurier A, Murray PJ.
J Am Acad Child Adolescent Psychiatry 1999 Jul;38(7):805-12.

This double-blind, placebo-controlled, crossover study was conducted on 11 children aged 4 to 5 years with attention-deficit disorder and developmental disabilities to determine the rate of adverse reactions associated with use of Ritalin. Forty-five percent of children experienced significant side effects from the medication, including "severe social withdrawal, increased crying, and irritability". These adverse events were more frequent in children who received higher doses of Ritalin. This study indicates that Ritalin use in very young children with developmental disabilities can significantly disrupt normal behavior. Of note, some of the behavioral adverse effects, like social withdrawal accompanied by decreased activity levels and decreased restlessness, were interpreted as improvements by the teachers and the doctors who were asked to evaluate children response to the drug, questioning the validity of assessing the efficacy and toxicity of treatment based on teachers or doctors personal judgment of children behavior.

Placebo-controlled evaluation of Ritalin side effects.
Ahmann PA, Waltonen SJ, Olson KA, Theye FW, Van Erem AJ, LaPlant RJ.
Pediatrics 1993 Jun;91(6):1101-6.

This double-blind placebo-controlled crossover study evaluated the frequency of side effects in 234 children aged 5 through 15 years treated with Ritalin for attention-deficit disorder. Parents, who did not know whether their child was taking Ritalin or placebo, were asked to report side effects at baseline and at the end of each session of treatment. The side effects that were reported significantly more often in children taking Ritalin, compared to those who took placebo, were: insomnia (3-fold increase), loss of appetite (19-fold increase), stomachache (7-fold increase), headache (5.3-fold increase), and dizziness (7.5-fold increase). The following side effects occurred significantly less often in children receiving Ritalin rather than placebo: 53% decrease occurrence of daydreaming and staring, 67% less irritability, 58% less anxiety, and 81% less nail biting. These results indicate that Ritalin enormously increases the incidence of several important adverse effects. The impact of these complications on the quality of children's lives has not been evaluated. The reduction of other so called "side effects" like daydreaming and staring, irritability, anxiety, and nail biting, stand as an indication of the benefits of treatment. It should be highlighted, however, that such reduction could very well be a sign of artificial suppression of the vitality and basic personality of the child, through direct modification of the chemistry of the central nervous system induced by Ritalin.

Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation.
Barkley RA, McMurray MB, Edelbrock CS, Robbins K.
Pediatrics 1990 Aug;86(2):184-92.

This triple-blind placebo controlled study evaluated the occurrence of adverse effects in 83 children with attention-deficit disorder treated with Ritalin, as reported by parents and teachers. Children who were randomized to receive Ritalin experienced significantly more insomnia, loss of appetite, stomachaches and headaches than those who received placebo. Treatment-related side effects occurred in almost 50% of children, and were of such severity to require immediate drug discontinuation in 3 children (3.6%). Teachers did not notice any significant change in medicated children, except for a reduction of staring, anxiety and sadness, which were reported also in association with placebo intake.

Adverse side effects of methylphenidate among mentally retarded children with ADHD.
Handen BL, Feldman H, Gosling A, Breaux AM, McAuliffe S.
J Am Acad Child Adolescent Psychiatry 1991 Mar;30(2):241-5.

This double-blind, placebo controlled study evaluated the frequency of adverse effects associated with intake of Ritalin in 27 mentally retarded children with attention deficit hyperactivity disorder. Irritability, anxiety, moodiness, and motor activity decreased in children receiving the drug, compared to those receiving placebo, indicating suppression of central nervous system activity. Twenty-two percent of children had to be discontinued from treatment, due to the occurrence of severe side effects like motor tics and severe social withdrawal.

Child and parent perceptions of stimulant medication treatment in attention deficit hyperactivity disorder.
Efron D, Jarman FC, Barker MJ.
J Paediatr Child Health 1998 Jun;34(3):288-92.

This double blind, crossover study assessed the effects of treatment with the stimulants methylphenidate and dexamphetamine in 102 children with attention-deficit disorder. Parents and children perceptions of treatment were evaluated. Thirteen percent and nineteen percent of children reported feeling worse after taking methylphenidate and dexamphetamine, respectively. In one quarter of the cases, there was disagreement between parent and child evaluation of treatment benefit, mainly due to parents reporting improvements associated with drug intake, when the child reported adverse treatment outcome. These results indicate that quality of life worsen in a significant number of children treated with stimulant drugs for attention-deficit disorder, and that parents ratings of treatment efficacy don't always reflect children experience of treatment.

Psychotic side effects of psychostimulants: a 5-year review.
Cherland E, Fitzpatrick R.
Can J Psychiatry 1999 Oct;44(8):811-3.

The results of this study show that children treated with stimulant drugs for attention-deficit disorder are at risk of developing psychotic symptoms (delusions, hallucinations, or other symptoms reflecting disruption of normal perception of reality) as side effect of treatment. The study was conducted on 98 children with a diagnosis of attention-deficit disorder treated with stimulants in an outpatient clinic over a 5-year period. Six children developed psychotic symptoms during treatment. The authors warn about the potential occurrence of this complication and call for further studies to better determine its frequency.

Attention deficit hyperactivity disorder: anxiety phenomena in children treated with psycho stimulant medication for 6 months or more.
Vance AL, Luk ES, Costin J, Tonge BJ, Pantelis C.
Aust N Z J Psychiatry 1999 Jun;33(3):399-406.

The results of this study indicate that treatment with stimulant medications can induce anxiety in children with attention-deficit hyperactivity disorder (ADHD). The authors highlight that the intermediate and long-term benefits of psycho stimulant drugs such as Ritalin are unclear, and that complications from treatment can mimic typical ADHD symptoms. The study evaluated the prevalence of anxiety in 20 children with ADHD on medications for 6 or more months whose symptoms had not improved with treatment and 20 children matched for age and IQ with ADHD who had never received medications. Symptoms of anxiety were found significantly more often in treated versus non-treated children. The authors conclude that anxiety can be a complication of treatment with psycho-stimulants in children with attention-deficit disorder with poor responses to medications. This adverse effect is often unrecognized by physicians, and can be mistaken as part of ADHD symptoms.

Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency.
Sallee FR, DeVane CL, Ferrell RE.
J Child Adolescent Psychopharmacology 2000 Spring;10(1):27-34.

This article reports on the death of a 9-year-old child due to Prozac' overdose. The child was treated with Ritalin, Prozac (Fluoxetine) and clonidine for attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette's syndrome. In spite of the development, over a 10-month period, of symptoms of toxicity such as diarrhea, low-grade fever, loss of coordination and disorientation, a diagnosis of Fluoxetine toxicity was not made until the child experienced generalized seizure, status epilepticus, cardiac arrest and death. Blood levels of Fluoxetine were several-fold those known to be toxic, and a genetic defect in the metabolism of the drug was demonstrated. This case indicates that side effects of treatment with psychotropic drugs can be unrecognized by parents and physicians and interpreted as signs of the underlying conditions the child is being treated for. This omission can have fatal consequences.

Side effects of methylphenidate and desipramine alone and in combination in children.
Pataki CS, Carlson GA, Kelly KL, Rapport MD, Biancaniello TM.
J Am Acad Child Adolescent Psychiatry 1993 Sep;32(5):1065-72.

The results of this double-blind placebo-controlled crossover study show that combined treatment with Ritalin and the tricyclic antidepressant desipramine in children with attention-deficit disorder and depression is associated with a significant high rate of adverse effects. In particular, the incidence of nausea, dry mouth, and tremor was at least 2 times higher in children taking both drugs simultaneously, than in those who took them individually. Additionally, simultaneous intake of both drugs was associated with higher rates of vomiting, headaches, generalized aches, food rejection, and tiredness. Cardiac rhythm evaluation through the ECG revealed increased ventricular heart rate in children exposed to Ritalin and desipramine, and prolongation of the PR interval (a risk factor for arrhythmias) in those taking desipramine, indicating an increased risk of dangerous cardiac arrhythmias associated with use of these drugs.

Evidence for long-term neurotoxicity associated with methamphetamine abuse. A 1H MRS study.
Ernst T, et al.
Neurology 2000;54:1344-1349.

The results of this study show that the drug methamphetamine, also known as "speed"
causes brain damage that persists after cessation of drug use. The study was conducted on 26 individuals who stopped using methamphetamine from 2 weeks to 21 months before initiation of the study, and 24 healthy volunteers used as controls. Using a technique called proton magnetic resonance spectroscopy, the researchers found that methamphetamine users had significantly reduced levels of certain brain metabolites such as N-acetyl-aspartate (NA) and creatine, compared to controls. NA reduction is indicative of brain cells damage or brain cells loss. Whether the damage can be reverted or is permanent is still to be determined, although the authors believe it to be long-term. These findings cause particular concern, since, even if at significantly lower doses than those taken by the individuals in the study, this drug is currently given to millions of children for the treatment of attention-deficit disorder.

Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis.
Hazell P, O'Connell D, Heathcote D, Robertson J, Henry D.
BMJ 1995 Apr 8;310(6984):897-901.

The results of this study show that tricyclic antidepressants are no better than a sugar pill in the treatment of child and adolescent depression. The study was performed to resolve issues concerning the efficacy of this class of drugs in children and young adults (age 6-18 years). Previous clinical trials have reported either no effects, or only small benefits associated with treatment. In addition, the trials were small and susceptible to methodological bias. In this meta-analysis, the results of 12 randomized, placebo-controlled trials where analyzed. No benefits could be observed in patients treated with tricyclic antidepressants compared to those treated with placebo, indicating that use of these drugs for childhood and adolescent depression is unsupported by scientific data, and is therefore unjustifiable. Physicians and parents should question why, in an era of evidence-based medicine, millions of children receive each year drugs that are associated with powerful and potentially fatal adverse effects, is spite of current evidence indicating the dangers and futility associated with this practice.

Critical review of tricyclic antidepressant use in children and adolescents.
Geller B, Reising D, Leonard HL, Riddle MA, Walsh BT.
J Am Acad Child Adolescent Psychiatry 1999 May;38(5):513-6.

This study reviewed the published literature on the effects of tricyclic antidepressant for the treatment of depression in children and adolescents. The authors emphasize that, of all the trials published, very few were double blind and placebo-controlled, and even less reported positive results from treatment. The lack of efficacy of treatment demonstrated in clinical trials is staggering, particularly when considering that these drugs have been associated with severe and potentially fatal adverse effects, as shown by the increasing number of reports of severe intoxication and sudden death in children taking the drugs.

Sudden death in children receiving Norpramin: a review of three reported cases and commentary.
Riddle MA, et al., J Am Acad Child Adolescent Psychiatry 1991 Jan;30(1):104-8.

This article reports on a change of label of the package insert for the tricyclic antidepressant Norpramin, of Merrell Dow Pharmaceuticals Inc., after the sudden death of 3 children who were taking the drug. The addition on the label stated: "There has been a report of an 'acute collapse' and 'sudden death' in an eight-year-old (18 kg) male, treated for two years for hyperactivity. There have been additional reports of sudden death in children."

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