Risks and benefits of antipsychotics in children and adolescents

Many of the psychiatric disorders observed in adults have their onset in childhood or adolescence. In fact some studies show that at least 20% of children and adolescents will fulfil a diagnostic criterion for a mental disorder before reaching adulthood. The presence of a major mental illness is certainly no less serious in children than in adults – in fact, childhood onset of several psychiatric disorders predicts a worse illness course. Early manifestations of mental disorders may substantially impact the child´s academic performance and achievement as well as his/her ability to develop age-appropriate social skills. Thus, appropriate identification and treatment of signs and symptoms of psychiatric illnesses during childhood and adolescence is critical for minimizing continued or additional psychiatric problems that put these children at risk later in life.

For many years old antipsychotics have been used for the treatment of conditions such as severe conduct disorders, Tourette syndrome, bipolar disorder and schizophrenia in children and adolescents. Treatment advances, particularly with the introduction of new-generation antipsychotic medications, have created a lot of expectations in the search for long-term, clinically effective treatments for this young population. The prescription of new-generation antipsychotics has become a widely accepted practice in the treatment of children and adolescents with psychotic disorders (Armenteros & David, 2006) and many other psychiatric conditions (Findling et al., 2005; Olfson et al., 2006). In fact, prescribing of new-generation antipsychotics has increased dramatically in recent years in the paediatric population (160% in the USA between 1990 and 2000) (Patel et al., 2005).

Few well-controlled studies have assessed the efficacy, safety, and tolerability of antipsychotics in children and adolescents (Arango et al. 2004; Kumra et al. 2007). In our context, the most commonly prescribed antipsychotics in this population are risperidone, quetiapine, and olanzapine (Castro-Fornieles et al., in press). Recently, the new EC regulation on medicinal products for paediatric use aimed to improve the information available to prescribers and families, forcing drug companies to conduct clinical trials with this population in order to reduce off-label use (=non-approved use).

Clinical trials of antipsychotic drugs traditionally focus on acute clinical efficacy and tolerability. However, pharmacological interventions in children and adolescents with mental disorders must meet broader requirements of clinical effectiveness to provide the best possible outcome in terms of individual well-being, social and educational and/or vocational functioning, and disease burden. They must also take into account long-term safety issues and the possible interaction of the drugs with a developing brain. Developmental changes occurring during childhood and adolescence may influence both treatment response and drug tolerability in ways not seen in adults. It is also possible that treatment may adversely affect cognitive development, exacerbating functional problems and limiting clinical effectiveness. Alternatively, early intervention with an effective and well-tolerated antipsychotic may provide benefits that may modify the actual course of the disease in some paediatric mental disorders (Arango et al., 2004).

Efficacy

Antipsychotics have shown efficacy in the treatment of psychotic disorders in children and adolescents (schizophrenia, bipolar disorders), as well as conduct disorders, Tourette syndrome, and tics (Jensen et al., 2007; Kumra et al., 2008; Findling et al., 2008). In the first study comparing 3 different second-generation antipsychotics (SGAs) in 110 patients with early onset psychosis (mean age 15.5), no significant differences were found in the reduction on any symptomatology scale in patients treated with risperidone, quetiapine, or olanzapine for six months (Castro-Fornieles et al., in press).

Metabolic and hormonal safety

Childhood obesity is increasing worldwide and is associated with an increase in other cardiovascular risk factors in childhood, such as dyslipidemia, hypertension, and impaired glucose tolerance (Weiss et al., 2004). In addition, there is increasing concern about second-generation antipsychotics having metabolic side effects such as weight gain, hyperglycaemia, and dyslipidemia in the paediatric population (Correll, 2008). In the first study directly comparing weight gain and other metabolic and hormonal risk factors after treatment with 3 different new-generation antipsychotics in children and adolescents (mean age 15.2 years), it was shown that, after 6 months, body mass index scores and total cholesterol levels increased significantly, with 33 patients (50.0%) with no previous antipsychotic exposure showing significant weight gain (Fraguas et al., in press). The number of patients at risk for adverse health outcomes increased from 11 (16.7%) to 25 (37.9%). These changes in metabolic parameters were different for the different antipsychotics studied.

In the naturalistic study conducted by our group in early-onset psychosis patients, weight gain was also greater with olanzapine than with risperidone or quetiapine (Castro-Fornieles et al., in press). Weight gain in children raises the concern that, if treated for long periods, these patients may be at higher risk of insulin resistance, diabetes, hypertension, and cardiovascular disease in the future. If drugs likely to induce weight gain must be used, compensatory behavioural or pharmacological approaches should be implemented (Laita et al. 2007; Correll, 2007). A further concern with antipsychotic treatment in paediatric populations is the hyperprolactinemia caused by many of these antipsychotics and its long-term consequences (osteoporosis, infertility). In our cross-sectional study with 66 children, hyperprolactinemia was present in 78.6% and 48.5% in the short-term and longer-term treatment groups, respectively.

Abnormal involuntary movements

The incidence of extrapyramidal symptoms (EPS), abnormalities in the motor system secondary to antipsychotic use, is known to be higher in younger patients than in adult patients (Findling, 2001). These side effects, more common with old antipsychotics than with new-generation antipsychotics, lead to problems participating in normal educational and social activities.

In a cross-sectional study by our group, the presence of abnormal involuntary movements was compared in 60 children and adolescents who had taken antipsychotic medication for less than 1 month and 66 who had been receiving treatment with antipsychotics for more than 12 months (Laita et al., 2007). The mean age of the total sample was 15.62 years. As many as 21.7% of short-term treatment group patients and 37.9% of longer-term treatment group patients presented mild dyskinetic movements. In a more recent study, a cohort of 110 early-onset psychosis patients followed for one year showed that neurological side effects (especially hypokinesia/akinesia) were more common with risperidone (Castro-Fornieles et al., in press).

Antipsychotics have shown efficacy in various paediatric mental disorders, but the use of these medications in children and adolescents merits careful scrutiny as this is a vulnerable population that has more side effects than adults.

Cardiovascular safety

Antipsychotic medications are among the most relevant identified risk factors associated with significant prolongation of the QTc interval (prolongation of the interval, as determined by electrocardiograms, can cause arrhythmias) (Mackin & Young, 2005). In antipsychotic drug-naïve adolescents, defined as adolescents with no prior antipsychotic treatment or total lifetime antipsychotic usage of fewer than 30 days, changes in duration of the QTc interval before and after 6 months of treatment were assessed, with no cardiovascular changes in the study population (Castro et al., in press).

What do we know?

  * Early intervention with an effective and well-tolerated antipsychotic provides symptomatologic improvement in some mental disorders in children and adolescents that may modify the actual course of the disease associated with these disorders.

  * Children and adolescents seem to have a higher risk than adults for experiencing adverse events such as extrapyramidal symptoms, prolactin elevation, sedation, weight gain, and metabolic effects when taking antipsychotics.

Patients and their families should be included in a careful risk-benefit assessment before prescribing any specific antipsychotic.

What do we need to know?

  * There is a need for controlled studies in the case of disorders in which antipsychotics are being used without clinical evidence of their efficacy or effectiveness.

  * We need short and long term safety data on issues such as cardiovascular, hormonal, and metabolic safety, sexual maturation, fertility, and growth changes induced by antipsychotics.

  * We need data on the interaction between the antipsychotics and the cognitive, emotional and behavioural development in different mental disorders.

  * Finally, we need controlled studies that not only assess efficacy, but also take into account the impact of the disease and that of the medications prescribed for the disease, on individual well-being, social, educational and/or vocational functioning, and disease burden in order to make reasonable risk/benefit ratios.

References

  1. Arango C., Parellada M., Moreno D.M. Clinical effectiveness of new generation antipsychotics in adolescent patients. European Neuropsychopharmacology 2004; 14:471-479
  2. Armenteros JL, Davies M. Antipsychotics in early onset schizophrenia: systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2006;15:141-148
  3. Castro MJ, Fraguas D, Laita P, Moreno D, Parellada M, Pascual D, Álvarez M, Merchán J, Leiva M, Rapado M, Giráldez M, Arango C. QTc changes after 6 months of second-generation antipsychotic treatment in children and adolescents, J Child Adolesc Psychopharmacol, in press
  4. Castro-Fornieles J, Parellada M, Soutullo CA, Baeza I, Gonzalez-Pinto A, Graell M, Paya B, Moreno D, de la Serna E, Arango C. Antipsychotic treatment in child and adolescent first-episode psychosis: a longitudinal naturalistic approach. J Child Adolesc Psychopharmacol, in press
  5. Correll J: Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. Am Acad Child Adolesc Psychiatry 2007; 46:687-700
  6. Correll CU. Monitoring and management of antipsychotic-related metabolic and endocrine adverse events in pediatric patients. Int Rev Psychiatry. 2008;20:195-201
  7. Findling RL. Paediatric psychopharmacology: closing the gap between science and practice. Expert Opin. Pharmacother 2001;2: 523-525
  8. Findling RL, Steiner H, Weller EB. Use of antipsychotics in children and adolescents. J Clin Psychiatry 2005;66:29-40
  9. Fraguas D, Merchán-Naranjo J, Laita P, Parellada M, Moreno D, Ruiz-Sancho A, Cifuentes A, Giráldez M, Arango C. Metabolic and Hormonal Side Effects in Children and Adolescents Treated With Second-Generation Antipsychotics. Journal Clinical Psychiatry, in press
  10. Jensen PS, Buitelaar J, Pandina GJ, Binder C, Haas M. Management of psychiatric disorders in children and adolescents with atypical antipsychotics: a systematic review of published clinical trials. Eur Child Adolesc Psychiatry. 2007;16(2):104-20
  11. Kumra S, Oberstar JV, Sikich L, Findling RL, McClellan JM, Vinogradov S, Charles Schulz S. Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia. Schizophr Bull. 2008;34(1):60-71
  12. Laita P, Cifuentes A, Doll A, Llorente C, Cortés I, Parellada M, Moreno D, Ruiz-Sancho A, Graell M, Arango C. Antipsychotic-related abnormal involuntary movements and metabolic and endocrine side effects in children and adolescents. J Child Adolesc Psychopharmacol. 2007;17:487-502
  13. Olfson M, Blanco C, Liu L, et al. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry 2006;63:679-685
  14. Patel NC, Crismon ML, Hoagwood K, et al. Trends in the use of typical and atypical antipsychotics in children and adolescents. J Am Acad Child Adolesc Psychiatry 2005;44:548-556
  15. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362-2374

Correspondence:
Dr. Celso Arango, M.D., Ph.D.
Hospital General Universitario Gregorio Marañón,
Department of Psychiatry, c/ Ibiza 43,
28009 Madrid, Spain
E-mail: .(JavaScript must be enabled to view this email address)

Contact: Sonja Mak
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43-140-557-340
European College of Neuropsychopharmacology