Safety of atypical antipsychotics in paediatrics

In the last ten years, atypical antipsychotics progressively substituted first generation drugs thanks to a more favourable tolerability profile, particularly for the minor frequency of neurological extrapyramidal effects.¹ Atypical antipsychotics have been widely used for few years also in paediatrics for treating children and teenagers with psychotics and behavioural disturbances. However, officially acknowledged indications for paediatric use are limited. In Italy, risperidone and aripripazole are indicated for treating schizophrenia in patients aged 13 years and older and bipolar disorder for 10 years old children upwards. Besides, the same drugs are indicated for treating aggressiveness associated to autistic disturbances patients aged 5 years and older. Still, off-label use for paediatric patients is quite widespread in clinical practice. In particular - besides the previously listed indications - these new antipsychotics are commonly used for controlling impulsive and aggressive behaviours associated to various conditions such as: attention deficit and hyperactivity disorder (ADHD), obsessive-compulsive disturbances, mental retardation, behavioural disturbances, Tourette syndrome and eating disorders.² The use of atypical antipsychotics in paediatrics constantly increased in the last years.³ In the United Kingdom, antipsychotics prescriptions for patients aged between 7 and 12 years old tripled from 1992 to 2005 and, in particular, prescriptions of second generation drugs increased 60 times.⁴ This trend has become even more pronounced in the most recent years. The perception of a higher safety profile for these drugs is probably one of the contributing factors to their increased use in paediatrics in the last few years. However, even the use of new antipsychotics is associated to adverse effects, in particular metabolic and cardiovascular ones, to which paediatric population seems quite susceptible.^5,6

Metabolic effects

Several evidences suggest that children and teenagers affected by psychiatric diseases have higher risks of weight gain and obesity.⁷ Lifestyles and nutrition, drugs and the disease’s neurobiology itself probably concur to age-inappropriate weight increase. A study on metabolic effects of atypical drugs conducted among children and teenagers aged 4-19 years showed that olanzapine, and to a least extent quetiapine and risperidone, was associated to more weight gain than the control group, whilst patients treated with aripiprazole reported less weight variations.⁸ Patients treated with olanzapine and quetiapine also had increased cholesterol and triglycerides levels. These results, combined with data on adults, allow asserting that the risk of weight increase and metabolic effects is maximum with olanzapine and clozapine, followed by risperidone, quetiapine, ziprasidone and aripiprazole.^5,9 Alert body-weight monitoring is recommended for all paediatric patients (and not only) when starting atypical antipsychotic therapies.

Hyperprolactinemia

Being D2-receptor antagonists, all antipsychotics (especially the first generation) cause hyperprolactinemia by blocking the dopaminergic stimulus that physiologically reduces this pituitary gland hormone. This undesired effect is significantly more frequent in teenagers and in children after puberty than in adults, probably for the lower dopaminergic activity at paediatric age.¹⁰ Prolactin level increase can induce oligo/amenorrhea, erectile dysfunction, libido decrease, hirsutism, gynecomastia and galactorrhea. Available data in literature suggest that hyperprolactinemia is dose-dependent, tends to normalize spontaneously with time and regresses when the treatment is discontinued.10 Second generation antipsychotics’ attitude at inducing hyperprolactinemia differs in relation to their different affinity for D2 receptors.^10,11 Based on the few available studies for paediatric age, risperidone seems to affect more pronouncedly prolactin levels, followed by aloperidole; olanzapine and ziprasidone have intermediate effects, whilst quetiapine, clozapine and aripiprazole seems to have a low potential for inducing hyperprolactinemia.¹¹

Extrapyramidal effects

Extrapyramidal effects were initially considered so intrinsic for first generation antipsychotics that these drugs were named “neuroleptics”. Also for this reason, second generation drugs – showing a higher tolerability profile on this front – have been defined “atypical”. In general, children and teenagers treated with antipsychotics tend to have more undesired extrapyramidal effects, such as dystonia and parkinsonism, than adults. This higher susceptibility seems due to relative dopaminergic depletion in paediatric age.¹⁰ Several studies show that atypical antipsychotics’ risk of extrapyramidal effects is much lower than for first generation drugs.¹²However, risperidone, especially at high doses, has been associated to extrapyramidal effects for a patients percentage variable between 8 and 26% at paediatric age.¹³ As for adults, olanzapine, quetiapine and aripiprazole are associated to low incidence of extrapyramidal effects.

Cardiovascular effects

All antipsychotics, even though differently, can prolong the QT interval of the electrocardiogram. Average QT values higher that 450 ms entail severe arrhythmia risk, potentially fatal (the so-called “torsades the pointes”).¹⁴ However, it must be underlined that the majority of studies conducted on children or teenagers treated with atypical antipsychotics reported only minor or no QT interval prolongation.¹⁴ Also a recent study conducted by our research group on children and teenagers under risperidone or aripiprazole therapy, showed no pathological QT values after the treatment.15 However ECG monitoring is advisable for all paediatric patients starting an antipsychotic therapy.