ECG parameters in children and adolescents treated with second-generation antipsychotics: a 2-year prospective study

In the last ten years developmental disorders and its psychopharmacology have profoundly changed the approach in child and adolescent psychiatry. Research in neuroscience have focused the attention to improve diagnosis of psychiatric disorders in children and its neurobiological pathway underlying that contribute to the continuation of diseases to adulthood. The early stages of life strongly affect the development of the central nervous system and can produce persistent effects on functioning, so the purpose is to stop the negative process before the “damage” may modify neurogenic process irreparably. To date there is no curative pharmacological intervention for psychiatric disorders in pediatrics. Most therapeutic interventions aim to reduce the most impairing symptoms of the targeted psychiatric disorders. Two main clusters of symptoms can be identified in childhood: externalizing symptoms with impulsivity, hyperactivity, and disruptive behavior and internalizing symptoms with mood and affective problems, anxiety, etc. Externalizing disorders include symptoms of ADHD, disruptive behavior, and impulsivity, as well as symptoms of tic disorder. Depressive disorders, anxiety disorders, and obsessive-compulsive disorders (OCD) are summarized as internalizing disorders (Kolch & Plener 2016). In general, pharmacotherapy of psychiatric disorders in children should be embedded in psychosocial treatment, which is recommended by many guidelines (Banaschewski et al., 2006; NICE 2005). In child psychiatry, pharmacotherapy represent a challenge: (i) treatment of a developing body and brain needs special caution; (ii) data concerning effectiveness, safety, tolerability, and long-term outcome are still scarce for many psychopharmacotherapeutic interventions within this age-group; (iii) parents often remain insecure about their treatment decision; and (iv) identifying adverse events can be challenging for caregivers and minors. To add to this, most of psychodrugs are used off-label. However, off-label use does not mean that there is no data on efficacy, effectiveness, or safety of medication in children (Kolch & Plener 2016). Since their introduction into clinical practice, antipsychotic medications have been used in the treatment of children and adolescents with a variety of psychiatric conditions especially for externalizing symptoms (Findling et al., 2005). In recent years, the pediatric use of antipsychotics has substantially increased, due to an increment in prescription of second generation antipsychotics (SGA). These drugs are often preferred to traditional antipsychotic drugs (AP) in reason of a better tolerability and safety profile (Briles et al., 2012; Germanò et al., 2014). The use of atypical AP in pediatric age has increased significantly in the last few years. Between 1993–1998 and 2005–2009, in the United States, visits with a prescription of antipsychotic medications per 100 persons increased from 0.24 to 1.83 for children and from 0.78 to 3.76 for adolescents (Olfson et al., 2012). The proportion of total visits including a prescription of antipsychotics increased during this period from 0.16% to 1.07% for youths (Olfson et al., 2012). Off-label use of AP which have not obtained clear pediatric indications is very common in clinical practice (Bazzano et al., 2009). However, only four drugs, such as aripiprazole, olanzapine, quetiapine, and risperidone have received FDA-approved pediatric indications, in particular for schizophrenia (age 13–17 years) and for bipolar mania (age 10–17 years; olanzapine, 13–17 years). In addition, risperidone is also indicated for irritability and aggression associated with autistic disorder (age 6–17 years), and controlled trial data exist for disruptive behavior disorders and tic disorders (FDA, Psychopharmacologic Drugs Advisory Committee, 2009). Moreover, the duration of treatment with these agents has been increasing (Kalverdijk et al., 2008; Rani et al., 2008). This rapid increase and the recognition that many antipsychotics induce metabolic adverse effects, thus increasing the risk for obesity, diabetes type II, and associated cardiovascular morbidity (Guo et al., 2006; Bobes et al., 2007), have raised concerns about the proper utilization of these agents and stirred controversy among both experts and the general public (Elias, 2006, Harris, 2008). After having been hailed as a safer alternative to first-generation antipsychotics because of their lower tendency to induce neurological effects, the SGA are now recognized to have a high propensity for causing other, equally problematic, adverse effects, thus triggering a reconsideration of their benefit/risk ratio, especially in children (Tyrer and Kendall, 2008; Correll, 2008a,b; Sikich et al., 2008). The clinicians’ perception that second-generation antipsychotics are safer than first-generation antipsychotics (FGA) and their expectation of better effectiveness may be one of the principal causes of the significantly increased use in the pediatric population in recent years (Vitiello et al. 2009; Zuddas et al. 2011). However, there are few safety studies of SGA in pediatric populations (Fraguas et al., 2011; Caccia et al., 2011; Arango 2014 et al., 2014; Correll et al., 2014; Alda et al., 2016). In the past decade, various AP such as sertindole, thioridazine, and droperidol were removed from the market because of cardiac side effects (Buckley and Sanders 2000; Glassman and Bigger 2001; Fraguas et al. 2008). Other AP drugs such as ziprasidone were examined in further specific safety studies (Ziprasidone Observational Study of Cardiac Outcomes [ZODIAC Study]) (Strom et al. 2011), triggering an extensive debate regarding the cardiac safety of specific AP drugs (Fraguas et al. 2008). Various studies found an association between AP use and increase in corrected QT interval (QTc) (Buckley and Sanders 2000; Glassman and Bigger 2001). Many AP drugs can, in various ways, prolong the QTc interval of the electrocardiogram and, in the presence of tachycardia, can provoke an increased risk of potentially lethal arrhythmias known as ‘‘Torsade de pointes’’ (Glassman and Bigger 2001; Zuddas et al. 2011). In children and adolescents, cardiovascular side effects associated with the use of SGA and FGA include orthostatic hypotension, tachycardia, QTc prolongation, and arrhythmias (Cheng-Shannon et al. 2004; Jones et al. 2013). In a study with a pediatric population, AP group, gender, age, smoking status, substance abuse, and diagnosis were unrelated to QTc change after introduction of the AP (de Castro et al. 2008). In a recent meta-analysis of 55 studies with >5000 youth patients, the risk of pathological QTc prolongation seemed low during treatment with the nine AP studied in otherwise healthy young people. Nevertheless, because individual risk factors interact with medication related QTc effects, both medication and patient factors need to be considered when choosing AP treatment ( Jensen et al. 2015). Although the cardiovascular side effects during treatment with AP drugs may be less common in children and adolescents than in adults (Masi and Liboni 2011, Arango et al. 2016), the benefit of the electrocardiogram (ECG) screening is not yet clear in the pediatric population. The purpose of the study is to evaluate cardiac symptoms of SGA in a large sample of treatment-naıve (no previous AP) or quasi-naıve (AP exposure for <30 days) pediatric patients for a period of 24 months.