Antipsychotic drug
Indication
FDA approval patient age (years)
EMA approval patient age (years)
FGAs
Haloperidola
Schizophrenia
–
≥3b
Behavioral disorders (hyperactivity, aggression)
–
≥3b
Gilles de la Tourette syndrome
–
≥3b
Chlorpromazine
Childhood schizophrenia
1–12
≥1b
Bipolar disorder (mania)
1–12
–
Autism
–
≥1b
SGAs
Clozapine
Schizophrenia in patients unresponsive or intolerant to other antipsychotics
–
>16
Risperidone
Schizophrenia
13–17
≥15
Bipolar I disorder
10–17
≥13
Irritability associated with autistic disorder
5–16
–
Persistent aggression in conduct disorderc
–
≥5
Olanzapine
Schizophrenia
13–17
–
Bipolar I disorder
13–17
–
Quetiapine
Schizophrenia
13–17
–
Bipolar I disorder
10–17
–
Aripiprazole
Schizophrenia
13–17
≥15
Bipolar I disorderd
10–17
≥13
Irritability associated with autistic disorder
6–17
–
).
13.2.3.2 Safety of Antipsychotics in Children and Adolescents
Because of the paucity of comparative studies in children, there is currently little evidence to support the superiority of SGAs over FGAs or a difference between SGAs for the treatment of children and adolescents with psychosis or behavioral disorders (Kennedy et al. 2007; Kumra et al. 2008; Sikich 2008; Sikich et al. 2008; Loy et al. 2012; Kumar et al. 2013). Conversely, the safety profile of antipsychotics differs substantially. Atypical antipsychotics are associated with a lower risk of neurological adverse reactions than first-generation drugs, but they are clearly associated with a higher risk of weight gain and metabolic abnormalities in both adults and children (Caccia 2013; Maher et al. 2011; Seida et al. 2012). Nevertheless and despite initial expectations, observed variability appears to be greater among specific agents than between the first- and second-generation antipsychotic classes (Masi and Liboni 2011; Muench and Hamer 2010; Vitiello et al. 2009; Fraguas et al. 2011).
Current knowledge on the most prevalent adverse reactions to antipsychotics in children and adolescents is provided in the following sections. Since the use of typical antipsychotics is actually limited in children and adolescents, safety issues are exposed mainly with regard to second-generation compounds. The strength of association between a given agent and a specific adverse event is given as compared to placebo since very few head-to-head comparisons of antipsychotics have been conducted in children and adolescents. Occurrence of neuroleptic malignant syndrome, a rare but potentially life-threatening adverse reaction, is not detailed in this section (see Chap. 10).
Neurological Toxicity
Sedation and somnolence are common with all antipsychotic medications, and they are usually dose dependent. Rates tend to be higher with FGAs, clozapine, ziprasidone, olanzapine, and risperidone and lower with aripiprazole and quetiapine (Cohen et al. 2012).
Another major neurological adverse reaction is the occurrence of extrapyramidal symptoms (EPS) which comprises drug-induced parkinsonism, akathisia, acute dystonia, and tardive dyskinesia. Children and adolescents appear to be more sensitive to EPS than adults especially when they present mental retardation or CNS damage or are drug-naïve patients. EPS are more common with typical antipsychotics like haloperidol, but newer antipsychotics are not totally free of such reactions. Treatment with risperidone, olanzapine, and aripiprazole are related to an elevated risk of EPS, especially at high doses. In fact, the incidence of EPS in schizophrenic patients treated with aripiprazole monotherapy compared to placebo treatment is much higher in pediatric patients compared to adults (Correll 2008). The risk of EPS appears to be low with clozapine and quetiapine. Data on ziprasidone are too scarce to draw reliable conclusions. The majority of extrapyramidal symptoms are reversible after discontinuation of the offending agent with the exceptions of tardive dystonia and tardive dyskinesia that may be difficult to treat and ultimately become permanent in some patients. Moreover, EPS often generate major psychological distress and poor compliance with therapy.
The majority of antipsychotics can lower the seizure threshold and should be used with caution in patients who have a history of seizures and in those with organic brain disorders. Convulsions are more common under treatment by certain FGAs and clozapine, especially at high doses (Masi and Liboni 2011).
Finally, for aripiprazole, a safety warning was issued on the potential risk of increased suicidal ideation and suicide in children, adolescents, and young adults with major depressive disorder. The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk patients should accompany drug therapy. Nevertheless, no suicides occurred in any of the pediatric trials.
Metabolic Disorders
All antipsychotics may be associated with weight gain and an increase of body mass index (BMI) though such effects are probably the most significant adverse reactions of atypical agents (Muench and Hamer 2010). Excessive weight gain should not be disregarded in treated children and adolescents because it may contribute to significant morbidity and mortality in adulthood. Being overweight is a major determinant of a general metabolic disorder, the metabolic syndrome (obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol levels, hypertension, and hyperglycemia) associated with atherosclerosis, coronary artery disease, and colorectal cancer in adults (Correll et al. 2006). Also, in long-term use, weight gain has been associated with liver enzyme abnormalities and fatty infiltration (Masi and Liboni 2011). In addition, it contributes to poor medication adherence, social withdrawal, and low self-esteem which may be sources of significant psychological morbidity. Mean weight gain during therapy appears to be important with olanzapine, clozapine, and risperidone; moderate with quetiapine; and low with aripiprazole and ziprasidone. Despite great interindividual variability in weight gain, possibly related to genetic predisposition, dietary recommendations and counseling (lifestyle, exercise) should be provided at the initiation of antipsychotic therapy for all patients. Treatment with metformin to stabilize weight has been proposed, but data are limited in children and adolescents (Klein et al. 2006; Shin et al. 2009).
Increase in the blood levels of glucose, triglycerides, and cholesterol may also be attributable to antipsychotic agents. Glycemic abnormalities may vary from hyperglycemia due to mild insulin resistance to new-onset diabetes and worsening of glycemic control in patients with preexisting diabetes mellitus (Pringsheim et al. 2011a). Incidence is not well established in children and adolescents under treatment, but the risk appears to be high with olanzapine and risperidone, moderate with quetiapine and aripiprazole, and low with ziprasidone and the first-generation agent haloperidol. Moreover, treatment with olanzapine, clozapine, and quetiapine has been associated with increased blood levels of triglycerides and cholesterol, whereas the risk is moderate with aripiprazole and low with risperidone, ziprasidone, and haloperidol. Adolescents treated with olanzapine have an increased potential for weight gain and hyperlipidemia compared to adult patients. Similar to weight gain, drug-induced metabolic changes may persist over time and become clinically meaningful only after prolonged use of antipsychotic medication. In the absence of long-term follow-up studies, cardiometabolic adverse effects are probably underestimated in children and adolescents.
Endocrine Disorders
Hyperprolactinemia is a direct consequence of the antagonism of dopamine D2 receptors by both first- and second-generation antipsychotic agents. In most cases, hyperprolactinemia is dose dependent, tends to normalize with time, and completely resolves after cessation of antipsychotic treatment. Clinical signs of hyperprolactinemia include amenorrhea and other menstrual cycle disorders, galactorrhea, hirsutism, and sexual disturbances (decreased libido, erectile difficulties, etc.). Nevertheless, hyperprolactinemia may persist throughout treatment and remain totally asymptomatic or cause clinical signs that are difficult to express for a child or an adolescent (e.g., sexual dysfunction). Additional long-term consequences of prolonged hyperprolactinemia and subsequent hypogonadism include pubertal delay, growth arrest, and osteoporosis (Masi and Liboni 2011; Vitiello et al. 2009). Risperidone and olanzapine tend to favor meaningful increase in prolactin secretion, whereas the effect of quetiapine and ziprasidone is moderate and aripiprazole may even lower levels of prolactin.
Hematological Toxicity
Antipsychotic agents may cause neutropenia mainly in patients presenting low baseline blood counts or using cytotoxic concomitant therapy. However, a risk of life-threatening agranulocytosis has been reported in patients treated with clozapine. Neutrophil blood counts generally normalize after discontinuation of clozapine (Masi and Liboni 2011).
Cardiovascular Toxicity
Orthostatic hypotension and tachycardia have been described with the use of antipsychotic medications. These effects are less common in children and adolescents than in elderly patients and in most cases are clinically irrelevant (Masi and Liboni 2011). Cardiovascular effects are more frequent with certain FGAs, such as chlorpromazine and clozapine, though they have also been observed with the use of quetiapine and risperidone especially with rapid uptitration of dose. In fact, quetiapine has been associated with hypertension in children, whereas this event was never observed in treated adults. Moreover, myocarditis occurring at the beginning of treatment has been reported with clozapine (Ronaldson et al. 2010).
A potentially serious adverse event related with antipsychotics’ use is prolongation of ventricular repolarization that may lead to ventricular arrhythmia (e.g., torsades de pointes) and ultimately to sudden cardiac death (SCD). The incidence of SCD in adults treated with antipsychotics is twice that of the general population (Muench and Hamer 2010). In children, only one such case has been described in a child treated with ziprasidone. However, subclinical QTc prolongation has been reported in children under ziprasidone (Caccia 2013; Correll 2008). Subsequently, cautious use of all agents is recommended in children especially those with existing cardiac disease or family history of QT prolongation (Germanò et al. 2014).
Overall, children and adolescents tend to be more sensitive to the toxicity of antipsychotics than adult patients, especially when polypharmacotherapy is used. They experience more frequently weight gain, metabolic abnormalities (hyperglycemia, dyslipidemia), hyperprolactinemia, and neurological adverse reactions (sedation/somnolence, extrapyramidal symptoms, seizures). Conversely, they appear to be less susceptible to cardiovascular adverse reactions.
To date, safety data derive almost exclusively from cohort studies and meta-analyses of randomized controlled trials (Caccia 2013; Cohen et al. 2012; Pringsheim et al. 2011a). Yet, these studies were limited in follow-up time and sample size and therefore cannot provide reliable conclusions especially with regard to insulin/glycemic control, metabolic disorders, and occurrence of rare and distant adverse events. Moreover, the impact of antipsychotic medications on the physical, mental, and neurological development of children and adolescents, a safety issue specific to this population, has not been evaluated yet. In recent years, several networks have been created to routinely assess the efficacy and safety of antipsychotics in children: The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) in Canada (http://camesaguideline.org/), the Pediatric Atypical Antipsychotic monitoring Safety (PAMS) Study in the UK (Rani et al. 2009), and the SafEty of NeurolepTics in Infancy and Adolescence (SENTIA) in Spain (http://SENTIA.es). Analyses of large population health databases and patient registries through collaborative projects are actually required to clarify antipsychotics’ safety profile and to define their distal risk-benefit ratio in children and adolescents (Rani et al. 2011).
13.2.3.3 Safety Monitoring of Children and Adolescents Treated with Antipsychotics
Antipsychotic medications present highly variable safety profiles. This may complicate prescribing and patient management; however it offers many therapeutic alternatives and, thus, the possibility to match patients with the most appropriate medication. Given the length of use of antipsychotics and the impact of patients’ family history or lifestyle on the choice of the antipsychotic agent, thorough evaluation of risks for each distinct patient seems appropriate.
Currently, clozapine and olanzapine are not considered to be first-line antipsychotic treatments in children and adolescents because of their unfavorable safety profile. In particular, clozapine is reserved to patients who are resistant to other agents. Risperidone is actually the most commonly prescribed (Patten et al. 2012) and one of the most extensively evaluated antipsychotic agent in the pediatric population (Pringsheim et al. 2011a). Nevertheless, its safety profile is far from ideal as risperidone is frequently associated with rapid weight gain, metabolic abnormalities, significant somnolence and sedation, and the occurrence of extrapyramidal neurological symptoms. More recently developed agents such as aripiprazole, quetiapine, and ziprasidone offer interesting alternatives; however their efficacy and safety need to be further evaluated in children and adolescents.
Regardless of the drug used, children and adolescents that receive antipsychotic drugs should be proactively monitored for side effects. Physical examination (weight, height, BMI, waist circumference, blood pressure, and neurological examination for EPS) and certain standard laboratory tests (fasting plasma glucose, total cholesterol, LDL and HDL cholesterol, triglycerides, aspartate and alanine aminotransferase, prolactin) should be systematically performed at least in the first month after treatment initiation. More specific laboratory tests should be carried out according to the specific risk of treating agents: insulin levels in olanzapine treatment, thyroid-stimulating hormone (TSH) in quetiapine treatment, and neutrophil counts in clozapine treatment. Guidance on the electrocardiogram monitoring of treated patients has also been developed (Blair et al. 2004).
Evidence-based recommendations for monitoring of children and adolescents under atypical antipsychotics have been developed by the CAMESA guideline group in Canada. These recommendations are extremely useful in practice; however they reflect the paucity of evidence-based knowledge in the area and the need for further targeted research. In addition, they are limited to the first year of treatment because of the absence of long-term prospective studies. Safety of antipsychotics is a major focus especially in the young; however monitoring rates are still very low and studies of pharmacologic and behavioral interventions are extremely limited (Maayan and Correll 2011).
13.2.4 Other Psychotropic Medications
Anxiolytics and sedatives have no marketing authorization for use in child and adolescent psychiatry except for certain drugs (e.g., diazepam, hydroxyzine) in certain countries and under exceptional clinical conditions. Specific safety data on children and adolescents are extremely limited, although the use in children can be very prevalent in some countries (Murray et al. 2004; Pringsheim et al. 2011b; Zito et al. 2008).
Mood regulators such as lithium and anticonvulsants, carbamazepine and valproic acid, are also used beyond their marketing authorizations in pediatric psychiatric indications. The safety of lithium in children and adolescents with bipolar I disorder has been evaluated in clinical trials of limited sample size (Geller et al. 2012), and adverse events are similar to those observed in adult patients (e.g., thyroid dysfunction). Toxicity of anticonvulsants used mainly for neurological indications has been extensively evaluated and is beyond the scope of this chapter.
13.3 Conclusion
The majority of psychotropic drugs provide only symptomatic management of clinical symptoms in lifelong psychiatric disorders. Children and adolescents are therefore exposed to these agents in a chronic manner or at least for a prolonged period of time. In fact, drug utilization studies have demonstrated not only that the incidence of the use of certain psychotropic drugs such as antipsychotics is increasing in children and adolescents but also that the duration of the therapy (Patten et al. 2012). In addition, young children are more likely to be receiving multiple psychotropic medications to control psychiatric comorbidities and improve social functioning. Currently, 60–70 % of pharmacological prescriptions in pediatric psychiatry are considered “off label” because they concern age ranges, doses, and indications that are not approved by regulatory authorities. For example, antipsychotic use in children and adolescents targets mainly nonpsychotic disorders. All these trends in psychotropic prescribing have significant implications for drug safety and patient monitoring during treatment (Steinhausen 2014). Furthermore, there is a significant rise of prescriptions of psychotropic drugs by family physicians and pediatricians (Ronsley et al. 2013; Meng et al. 2014) that may lack professional experience and resources to monitor children for potential side effects. Physicians who do not have sufficient knowledge and resources to carefully follow patients and assess drug safety should refrain from prescribing these medications and refer the patient to a specialist.
The substantial increase of psychotropic use in children and adolescents has not been accompanied by a similar increase in research-based evidence about the efficacy and safety of these medications. This increase in psychotropic drug use calls for long-term efficacy and, most importantly, safety studies in large samples in order to account for the dynamic processes of growth and brain development in the young patients. Further research should also attempt to elucidate the physiopathological mechanisms of psychotropic-induced toxicity and the potential value of personalized approaches based on genetics and neurobiology. Additional safety data are urgently needed to clarify the risk-benefit ratio of psychotropic medications in children and adolescents and to adequately guide medical decision-making. In the meantime, psychotropic prescribing in children and adolescents should involve a cautious balance between patients’ therapeutic needs and a proactive monitoring of clinical efficacy and drug-induced toxicity.
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