Atypical Antipsychotics in Children and Adolescents:

Balancing Safety and Efficacy

Educational Objectives

The goals of this program are to improve treatment outcomes and reduce adverse effects associated with the use of atypical antipsychotics in children and adolescents. After hearing and assimilating this program, the clinician will be better able to:

1.   Detail the approved clinical indications for atypical antipsychotic agents in children and adolescents.

2.   Educate patients and parents about potential risks and benefits associated with atypical antipsychotics.

3.   Recognize adverse effects that may be caused by atypical antipsychotics.

4.   Mitigate adverse effects of antipsychotic therapy through monitoring, dose adjustment, lifestyle interventions, and adjunctive therapy, when appropriate.

5.   Report serious adverse effects to the Food and Drug Administration through MedWatch.

Faculty

Ingrid Kohlstadt, MD, MPH, Commissioners Fellow, Food and Drug Administration (FDA), Office of Pediatric Therapeutics, Rockville, MD (Moderator); Christoph Correll, MD, Associate Professor of Psychiatry, Albert Einstein College of Medicine, New York, NY; Marsha Rappley, MD, Dean, College of Human Medicine, Michigan State University, and Chair, Pediatric Advisory Committee to the FDA, East Lansing, MI; Ade­laide Robb, MD, Associate Professor of Psychiatry and Pediatrics, Children’s National Medical Center, Washington, DC; Benedetto Vitiello, MD, Chief, Child and Adolescent Treatment and Preventive Intervention Research Branch, National Institute of Mental Health (NIMH), Bethesda, MD

Faculty Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified con­flicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial in­terest. For this program, the following has been disclosed: Dr. Correll is a consultant, paid speaker or teacher, and/or member of advisory committees or review panels for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Otsuka, and Pfizer; Dr. Robb has received research grants and/or is a member of the advisory board and speakers bureau for Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Ot­suka, and Pfizer; Drs. Kohlstadt, Rappley, and Vitiello and the planning committee reported nothing to disclose.

Indications

Introduction: approved for treatment of children and adolescents with schizophrenia, mania associated with bipolar-I disorder (BPD), or autism (for managing irritability); rigorous adherence to diagnostic criteria important to ensure appropriate use; not indicated for attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder

Labeled indications: see table, page 3; note  —  intramuscular formulations not approved for use in children and ado­lescents

Approval process: formerly, studies not conducted in pediatric population; data from controlled studies in children now available; pending decisions  —  see table, page 3

Initiating therapy: start with low dose of approved medication (indicated for diagnosis); titrate up, based on patient response and adverse effects; dissolvable tablets or liquid preparations good options for patients unable to swallow pills; consult psychiatrist if patient not improved at target dose

Switching or discontinuing agents: switching  —  first assess adherence (eg, does patient swallow medication?); con­sider switching medications if desired effect not achieved after patient adherent at maximum labeled dose for 7 days; switch medications if patient becomes threatening or dangerous to self or others (psychiatric emergency); discontinuing  —  taper gently, when possible

Adverse Effects

Drug label: information also accessible online (www.accessdata.fda.gov/Scripts/cder/DrugsatFDA); highlights page  —includes warnings, indications, information about dosing and available preparations, contraindications, ad­verse reactions, drug interactions, and population-specific information; boxed warnings  —  prominently displayed information about potentially serious adverse reactions

Cognitive effects: somnolence and sedation  —  reduced by up-titrating slowly; children generally accommodate ef­fects within »1 wk; cognitive impairment  —  unknown whether atypical antipsychotic agents impair thinking and mem­ory

Extrapyramidal adverse effects: include muscular stiffness, tremor, akinesia (loss of voluntary movement), and akathisia (restlessness); more commonly associated with typical antipsychotic agents; occur more frequently and at lower doses in children and adolescents than in adults, but accommodation may occur; frequencies increase with increasing dose; dystonia  —  generally occurs shortly after initiation of therapy; may reduce adherence, es­pecially when severe; akinesia  —generally occurs during first week of therapy; akathisia  — generally occurs in first or second week; patients feel restless and uncomfortable (especially when trying to remain still); to distin­guish from agitation (sign of undertreatment), ask about quality of feeling (eg, presence of physical discomfort, whether symptoms exacerbated when trying to remain still)

Tardive dyskinesia: presents later; persistent abnormal movements, generally affecting face and tongue but may affect arms, hands, and/or fingers; associated with reduced quality of life; risk factors  —  older age; white race; fe­male sex; typical vs atypical antipsychotics  —  studies in adults show lower incidence with atypical agents; rate may increase with prolonged use or higher doses; differential diagnosis  —  before initiating treatment, perform baseline neurologic assessment for un-derlying movement disorders; mechanism  —  not fully un-derstood; agents affect transmission of dopamine; management  —  stop agent (if possible) or adjust dose

Withdrawal dyskinesia: especially common in children and adolescents; may occur when tapering medication too quickly; if severe, increase dose (so that withdrawal symptoms subside) then taper very slowly (eg, by 25% each month); note  —unexpected withdrawal dyskinesia may result from poor adherence (and may be mistaken for tar­dive dyskinesia); use of dissolving tablets or liquids may improve adherence

Suicidality: children and adolescents with schizophrenia or bipolar mania have increased risk (compared to general population); vigilance required; important to establish baseline (eg, for suicidal ideation) before initiating therapy and to monitor patient

Mental illness and mortality: average life span shortened by »25 yr in patients with mental illness; loss of »15 yr at­tributed to accelerated onset and rapid progression of chronic medical conditions

Adverse metabolic effects: include inappropriate weight gain, hyperglycemia or diabetes, and dyslipidemia (in­crease in levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides); before initiating therapy  —  take detailed family history (relevant to metabolic disorders); record baseline levels (eg, fasting glu­cose, lipid panel, blood pressure (BP), weight, and height); monitoring  —  at 3 mo, then every 6 mo; record weight and height at every visit; ask about increased thirst and urination; if present, measure blood glucose and electrolyte levels; (note, dry mouth [distinguishable from thirst] may occur after initiating some agents); assess­ing obesity  —  waist circumference sometimes helpful as indicator of central obesity (increased risk for metabolic syndrome), but not recommended as screening tool; body mass index (BMI) adjusted for growth (expressed as percentile or z-score) recommended

Metabolic syndrome in children and adolescents: obesity  —³95th percentile for sex and age; BP  —  ³90th percen­tile, based on age and height; triglyceride level  —  ³110 mg/dL; high-density lipoprotein cholesterol  —  <40 mg/dL; blood glucose  —  ³100 mg/dL; other measures of cardiovascular risk  —  level of C-reactive protein (CRP) associated with risk in adults, but not recommended as screening tool

Interventions: pay attention to increases from baseline; do not delay interventions until criteria for metabolic syn­drome reached; emphasize importance of lifestyle interventions; changes in appetite  —  sugared and diet drinks may increase appetite; medications may alter appetite and satiety signals (via changes in neurotransmitters); edu­cation and dietary adjustments important

Liver toxicity: some agents (eg, olanzapine, risperidone) associated with abnormalities on liver function tests (LFTs); repeat LFTs when monitoring blood glucose, lipids, and BP

Relative risk: all antipsychotic agents associated with metabolic effects; clozapine and olanzapine associated with highest risk, risperidone and quetiapine intermediate, and ziprasidone and aripiprazole associated with least risk; emerging evidence suggests that children at higher risk than adults and that risk may increase with lower BMI and younger age (conflicting data); some patients protected against weight gain (mechanism unknown)

Weight gain: early recognition  —  assess at 1 to 4 wk; early response gives clues about risk (assuming patient adher­ent); issues  —  patient more difficult to manage physically (may affect activities of daily living); some patients do not accept dietary changes (common among children with autism) and/or have activity limitations

Hyperprolactinemia: risk  —  higher in children and adolescents compared to adults; risk varies with drug; greater risk with risperdone (indicated on label); effects  —  elevated levels of prolactin suppress production of sex hor­mones, potentially resulting in hypogonadism; long-term effects include osteoporosis; unanswered questions in­clude level of prolactin required to suppress production of sex hormones and effect on onset of puberty; long-term studies needed; recommendations  —  look for clinical signs and symptoms of hypogonadism; monitor pro­lactin level

Signs and symptoms: sometimes difficult to assess in children and adolescents; amenorrhea or oligomenorrhea  —  often due to normal menstrual irregularity during early adolescence; galactorrhea  —  more likely to occur in girls with estrogen-primed breasts; patients rarely volunteer information (often not recognized as adverse effect of medication; important to ask); gynecomastia  —  presence of glandular resistance distinguishes true gynecomastia from that which may occur with weight gain in boys; sexual dysfunction  —  sometimes related to prolactin level; adolescents may not recognize dysfunction

Follow-up: consider switching medications when prolactin level ³20 ng/dL; refer patient to endocrinologist if vi­sual field effects present (may signal pituitary tumor)

Differential diagnosis in girls with amenorrhea: delayed onset of puberty  —  assess Tanner stage; ask about family history (eg, late menarche); check growth (looking for growth spurt near time of menarche); pregnancy  —  ask about sexual history and method of contraception; hyperprolactinemia  — relevant history includes antipsychotic therapy and complaints of breast tenderness and/or discharge, followed by abrupt amenorrhea or oligomenor­rhea; polycystic ovary syndrome  —  associated with valproic acid therapy (in children, approved only for manage­ment of epilepsy); other signs and symptoms include hirsutism, increased acne, and increased BP

Cardiovascular effects: heart rate and BP may increase, but generally not clinically significant; measure at each visit and track over time to identify significant elevations; children with highly variable BP at increased risk of develop­ing hypertension; persistent hypertension warrants referral for evaluation; a-adrenergic effects of antipsychotic agents may cause BP to decrease; sudden cardiac death  —  study in adults showed increased risk associated with antipsychotics; risk in children unknown; ziprasidone associated with QT prolongation (risk factor for sudden car­diac death); vigilance and monitoring important

Drug interactions: may exacerbate adverse effects (eg, antiepileptic agents and lithium increase risk for weight gain when paired with atypical antipsychotics); tremor, sedation, and cognitive effects may increase greatly when anti­psychotic agent paired with other drugs with similar adverse effects; online sources helpful in identifying potential drug interactions; some agents interfere with efficacy of oral contraceptives; many antipsychotics lower threshold for seizures; smoking  —  patients may increase (or initiate) smoking because nicotine reduces extrapyramidal ef­fects, but smoking can reduce serum levels of clozapine and olanzapine; absorption  —  taking ziprasidone with food increases absorption (³500 kcal recommended; not dependent on fat content); recreational drugs (including alco­hol) should be avoided; alcohol increases sedation

Adherence: study found »45% of adolescents comply with treatment regimen; issues cited for noncompliance in­clude adverse effects, peer pressure, and general unwillingness to take medication; early and rapid weight gain also associated with decreased adherence; tips to improve adherence  —  foster positive relationship and honest, open communication with patient; when asking about adherence, avoid yes/no questions; instead, ask “How many times did you forget to take your medication?”; establish dosing schedule to accommodate patient’s routine; educate pa­tient about potential adverse effects; ask about patient’s concerns

Reporting: communication crucial when ³1 clinician prescribes medication for patient; monitoring for and minimiz­ing adverse effects important; adverse effects should be reported to MedWatch (reports can be filed through website [www.fda.gov/Safety/MedWatch/default.htm] even if information incomplete)

Future Steps

Needed research: information about long-term safety; direct comparisons among atypical antipsychotics; identifica­tion of biomarkers that predict therapeutic response or risk for adverse effects (eg, obesity, metabolic syndrome)

Clinical trials: in progress  —  comparison of treatments (risperidone vs lithium or valproic acid [eg, Depakote]) for children and adolescents with early-onset mania associated with BPD; comparison of strategies (dietary interven­tion, switching medications, or adding metformin) for managing metabolic effects of atypical antipsychotic agents; efficacy and safety of risperidone for treating children without psychosis or mania but with severe outbursts of vio­lence or aggression; studies comparing medical and behavioral therapies; unanswered questions  — long-term ef­fects of weight gain and metabolic syndrome; relationship between treatment-associated weight gain and development of metabolic syndrome; impact of dose and duration of therapy on extrapyramidal effects

Take-home messages: periodic reevaluation important; if patient not responding as expected, reconsider diagnosis and/or treatment approach; monitoring and education important for maximizing efficacy of treatment; reporting se­rious adverse effects (eg, new-onset diabetes, sudden death, tardive dyskinesia, and suicide attempts) important for appropriate labeling and for designing strategies that mitigate risk; as patients mature, changes in cognitive de­mands, schedule, and adverse effects may require alteration of strategy and/or dosing

Pediatric Indications for Atypical Antipsychotics