The prevalence of childhood and adolescent psychiatric disorders is rising, as is the prescribing of various psychiatric medications.1'2 With a continued shortage of child and adolescent psychiatrists, primary care pediatricians often initiate and modify the use of these medications. They also manage the adverse effects seen with chronic use, misuse, or both.3 This article describes select psychiatric medication adverse effects the primary care pediatrician may encounter or may have been made aware of from recent media attention. This article discusses adverse effects of the atypical antipsychotics, the potential increase in suicide risk from serotonergic antidepressants, and the possible relationship of an extended-release mixed amphetamine salts medication to sudden death. Additionally, the adverse effects of atomoxetine are examined, along with the hepatotoxicity and hyperammonemia often seen with valproic acid.
Antipsychotic medications have been used in the management of schizophrenia since the 1950s. The traditional antipsychotic agents (eg, phenothiazines, haloperidol, droperidol) effectively treat positive signs and symptoms, such as delusions, hallucinations, and aggressive behavior. They have little effect on negative symptoms, such as flat affect, social withdrawal, and avolition. Extrapyramidal symptoms (EPS), neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), weight gain, sedation, prolonged QT interval, and other adverse effects are commonly seen with these medications, limiting compliance and efficacy.
In 1990, the first atypical antipsychotic, clozapine, was introduced with the promise of attenuating adverse effects while enhancing treatment efficacy for negative symptoms. Since then, five additional antipsychotics have been approved - risperidone ( 1 994), olanzapine (1996), quetiapine (1997), ziprasidone (2001), and aripiprazole (2002). Since their introduction, these agents have supplanted traditional agents as first-line therapy for schizophrenia, bipolar disorder, and other behavioral disorders.
Atypical antipsychotics have minimized the risk of TD, NMS, EPS, and adverse neuroendocrine effects (eg, hyperprolactinemia) while effectively treating the signs and symptoms.4 Explanation for decreased adverse effects is thought to be due to different pharmacodynamics - lower affinity for the dopamine (D2) receptors and greater antagonism of the serotonin (5-HT2) receptors.4
A number of adverse effects have been noted with atypical antipsychotic use (Sidebar 1). Clozapine, the first of this class, interacts with multiple receptor classes and has been associated with the most adverse effects. Ziprasidone and aripiprazole, the latest to be introduced, have shown the fewest.
Anticholinergic effects (eg, tachycardia, dry mouth, sedation, urinary retention, constipation) are most common with clozapine, olanzapine, and quetiapine.5 Antagonistic activity at the a? receptor results in mild orthostatic hypotension and miosis and is associated with all second generation antipsychotics.6
EPS (dystonia, akathisia, Parkinsonism, and tremor) and tardive dyskinesia are less frequent with atypical antipsychotics than with conventional agents.7 NMS has been reported rarely with all atypical antipsychotics.5'8 Many second-generation agents produce clinically significant weight gain.4 This may relate to the increase in diabetes and rare reports of diabetic ketoacidosis in these patients.9'10 Clinically significant hyperlipidemia has also occurred.11 Prolonged QTc has been noted with all second-generation antipsychotics except aripiprazole, which shortens the QTc at therapeutic doses.12 Ziprasidone significantly increases the QTc interval; its initial Food and Drug Administration (FDA) approval was delayed because of this concern.
No published cases have associated a second-generation agent with Torsades de Pointes or ventricular dysrhythmias. However, sudden unexplained death has been reported and may have resulted from dysrhythmias induced by atypical antipsychotics.5'13
Generalized tonic-clonic seizures are rare but have occurred most frequently with clozapine and olanzapine. With clozapine, the risk is increased at higher doses and in those with a history of epilepsy, and during initiation or rapid decreasing of dosage.5 Clozapine also is unique in causing agranulocytosis in 1% of patients; this typically occurs within the first 8 to 12 weeks of treatment.14 Agranulocytosis is life threatening, but mortality has decreased with limited drug use and greater surveillance. Clozapine also causes myocarditis in 0.032% of patients (fatality rate of 0.012%) and sialorrhea in 13%. 15
Aripiprazole, the newest antipsychotic, thus far has not been associated with adverse effects such as hyperprolactinemia, significant weight gain, hyperlipidemia, hyperglycemia, or increased QTc interval. Post-marketing surveillance will continue to assess for these effects. Other rare adverse effects of atypical antipsychotics include mild, reversible elevated liver enzymes, lens opacities with clozapine, and hyperprolactinemia with risperidone.
Recommended Physical and Laboratory Assessments for Patients Treated With Atypical Antipsychotics6"2
Treatment and Monitoring for Adverse Effects
Monitoring guidelines have been published based on consensus and review of current literature (Table I).6'12 For most, adverse effects can be attenuated or eliminated by reducing the dose, changing to a different medication within the class, or switching to another treatment category (Sidebar 1). However, some effects may be irreversible; therefore, periodic monitoring is paramount.
Because of interindividual variability in the metabolism of antipsychotics, there is little correlation among half-life, dose, serum concentration, and clinical effects.5 After acute intoxication, toxic effects begin within 1 to 2 hours and peak approximately 4 to 6 hours following ingestion. Delayed onset of symptoms has not been reported. In general, toxicity includes significant sedation, tachycardia, and mild hypotension. The early second-generation antipsychotics have anticholinergic effects as well. The sedating effects can be quite profound and occasionally requiring intubation for 24 to 36 hours in large ingestions. Ziprasidone and aripiprazole are less likely to produce tachycardia. Miosis is more common than mydriasis due to a? receptor blockade.5 EPS, in particular dystonia, is seen occasionally and is most common with children. Prolonged QTc has been described after overdose, but no case of torsade de pointes has been published.16'17 Clozapine-induced seizure may occur, although rarely, along with dysrhythmias and NMS.
Treatment is supportive. Supplemental oxygen and trachéal intubation may be needed for severe central nervous system (CNS) and respiratory depression. Stabilization of blood pressure with intravenous fluids and gastrointestinal decontamination with activated charcoal should be administered.5 Acetaminophen and salicylate levels, electrolytes, and an electrocardiogram should be obtained to exclude other common toxic ingestants. Prolonged observation in a monitored setting is required until the patient is sufficiently awake and conversant.
Dystonia, a manifestation of EPS, is treated with diphenhydramine (1 mg/ kg intravenously) or benztropine (0.02 to 0.05 mg/kg orally or intravenously in children; 1 to 2 mg in adolescents). A response should occur within 5 to 10 minutes. If symptoms persist after the initial dose, another should be repeated. If no response to anticholinergic agents is observed, one dose of a benzodiazepine (lorazepam 0.1 mg/kg) should be attempted. Symptoms refractory to benzodiazepine treatment indicate an alternate diagnosis. Patients should be treated for EPS for 72 hours to prevent recurrence. Additional acute management recommendations can be found in other toxicology references.5'17
SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND SUICIDE RISK
Depression and suicide are national public health problems for children and adolescents. Major depression affects approximately 2.5% of United States children and 8.3% of adolescents, accounting for 2.6 million of those ages 6 to 17. 18 Physicians and parents realize depression can affect every aspect of a child's life - academics, athletics, sleeping, interpersonal relationships, and eating. Selective serotonin reuptake inhibitors (SSRIs), similar antidepressants, and psychological therapies have been demonstrated to benefit adults and youth suffering from depression.
Characteristics of Sudden Death Cases Related to Use of a Mixed Amphetamine Salts Medication for Attention-Deficit/Hyperactivity Disorder, 1999-200332
Recently, concerns have been raised about the association between SSRIs and similar antidepressants and the increasing risk of suicidal ideation in adolescents and children.19 Evidence for and against this association comes from randomized controlled trials, and observation and population-based studies.19"21 Varying opinions exist as to the legitimacy of this association.22'23
In 2004, 23 clinical trials involving 9 different antidepressant medications used in children and adolescents were reviewed. These involved more than 4,300 patients and prompted the British Department of Health's Medicine and Healthcare Products Regulatory Agency (MHPRA) and the United States counterpart, the Food and Drug Administration, to issue a "black box" warning. This warning states that patients taking these medications should be "monitored closely for worsening depression or the emergence of suicidiality" and SSRI use in youth could "... increase the risk of suicidal thinking and behavior ('suicidality') in children and adolescents with major depressive disorder or other psychiatric disorders."24
In the PDA's review, there were no completed suicides in the study population treated with SSRIs; however, the rate of suicidal thinking and behavior (including suicide attempts) was 4% for those taking SSRIs and 2% for placebo - a small but statistically significant difference. Of note, these were spontaneously reported suicidal thoughts or behavior. When subjects were asked specifically about these thoughts or behaviors, a slight decrease in "suicidality" in the treatment group was present Also, determining the risk of completed suicide with SSRI use is difficult because depression itself increases the suicide risk, effective treatment increases the patient's mood and increases the risk, patients at high risk for suicide are excluded from studies, and the studies were underpowered to detect the rare event of completed suicides in children or adolescents.25'26
Despite the PDA's action, there is evidence from federally funded, doubleblind, randomized controlled trial that fluoxetine is effective for treating depression in children and adolescents.21 March et al.21 demonstrated fluoxetine not only improves the symptoms of depression but also decreases suicidal thinking. The combination of fluoxetine and cognitive-behavior therapy produced the greatest benefit. Fluoxetine is the only SSRI medication the FDA has approved for major depressive disorder in children and adolescents.
Another reason the potential risk of completed suicide received much attention by families and the media is the concern that pharmaceutical manufacturers may have "manipulated the results of published research" and the handling of the issue by the FDA.19-27 The American Psychiatric Association and the American Medical Association may collaborate on a resolution to dispute the warning label's placement on SSRI medications.28
Future studies by the National Institutes of Mental Health (NIMH) hope to resolve the controversy. Additional data from the Treatment for Adolescents with Depression Study (TADS) are being analyzed and may shed some light of this issue. NIMH also is conducting the Treatment of Resistant Depression in Adolescents (TORDIA) and Treatment of Adolescent Suicide Attempters (TASA) studies in a select group of high-risk subjects who receive SSRI medications and other therapies.
As with any medication, the necessity of continued SSRI use in a child should be reassessed frequently. If an SSRI is to be discontinued, this should be done gradually over several weeks and without the intervening introduction of another serotonergic agent. If, after consultation with a psychiatrist and the parents, a decision is made to initiate or continue an SSRI, the treating physician should monitor the child carefully for suicidal thoughts and behaviors, particularly during the first 4 weeks of therapy. If signs of "suicidality," agitation, irritability, mood instability, or nervousness develop, urgent intervention by the treating clinician is indicated.25
Stimulant therapy is a mainstay of attention-deficit/hyperactivity disorder (ADHD) and is recommended along with behavioral modification as first line therapy. The exact mechanism behind the efficacy of stimulant therapy in ADHD is unclear. Common adverse effects of all amphetamine-derived stimulants used for ADHD include insomnia, anorexia, weight loss, palpitations, tachycardia, tics, stunted growth, and concern for abuse and overdose.
Controversy Over Alleged Risk of Sudden Death
The impetus for the development of long-acting stimulants was the need to improve medication compliance, balance the therapeutic effects evenly throughout the day, and limit the need for dispensing medication at school. Examples include long-acting formulations of methylphenidate, dextroamphetamine, and a mixed amphetamine salt.29 The FDA approved the long-acting mixed amphetamine salt medication in October 2001 for treatment of ADHD. Two well-controlled trials of more than 600 patients demonstrated the efficacy of the long-acting version of this medication when compared with placebo for improvement in attention and behavior.30 The FDA approved the medication on the basis of these two studies and the known efficacy of the standard version of the medication. It was approved for use in Canada on January 23, 2004.
In February 2005, Health Canada, the Canadian drug regulatory agency, halted sales of the medication after 20 cases of sudden death were reported internationally.31 During the preliminary review of these reports, Health Canada suspended sales but did not withdraw the medication from the market completely.32
However, the number of sudden death cases reported with the medication is only slightly greater, per million prescriptions, than that reported for methylphenidate products. A review of the PDA's spontaneous, post-marketing Adverse Event Reporting System for both the regular and long-acting versions of the medication between 1999 and 2003 produced 12 reports of pediatrie death. These children ranged in age from 7 to 16.32 Daily doses ranged from 10 to 50 mg, although most were 20 mg. Cardiac abnormalities were noted in 5 of the 12 patients, and other possible risk factors for sudden death were noted (Table 2, see page 450).
The FDA has stated, based on the approximately 30 million prescriptions written for these medications between 1999 and 2003, that the incidence of death does not appear to be greater than would be expected in this population without treatment.24 Pediatrie patients with structural heart defects are known to have an increased risk of sudden death even without stimulants.24'33
Based on these 12 deaths, the FDA in August 2004 recommended labeling changes for the long-acting mixed amphetamine salt medication, stating that pediatrie patients with known structural heart defects might be at higher risk for sudden death and should not be treated with the medications.32 Neither a "black box" warning nor withdrawal from the market was recommended. The FDA will continue to evaluate this and other adverse effects through post-market reporting.24
A statement from the American Academy of Child and Adolescent Psychiatry (AACAP) recommends continuing therapy for patients already receiving the medication, with four guidelines:
* Obtain a thorough psychiatric and medical history before treatment.
* Continue previous prescription practices without immediate changes (except for high-risk patients).
* Discuss risks and benefits of therapy with patient and parents or caregivers.
* Monitor patient on a schedule reflecting individual needs and medical history.
Atomoxetine, a novel nonstimulant selective norepinephrine reuptake inhibitor, is used in the treatment of ADHD. It was approved in 2002 by the FDA for use in adults, adolescents, and children 6 or older. Its mechanism of action is different from clonidine, stimulants, or antidepressants, in that it selective enhances noradrenergic function via inhibition of presynaptic norepinephrine transporters. Atomoxetine has little activity at other receptors.34 It has also demonstrated increased norepinephrine and dopamine concentrations in the prefrontal cortex, the area responsible for attention, memory, impulse control, and judgment.34 The current guidelines from the American Academy of Pediatrics recommend stimulants and behavior modification as initial therapy for patients with ADHD.35 However, these recommendations were last revised in October 2001, prior to the FDA approval of atomoxetine.
Efficacy in ADHD
Several studies have demonstrated clinical efficacy of atomoxetine compared with placebo, and at least one study demonstrated efficacy similar to methylphenidate.34'36 Patients excluded from most of these studies include those with major depression, history of anxiety or bipolar disorder, major physical illness, alcohol abuse, active use of illicit drugs, or an IQ less than 75. 34 Data are lacking for outcomes more than 9 weeks beyond initiation of therapy and for efficacy compared to stimulants.34
In clinical trials and other published cases, few serious adverse effects have been reported. Atomoxetine seems relatively free of the common cardiovascular and neurologic adverse effects seen with stimulants.37 In children and adolescents, a mild increase in heart rate and blood pressure was seen during cardiovascular safety monitoring in clinical trials.38 No statistically significant difference was noted in systolic blood pressure, QT interval, or cardiac conduction compared with placebo.38
Transient decrease in appetite and resultant weight loss have been reported consistently but have resolved with continued use.37 Dizziness and dyspepsia occur with an incidence greater than with placebo. A possible allergic reaction to atomoxetine with edema and urticaria occurred in one case.37 A discontinuation syndrome with withdrawal symptoms was not described in a youth who abruptly stopped the medication.37
Abuse potential is limited. Atomoxetine does not increase dopamine in the nucleus accumbens, a region associated with pleasurable behaviors.39 In addition, no pleasurable effects were noted in a small study of adults with a history of alcohol and marijuana use.40
Effects With Acute Intoxication
Limited information is available regarding the effects seen after accidental or intentional poisoning. In a series of 40 cases reported to poison centers, no fatalities or major adverse outcomes were reported.41 The most common symptoms reported were tachycardia, drowsiness, nausea, hypertension, and vomiting. The majority of exposures were unintentional or a result of therapeutic error; only seven patients reported suicide attempts or intentional abuse.41
All patients were treated with supportive care and gastrointestinal decontamination. Delayed onset of clinical effects was not described. Two additional cases of acute intoxication reported seizures, tachycardia and prolonged QTc interval; however, these effects were more likely due to co-ingestants.42'43
Atomoxetine is clinically effective for ADHD. Further trials comparing it with stimulant therapy are needed to determine its place in the ADHD treatment paradigm. It appears to have a paucity of adverse effects, in particular an improved cardiovascular profile over tricyclic antidepressants and stimulants. Weight, blood pressure, and heart rate should be followed closely.
Careful consideration should be used before prescribing atomoxetine to patients with cardiovascular disease, hypertension, or history of drug abuse or drug dependence. After overdose, intentional or accidental, patients should be observed closely until clinical effects resolve. Further data on adverse effects and outcomes after overdose are needed.
Valproic acid is a branched chain carboxylic acid first introduced in the US in 1978 as an anti-epileptic drug in partial and generalized seizure disorders.44 In 1995, the FDA approved valproic acid for the management of mania in bipolar disorder. It also is used for migraine headaches and neuropathic pain. The increased availability and use of valproic acid has led to an increase in the number of cases reported to regional poison centers, with a recent sharp increase in intentional exposures.45
Although valproic acid is best known to cause central nervous system depression with supratherapeutic doses, it also is associated with other serious adverse effects as well (Sidebar 2). Valproic acid-associated hyperammonemia and hepatoxicity are discussed below.
Pharmacology and Preparations
Valproic acid has several mechanisms of action, including inhibition of sodium channels, enhancement of potassium conductance, reduction of calcium currents, and increase in gamma aminobutyric acid (GABA), an inhibitory neurotransnatter.46 Valproic acid is available in immediate-release and extended-release formulations. It is metabolized mostly by glucuronic acid conjugation and then by beta oxidation. However, when beta oxidation is overwhelmed, omega oxidation is increased, and multiple toxic metabolites are produced. These metabolites are thought to be the inciting agents for cerebral edema, as well as hepatotoxicity, and hyperammonemia.46
Hyperammonemia. Hyperammonemia occurs during therapeutic use and after acute intoxicatioa Blood levels of hepatic enzymes may be normal. Although hyperammonemia occurs in 50% of patients receiving valproic acid, almost half of these are asymptomatic.47 Propionic acid, a metabolite from omega oxidation, is thought to be the main culprit. Depletion of carnitine during beta oxidation also may be a factor. Serum ammonia concentrations correlate with serum valproic acid levels.46 Valproaterelated hyperammonemic encephalopathy (VHE) is symptomatic hyperammonemia occurring while taking valproic acid. It can also occur without a rise in amino transaminase levels and presents with confusion, lethargy, vomiting, and occasionally seizures. Coma and death rarely occur. The degree of encephalopathy is not clearly related to valproic acid levels, which may be normal.46 Ammonia levels should be monitored in patients taking valproic acid and obtained if VHE is suspected.
Hepatotoxicity. Two forms of valproic acid-induced hepatotoxicity are apparent - dose-related reversible hepatoxicity and a severe idiosyncratic reaction. Dose-related reversible hepatoxicity usually results in mild elevation of hepatic transaminases in 44% of patients taking valproic acid chronically.48 Cessation of valproic acid results in improvement of hepatic function tests. An idiosyncratic hepatitis occurs within the first 6 months of use and often is not preceded by mild elevations in hepatic enzymes.48 Hepatic microvesicular steatosis, similar to Reye's syndrome, develops. Risk factors for fatal hepatotoxicity include age younger than 2, history of organic brain disease, congential metabolic disorders, use of multiple anticonvulsants, and developmental delay.48 The incidence of idiosyncratic liver failure in patients with these risk factors is as high as 1:500, compared with the general population (1:50,000).49 The incidence of fatal liver toxicity has decreased, mostly likely due to recognition of this adverse effect and its associated risk factors. Both forms of hepatotoxicity are likely due to the depletion of carnitine (a cofactor for beta oxidation) and production of 4-en-valproic acid (a metabolite of omega oxidation).
Supportive care is the mainstay of treatment for these two adverse effects. Intubation may be needed for severely decreased mentation, and gastrointestinal decontamination with activated charcoal should be used for a recent acute ingestión. Repeating the dose of activated charcoal may result in a more rapid decline in the serum valproic acid concentration, but this has not been shown to change outcome.
Hydration, correction of metabolic abnormalities, and close monitoring are indicated. Decreasing the dose or cessation of valproic acid often results in resolution of the hyperammonemia and mildly elevated transaminases (Sidebar 3). However, valproic acid-induced hepatic encephalopathy and idiosyncratic hepatotoxicity arerelated to carnitine deficiency, can be severe, and are not responsive to cessation of valproic acid. Therefore, carnitine supplementation may be helpful. Also, previous guidelines have been published on L-carnitine use by the 1 996 Pediatrie Neurology Advisory Committee.50 However, L-carnitine administration is recommended for patients with hyperammonemia, lethargy, coma, and severe hepatic dysfunction.46 Based on one retrospective study, it may decrease mortality in severe, symptomatic valproic acid-induced hepatotoxicity.51
L-carnitine has minimal adverse effects except for a fishy odor. Dosing is 50 to 100 mg/kg per day orally (maximum 2 grams per day) or 150 to 500 mg/kg per day intravenously (maximum 3 grams per day).50 Extracorporeal methods of valproic acid removal are not indicated for valproic acid-induced hepatic encephalopathy and hepatic failure but may be considered for refractory hypotension and seizures.46
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Recommended Physical and Laboratory Assessments for Patients Treated With Atypical Antipsychotics6"2
Characteristics of Sudden Death Cases Related to Use of a Mixed Amphetamine Salts Medication for Attention-Deficit/Hyperactivity Disorder, 1999-200332