Psychopharmacologic Management of Children and Adolescents

Overview

Similar to adults, hospitalized children can develop psychiatric illness as a result of psychosocial stresses of hospitalization (e.g., loss of control, threat of illness, separation from caregivers), effects of general medical conditions (e.g., infections), use of medications or substances (e.g., drug–drug interactions, drug withdrawal), and exacerbation of pre-existing psychiatric vulnerabilities. The decision to use psychotropics in this population should be based on a careful diagnostic formulation and consideration of the limited database on the risks and benefits of using, as well as not using, psychotropics. Despite increasing research efforts, expanding clinical experience, and a continued rise in prescriptions for psychoactive medications to pediatric patients, a large gap remains between empirical support and clinical practice. Children represent a significant proportion of those affected with depression, schizophrenia, and bipolar disorder—medical conditions with a prominent global health burden—though their representation among clinical drug trials worldwide is less than 15%. General guidelines for the use of psychoactive medications in children and adolescents are provided in Table 39-1 ; they are consistent with the American Academy of Child and Adolescent Psychiatry's (AACAP) policy statement on prescribing psychotropic medications for children and adolescents.

Issues in Clinical Management

The safe and effective use of psychotropics in pediatric patients rests on many of the same principles reviewed in Chapter 38 . However, there are special factors to consider when prescribing or recommending psychiatric medications for youth.

The first of these issues is the off-label use of medications. The Food and Drug Administration (FDA) approves the use of medications in specified clinical situations. However, the FDA allows practitioners to use medications in clinical situations not included in the official labeling—that is, practitioners may use a medication for clinical situations other than the approved use or use it in age groups in which it has not been formally studied. Medical advances are often made with use of drugs in conditions that are not yet approved by the FDA.

The second issue deals with obtaining consent to use medications. Except in emergency situations, consent must be obtained from the custodial parent or the legal guardian before any compounds can be used in pediatric patients. This consent process involves a discussion of the diagnosis being treated, the prognosis with or without treatment, the potential risks and benefits of the proposed intervention, and a discussion of treatment alternatives. The practitioner also needs to assess the reliability of the parents before initiation of outpatient treatment because it will be their responsibility to administer the drugs on an outpatient basis. If the parents cannot reliably administer the medication, this type of intervention may be precluded.

A third issue involves developmental factors. Both pharmacodynamic and pharmacokinetic factors may influence the safety, tolerability, and efficacy of medications in the pediatric population. Pharmacodynamic factors, such as the ongoing development of neural networks, may affect the response to medications. Similarly, pharmacokinetic factors may influence the absorption, distribution, metabolism, and excretion of medications. Pediatric patients may require higher doses of medication to achieve the same benefit as adults, perhaps as a result of more extensive or rapid metabolism by the liver or increased renal excretion (owing to a higher glomerular filtration rate). Furthermore, the pharmacokinetics in children and adolescents may be different for short- and long-term exposures.

Medical Precautions and Contraindications

In the presence of active pediatric illness, special precautions apply when using psychotropics. For example, in the presence of pre-existing cardiac disease that might impair cardiac conduction, tricyclic antidepressants (TCAs) either alone or in combination with antipsychotics should be used cautiously; a cardiac evaluation should be considered before initiating treatment.

Because non-selective β-blockers may cause severe bronchoconstriction and bradycardia, they are contraindicated in patients with asthma, congestive heart failure, sinus bradycardia, first-degree atrioventricular block, and Wolff–Parkinson–White syndrome. Similarly, β-Blockers should not be used in conjunction with α-adrenergic medications because of concerns over heart block. β-blockers can mask the symptoms of hypoglycemic crisis and thyrotoxicosis and therefore should be used with caution in patients with diabetes and hyperthyroidism.

Atypical antidepressants (e.g., bupropion), antipsychotics, and TCAs may lower the seizure threshold. The Physicians' Desk Reference (PDR) notes that stimulants are associated with seizures (as illustrated in the case study), though clinical experience and recent investigations show this is a rare occurrence at manufacturer-recommended dosage ranges. Patients with ADHD and an epileptiform EEG have an increased risk of seizures. However, published guidelines for the evaluation of attention deficit/hyperactivity disorder (ADHD) do not recommend a baseline electroencephalogram (EEG) as part of the work-up, and recent data indicate that patients with ADHD and a normal EEG are at minimal risk for seizures.

Antidepressants, antipsychotics, and anti-anxiety agents can produce central nervous system (CNS) depression; therefore, these agents should be used with caution in patients with a chronic respiratory disease.

Known drug interactions should also be considered. Psychostimulants generally do not generate significant interactions with other agents, with the exception of monoamine oxidase inhibitors (MAOIs); however, many antidepressants, antipsychotics, and anticonvulsants can interact with a wide array of drugs (see Chapter 38 ). Psychotropics should be used with caution in pediatric patients with renal or hepatic dysfunction. In these patients psychotropics with specific metabolic pathways (i.e., renal or hepatic) should be selected or the dose decreased and serum levels closely monitored.

Clinicians are encouraged to access readily available databases to receive up-to-date information about their metabolism and interactions with other medications.

Emergency Interventions: Treatment of Acute Agitation or Aggression

Typically, the request for the emergency use of psychotropics deals with the initial management of acutely assaultive or self-injurious behaviors. Use of emergency psychotropics should be conducted in concert with behavioral interventions and aimed at addressing the crisis situation, its causes, and its psychosocial impact. If reduced stimulation and general calming measures are ineffective, pharmacotherapy should be considered. Low doses of a short-acting benzodiazepine (e.g., lorazepam 0.5 to 1 mg) or a sedating antihistamine (e.g., diphenhydramine 25 to 50 mg) can be used to reduce acute anxiety, agitation, and insomnia with few side effects. These agents can be administered orally, intravenously (IV), or intramuscularly (IM). Behavioral disinhibition can occur among children and should be monitored. In severe or agitated psychotic states, low to medium doses of a sedating antipsychotic (e.g., chlorpromazine 25 to 150 mg, olanzapine 2.5 to 10 mg, or quetiapine 25 to 300 mg) may be very effective in reducing concomitant anxiety, agitation, or psychosis. For children with active hallucinations or severe disturbances of reality, a higher-potency antipsychotic (e.g., risperidone at 0.25 to 3 mg orally or haloperidol 2.5 to 10 mg orally, IV, or IM) may be necessary. Often a combination of a benzodiazepine and an antipsychotic may be necessary for severe agitation. Extra caution is advised when co-administering IM lorazepam and olanzapine due to elevated risk of cardiorespiratory depression. Medications used for crisis management should not be continued indefinitely, unless they are indicated for the treatment of a co-existing psychiatric disorder.

Delirium

Delirium is a transient derangement of cerebral function with global impairment of cognition and attention. It is frequently accompanied by disturbances of the sleep–wake cycle and changes in psychomotor activity. Delirium may be an early warning of a deteriorating medical condition, a toxic insult, or a brain injury, and it may be accompanied by self-injurious behaviors, such as pulling out IV lines. In adolescents, clinicians should consider substance intoxication and drug interactions (between prescribed medications and illicit substances, such as marijuana) in the differential.

Treatment is usually directed at both the cause and the symptoms. Correction of metabolic abnormalities, removal of agents that may be exacerbating the symptoms, or treatment of the underlying injury or infection is generally followed by reversal in the delirium. After attempting to re-orient and decrease the sensory input, the practitioner may need to implement pharmacologic intervention. Generally, antipsychotics are useful if hallucinations or delusions are present, whereas anxiolytics (i.e., benzodiazepines) help reduce anxiety and apprehension. As mentioned previously, antihistamines (e.g., diphenhydramine 25 to 50 mg orally or IM every 6 to 8 hours) or benzodiazepines (e.g., lorazepam 0.5 to 2 mg orally, IM, sublingually [SL], or IV every 4 to 6 hours) are among the most benign choices for agitation and anxiety. In older children or adolescents who do not respond to these treatments or in those with psychosis, severe dyscontrol, or agitation, risperidone or haloperidol can be used, with the dose repeated every 6 hours if needed. Psychotropic medications should be withdrawn with resolution of the delirium.

Childhood Anxiety Disorders

Children tend to be anxious when receiving care in any medical setting. When the level of anxiety impairs the child (or practitioner) and is unremitting, a child should be assessed for an anxiety disorder. Anxiety problems may also manifest in children as multiple somatic complaints, such as headaches and stomachaches. Childhood anxiety disorders are relatively common and tend to persist into adult life. The three most common childhood anxiety disorders seen in medical settings are separation anxiety disorder, generalized anxiety disorder (GAD) of childhood, and acute stress disorder. Other anxiety disorders, such as post-traumatic stress disorder (PTSD), obsessive–compulsive disorder (OCD), and tic disorders may be present in hospitalized children.

In separation anxiety disorder, the predominant disturbance is a developmentally inappropriate excessive anxiety on separation from familial surroundings. It is called separation anxiety because it is assumed that the main disturbance is the child's inability to separate from the parent or major attachment figures. When separation occurs or is anticipated, the child may experience severe anxiety to the point of panic. Although it may develop during the pre-school age, it more commonly appears in older children.

Similar to GAD in the adult patient, the essential feature of childhood GAD is excessive worry and fears that are not focused on a specific situation or a result of psychosocial stressors. Affected children may manifest an exaggerated or unrealistic response to the comments or criticisms of others.

Four medications have been approved for OCD treatment in children and adolescents; to date, only duloxetine (Cymbalta) is FDA-approved for non-OCD anxiety in pediatric patients. Duloxetine is approved for the treatment of GAD in patients aged 7 to 17 years, but is not routinely used clinically. A ten-week randomized controlled trial demonstrated duloxetine was superior to placebo as evidenced by changes from baseline Pediatric Anxiety Rating Scale scores. However, based on the efficacy and safety demonstrated in multiple randomized controlled trials (RCTs), the selective serotonin re-uptake inhibitors (SSRIs) fluoxetine, sertraline, and fluvoxamine appear to be the first-line medications for the treatment of separation anxiety disorder and GAD in children. The literature on benzodiazepines, tricyclic antidepressants (TCAs), buspirone, pregabalin, gabapentin, and β-blockers is mixed (at best). Acute stress disorder develops within 1 month of an acute traumatic event and lasts for a maximum of 1 month. It is manifest by anxiety, dissociative symptoms, persistent re-experiencing of the trauma, and avoidance of stimuli that evoke recollections of the trauma. The nature, severity, duration, and proximity to the trauma are factors that influence the development of acute stress disorder. In a number of patients, acute stress disorder may continue beyond 1 month and develop into PTSD. Effective management is focused on ensuring safety and reducing pain, anxiety, and fear. Recent investigations of children with burns suggest that aggressive management of pain with morphine may reduce and secondarily prevent PTSD. Pediatric patients with PTSD are likely to have co-morbidity with other psychiatric disorders, a history of neglect or abuse, or both.

In adults with PTSD, SSRIs have been shown to be useful in reducing symptoms of anxiety, depressed mood, rage, and obsessional thinking. In fact, both sertraline and paroxetine are approved for treatment of PTSD in adults and are often used in pediatric patients. β-Blockers, in particular propranolol, have been studied as a means of reducing arousal symptoms of PTSD. Similarly, α-adrenergic agents, such as prazosin, clonidine, and guanfacine, may similarly reduce nightmares, anxiety, hyperarousal, impulsivity and—in the case of clonidine and guanfacine—improve attention.

In patients with dissociation, medications (such as the benzodiazepines or gabapentin) that enhance gamma-aminobutyric acid (GABA), may reduce the severity of anxiety. In patients with fear or terror, the short-term use of atypical antipsychotics in low doses may be useful. Long-term treatment of acute stress disorder and PTSD uses both pharmacologic and psychotherapeutic modalities.

High-potency (e.g., clonazepam 0.25 to 1 mg three times per day) or medium-potency (e.g., lorazepam 0.25 to 1 mg three times per day) benzodiazepines can be effective for short-term relief of anxiety. A shorter-acting compound (e.g., lorazepam) can be very effective in managing more acute situations (e.g., anxious or agitated reactions to psychosocial crises). Doses of 0.5 to 1 mg of lorazepam given orally or SL are often effective. Lorazepam may be administered IM in an emergency. Use of short-acting benzodiazepines requires multiple daily doses. Long-term use should be avoided whenever possible.

In general, the clinical toxicity of benzodiazepines is low, but higher rates of disinhibition are observed in the pediatric population than in adults. Children who become disinhibited on high-potency benzodiazepines may respond more favorably to the mid- or low-potency agents (e.g., diazepam). The most commonly encountered short-term adverse effects of benzodiazepines are sedation, disinhibition, and depression.

When long-term treatment in older adolescents is warranted, long-acting benzodiazepines (such as clonazepam) may be preferable. For clonazepam an initial dose of 0.25 to 0.5 mg can be given at bedtime. The dose may be increased by 0.5 mg every 5 to 7 days depending on the clinical response and the side effects. Typically, doses between 0.25 and 2 mg per day are effective. Potential benefits of the longer-acting compounds are once-daily dosage and a decreased risk of withdrawal symptoms on discontinuation of treatment.

Buspirone is a non-benzodiazepine anxiolytic without anticonvulsant, sedative, or muscle-relaxant properties. Clinical experience with this drug suggests limited anti-anxiety efficacy in the acute setting, but greater utility in the chronic management of pediatric anxiety. The effective daily dose ranges from 0.3 to 0.6 mg/kg.

One controlled study with high-dose imipramine demonstrated efficacy under controlled conditions. However, TCAs have had only limited usefulness for management of pediatric anxiety disorders given their narrow therapeutic window.

Akathisia

Akathisia is a movement disorder experienced as inability to sit still (the term is derived from the Greek and literally means “not to sit”). In children and adolescents, it is most often seen as a side effect of antipsychotics or antidepressants. Akathisia may be confused with ADHD or agitation. Historically, patients are free from akathisia before starting an antidepressant or antipsychotic or reducing an anticholinergic medication. As with adults, treatment of akathisia in the pediatric population involves reducing the dose of the offending medication to the lowest effective dose and then adding either β-blockers or benzodiazepines (0.5 to 1 mg three times per day of lorazepam). Although several β-blockers are likely to be effective, propranolol has good CNS penetration and is typically used. Propranolol should be initiated at 10 mg two times per day and the dose increased every several days to effect.

Studies in adults have demonstrated the efficacy of the potent selective β-1 blocking agent betaxolol in reducing akathisia. Betaxolol has a long half-life (allowing once-daily dosing) and has minimal medication interactions. Betaxolol is generally started at 5 mg and can be titrated as tolerated to doses between 10 mg and 20 mg/day.

Attention Deficit Hyperactivity Disorder

A common psychiatric condition, ADHD, is found in 3% to 10% of school-age children. ADHD is characterized by the classic triad of impaired attention, increased impulsivity, and excessive motor activity, although many children manifest only inattentiveness. With developmental variations, ADHD affects children of all ages (as early as age 3), and it persists into adulthood about half of the time. Within the medical setting, ADHD needs to be differentiated from environmental stimulation, iatrogenic causes (e.g., use of β-agonists), or other psychiatric disorders (e.g., anxiety, depression, mania, or intoxication). Pharmacotherapy remains the cornerstone of ADHD treatment ( Table 39-2 ).