Psychopharmacology

Ajit N. Jetmalani MD

Introduction

Research over the past 30 years has elucidated many neurobiological processes associated with psychiatric disorders. These findings have coincided with a growing understanding of early-onset psychopathology leading to new conceptualizations of mental illness, its etiology, and treatment. Many psychiatric disorders are now known to represent developmental anom-alies that begin in childhood and persist over the lifespan. Psychotropic medications have in-creasingly been used to treat children and adolescents with these neuropsychiatric disorders, however, Roberts and colleagues note that, “50% to 75% of drugs used in pediatric medicine have not been studied adequately to provide appropriate labeling information.” In 1997, the United States (U.S.) Congress passed the “Food and Drug Administration Modernization Act” which encouraged pharmaceutical companies, with the promise of 6-month exclusivity, to develop pediatric studies to evaluate medication efficacy. Over the past decade, the National Institute of Mental Health (NIMH), National Institute of Child Health and Human Development (NICHD), and the pharmaceutical industry have launched a range of pediatric studies focused on the short-term efficacy of various medications, including psy-chotropics. Pharmacotherapy is now an integral part of biopsychosocial treatment planning for youth with neuropsychiatric disorders. This chapter presents concepts and practical infor-mation to guide optimal prescribing for youth in the context of the rapidly expanding, and at times confusing, research.

General Principles of Psychopharmacology

The following sections focus on the essential elements underlying the successful utilization of psychotropic medications with youth. They are based in part on the Practice Parameter on the Use of Psychotropic Medication in Children and Adolescents recently published by the American Academy of Child and Adolescent Psychiatry (AACAP). Their 12 principles are summarized in Table 25-1.

TABLE 25-1 Use of Psychotropic Medications in Children and Adolescents

Principles of Prescribing:

Assessment

Before initiating pharmacotherapy, a psychiatric evaluation is completed.
Before initiating pharmacotherapy, a medical history is obtained, and a medical evaluation is considered when appropriate.
The prescriber is advised to communicate with other professionals involved with the child to obtain collateral history and set the stage for monitoring outcome and side effects during the medication trial.

Treatment and Monitoring Plan

The prescriber develops a psychosocial and psychopharmacological treatment plan based on the best-available evidence.
The prescriber develops a plan to monitor the patient, short and long term.
Prescribers should be cautious when implementing a treatment plan that cannot be appropriately monitored.

Assent and Consent for Treatment

The prescriber provides feedback about the diagnosis and educates the patient and family regarding the child’s disorder and the treatment and monitoring plan.
Complete and document the assent of the child and consent of the parents before initiating medication treatment and at important points during treatment.
The assent and consent discussion focuses on the risks and benefits of the proposed and alternative treatments.

Implementation of Treatment

Implement medication trials using an adequate dose and for an adequate duration of treatment.
The prescriber reassesses the patient if the child does not respond to the initial medication trial as expected.
The prescriber needs a clear rationale for using medication combinations.
Discontinuing medication requires a specific plan.

Comprehensive Biopsychosocial Evaluation

A thorough psychiatric assessment should precede the initiation of pharmacotherapy. The biopsy-chosocial model provides an optimal framework for integrating aspects of the evaluation into a formulation from which is derived a treatment plan. Biological factors begin with the child’s genetic potential and progress through intrauterine life to environmental insults and developmental setbacks. Psychological components include a core capacity for interpersonal relationships and the ability to understand others and express oneself verbally and nonverbally. Psychological factors also relate to executive functioning skills that overlap with biological endowment such as the abil-ity to regulate sensory inputs and organize responses to internal and external stressors. Social com-ponents include contextual aspects of youths’ lives at home, school, and the community, including any traumatic experience. A formulation is not a simple reiteration of these factors but integrates the most salient factors into a statement of how the youth came to his/her current status in life. It is intended to help the clinician to individualize decision making. For example, if diagnosis drives treatment planning for an autistic child living in a chaotic home, treatment might consist only of a medication trial. By contrast, if a biopsychosocial formulation drives treatment planning, recommendations might include support services, in-home parent training, coordination with the school, as well as a medication trial. This approach protects children against more restrictive, and traumatizing, interventions.

Establishing a Strong Treatment Alliance

Implementing a medication plan with a strong treatment alliance is the major goal for clinicians. A treatment alliance can be defined as the working relationship among a child, his parents or guardians, and the clinician. It has several pivotal aspects. The engagement of the child and family as a partnership is key to achieving compliance, satisfaction, and outcomes. Presenting a confident and empathic demeanor while addressing the chief complaint, will improve adherence to any medical prescription. A child and his/her parents will view the areas of concern from their individual perspectives, which may vary from the clinician’s perspective. Keeping everyone engaged in the treatment process requires the clinician to balance these perspectives and share responsibility for the child’s treatment with the family. When developing a treatment plan, time must be set aside for questions both to minimize misunderstandings and to create a shared treatment vision.

Completing the informed-consent procedure is another alliance building opportunity. A family that hears a well-reasoned plan from a clinician will have greater confidence in the plan and will better participate in the decision-making process. This process should focus on creating a set of outcome expectations and their means of measurement so as to engage the family in data gathering during a medication trial. Setting shared expectations up-front will yield better communication throughout treatment and satisfaction with outcome.

Understanding Pharmacokinetics and Pharmacodynamics

Pharmacokinetics are the effects of the body on medications. Pharmacodynamics are the effects of medication on the body. Several variables may affect both pharmacokinetics and pharmacodynamics of medications in youth compared to adults.

Pharmacokinetics include the effects on drug metabolism of the rates and the extent of absorption, the range of distribution in bodily compartments (tissues and fluids), the efficiency and extent of degradation into smaller bioactive or inactive compounds, and the eventual rate and extent of excretion. In pediatric psychopharmacology, distribution, metabolism, and excretion diverge from adult kinetics. The main factors involve differences in fluid to tissue ratios, relatively higher ratios of hepatic and renal capacity to size, available circulating proteins that bind drugs, and development of cytochrome P450 enzymes. Overall, compared to adults, children may metabolize medications more rapidly based on weight. Unfortunately, weight-based prescribing guidelines are of limited predictive utility for most psychotropic medications. Understanding the cytochrome system is particularly important in understanding the potential interactive effects of drugs that are inducers (increase enzyme activity), substrates (subject to breakdown), and inhibitors (reduce effectiveness of enzymes) in order to avoid interactions that may lead to uncomfortable, or even lethal, complications. Finally, due to genetic polymorphism in the P450 system, a small portion of the population is defined as “slow metabolizers.” They risk accumulating high levels of medications at usual therapeutic doses. An Indiana University School of Medicine website maintains a list of cytochrome enzyme categories of commonly used drugs that can assist physicians in identifying drug-drug interactions.

Pharmacodynamics refers to the physiological effects of drugs on the body. Drug effects include actions on enzymes, agonist and antagonist actions on receptors, storage, release and reuptake of neurotransmitters, secondary effects on receptor numbers and sensitivity, and membrane permeability. Drugs may also induce immune system reactions by direct cell toxicity, effects on replication, or cellular metabolism. These actions are further influenced by the protein binding of drugs which affect their bioavailability.

Medications have a dose-response curve which describes the range of their effects at various blood concentrations. Some medications also have a therapeutic window, that is, a narrow range of serum levels within which a drug exerts therapeutic effects without toxicity. For
example, lithium has a narrow therapeutic window of 0.7 to 1.2 meq/L. Serum levels below this range are generally ineffective and levels above this range cause serious complications.

Evidence-Based Treatment (EBT)

Randomized clinical trials (RCT) now support the efficacy of psychotropic medications for a variety of pediatric psychiatric disorders. Classification systems have been developed to rate the quality of research cited as EBTs. In 1995, the International Psychopharmacology Algorithm Project Report categorized levels of evidence as follows:

Class A includes medications with good empirical support, based on consistently positive results in RCTs.

Class B consists of drugs with fair empirical support showing positive, but inconsistent, results in RCTs or positive results from small sample trials.

Class C includes drugs with minimal empirical support, based primarily on accumulated clinical experience from case reports and open-label studies.

Many medications are rated in the B and C categories, or even unrated, particularly for children under the age of 11 years. Furthermore, medications that are shown to be efficacious in short-term controlled studies may not prove effective in a longer-term or “real life” settings.

Consensus Guidelines for Care

Ideally, all pharmacotherapy would be evidence-based derived from large RCTs. Until such Level A studies are available, physicians should rely on best practices developed by the AACAP, and/or various state or academic centers. One such set of guidelines based on a combination of empirical data and consensus guidelines is available from the Texas Children’s Medication Algorithm Project (CMAP) for several disorders such as major depressive disorder, attentiondeficit hyperactivity disorder (ADHD), and ADHD comorbid with anxiety, depression, tics, or aggression. There is some evidence that such an approach produces more uniform and effective outcomes. For example, the Multimodal Treatment of Children with ADHD study found that algorithm-driven pharmacologic care produced better outcomes than did community care. However, such approaches often do not consider comorbid disorders, despite their frequency in child and adolescent psychiatric disorders.

Current Controversies

Prescribing medications for neuropsychiatric disorders of children and adolescents has raised many controversies related to their safety, the use of such medications with vulnerable youth, and the lack of evidence regarding their long-term risks and benefits.

Developmental Effects of Psychotropic Medication

In 2007, Leckman and King discussed the rapid increase in prescriptions of selective serotonin reuptake inhibitors (SSRIs) for children and the lack of studies examining their impact on central nervous system (CNS) development and functioning. The limited studies with laboratory animals exposed to SSRIs suggested negative impact on anatomic development and functioning. Such findings mandate physicians to weigh such potential undiscovered risks against current need in deciding whether to prescribe these medications during developmentally sensitive periods.

In contrast to these potential risks, there is some evidence that treatment of early-onset disorders may be protective. For example, schizophrenia is a neurodegenerative disorder with gray and white matter abnormalities. Research with neural cell cultures and the brains of humans who have suffered a first episode of psychosis suggests that the second-generation antipsychotics (SGAs) may have a neuroprotective role in schizophrenia compared to no treatment, and even compared to treatment with first-generation antipsychotics (FGAs). The
SGAs appear to enhance neurotrophic factors and antioxidation effects due to decreased apoptosis of neurons. These encouraging findings are tempered by conflicting studies with nonhuman primates. Overall, a neuroprotective role for the SGAs is intriguing, but unproven. A discussion of such potential benefits and risks for CNS development should be integrated into the informed-consent process.

Early Childhood Prescribing

The past decade has seen a dramatic increase in the prescription of psychotropic medications for preschool children. The Preschool ADHD Treatment Study (PATS) found that low doses of methylphenidate could help very young children diagnosed with ADHD without major side effects. In a separate study, risperidone was found to help young autistic children to regulate disruptive behaviors. Multiple psychotropic medications are used off-label for various problems experienced by preschoolers. In response, the Preschool Psychopharmacology Working Group of the AACAP developed guidelines for pharmacotherapy with young children, including the formulation of algorithms for several diagnoses and overall recommendations. In brief, these recommendations emphasize the preferential use of psychotherapy, reserving medication for major functional impairment, conducting an appropriate consent procedure with the parents regarding the lack of an evidence base for such prescribing, and tracking outcomes.

Prescribing for Children in Foster Care

Children and adolescents placed in foster homes are particularly vulnerable. Zito and colleagues reviewing data in Texas noted that 37.9% of youth in foster care were prescribed psychotropic medications, and of these 41.3% were prescribed three or more medications. These rates were considerably higher than the general Medicaid population of youth living with their families. The meaning of these findings is subject to interpretation; but concerns about polypharmacy has led several states to legislate independent monitoring of psychotropic prescribing practices for youth in foster care. The impact of such monitoring is not yet known. Meanwhile, physicians must ensure that evidence-based and consensus-guideline care remains the criterion for psychopharmacotherapy with all youth, regardless of residence.

Polypharmacy

Polypharmacy has become commonplace. There are conditions in which more than one psychotropic medication is indicated, for example, bipolar disorder. But, in many, perhaps most, cases of polypharmacy, the risks are not counterbalanced by evidence of efficacy. Many commercial insurers and states’ departments of health now monitor such practices. In 2007, the Texas Department of State Health Services developed the following screens which may suggest problem prescribing practices for youth: absence of a diagnostic assessment; concurrent use of more than three psychotropic medications; prescribing of two or more medications in the same class (use of a long-acting and immediate-release stimulant of the same chemical entity does not apply); polypharmacy is utilized prior to monotherapy; the psychotropic doses exceed recommended guidelines. The Practice Parameter on the Use of Psychotropic Medications in Children and Adolescents developed by the AACAP further notes the need to develop a treatment and monitoring plan with the family that includes an approach for patients who do not respond typically, alternatives to polypharmacy, and discontinuation of ineffective medications.

Cardiovascular Risks of Stimulants

Since the late 1980s, the potential cardiotoxicity of the stimulants has been noted. In February 2005, Health Canada suspended the marketing and distribution of Adderall-XR after reports of sudden unexplained death in children with and without cardiac defects who were prescribed Adderall-XR. This ban was rescinded in August 2005 and a warning was issued regarding the
risk of sudden unexplained death in patients with known cardiac anomalies who were taking Adderall-XR. In 2008, Vetter and colleagues published a scientific statement from the American Heart Association (AHA) summarizing the evaluation that should be conducted when prescribing stimulants. The recommendation that all children should receive a screening electrocardiogram (ECG) caused a controversy because of the expense and the lack of data demonstrating risk reduction. Furthermore, the American Academy of Pediatrics (AAP) and the AACAP have noted that there is no established relationship between stimulants and cardiac death. The AAP recommends that clinicians carefully assess all children for cardiac abnormalities, including those for whom ADHD treatment is being considered, and does not recommend routine screening ECGs.

This controversy will likely continue. In 2009, Gould and colleagues found that of 564 cases of sudden cardiac death among youths 7 to 17 years old, 10 were prescribed methylphenidate compared to only 2 of the matched 564 youth who died accidentally. These results may be interpreted as supporting the AHA’s concerns. Thus at this point of scientific knowledge, physicians must make their own decision regarding the use of screening ECGs based on thorough consideration of elements of history and physical exam.

Antidepressants and Suicide Risk

In April 2004, the Food and Drug Administration (FDA) published a review of SSRI studies with children and adolescents that in the aggregate indicated that the SSRIs were associated with twice the rate of suicidal thinking and behavior compared to placebo, 4% versus 2% respectively. There were no completed suicides. In response, the FDA issued a “black-box” warning for all antidepressants. This risk has now been confirmed in several other studies. Subsequent to the blackbox warning, Gibbons and colleagues found that the rate of SSRI prescriptions fell 22% in the Netherlands and the United States. At the same time, completed suicides rose 49% in the Netherlands and 14% in the United States. This temporal relationship suggests a cause and effect relationship between untreated depression and suicide. During this period, a large multicenter study, The Treatment for Adolescents with Depression Study (TADS), found efficacy for fluoxetine combined with Cognitive Behavioral Therapy (CBT) in speeding the recovery from moderate to severe depression. An additional finding was that the fluoxetine group had higher rates of suicidal ideation, but not completed suicide, which was completely ameliorated for the patients who also received CBT. Thus, ongoing caution is warranted in using SSRIs with youth, and most of these youth should concurrently be engaged in psychotherapy.

Patterns of Publishing

Finally, physicians depend on the findings of empirical studies to guide their care. Unfortunately, withholding negative outcomes was common until recently. Eric Turner and colleagues have reviewed the impact of selective publication of positive studies on effect size for selected treatments. They note that of 74 registered studies, 31% were never published. Further analysis confirmed a clear pattern of withholding negative findings which greatly distorted the effect size of various drug trials upward by 32%. In 2005, the FDA mandated that all studies that are submitted to the FDA in support of medication efficacy should be prospectively registered to preclude the obfuscation of negative outcomes. Hopefully, increased scrutiny by the FDA and individual investigators will remedy this scientific duplicity.

Psychotropic Medications

This section presents essential information for prescribing psychotropic medications with youth, including both major classes of medications and those with idiosyncratic uses. Most of these medications are not FDA-approved for pediatric populations. Many are supported by
systematic studies, but others are used “off-label” without an evidence base. Finally, while neurobiological mechanisms are based on current research and theory, the actual therapeutic mechanisms of psychiatric medications, in youth and adults, remain unknown.

Stimulants

Stimulants are the most studied psychotropic medication class among the youth. The two major types of stimulants are methylphenidate and amphetamines. In controlled studies, all stimulants are equally efficacious. However, an individual youth may respond differentially to a particular type of stimulant, for example, amphetamines rather than methylphenidates, or even to a specific medication within a type, for example, Metadate rather than Ritalin. Table 25-2 summarizes relevant prescribing information for the available stimulant preparations.

Indications

Stimulants are FDA-approved for the treatment of ADHD. Amphetamines are approved for children over 3 years old and methylphenidate for children over 6 years old.

Mechanism of Action

Stimulants are sympathomimetic drugs structurally similar to catecholamines. They boost norepinephrine and dopamine signals in a number of different ways. According to Stahl, methylphenidate blocks the norepinephrine and dopamine reuptake pumps making more of these neurotransmitters available in the synaptic cleft. In contrast to methylphenidate, amphetamines are also a competitive inhibitor and pseudosubstrate for the presynaptic norepinephrine and dopamine transporters. Therefore, amphetamines not only block neurotransmitter reuptake but are also transported into the neuron itself. Ultimately, both mechanisms optimize dopamine and alpha₂A activity in the prefrontal cortex with resulting increase in attention and decrease in impulsivity.

The parts of the CNS that are hypothesized to be affected in ADHD are also the areas where stimulant medications exert their effects. The most important areas appear to be the frontal and prefrontal cortex, the seat of attention, focus, memory, and other executive functions such as information processing, planning, organizing, and self-regulation. As Stahl notes, dopamine and norepinephrine modify the signal to noise ratio of data processed by the frontal and prefrontal cortex thereby improving inhibitory capacities of these cortical structures. Additionally, the prefrontal cortex sends long nerve tracts to other parts of the CNS, including the basal ganglia and the cerebellum, to further coordinate planning and motor activity. Stimulants are likely active in improving transmission in these tracts.

Major Complications and Their Management

The well-known potential side effects of stimulants are summarized in Table 25-2. Most of theses can be managed by adjusting the dose and/or timing of administration. The more concerning potential major complications are discussed below.

Cardiotoxicity and the aforementioned risk of sudden death are the major concern. The AHA, AAP, and AACAP all recommend gathering a more detailed medical history for the child and family along with a cardiac examination, as summarized in Table 25-3. Blood pressure, pulse rate and rhythm, and cardiac tolerance should be assessed at each follow-up visit. The use of a pretreatment ECG remains controversial. Potential cardiac risks, including the risk of sudden death, should be discussed with guardians as part of the informed-consent process.

Appetite suppression and growth inhibition are due to the anorectic effects of stimulants. In 2007, Caron reported that after 3 years of methylphenidate treatment, children 7 to 9 years of age showed decreases in growth rates without evidence of growth rebound. These children may be over an inch shorter than their untreated peers at maturity. Remedies include the use of nutritious snacks in the evening, dietary supplements at lunch and after school, medication “holidays” on weekends and summers if possible. Additionally, the clinician may consider a medication that does not last into the dinner hour; the downside is that children may then struggle with completing their homework.

TABLE 25-2 Stimulant Medications

Drug	Dosing	Common Side Effects	Duration of Action
Methylphenidate
Methylphenidate (Ritalin, Methylin, Methylin Chewables, Methylin Liquid, Metadate ER, generic methylphenidate)	Initiate 5 mg BID to TID Increase by 5-10 mg increments up to 60 mg max. Estimated dose range 0.3-0.6 mg/kg/dose.	Insomnia, headache, stomachache, decreased appetite, weight loss, repetitive behaviors, growth retardation, tics, irritability, dysphoria, and rebound agitation. Also, psychotic symptoms with visual hallucinations possible.	About 3-4 hours.
Dexmethylphenidate (Focalin) (Isolated dextroisomer of methylphenidate)	Half the dose noted for methylphenidate.	Same as above. May be less prone to causing sleep or appetite disturbance.	About 3-4 hours.
Dexmethylphenidate (Focalin XR 50% short acting and 50% long acting)	Double the dose of regular release Focalin. Once daily.	Same as above.	About 8 hours.
Methlylphenidate (Ritalin SR)	Start with 20 mg daily. May combine with short acting for quicker onset (only available as 20 mg dose).	Same as above.	Onset delayed for 60-90 minutes. Duration supposed to be 6-8 hours, but can be quite individual and unreliable.
Methylphenidate (Ritalin LA) 50% immediate release beads and 50% delayed release beads (Metadate CD) 30% immediate release and 70% delayed release beads	Initiate at 10-20 mg daily. Adjust weekly in 10 mg increments to maximum of 60 mg taken once daily.	Same as above.	Onset in 30-60 minutes. Duration about 8 hours.
Methylphenidate (Concerta) 22% immediate release and 78% gradual release	Starting dose is 18 mg once daily up to a max of 72 mg daily.	Same as above but less rebound risk.	Onset in 60-90 minutes. Duration about 10-14 hours.
Dextroamphetamine
Dextroamphetamine (Dextrostat, Dexedrine)	For ages 3-5 years: Initiate at 2.5 mg. Increase by 2.5 mg at weekly intervals. 6 years and older: initiate at 5 mg once or twice daily. 40 mg/day max.	Insomnia, headache, stomachache, decreased appetite, weight loss, growth retardation, tics, repetitive behaviors, irritability, dysphoria, rebound agitation. May also elicit psychotic symptoms and mania at higher rate than methylphenidate.	Onset in 30-60 minutes. Duration about 4-5 hours.
Dextroamphetamine (Dexedrine Spansules)	Single daily dosing up to a maximum of 40 mg/day.	Same as above.	Onset in 30-60 minutes. Duration about 5-10 hours.
Amphetamine Salts
Amphetamines salts (Adderall)	Age 6 years and older, initiate at 5 or 10 mg, up to 30 mg per dose.	Same as above.	Onset in 30-60 minutes. Duration about 4-5 hours.
Amphetamine salts (Adderall-XR) 50% immediate release beads and 50% delayed release beads	Age 6 and older: Starting dose is 5 or 10 mg. May be adjusted in 5-10 mg increments up to 40 mg per day.	Same as above.	Onset in 60-90 minutes (possibly sooner). Duration 10-12 hours.

TABLE 25-3 American Heart Association History Guidelines for Stimulant Use

Child’s History

History of fainting or dizziness (particularly with exercise)
Seizures
Rheumatic fever
Chest pain or shortness of breath with exercise
Unexplained, noticeable change in exercise tolerance
Palpitations, increased heart rate, or extra or skipped heart beats
History of high blood pressure
History of heart murmur other than innocent or functional murmur or history of other heart problems
Intercurrent viral illness with chest pains or palpitations
Current medications (prescribed and over the counter)
Health supplements (nonprescribed)

Family History

Sudden or unexplained death in someone young
SCD or “heart attack” in members <35 years of age
Sudden death during exercise
Cardiac arrhythmias
HCM or other cardiomyopathy, including dilated cardiomyopathy and right ventricular cardiomyopathy (right ventricular dysplasia)
LQTS, short-QT syndrome, or Brugada syndrome
WPW or similar abnormal rhythm conditions
Event requiring resuscitation in young members (<35 years of age), including syncope requiring resuscitation
Marfan’s Syndrome

SCD, sudden cardiac death; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; QT, QT interval; WPW, Wolff-Parkinson-White Syndrome

Tics may be caused by or exacerbated by stimulants. The child and family will need to make a risk-benefit decision with the clinician to decide whether to stop the stimulant, ignore the tics as long as they are not stigmatizing, or to treat the tics with a second medication. This decision will largely be based on how successful the child is with stimulants.

Finally, the stimulants are cleared by the kidneys. This makes them readily compatible with many other psychiatric and somatic medications that are hepatically metabolized.

Prescribing Essentials

All stimulants demonstrate comparable efficacy in controlled studies, although individual children may respond preferentially to a specific medication. Recent advances in drug-delivery technology for the stimulants have made available a wide range of dosing forms and properties allowing the physician to individualize treatment. Medication selection is based on factors such as dosing frequency, compliance, feasibility of medication administration during the school day, duration of action, side-effect profiles, and cost. For most children, the longer-acting preparations are preferable for convenience and compliance, particularly to avoid having to take medication at school.
Longer-acting preparations also lead to less rebound and withdrawal effects and are less likely to cause anxiety and mood fluctuations. On the other hand, if a child is sleeping poorly or eating poorly, a shorter-acting preparation may be preferable. Some children respond better to a rapidonset stimulant at the beginning of the day. In these cases, augmenting a long-acting stimulation preparation with a rapid-onset preparation in the morning will provide optimal benefits. Children who experience irritability when their medication wears off may benefit from a small dose of a short-acting stimulant in the late afternoon. As per the CMAP, if one type of stimulant is not tolerated or effective, it is reasonable to try one more medication of the same type before switching to a different type of stimulant. The concomitant use of methylphenidate and an amphetamine is not consistent with guideline care.

Antidepressants

Antidepressant medications are used to treat numerous psychiatric disorders in children and adolescents, including: depression, obsessive-compulsive disorder (OCD), other anxiety disorders, trauma-related symptoms, bulimia, enuresis, ADHD, and smoking cessation. There are many types of antidepressants which are classified based on their mechanisms of action rather than their chemical structure. The various antidepressants, their chemical effects, and clinical guidelines are summarized in Table 25-4.

Indications

Tricyclic antidepressants (TCAs) include imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, and doxepin. They are highly effective in treating adult depression.

The TCAs with FDA-approval for youth include: doxepin (over 12 years), clomipramine (over 10 years), and imipramine (over 6 years). The TCAs were the first antidepressants to be used to treat depression, obsessive-compulsive and other anxiety disorders in children and adolescents. Other uses with youth have included enuresis, ADHD, sleep disorders, and pain syndromes. Systematic studies with youth have focused on their use for depression, and to a lesser extent anxiety. Double-blinded placebo-controlled trials have found the TCAs to be no more effective than placebo in treating juvenile-onset major depression. Use in anxiety disorders has shown limited effectiveness as well, except for clomipramine which has demonstrated efficacy for the treatment of OCD. Interestingly, they have demonstrated efficacy for ADHD. Eighteen controlled studies involving 953 children demonstrated at least moderate benefit compared to placebo. TCAs are now considered a third-line treatment of ADHD, limited by their adverse effects and narrow therapeutic window, and thus potential toxicity. The TCAs are not used much for depressive or anxiety disorders any more. The exception is clomipramine, although side effects limit its use to refractory OCD.

SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are not more effective than the TCAs in treating depressed adults, but they have many fewer serious and annoying side effects leading to their popularity. The SSRIs that are approved by the FDA for use in pediatric populations include fluoxetine (8 years and older), sertraline (6 years and older), escitalopram (12 years and older), and fluvoxamine (8 years and older). The SSRIs have an established evidence base for use with youth including fluoxetine and escitalopram for major depression, sertraline for anxiety disorders, and fluvoxamine for OCD. While not FDA-approved for use in pediatric populations, citalopram has shown efficacy in randomized controlled trials for the treatment of depression and anxiety in youth.

Atypical antidepressants include bupropion, venlafaxine, and mirtazapine. All have FDA-approval and indications for the treatment of depression in adults. Bupropion is also indicated for the treatment of smoking cessation. However, there are few randomized controlled studies demonstrating efficacy for these atypical antidepressants for any psychiatric disorder in youth. A single study has shown bupropion to be more efficacious than placebo but less efficacious than stimulants in treating youth with ADHD. Clinical lore posits that bupropion may be less likely to induce mania, and many clinicians prefer it for the treatment of bipolar depression. Mirtazapine and venlafaxine are usually reserved for youth who have failed two SSRI trials. Venlafaxine is reputed to have a quicker onset of therapeutic action and be more effective in treatment-resistant depression, but there are no systematic studies regarding its use in early-onset major depression. Thus, it is currently indicated as a third or fourth-line intervention in medication algorithms for depressed youth. Venlafaxine does have demonstrated efficacy in the treatment of youth with anxiety and open-label studies suggest efficacy in the treatment of ADHD. Mirtazapine has also found a role for depressed youth suffering insomnia or weight loss. To date there are no systematic studies supporting the use of mirtazapine in pediatric populations. There are some open-label studies supporting its use in anxiety. Finally, trazodone is FDA-approved for the treatment of depression in adults. It is also commonly used to treat anxiety in adults and insomnia in both adults and youth. The sedative effects have immediate onset. In children, the safety and efficacy of trazodone have not been established. Nonetheless, it is widely used.

TABLE 25-4 Antidepressant Medications

Drug	Chemical Effect	Average Daily Dose	Side Effects	Indications
Tricyclic Antidepressants (TCAs)
Amitriptyline (tertiary amine) (Elavil)	5HT, ±NE	Children: 1-3 mg/kg/day Adolescents: 25-100 mg/day	Cardiac arrhythmia, potentially lethal in overdose, anticholinergic side effects, orthostasis, sedation, GI intolerance, weight gain, sexual dysfunction. May increase risk of suicidal behavior.	Not FDA-approved for use in children. Historic uses: Insomnia, night terrors, enuresis, ADHD, chronic pain.
Imipramine (tertiary amine) (Tofranil)	Primary effects on NE	For enuresis, initial dose usually 25 mg/day ages 6 years and older. May increase by 25 mg/day/week not to exceed 75 mg/day.	As above.	FDA-approved for treatment of enuresis for youth 6 yrs and older.
Clomipramine (tertiary amine) (Anafranil)	5HT (more potent than other TCAs) +NE	Recommended starting dose is 25 mg/day. May increase 25 mg/day/wk up to 100-200 mg/day or 1.4 mg/pound whichever is smaller. Recommended max dose 200 mg/day.	As above.	FDA-approved for pediatric 0CD in youth 10 years and older.
Doxepin (tertiary amine) (Sinequan)	5HT, NE, H1, H2, M	For sleep 10-25 mg 1 hour before bedtime. For depression start 10-25 mg/day. Increase slowly up to 50-100 mg/day. Usually more than 100 mg/day not needed in teens.	As above. Considered to have the least cardiotoxic potential of the TCAs.	FDA-approved for depression in children over age 12. May also be helpful for pruritis, insomnia, and anxiety.
Nortriptyline (secondary amine) (Pamelor)	NE, ±5HT	Suggested doses for Children: 1-3 mg/kg/day in 3-4 divided doses. Adolescents: 30-150 mg/day in 3-4 divided doses.	Same as for amitriptyline, but anticholinergic effects less pronounced.	Not FDA-approved for use in children.
Desipramine (secondary amine) (Norpramin)	Primary effects on NE	For children 6-12 years old, the suggested dose ranges from 10 to 30 mg per day in divided doses. For adolescents, daily dosages range from 25 to 50 mg but may be increased up to 100 mg, if needed.	Same as for imipramine, but anticholinergic effects less pronounced. Occasional insomnia.	As above.
Desipramine (secondary amine) (Norpramin)	Primary effects on NE		While sudden death from arrhythmias is rare, concerns persist.	As above.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram (Celexa)	5HT reuptake inhibitors	5-40	May increase risk of suicidal behavior. Activation and agitation. Serotonin syndrome. Weight gain. Sexual side effects.	Not FDA-approved in children, although widely used in pediatric populations.
Escitalopram (Lexapro)		2.5-20		FDA-approved for depression in children 12 years and older.
Fluoxetine (Prozac)		5-60 mg/day.		FDA-approved for depression and OCD in youth 8 years and older.
Sertraline (Zoloft)		25-200 mg/day Divided dosing.		FDA-approved for OCD in youth 6 years and older. Off-label used for depression and PTSD.
Fluvoxamine (Luvox)		25-200 mg/day divided dosing.		FDA-approved for OCD in youth 8 years and older.
Paroxetine (Paxil)		No pediatric dosing recommendations.		Not FDA-approved for children and not recommended for off-label use with pediatric populations.
Atypical Antidepressants
Bupropion (Wellbutrin)	DA and NE reuptake inhibitor	Starting dose is 37.5 mg increasing gradually (wait at least 3 days) to a maximum of 2-3 doses, no more than 150 mg/dose.	Irritability, decreased appetite, and insomnia. Lowers seizure threshold especially for individuals with eating disorders and seizure disorders, and particularly with short acting dose preparation over 200 mg (adult data) May increase risk of suicidal behavior.	Not FDA-approved in children, though used in pediatric populations for ADHD and depression.
Atypical Antidepressants
Bupropion (Wellbutrin SR)	DA and NE reuptake inhibitor	Usually dosed twice daily. Starting dose is 100 mg/day increasing gradually to a maximum of 100 mg bid in youth. Maximum recommended dose in adults 200 mg bid.	As above.	As above.
Buproprion (Wellbutrin XL)	DA and NE reuptake inhibitor	Usually dosed once daily. Starting dose is 150 mg/day Usual maximum dose 300 mg/day in youth. Maximum dose in adults 450 mg/day.	As above.	As above.
Venlafaxine (Effexor, Effexor XR)	5HT and NE reuptake inhibitor	No dosing information available for children. Start at lowest dose 25 mg once daily. Common maintenance dose in youth 25-100 mg/day. Usual maximum dose 225 mg/day for adults.	GI intolerance, sexual dysfunction, activation, mania, sleep disturbance, hypertension. May increase risk of suicidal behavior.	Not FDA-approved in children, though used in pediatric populations as third-line antidepressant for refractory depression. Consider use for ADHD.
Mirtazapine (Remeron)	5HT, NE reuptake inhibitor	No dosing information available for children. Start at lowest dose possible 15 mg once daily. Maximum recommended dose in adults 45 mg/day.	Somnolence, weight gain, rare agranulocytosis. May increase risk of suicidal behavior. Sedation is more common in low doses.	Not FDA-approved in children, though used in pediatric populations as third-line antidepressant for refractory depression and to take advantage of its therapeutic and side effects of sedation.
Trazodone (Desyrel)	5HT 2A reuptake inhibitor	Suggested initial dosing for insomnia 25 mg qhs, May increase in 25 mg increments to 100-150 mg qhs.	Somnolence. Priapism is rare, more common in younger boys then in teens.	Not FDA-approved in children, though commonly used in pediatric populations for insomnia.
5HT, serotonin; NE, norepinephrine; DA, dopamine; H, histamine; M,muscarinic; SI, suicidal ideation; FDA, Food and Drug Administration; GI, gastrointestinal; 0CD, obsessive compulsive disorder; ADHD, attention-deficit hyperactivity disorder.

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Tags: Child and Adolescent Psychiatry The Essentials

Jul 5, 2016 | Posted by drzezo in PSYCHIATRY | Comments Off

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