Use of Psychotropic Medications in Children with Developmental Disabilities

Us e of Psychotropic Me dic ations in Children with Development al Dis abilities Joseph L. Calles, Jr., MDa,b,* KEYWORDS  Developmental disabilities  Intellectual disabilities  Psychotropic drugs

Children and adolescents with ‘‘special needs’’ comprise a small part of most pediatric practices, yet often require an inordinate amount of time and resources in their clinical care. These children are usually described as having developmental disabilities (DD), which denotes impairments in several areas of functioning, such as communication and motor control. A commonly associated condition is mental retardation (MR), also known as intellectual disability, which is defined by below average performance on standardized intellectual testing (representing the lowest 2.5 percent), in addition to functional impairments. Another group is the pervasive developmental disorders (PDD), which are increasingly referred to as the autistic spectrum disorders (ASD). Abnormal neural development may manifest not only as physical problems, but also as mental symptoms. This article describes various neuropsychiatric disturbances seen in DD (with or without MR) and discusses psychopharmacologic approaches to their treatment. Before beginning, however, some words of caution are in order. Firstly, whenever one is considering the use of psychotropic medications in a DD patient, one should make sure that the emotional and behavioral symptoms are not due to an undiagnosed medical illness.1 Secondly, if medications are already being used or if symptoms worsen after treatment is initiated, the medications themselves should be suspected as possible causes of the problem behaviors.1,2 Thirdly, medications should be started at low doses, titrations should be performed slowly, and the lowest

a

Department of Psychiatry, College of Human Medicine, Michigan State University, A236 East Fee Hall, East Lansing, MI 48824, USA b Child and Adolescent Psychiatry, Psychiatry Residency Training Program, Michigan State University/Kalamazoo Center for Medical Studies, 1722 Shaffer Road, Suite 3, Kalamazoo, MI 49048, USA * Child and Adolescent Psychiatry, Psychiatry Residency Training Program, Michigan State University/Kalamazoo Center for Medical Studies, 1722 Shaffer Road, Suite 3, Kalamazoo, MI 49048. E-mail address: [email protected] Pediatr Clin N Am 55 (2008) 1227–1240 doi:10.1016/j.pcl.2008.07.002 pediatric.theclinics.com 0031-3955/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

1228

Calles

effective doses to achieve symptomatic control should be used (versus shooting for an arbitrary ‘‘target dose’’). Lastly, psychotropic medications should never be the sole treatments for psychiatric symptoms in the DD population. Ideally, behavioral interventions and other environmental modifications should be tried first, before starting pharmacotherapy. EPIDEMIOLOGY Prevalence of Developmental Disabilities

In the mid-1990s, an American survey3 of noninstitutionalized, community samples of all ages estimated the following DD prevalence rates: for DD alone, 7.1 per 1000; for MR alone, 3.6 per 1000; for the combined presence of MR and DD, 4.2 per 1000; and, for the total of all MR and DD, 14.9 per 1000. The prototypical ASD, classic autistic disorder, has a prevalence somewhere between 10 and 20 per 10,000, while, as a group, the ASD have an estimated prevalence of about 60 per 10,000.4 Prevalence of Neuropsychiatric Disorders

Compared with the general population, neuropsychiatric disorders are overrepresented in the DD population. Epilepsy

In North America, the overall incidence of epilepsy is about 50 per 100,000 per year, with the highest rate being in children less than 5 years of age. The best estimates of prevalence are between 5 and 10 per 1000.5 In individuals with MR, the lifetime prevalence of epilepsy is over 10 times higher, with estimates between 14% and 24%.6 Sleep disorders

Sleep problems are common in children, but more so in the intellectually disabled population. A study that compared the sleep characteristics of children with intellectual disability (of mixed etiologies) to those of normal controls showed that current sleep problems were seen in 57.7% of intellectually disabled children versus 16% of controls, and past sleep problems were twice as common in the intellectually disabled group (66.7% versus 33.3%).7 Psychopathology

There are various psychiatric symptoms and disorders that commonly occur in children with DD. Table 1 lists four selected problem areas and compares prevalence rates in the DD population to those in the general child population.8–12 To facilitate the discussion of which psychotropic medications to use for which conditions, the following section discusses three common DD syndromes, associated neuropsychiatric disorders, and recommended pharmacologic interventions.

Table 1 Psychopathology in developmental disabilities versus non^developmental disabilities children Problem

DD %

Non-DD %

ODD

488

2.39

ADHD

338

8.710

SIB

448

5–911

Aggression

488

0.5–3.712

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ODD, oppositional defiant disorder; SIB, self-injurious behavior.

Use of Psychotropic Medications in Children

AUTISTIC SPECTRUM DISORDERS

The heterogeneous group that forms the autistic spectrum disorders includes autistic disorder, Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and PDD–not otherwise specified (PDD-NOS).13 Autistic disorder, which adversely affects a child’s socialization, communication, and patterns of interests and activities, is associated with various medical disorders, many of which are genetic in origin.14,15 Given the profound deficits that can be seen in children with autistic disorder, clinicians may be tempted to attribute psychiatric symptoms to the autism itself. However, as is shown below, there are high rates of psychopathology comorbid with autistic disorder (and other ASD).16 There have yet to be discovered pharmacotherapeutic agents that treat the core symptoms of ASD. Aggression

Xue Ming and colleagues17 reported that of 160 autistic children, 32% displayed aggressive behaviors (toward others or self). Palucka and colleagues18 consulted on a small group of community-living DD patients (ages not given, but presumed to be adults), with or without PDD. Irrespective of DD diagnoses, aggression was more likely to be present if a mood disorder was present. Treatment

Aggression is not a diagnosis, but a symptom of another condition. The Palucka study18 found that, in 80% of aggressive patients, recommendations were made to reduce or eliminate atypical antipsychotics (AA) and to maximize treatment of mood disorders with antidepressants or mood stabilizers (see section on mood disorders). In the absence of a clearly defined mood disorder, risperidone is a good first-line agent to treat aggression in children with autistic disorder,19 and perhaps with other ASD (although not approved by the Food and Drug Administration except in autistic disorder). In the United States, five other AA—clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole—are available, but to date there are no large, controlled studies of their use in ASD. In smaller studies, ziprasidone and aripiprazole also demonstrated amelioration of aggressive symptoms.20 A novel approach to the treatment of disruptive behaviors in autistic disorder used the acetylcholinesterase inhibitor galantamine.21 Although further studies are necessary, galantamine did produce significant reductions in anger and aggression. Dosages ranged from 12 to 24 mg daily over 12 weeks. Self-Injurious Behavior

Baghdadli and colleagues22 found that in 222 autistic children (under 7 years of age) 50% exhibited self-injurious behavior (SIB), and almost 15% exhibited severe SIB, defined as producing ‘‘functional or life-threatening lesions.’’ People with autistic disorder don’t necessarily outgrow SIB. Bodfish and colleagues23 found that, when compared to adults with MR (without autism), almost twice as many of the autistic adults displayed SIB; the severity of injuries was also greater in the autism group. Treatment

Similar to its effects on aggression, risperidone has also been found to reduce SIB in people with autistic disorder; the other AA may also be helpful in this regard.20 Risperidone does have its limitations. For example, although SIB frequency is reduced in autistic patients, duration and severity of the SIB may not be significantly altered.24 Another concern is AA-related weight gain and obesity,25 which is a risk factor for the development of metabolic syndrome.26 In the event that the SIB in autistic patients

1229

1230

Calles

doesn’t respond to the AA, or the medications are not tolerated, a trial of the opioid antagonist naltrexone may be beneficial.27 Common doses are in the range of 0.5 to 2 mg/kg/d. Hyperactivity, Impulsivity, and Inattention

The rates of attention deficit/hyperactivity disorder (ADHD) are quite high in the ASD. In a university ASD specialty clinic, 78% of patients met criteria for ADHD, with the highest rate (83%) being in those with autistic disorder.28 Treatment

More recent studies, with better designs, have demonstrated that PDD patients with ADHD can respond sufficiently to psychostimulants to warrant trials of those medications.29 If the stimulant is ineffective or intolerable, a subsequent trial of atomoxetine may be effective.30,31 Reports on side effects are mixed and inconsistent. Sleep Disturbances

Disorders of sleep are common in ASD, occurring in 52% of affected children in one study.17 Sleep problems have a highly significant association with mood disorders. Treatment

It is desirable to identify and treat comorbid mood disorders first, in the hope that the associated sleep disturbances will be corrected (see discussion of mood disorders below). In the absence of a mood disorder—or when mood has improved but poor sleep persists—regular melatonin32 or controlled-release melatonin33 may be tried. Synthetic melatonin is preferred, as natural-source melatonin is extracted from the pineal glands of livestock and could theoretically be contaminated with prions. Another option is the synthetic melatonin receptor agonist ramelteon.34 Mood Disorders

When a group of children with ASD were compared to a community sample, 16.9% of those with ASD scored two standard deviations above the normal population mean for depression.35 In another group of ASD children at a specialized autism program, 26% were diagnosed with ‘‘mood disorder.’’17 Treatment

The treatment of mood disturbances in the ASD population has been attempted using various antidepressants, mood stabilizers, and even antipsychotics. For depression, a selective serotonin reuptake inhibitor (SSRI) antidepressant has been most often used, and fluoxetine has been the most common agent from that class.36 Effective treatment of depression seems to reduce aggressiveness and SIB. If a cyclic mood disorder, such as bipolar disorder, is suspected, the use of antiepileptic drugs (AED) that are also mood stabilizers (eg, sodium valproate or lamotrigine) is preferred over lithium or the AA, given the high rate of seizure disorders in those with ASD (see below). Seizures

It is estimated that about one third of children with ASD develop a seizure disorder.37 The most common types are partial-complex and generalized tonic-clonic. Although the exact connection between neuropsychiatric symptoms and seizure activity has yet to be elucidated, treating seizures or electroencephalographic abnormalities (suspicious for epileptogenicity) with anticonvulsants may lead to symptomatic improvement.38

Use of Psychotropic Medications in Children

Treatment

No specific anticonvulsant is currently recommended, and choice of AED must be a balance between potential efficacy and potential for adverse effects, including negative behavioral changes.39 FRAGILE X SYNDROME

The fragile X syndrome (FXS) is the most commonly inherited cause of MR and, in almost all cases, derives from excessive repeats of the CGG trinucleotide sequence in the FMR1 gene, located on the X chromosome. The prevalence of the full mutation/clinical syndrome is estimated at 1 per 4000 males, and prevalence of female carrier status is estimated at 1 per 350.40 In addition to cognitive difficulties (ranging from normal IQ with learning disorders to MR), people with FXS have a variety of emotional and behavioral disorders.41 Aggression

Patients with FXS can display aggressive behaviors in the context of noxious external stimuli (eg, loud noises) or intolerable internal processes (eg, anxiety). Treatment

To prevent disruptive behaviors, it is crucial to identify factors that predispose to or trigger aggressive episodes. Minimizing or avoiding environmental changes is an ongoing endeavor both for the family and the school. Sadness, anxiety, irritability, impulsivity, sleep deprivation, psychosis, and poorly controlled seizure disorder are all potential targets for pharmacotherapy. Self-Injurious Behavior

Symons and colleagues42 found that in boys with FXS, 58% engaged in SIB (with 72% of those biting the hands or fingers), which had its onset before age 3 years and was associated with environmental stressors. Treatment

Follow the same recommendations made in the previous section on aggression. Hyperactivity, Impulsivity, and Inattention

When compared to peers with equivalent mental ages, 53.7% of children with FXS were rated by parents as having symptoms consistent with ADHD; teachers rated 59.2% as meeting the ADHD criteria, with higher scores for hyperactivity-impulsivity than reported by parents.43 Treatment

The ADHD symptoms seen in FXS patients respond well to the psychostimulants, although younger children and those with lower levels of functioning may not do as well.44 Patients should be monitored closely for newly emergent or exacerbated insomnia, anxiety, mood instability, and aggression. If the stimulants are ineffective or intolerable, a cautious trial of the alpha2-agonists clonidine or guanfacine may be given.44 Sleep Disturbances

Sleep in patients with FXS can be of low quantity and quality, and can be secondary to neuropsychiatric disorders (eg, ADHD, depression, or epilepsy) or can be due to primary sleep disorders, such as obstructive sleep apnea.45

1231

1232

Calles

Treatment

If appropriate treatment of comorbid conditions doesn’t appreciably improve sleep, patients should be referred for polysomnographic evaluation. The use of sedativehypnotic medications should be avoided. Mood Disorders

Compared with those without FXS, females (ages 4–27 years) with FXS had higher rates of mood disorders (47% versus 6%) and one half of those had major depression.46 It is unclear if males with FXS are more or less likely than their female counterparts to experience depression. In one comparison study there was no statistical difference in either ‘‘anxious/depressed’’ or ‘‘withdrawn’’ scores between the two groups.47 Bipolar disorder may co-occur with FXS, albeit uncommonly; there may also be clustering in some families.48 Treatment

The antidepressant of choice for depression in FXS seems to be an SSRI, with at least a 50% response rate to be expected.44 Patients should be monitored for agitation, insomnia, gastrointestinal symptoms, and suicidal ideation. For symptoms of bipolar disorder, mood-stabilizing AED are the medications of choice, especially if there is a comorbid seizure disorder (see discussion of seizures). Anxiety Disorders

Symptoms of anxiety can be difficult to elicit in children with intellectual disability. When asked to identify the presence of anxiety symptoms (as manifested in specific behaviors) in a group of FXS children, parents rated 26% as having ‘‘clinically significant anxiety problems,’’ whereas teachers rated 42% of the children as having high levels of anxiety.49 Treatment

The SSRI antidepressants can effectively reduce anxiety, especially the type that is provoked by social interactions.44 In the event of nonresponse to adequate SSRI trials, other strategies could include (1) adding a beta-adrenergic blocker (eg, propranolol or nadolol) to the SSRI; (2) using buspirone; or (3) cautious use of a long-acting benzodiazepine (eg, clonazepam) while watching for behavioral disinhibition.50 Autistic Behaviors

It has been noted for some time that autistic disorder is associated with FXS at much higher rates than those found in the general population. For example, in a large group of young children with FXS, 25.9% of boys met criteria for autism, a rate four times greater than that seen in FXS girls.51 Treatment

As noted previously, specific treatments for core autistic symptoms are not available. These particular problems are mentioned here because their presence in FXS increases the risk for comorbid psychiatric disorders. They also increase the complexity of overall assessment and management. Psychopathology should be looked for and aggressively treated if found. Seizures

As previously noted, seizure disorders are present in 10% to 20% of FXS patients52 and have implications for choosing psychotropic medications that are effective for

Use of Psychotropic Medications in Children

treating comorbid psychiatric disorders, but do not provoke or increase seizure activity. Treatment

Choice of AED should be based on seizure type and patient characteristics. The most effective agents for seizure control are also likely to provide relief of some psychiatric symptoms (eg, aggression, mania, and anxiety), but could also exacerbate them.39 FETAL ALCOHOL SYNDROME

Fetal alcohol syndrome (FAS) and related disorders, commonly termed fetal alcohol spectrum disorders (FASD), are the direct result of prenatal alcohol exposure. The physical, cognitive, and behavioral manifestations can be reliably identified using consensus diagnostic criteria.53 Estimated United States prevalence of FAS from the preceding 2 decades is 0.5 to 2.0 per 1000 live births, while prevalence of FASD (including birth defects and neurodevelopmental disorders) may be 1% or more of live births.54 The high rates of psychopathology in FAS have been well documented.55 Aggression

Compared with non–prenatally exposed youth, those with prenatal alcohol exposure show higher rates of delinquent behaviors, including fighting.56 Interestingly, in those with prenatal alcohol exposure, but without FAS, one half met probable conduct disorder criteria, whereas none of the patients with FAS met the criteria. Burd and colleagues55 similarly found that partial FAS patients had significantly higher scores related to ‘‘anger problems’’ (a risk factor for aggression) than those with full FAS. These findings are counterintuitive and not adequately explained to date. Treatment

Proper treatment of comorbid psychiatric disorders, such as ADHD or mood disorders (see the relevant discussions below), generally reduces or eliminates aggressive behaviors. For nonspecific or refractory aggression, use of risperidone may work when other agents have failed.57 Self-Injurious Behavior

Although the rate of SIB in people with FAS may not be higher than in those without FAS,55 actual suicide attempts are higher in FAS, with over one half having attempted suicide (18% of a severe degree, 27% moderate, and 9% low), versus only 4.6% of the general population who have a history of suicide attempts.58 Treatment

Two important risk factors for suicide are depression and substance abuse, especially alcohol abuse. It is imperative that those disorders be identified and treated in FAS patients (see discussion of mood disorders and substance-use disorders below). Hyperactivity, Impulsivity, and Inattention

Comparing the prevalence of ADHD in patients with FAS, partial FAS, or no FAS, Burd and colleagues55 found rates of 73.0%, 71.5%, and 36.8%, respectively. Unlike idiopathic ADHD, in which hyperactivity and impulsivity tend to attenuate during adolescence, the ADHD associated with FAS seems to persist from preschool age up through adolescence.59

1233

1234

Calles

Treatment

The first-line treatment for ADHD in FAS is a psychostimulant. There is some evidence that preparations containing dextroamphetamine work better than does methylphenidate.57,60 Sleep Disturbances

Not only does the risk for ADHD increase with the degree of prenatal alcohol exposure, but so, too, does the risk of having a sleep disorder. Bhatara and colleagues61 found that in those children with confirmed, but low, prenatal exposure to alcohol, 25.5% met criteria for a sleep disorder; in those with confirmed high-level exposure, 52.3% had a sleep disorder. Treatment

Given the overlap of ADHD and sleep disorders in FAS, it would be reasonable to give a trial of clonidine for sleep, as it has been useful in ADHD children without DD62 and in DD patients with severe sleep problems.63 An alternative agent is melatonin, although it may only improve sleep onset latency and not other sleep parameters.64 Mood Disorders

O’Connor and colleagues65 looked at a group of children who had been prenatally exposed to high levels of alcohol, but who did not have MR. They were identified as having FAS, partial FAS, or alcohol-related neurodevelopmental deficits. In the FAS/ partial-FAS group, there were no cases of major depressive disorder, but 33% were diagnosed with bipolar disorder. In the group with alcohol-related neurodevelopmental deficits, 18% were diagnosed with major depressive disorder and 35% were diagnosed with bipolar disorder. Treatment

There is insufficient data in the literature to guide the treatment of mood disorders in those with FASD. A conservative approach, therefore, would be to follow the algorithms already established for the treatment of major depressive disorder66 and bipolar disorder67 in children and adolescents. It must be kept in mind, however, that some medication choices need to be modified to take into consideration such factors as comorbid conditions and potential adverse medication interactions. Psychosis

On a parent-completed behavioral questionnaire, children with prenatal alcohol exposure scored more than two standard deviations higher than children with no prenatal exposure to alcohol on the ‘‘psychosis’’ scale (specific symptoms not specified).68 One could make the argument that parental feedback on a questionnaire and clinical diagnosis are not equivalent, but in this case there may some validity to the study, if one considers what happens to FAS children who grow up. Famy and colleagues69 evaluated 25 adults with FASD. They found that 40% had a psychotic disorder, the majority being of the brief psychotic disorder type. Treatment

It is incumbent on the clinician to thoroughly evaluate the patient, generate a differential diagnosis, and identify treatable causes of the psychosis.70 The proper treatment of psychotic symptoms depends on the illness that is generating the psychosis (eg, monotherapy with an AA in schizophrenia versus a combined mood stabilizer–AA regimen for bipolar disorder with psychosis).67

Use of Psychotropic Medications in Children

Table 2 Medications for neuropsychiatric problems in developmental disabilities Problem

1st Choice

2nd Choice

3rd Choice

Aggression

Risperidone

Ziprasidone or aripiprazole

Aripiprazole or ziprasidone

SIB

Risperidone

Second AA

Naltrexone

ADHD

Stimulant

Second stimulant

Atomoxetine

Sleep

Melatonin

Ramelteon

Clonidine

SSRI

Second SSRI

ASD

Mood Depression

Bipolar disorder Sodium valproate Lamotrigine

SNRI AA

FXS Aggression

a

a

a

SIB

a

a

a

Sleep

a

a

a

ADHD

Stimulant

Second stimulant

Alpha2 agonist

SSRI

Second SSRI

Third SSRI

Bipolar disorder AED

Second AED

Third AED

SSRI

Second SSRI

Any SSRI  BB, or buspirone, or long-acting benzodiazepine

Mood Depression Anxiety FAS Aggression

a

a

Risperidone

SIB

a

a

a

ADHD

Stimulantb

Second stimulantb Third stimulantb

Sleep

Clonidine

Melatonin

Ramelteon

Mood

c

c

c

Psychosis

a

a

a

Abbreviations: BB, beta adrenergic blocker; SNRI, serotonin and norepinephrine reuptake inhibitor. a Treatment is targeted to the specific identified psychiatric disorder or disorders producing these nonspecific symptoms. b Dextroamphetamine may be preferable to methylphenidate. c Follow treatment algorithms for specific mood disorders.68,69

Substance-Use Disorders

Prenatal exposure to alcohol increases the risk for substance-use disorders later in life. Baer and colleagues71 followed a 1-year birth cohort up to young adulthood. They found that mothers who drank heavily during pregnancy had children who, at age 21 years, had a three times greater risk of developing ‘‘at least mild alcohol dependence’’ when compared with offspring of mothers who drank less during pregnancy. Famy and colleagues69 also reported that, in their adult FASD group, 60% met diagnostic criteria for alcohol or drug dependence. Treatment

The pediatrician can provide a very valuable service by screening FASD patients and making referrals for formal evaluation and treatment of substance-use disorders.72

1235

1236

Calles

Table 3 Medication classes and dosages used in developmental disabilities Class

Agent

Dosage Range (Daily)

Immediate release

5–60 mg, divided

Psychostimulants Methylphenidate

Dex-methylphenidate

Extended release

10–60 mg in the

Patch

10–30 mg for 9 hours

Immediate release

5–20 mg, divided

AM

Extended release

5–20 mg in the

Dextroamphetamine

Immediate release

5–40 mg, divided

Extended release

5–40 mg in the

Mixed amphetamine salts

Immediate release

5–40 mg, divided

AM

AM

Extended release

5–30 mg in the

Lisdexamfetamine

Extended release

20–70 mg in the

Methamphetamine

Immediate release

5–25 mg, divided

Fluoxetine

5–60 mg in the

Paroxetine

5–40 mg, divided

Sertraline

25–200 mg, divided

Citalopram

10–40 mg, divided

AM AM

Antidepressants SSRI

AM

Escitalopram

5–20 mg in the

SNRI

Venlafaxine

50–225 mg, divided

Duloxetine

20–60 mg in the

Other

Atomoxetine (for ADHD)

10–100 mg in the AM, divided

Risperidone

0.25–4 mg in the PM, divided

Olanzapine

2.5–20 mg in the PM, divided

Quetiapine

50–600 mg in the PM, divided

Antipsychotics

AM

AM,

divided

Ziprasidone

40–160 mg, divided

Aripiprazole

2–30 mg in the

Carbamazepine

7 mg/kg, divideda

Valproic acid

20 mg/kg, divideda

Lamotrigine

0.15–15 mg/kg, divided

Oxcarbazepine

8–60 mg/kg, divided

Gabapentin

10–50 mg/kg, divided

Topiramate

1–9 mg/kg, divided

AM

Mood stabilizers Anticonvulsants

Anxiolytics Benzodiazepines Other Alpha2-agonists Beta-blockers

Opioid antagonist a

Adjust dosage to level.

Diazepam

1–10 mg in the PM, divided

Clonazepam

0.01–0.2 mg/kg, divided

Buspirone

5–60 mg, divided

Clonidine

0.1–0.4 mg in the PM, divided

Guanfacine

1–2 mg in the

Propranolol

10–40 mg, divided

Metoprolol

50–200 mg, divided

Nadolol

20–80 mg, divided

Naltrexone

0.5–2 mg/kg, divided

PM,

divided

Use of Psychotropic Medications in Children

SUMMARY

Our child and adolescent patients with DD are challenging, especially given their high risk for developing neuropsychiatric disorders. This article has attempted to make the practicing pediatrician aware of the prevalence and types of psychopathology encountered in three common DD: ASD, FXS, and FAS. Recommended medications for the various disorders described in the text are listed in Table 2, and typical dosage ranges for each medication are listed in Table 3. REFERENCES

1. Kastner T, Walsh KK, Fraser M. Undiagnosed edical conditions and medication side effects presenting as behavioral/psychiatric problems in people with mental retardation. Mental Health Aspects of Developmental Disabilities 2001;4(3): 101–7. 2. Valdovinos MG, Caruso M, Roberts C, et al. Medical and behavioral symptoms as potential medication side effects in adults with developmental disabilities. Am J Ment Retard 2005;110(3):164–70. 3. Larson SA, Lakin KC, Anderson L, et al. Prevalence of mental retardation and developmental disabilities: Estimates from the 1994/1995 National Health Interview Survey Disability Supplements. Am J Ment Retard 2001;106(3):231–52. 4. Newschaffer CJ, Croen LA, Daniels J, et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007;28:235–58. 5. Theodore WH, Spencer SS, Wiebe S, et al. Epilepsy in North America: a report prepared under the auspices of the Global Campaign Against Epilepsy, the International Bureau for Epilepsy, the International League Against Epilepsy, and the World Health Organization. Epilepsia 2006;47(10):1700–22. 6. Deb S. Epidemiology and treatment of epilepsy in patients who are mentally retarded. CNS Drugs 2000;13(2):117–28. 7. Richdale A, Francis A, Gavidia-Payne S, et al. Stress, behaviour, and sleep problems in children with an intellectual disability. J Intellect Dev Disabil 2000;25(2): 147–61. 8. Hardan A, Sahl R. Psychopathology in children and adolescents with developmental disorders. Res Dev Disabil 1997;18(5):369–82. 9. Maughan B, Rowe R, Messer J, et al. Conduct disorder and oppositional defiant disorder in a national sample: developmental epidemiology. J Child Psychol Psychiatry 2004;45(3):609–21. 10. Froehlich TE, Lanphear BP, Epstein JN, et al. Prevalence, recognition, and treatment of attention-deficit/hyperactivity disorder in a national sample of US children. Arch Pediatr Adolesc Med 2007;161(9):857–64. 11. Skegg K. Self-harm. Lancet 2005;366(9495):1471–83. 12. Lee KH, Baillargeon RH, Vermunt JK, et al. Age differences in the prevalence of physical aggression among 5–11-year-old Canadian boys and girls. Aggress Behav 2007;33(1):26–37. 13. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edition [text revision]. Washington, DC: American Psychiatric Association; 2000. 14. Kielinen M, Rantala H, Timonen E, et al. Associated medical disorders and disabilities in children with autistic disorder: a population-based study. Autism 2004;8(1):49–60. 15. Zafeiriou DI, Ververi A, Vargiami E. Childhood autism and associated comorbidities. Brain Dev 2007;29(5):257–72.

1237

1238

Calles

16. Tsai LY. Brief report: comorbid psychiatric disorders of autistic disorder. J Autism Dev Disord 1996;26(2):159–63. 17. Ming Xue, Brimacombe M, Chaaban J, et al. Autism spectrum disorders: concurrent clinical disorders. J Child Neurol 2008;23(1):6–13 [Epub 2007 Dec 3]. 18. Palucka AM, Nyhus N, Lunsky Y. Aggression as a symptom of mood destabilization in pervasive developmental disorders. J Dev Disabil 2003;10(1):101–5. 19. Horrigan JP, Barnhill LJ. Risperidone and explosive aggressive autism. J Autism Dev Disord 1997;27(3):313–23. 20. Chavez B, Chavez-Brown M, Sopko MA Jr, et al. Atypical antipsychotics in children with pervasive developmental disorders. Pediatr Drugs 2007;9(4):249–66. 21. Nicolson R, Craven-Thuss B, Smith J. A prospective, open-label trial of galantamine in autistic disorder. J Child Adolesc Psychopharmacol 2006;16(5):621–9. 22. Baghdadli A, Pascal C, Grisi S, et al. Risk factors for self-injurious behaviours among 222 young children with autistic disorders. J Intellect Disabil Res 2003; 47(Pt 8):622–7. 23. Bodfish JW, Symons FJ, Parker DE, et al. Varieties of repetitive behaviour in autism: comparisons to mental retardation. J Autism Dev Disord 2000;30(3):237–43. 24. Canitano R. Self injurious behavior in autism: clinical aspects and treatment with risperidone. J Neural Transm 2006;113(3):425–31 [Epub 2005 Aug 3]. 25. Fedorowicz VJ, Fombonne E. Metabolic side effects of atypical antipsychotics in children: a literature review. J Psychopharmacol 2005;19(5):533–50. 26. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350(23):2362–74. 27. Elchaar GM, Maisch NM, Augusto LM, et al. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Ann Pharmacother 2006;40(6): 1086–95. 28. Lee DO, Ousley OY. Attention-deficit hyperactivity disorder symptoms in a clinic sample of children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006;16(6):737–46. 29. Abanilla PK, Hannahs GA, Wechsler R, et al. The use of psychostimulants in pervasive developmental disorders. Psychiatr Q 2005;76(3):271–81. 30. Arnold LE, Aman MG, Cook AM, et al. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry 2006;45(10):1196–205. 31. Troost PW, Steenhuis MP, Tuynman-Qua HG, et al. Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study. J Child Adolesc Psychopharmacol 2006;16(5):611–9. 32. Garstang J, Wallis M. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev 2006; 32(5):585–9. 33. Giannotti F, Cortesi F, Cerquiglini A, et al. An open-label study of controlledrelease melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord 2006;36(6):741–52. 34. Stigler KA, Posey DJ, McDougle CJ. Ramelteon for insomnia in two youths with autistic disorder. J Child Adolesc Psychopharmacol 2006;16(5):631–6. 35. Kim JA, Szatmari P, Bryson SE, et al. The prevalence of anxiety and mood problems among children with autism and Asperger syndrome. Autism 2000;4(2): 117–32. 36. Stewart ME, Barnard L, Pearson J, et al. Presentation of depression in autism and Asperger syndrome. A review. Autism 2006;10(1):103–16.

Use of Psychotropic Medications in Children

37. Persad V, Thompson MD, Percy ME. Epilepsy and developmental disability part I: developmental disorders in which epilepsy may be comorbid. Journal on Developmental Disabilities 2003;10(2):123–51. 38. Tuchman R. Treatment of seizure disorders and EEG abnormalities in children with autism spectrum disorders. J Autism Dev Disord 2000;30(5):485–9. 39. Schmitz B. Effects of antiepileptic drugs on mood and behavior. Epilepsia 2006; 47(Suppl 2):28–33. 40. Sherman S, Pletcher BA, Driscoll DA. American College of Medical Genetics Practice Guideline: fragile X syndrome: diagnostic and carrier testing. Genet Med 2005;7(8):584–7. 41. Visootsak J, Warren ST, Anido A, et al. Fragile X syndrome: an update and review for the primary pediatrician. Clin Pediatr (Phila) 2005;44(5):371–81. 42. Symons FJ, Clark RD, Hatton DD, et al. Self-injurious behavior in young boys with fragile X syndrome. Am J Med Genet 2003;118(2):115–21. 43. Sullivan K, Hatton D, Hammer J, et al. ADHD symptoms in children with FXS. Am J Med Genet A 2006;140(21):2275–88. 44. Berry-Kravis E, Potanos K. Psychopharmacology in fragile X syndrome—present and future. Ment Retard Dev Disabil Res Rev 2004;10(1):42–8. 45. Tirosh E, Borochowitz Z. Sleep apnea in fragile X syndrome. Am J Med Genet 1992;43(1–2):124–7. 46. Freund LS, Reiss AL, Abrams MT. Psychiatric disorders associated with fragile X in the young female. Pediatrics 1993;91(2):321–9. 47. Hessl D, Dyer-Friedman J, Glaser B, et al. The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome. Pediatrics 2001;108(5):E88. 48. Jeffries FM, Reiss AL, Brown WT, et al. Bipolar spectrum disorder and fragile X syndrome: a family study. Biol Psychiatry 1993;33(3):213–6. 49. Sullivan K, Hooper S, Hatton D. Behavioural equivalents of anxiety in children with fragile X syndrome: parent and teacher report. J Intellect Disabil Res 2007;51(1): 54–65. 50. Tsiouris JA, Brown WT. Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy. CNS Drugs 2004;18(11):687–703. 51. Hatton DD, Sideris J, Skinner M, et al. Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP. Am J Med Genet A 2006;140A:1804–13. 52. Berry-Kravis E. Epilepsy in fragile X syndrome. Dev Med Child Neurol 2002; 44(11):724–8. 53. Hoyme HE, May PA, Kalberg WO, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 Institute of Medicine Criteria. Pediatrics 2005;115(1):39–47. 54. May PA, Gossage JP. Estimating the prevalence of fetal alcohol syndrome. A summary. Alcohol Res Health 2001;25(3):159–67. 55. Burd L, Klug MG, Martsolf JT, et al. Fetal alcohol syndrome: neuropsychiatric phenomics. Neurotoxicol Teratol 2003;25:697–705. 56. Schonfeld AM, Mattson SN, Riley EP. Moral maturity and delinquency after prenatal alcohol exposure. J Stud Alcohol 2005;66(4):545–54. 57. Hagerman RJ. Psychopharmacological interventions in fragile X syndrome, fetal alcohol syndrome, Prader-Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, and velocardiofacial syndrome. Ment Retard Dev Disabil Res Rev 1999;5:305–13.

1239

1240

Calles

58. Merrick J, Merrick E, Morad M, et al. Fetal alcohol syndrome and its long-term effects. Minerva Pediatr 2006;58(3):211–8. 59. Steinhausen HC, Spohr HL. Long-term outcome of children with fetal alcohol syndrome: psychopathology, behavior, and intelligence. Alcohol Clin Exp Res 1998; 22(2):334–8. 60. O’Malley KD, Koplin B, Dohner VA. Psychostimulant clinical response in fetal alcohol syndrome. Can J Psychiatry 2000;45(1):90–1. 61. Bhatara V, Loudenberg R, Ellis R. Association of attention deficit hyperactivity disorder and gestational alcohol exposure: an exploratory study. J Atten Disord 2006;9(3):515–22. 62. Prince JB, Wilens TE, Biederman J, et al. Clonidine for sleep disturbances associated with attention-deficit hyperactivity disorder: a systematic chart review of 62 cases. J Am Acad Child Adolesc Psychiatry 1996;35(5):599–605. 63. Ingrassia A, Turk J. The use of clonidine for severe and intractable sleep problems in children with neurodevelopmental disorders: a case series. Eur Child Adolesc Psychiatry 2005;14:34–40. 64. Phillips L, Appleton RE. Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment. Dev Med Child Neurol 2004;46:771–5. 65. O’Connor MJ, Shah B, Whaley S, et al. Psychiatric illness in a clinical sample of children with prenatal alcohol exposure. Am J Drug Alcohol Abuse 2002;28(4): 743–54. 66. Hughes CW, Emslie GJ, Crismon ML, et al. Texas Children’s Medication Algorithm Project: update from Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. J Am Acad Child Adolesc Psychiatry 2007;46(6):667–86. 67. Kowatch RA, Fristad M, Bimaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005; 44(3):213–35. 68. Roebuck TM, Mattson SN, Riley EP. Behavioral and psychosocial profiles of alcohol-exposed children. Alcohol Clin Exp Res 1999;23(6):1070–6. 69. Famy C, Streissguth AP, Unis AS. Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. Am J Psychiatry 1998;155(4):552–4. 70. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 2001;40(Suppl 7):4S–23S. 71. Baer JS, Sampson PD, Barr HM, et al. A 21-year longitudinal analysis of the effects of prenatal alcohol exposure on young adult drinking. Arch Gen Psychiatry 2003; 60(4):377–85. 72. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with substance use disorders. J Am Acad Child Adolesc Psychiatry 2005;44(6):609–21.