Use of Psychotropic Medications in Children with Developmental Disabilities
Joseph L. Calles, Jr., MD a, 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: calles@kcms.msu.edu
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.
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 survey 3 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.
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 colleagues 17 reported that of 160 autistic children, 32% displayed aggressive behaviors (toward others or self). Palucka and colleagues 18 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 study 18 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 colleagues 22 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 colleagues 23 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 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 melatonin 32 or controlled-release melatonin 33 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
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 colleagues 42 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
Treatment
If appropriate treatment of comorbid conditions doesn’t appreciably improve sleep, patients should be referred for polysomnographic evaluation. The use of sedative-hypnotic 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 patients 52 and have implications for choosing psychotropic medications that are effective for
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 colleagues 55 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 colleagues 55 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
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 colleagues 61 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 DD 62 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 colleagues 65 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 disorder 66 and bipolar disorder 67 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 colleagues 69 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
Table 2 Medications for neuropsychiatric problems in developmental disabilities
Problem 1st Choice 2nd Choice 3rd Choice ASD Aggression Risperidone Ziprasidone or aripiprazole Aripiprazole or ziprasidone SIB Risperidone Second AA Naltrexone ADHD Stimulant Second stimulant Atomoxetine Sleep Melatonin Ramelteon Clonidine Mood Depression SSRI Second SSRI SNRI Bipolar disorder Sodium valproate Lamotrigine AA FXS Aggression a a a SIB a a a Sleep a a a ADHD Stimulant Second stimulant Alpha2 agonist Mood Depression SSRI Second SSRI Third SSRI Bipolar disorder AED Second AED Third AED Anxiety SSRI Second SSRI Any SSRI � BB, or buspirone, or long-acting benzodiazepine 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. 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 colleagues 71 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 colleagues 69 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
a Adjust dosage to level.
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 .
