TRIPASS XR تري باس

 

risperidone resulted in significantly greater reductions, compared

to placebo, in the scores on the modified compulsion subscale of the CY-BOCS

(effect size, 0.55), and the sensory motor behaviors subscale of the Ritvo–Freeman

Real Life Rating Scale (effect size, 0.45). Similar findings for risperidone’s benefit

for reducing repetitive behaviors have been found in adults with ASD, including

McDougle et al.’s RCT,

66 which found statistically significant reductions in the

modified version of the Y-BOCS (focusing only on repetitive behavior, not thoughts).

Stimulants

In Reichow et al. recent meta-analysis of medications for the treatment of ADHD

symptoms in children with PDD, methylphenidate had moderate, though not

statistically significant, benefits in treating stereotypies.

40

Other Medications

Despite valproate demonstrating efficacy for the treatment of irritability in Hollander

et al.’s study of children with ASD, it showed no significant improvement in

repetitive behavior, compared to placebo.

36 One small RCT of 1.5 g/day of omega-3

fatty acids (fish oil n = 7, placebo n = 5) showed no significant difference compared

to placebo in reduction of ABC Stereotypy, though effect size was 0.72.

59

SELF-INJURIOUS BEHAVIOR

Depending on the rating scale or etiologic theory, self-injurious behavior is

commonly thought of as either an act of aggression toward the self, or as a repetitive,

stereotyped behavior. Consequently, pharmacologic approaches to the treatment of

self-injury have been rooted in the approaches for the treatment of aggression or

repetitive behavior. Self-injurious behavior has its own literature base though, with

similar and dissimilar findings.

Typical and Atypical Antipsychotics

RCTs of typical antipsychotics for the reduction of self-injurious behavior in

individuals with developmental disabilities have had mixed findings. There has been

relatively unconvincing data for the benefit of haloperidol, fluphenazine,

chlorpromazine, or thioridazine in reducing self-injurious behavior.

82 Risperidone is

the atypical antipsychotic with the most robust RCT data for improving self-injurious

behavior, with two relatively large RCTs in children with ID showing improvement

in the self-injury/stereotypic subscale of the Nisonger Child Behavior Rating

Form,

83,84 one of which was statistically significant,

84 and statistically significant

reductions in self-injurious behavior in adults with ASD, as measured by the Selfinjurious Behavior Questionnaire.

66 Similar to studies in children with ASD, weight

gain and somnolence were markedly higher in children taking risperidone than

placebo.

Antidepressants

Clomipramine has been shown to be effective in reducing self-injurious behavior, but

again with significant adverse effects.

82 Fluoxetine has been shown to be effective at

reducing compulsive skin picking in two RCTs,

85,86 and fluvoxamine has been

effective for reducing repetitive behavior and aggression in adults with ASD.

76 Case

reports and open-label studies have shown possible benefit for buspirone and

paroxetine as well.

82

Naltrexone

A recent systemic review of naltrexone used in adults with intellectual disability

showed 8 out of 10 RCTs demonstrating a reduction in the frequency of self-injurious

behavior.

87 More specifically, 50% of participants had improvement in self-injury,

with improvement being more pronounced in individuals with severe and profound

ID. Nine percent experienced minor adverse events, which included weight loss, loss

of appetite, thirst, yawning, mild liver function test abnormalities, nausea, and

tiredness. Dosing ranged from 0.5 to 2 mg/kg, and doses from 25 to 100 mg.

Overall, despite very limited evidence, it seems the literature supports the use of

risperidone, naltrexone, and clomipramine for the reduction of self-injurious

behavior in individuals with developmental disabilities. Additionally, fluoxetine and

fluvoxamine may have benefits as well, though less well evidenced.

ANXIETY/DEPRESSION

Selective Serotonin Reuptake Inhibitors

Studies have found that individuals with PDDs are at high risk of comorbid anxiety

and mood disorders.

37,38 Due to the demonstrated benefits and relative safety of

SSRIs in typically developing children, SSRIs are very commonly prescribed for

anxiety and depression in children with developmental disorders. No large doubleblind, placebo-controlled trials have been conducted looking at the use of SSRIs for

depression or anxiety in children with developmental disorders, though the literature

has numerous case reports and open-label studies demonstrating SSRI-induced

improvements in anxiety in individuals with ASD.

88,89

Overall, the literature indicates that children with DD may respond differently to

SSRIs compared to children with typical development. Three areas in which

response to SSRIs may differ include risk of adverse events, dosing requirements,

and target symptoms.

Adverse Events

Compared to children with typical development, children with DD are more likely to

experience adverse events to SSRIs and specifically are more likely to endorse

emotional/behavioral adverse events. The only two RCTs looking at SSRIs in

children with DD evaluated fluoxetine

78 and citalopram79

for the treatment of

repetitive behaviors. In the crossover study (8 weeks each phase) of low-dose

fluoxetine by Hollander et al.

78

(n = 39, mean age, 8.2 years), although there was no

statistically significant difference in treatment-emergent adverse events between

fluoxetine and placebo, the most common adverse events emerging during

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p. 1860

fluoxetine treatment were agitation (46%), insomnia (36%), and anxiety/nervousness

(16%). Additionally, 16% of subjects required a dose reduction due to agitation

while on fluoxetine, compared to 5% on placebo.

In contrast, both Geller et al.

90 and Liebowitz et al.

91 conducted RCTs of fluoxetine

for the treatment of OCD in typically developing children (Geller: 13 weeks; n = 71

fluoxetine, 32 placebo; mean age 11.4 years/Liebowitz: 8-week acute phase; n = 21

fluoxetine, 22 placebo; mean age, 12–13). In Geller et al.,

90

there was no statistically

significant difference in reported adverse events, and the most common adverse

events reported in the fluoxetine group were headache (28%), rhinitis (27%), and

abdominal pain (16%), with no reports of agitation. In Liebowitz et al.,

91 six adverse

events occurred significantly more frequently in the fluoxetine group: palpitations,

weight loss, drowsiness, tremors, nightmares, and muscle aches, and the most

common adverse events reported by those taking fluoxetine were headache (52%),

abdominal pain (43%), decreased appetite (38%), difficulty staying asleep (38%),

and drowsiness (38%).

For citalopram, in the 12-week study by King et al.

79

(n = 73 citalopram, 76

placebo; mean age ~9 years), 97.3% of subjects with ASD treated with citalopram

experienced at least one treatment emergent adverse event. They were significantly

more likely to experience adverse events compared to those treated with placebo,

specifically: increased energy level (38%), impulsiveness (19%), decreased

concentration (12%), hyperactivity (12%), stereotypy (11%), diarrhea (26%),

insomnia (23.3%), and dry skin or pruritus (12%).

In contrast, in RCTs of citalopram for the treatment of depression in children and

adolescents with typical development, the most commonly reported adverse events

were headache, gastrointestinal issues, and insomnia.

92 Specifically in the 8-week

RCT by Wagner et al.

93 of citalopram for typically developing children with

depression (n = 89 citalopram, 85 placebo; mean age, 12 years), rhinitis (14%),

nausea (14%), and abdominal pain (11%) were the only adverse events reported in

>10% of subjects taking citalopram, and in the 12-week RCT by von Knorring et al.

94

of citalopram for typically developing adolescents with depression (n = 124

citalopram, 120 placebo; mean age, 16 years), headache (26% and 25%), nausea

(19% and 15%), and insomnia (13% and 11%) were the most common in both groups

(citalopram and placebo, respectively), with only fatigue being the adverse event

reported significantly more often in the citalopram group (6%) than the placebo

group (1%).

Dosing

Children with PDD typically require smaller doses of SSRIs compared to children

with typical development and may experience adverse emotional/behavioral events

at higher doses. For fluoxetine, the mean final daily dose of fluoxetine in Hollander et

al.’s study

78 of children with PDD was 9.9 mg, or 0.36 mg/kg. This is compared to

Geller et al.

90 and Liebowitz et al.’s

91 studies of typically developing children with

OCD, in which mean final daily fluoxetine dose was 24.6 and 64.8 mg (after the

acute phase), respectively. Additionally, in RCTs of typically developing children

with depression and other forms of anxiety, fluoxetine was well tolerated at mean

daily doses of 20 mg,

95–97 28.4 mg and 33.3 mg,

98 and 40 mg.

99

For citalopram, the mean daily dose in the King et al. study

79 of children with ASD

and repetitive behavior was 16.5 mg. In studies of citalopram use in typically

developing children and adolescents with depression, citalopram was tolerated at

mean daily doses of 24

93 and 26 mg.

94

The issue of individuals with PDD requiring lower dosages of SSRI might

diminish in adulthood, because RCTs of SSRIs in adults with ASD demonstrate mean

daily doses close to that expected for typically developing adults: fluoxetine—36.7

101

and 64.8 mg

101

; fluvoxamine 276.7 mg.

76

CASE 88-3

QUESTION 1: N.W. is a 6-year-old girl with a history of supraventricular tachycardia (SVT) at birth, well

controlled on propranolol since infancy. N.W. also has a diagnosis of ASD. Over the past year, she has been

trialed on varying stimulant formulations and doses for the treatment of ADHD symptoms. However, N.W.’s

mom reports only small improvement, but significant worsening of repetitive behavior and aggression. N.W. has

been pushing, hitting, and throwing things at school and home. Additionally, N.W. has had a decrease in appetite

and lost ∼4 lb. At home, N.W. has recently developed a lot of anxiety, refusing to go to school and participate in

outdoor activities. Her mother notes that N.W. appears to be isolating herself more and not enjoying activities

that used to make her happy. The prescriber discontinues methylphenidate and starts N.W. on risperidone 1

mg/day for aggression and repetitive behaviors. She also starts her on fluoxetine 10 mg/day for depression and

anxiety.

You get a call from N.W.’s mother 3 days after N.W. starts the new medication regimen. N.W.’s mother

reports that N.W. is extremely lethargic, and seems confused. She fell the last few times she tried to get out of

bed. You have the mother use a blood pressure cuff she has at home to measure N.W.’s vital signs. Based on

the results, N.W. is bradycardic and hypotensive. What is your recommendation?

The dose of risperidone that N.W. was started on is high. Additionally, you know

that fluoxetine is a strong 2D6 inhibitor, although risperidone and propranolol are

2D6 substrates. Therefore, fluoxetine may be decreasing the clearance of both the

risperidone and propranolol. You decide to call the provider and discuss the

interaction and adverse effects that N.W. is experiencing.

CASE 88-3, QUESTION 2: The prescriber is thankful for the call and asks for your advice on altering the

current regimen. What changes would you recommend?

You recommend discontinuation of the fluoxetine and initiation of sertraline 12.5

mg/day, because sertraline is a weaker inhibitor of 2D6. You would recommend the

continuation of risperidone at a reduced dose of 0.5 mg/day.

Target Symptoms

Most studies looking at symptoms of anxiety and depression in children with ASD

have used rating scales validated in typically developing children. For anxiety,

predictors that children with ASD will manifest a high level of parent-reported

anxiety include the following: IQ > 70,

102–104 higher levels of parent-rated social

impairment,

102,103 and increased age

103

; additionally, it seems that children with IQ <

70 might experience higher levels of parent-reported anxiety if they demonstrate

more adaptive social behaviors.

102,103 For depression, higher IQ and age seem

correlated with higher depression ratings

105 and both seem to predict lower selfperceived social competence in children with ASD.

106 Lower self-perceived social

competence, in turn, seems to predict high levels of depression symptomatology.

106

Additionally, it seems that adults with ASD with less social impairment (higher

social functioning) were more likely to be categorized as depressed.

107 All of this

seems to indicate that the more individuals with ASD are aware of social

impairments, or exposed to social interactions, the more likely they are to

demonstrate classically recognizable symptoms of anxiety or depression.

However, this body of literature, due to the scales that are used, only addresses

anxiety and depressive mood symptoms that are also seen in typically developing

individuals. Clinicians

p. 1860

p. 1861

who work with individuals with PDD are well aware that anxiety and depression

might manifest in alternative ways in this population. Individuals with ASD often

have impaired abilities to communicate their emotional experiences to others and can

have significant trouble managing their emotions. This routinely leads to alternative

manifestations of emotions like anxiety and depression, in the forms of rigidity,

tantrums, oppositionality, social avoidance, hyperactivity, repetitive behaviors,

irritability, aggression, and self-injury. As mentioned above, studies of SSRIs to

target some of these behaviors, have been mixed.

Overall though, it seems that case studies and open-label trials have shown

possible benefits for the use of SSRIs in children with PDD for the treatment of

classically recognized symptoms of anxiety and depression. To avoid significant

emotional and behavioral adverse events though, target dosing should be lower than

in children with typical development.

SLEEP

Melatonin

The medication with the strongest research backing for the treatment of sleep

disturbance in individuals with developmental disabilities is melatonin. Hollway and

Aman’s excellent review108

found thirteen RCTs of individuals with sleep

disturbance, many of which also with developmental disabilities. All thirteen RCTs

had positive findings, particularly for sleep initiation and sleep maintenance, with the

longest trial being 10 weeks in duration. The effect sizes for sleep onset latency

ranged from .25 to 1.63, and for total sleep time from .25 to 1.0. Adverse effects

were generally mild and similar to placebo. Doses ranged from 2.5 to 10 mg.

Ramelteon

The MT1

/MT2 melatonin receptor agonist has limited evidence in children with

developmental disabilities, though considerable positive findings in adults with

typical development, specifically in primary insomnia and sleep maintenance.

108

Adverse effects were mild and similar to placebo, and doses ranged from 4 to 64 mg.

Clonidine

Although no RCTs have been conducted in children with developmental disabilities

and sleep disturbance, retrospective reviews have shown benefits in helping with

sleep disturbance, with doses ranging from 0.05 to 0.1 mg.

108

Trazodone

Although no RCTs have been conducted in children with sleep disorders, four openlabel studies in children and two in adults showed benefits for improving sleep,

including sleep architecture.

108 Doses ranged from 25 to 150 mg.

Mirtazapine

One open-label study in children and one RCT in adults showed benefits for the

treatment of sleep problems, with mild adverse effects, which included increased

appetite, irritability, and sedation.

108 Doses ranged from 7.5 to 45 mg.

Diphenhydramine

Despite its abundant use in pediatric patients for sleep disturbance, only three RCTs

were identified by Hollway and Aman for its use in pediatric subjects.

108 Two of the

studies were negative, one showed benefit, and none of them were specifically in

children with developmental disabilities.

Zolpidem

Studies are limited, and none seem to have studied individuals with developmental

disabilities, though benefits seem greater in adolescents and adults, and less effective

in children.

108

Benzodiazepines

In partially or uncontrolled studies in children, and controlled studies in adults, it

seems that benzodiazepines may be most effective at helping sleep disturbances

associated with parasomnias (e.g., periodic limb movement disorder, tongue biting,

REM sleep behavior disorder) though with considerable risks of adverse effects,

including tolerance, dependence, rebound insomnia, daytime sedation, and cognitive

impairment.

108

Overall, it seems that melatonin is the most well-studied, effective, and safe

medication option for treating sleep disturbance in individuals with developmental

disabilities. Although promising evidence for ramelteon, trazodone, mirtazapine, and

clonidine exists, further research is needed in individuals with developmental

disabilities. Research evidence does not seem to support the wide use of

diphenhydramine for sleep disorders in children, and although zolpidem and

benzodiazepines may be of benefit for sleep in some, they should be used with

caution, and primarily in adults for zolpidem, and those with parasomnias for

benzodiazepines.

CASE 88-4

QUESTION 1: T.T. is a 10-year-old boy with ASD and significant sleep disturbances. His father has tried

diphenhydramine for the last few weeks but has not seen any meaningful improvement in T.T.’s total sleep

time. Last year, T.T. had a trial of melatonin 2.5 mg daily with only a small recognized improvement. T.T.’s

clinician is thinking about starting a low-dose benzodiazepine, however, is weighing the concerns for adverse

effects. T.T.’s clinician asks for your opinion.

You note that the dose of melatonin last year may have been on the lower range

and you would recommend another trial of melatonin before considering a controlled

substance. The dose you would recommend is 5 mg taken approximately 1 hour to

T.T.’s bedtime. You note that this dose can be increased to 10 mg if an adequate

response is not seen.

Table 88-2

Summary of Target Symptoms and Pharmacologic Treatment

Target Symptom Treatment Medications/Classes to Consider

Hyperactivity Stimulants, atomoxetine, α2

agonists

Irritability/aggression Risperidone, aripiprazole

Repetitive behaviors Risperidone, aripiprazole, fluoxetine, clomipramine, fluvoxamine,

Self-injurious behavior Risperidone, clomipramine, naltrexone

Anxiety/depression SSRIs

Sleep Melatonin, ramelteon, clonidine, trazodone, mirtazapine, zolpidem,

benzodiazepines

SSRI, selective serotonin reuptake inhibitors.

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p. 1862

KEY REFERENCES AND WEBSITES

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p. 1862

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous

psychiatric disorder that consists of multiple subtypes, including

inattention, hyperactivity/impulsivity, and a combination of these two

types. For diagnostic criteria to be met, there must be evidence that

these symptoms are present in multiple settings and that the individual

exhibited this psychopathology before the age of 12 years. These

symptoms cannot be because of other illnesses.

Case 89-1 (Question 1),

Table 89-1

Behavioral therapy is an important component of any effective treatment

plan and typically includes educational interventions, creation of a

structured environment for the child, and introducing contingency

training.

Case 89-1 (Questions 1-3)

Stimulant medications are highly effective for the rapid relief of ADHD

symptoms and substantially improve a child’s prognosis. Individuals who

fail to respond adequately to one type of stimulant will often do well

with another, suggesting that subtle differences exist in the

pharmacologic mode of action. Although the duration of pharmacologic

action is relatively brief for stimulants, a variety of preparations have

been approved that can prolong the relief of ADHD symptoms and

permit once-daily dosing.

Case 89-1 (Questions 3-5),

Table 89-2

There are a number of non-stimulant medications that have proven to be

effective for ADHD over the years, including atomoxetine a NE

reuptake inhibitor, and α-agonists. These medications may be viable

options for the management of treatment-resistant illness as well as in

patients with a history of substance abuse. They also possess a different

side effect profile than stimulants and have a delay until therapeutic

effects are evident.

Case 89-1 (Question 6),

Table 89-2

Many people are reluctant to consider stimulant medications for ADHD

treatment because of unfounded fears about drug tolerability and abuse.

As a result, there have been a wide variety of alternative treatments

considered for use, including changes in dietary habits, ingestion of

herbs and supplements, and other somatic interventions. At the present

time, the evidence supporting these options is sparse, although the rigor

of investigations has steadily improved in recent years, and there is hope

that some of these options may prove to be beneficial.

Case 89-2 (Question 1)

ADHD is commonly associated with several psychiatric and medical

comorbidities, and these concurrent conditions often influence treatment

plans. Tic disorders such as Tourette syndrome are frequently found in

children with ADHD, but research evidence suggests that stimulants

are not only safe but also effective in this particular population.

Case 89-1 (Question 1)

Some children with ADHD will continue to have symptoms of their

illness well into their adult years, usually of the inattention subtype.

There is a growing awareness that adults with ADHD have significant

social and occupational impairments. Fortunately, medications used to

treat ADHD in children appear to be equally effective in adults.

Stimulants are the most effective agents but have the unique side effect

risk of abuse and diversion. Monitoring for this is essential. If abuse or

diversion occurs then a reevaluation of the diagnosis is necessary as

well as a change to a medication with less risk of misuse.

Case 89-2 (Question 2)

p. 1863

p. 1864

Although the diagnosis and treatment of attention deficit and hyperactivity disorder

(ADHD) have been associated with considerable controversy, ADHD is a serious

psychiatric condition that has been well described in the medical literature for more

than two centuries.

1 There are highly effective pharmacologic treatments that

ameliorate the core symptoms of the illness. These agents are generally safe and have

been shown to improve long-term prognosis.

2

By definition, ADHD symptoms manifest in childhood and will often persist into

adulthood in many cases. If left untreated, ADHD can produce significant

impairments in academic performance and social functioning; adults with ADHD are

often hindered in occupational settings as well.

3 Psychiatric comorbidities are

commonly encountered among individuals suffering from ADHD, including

developmental disorders, mood disorders, and substance abuse.

Although hyperactivity had been recognized as a troublesome childhood behavior

for many years, ADHD was not formally described in the Diagnostic and Statistical

Manual of Mental Disorders until the third edition was released in 1980. The

recently released DSM-5 describes three different subtypes of ADHD including

“Predominantly inattentive presentation,” “Predominantly hyperactive/impulsive

presentation,” and “Combined presentation.”

4 The DSM-5 also requires the diagnosis

by age 12, in contrast to DSM IV that required the onset of impairment before age 7.

Qualitatively the core symptoms of ADHD will differ according to gender, with boys

more likely to exhibit the hyperactive/impulsive subtype (vs. girls).

5 These symptoms

often change with time as hyperactive and impulsive behaviors recede during

adolescence, and inattention predominates among adolescents and adults with

ADHD.

6