57 studies of aripiprazole versus placebo in
children and adolescents with autistic disorder were 8 weeks in duration. Prevalence
of comorbid ID was not mentioned in either study. Both studies showed statistically
significant improvement in children treated with aripiprazole, compared to placebo,
for ABC-I, CGI-I, as well as ABC subscales of hyperactivity and stereotypy.
flexible dosing schedule showed statistically significant
improvements in the ABC subscale for inappropriate speech with aripiprazole versus
fixed-dose study, only the 15 mg/day dose of
aripiprazole showed statistically significant improvement in inappropriate speech.
Neither study showed statistically significant improvement for aripiprazole, versus
placebo for the ABC lethargy/social withdrawal subscale. Both studies defined
response as at least a 25% reduction from baseline to endpoint in the ABC-I subscale
and a CGI-I score of 1 (very much improved) or 2 (much improved) at endpoint.
With this definition, response rate was 52.2% for aripiprazole in Owen et al.’s
(14.3% for placebo) and although response rates for each dose of
aripiprazole (5 mg—55.8%*, 10 mg—49.2%, 15 mg—52.8%) were higher than
placebo (34.7%) in Marcus et al.’s study,
58 only the response rate at 5 mg/day
separated from placebo with statistical significance.
the three most common adverse events leading to
discontinuation of aripiprazole were sedation, drooling, and tremor, none of which
were reported in the placebo group. The most common adverse events reported in the
aripiprazole group of Owen et al.’s study
57 were fatigue, somnolence, vomiting,
increased appetite, and sedation. In Owen et al.,
57 14.9% of aripiprazole-treated
subjects (vs. 8% for placebo) endorsed EPS symptoms, with the most common being
tremor (8.5%). In Marcus et al.,
58 EPS symptoms were reported at roughly twice the
rate in all aripiprazole doses (5 mg/day—23.1%, 10 mg/day—22.0%, and 15 mg/day
—22.2%) compared to placebo (11.8%), the most common of which were tremor
and extrapyramidal disorder. Aripiprazole was associated with statistically
significant gains in weight compared to placebo after 8 weeks, with the mean weight
gain on aripiprazole in Owen et al.
57 being 2.0 kg, and for Marcus et al.,
mg/day), 1.3 kg (10 mg/day), and 1.5 kg (15 mg/day). Interestingly, both studies
showed aripiprazole to have statistically significant reductions in prolactin levels
compared to placebo. Mean final daily dosing for aripiprazole in Owen et al.
8.9 mg/day. In a 52-week open-label follow-up study of participants from both Owen
58 as well as newly enrolled subjects, mean final daily
dosing of aripiprazole was 10.6 mg/day.
In a 2-month RCT of aripiprazole versus
risperidone in children with ASD, the mean final daily dose of aripiprazole was 5.5
69 Manufacturer recommended daily dosing of aripiprazole in pediatric patients
with schizophrenia or bipolar disorder is 10 mg/day.
Overall, the literature shows that risperidone and aripiprazole, in doses likely
lower than that used in children with schizophrenia or bipolar disorder, can be used
effectively to reduce symptoms of irritability and aggressive behavior in children and
adolescents with ASD, though treatment should be monitored closely for relatively
common adverse events of sedation, weight gain, and EPS. Of note, although
risperidone has been shown to consistently increase prolactin levels, aripiprazole
was shown to consistently lower prolactin levels.
Although risperidone and aripiprazole are the two antipsychotic medications with
FDA approval for the treatment of irritability in children with ASD, other typical and
also demonstrated benefits for treating symptoms of irritability in children with
ASD. Haloperidol, dosed in the range of 0.5 to 4.0 mg/day, has shown benefits in
four RCTs and two long-term follow-up studies, though with significant rates of
71 One RCT supports the benefits of pimozide, one RCT supports
the use of olanzapine, and either open-label studies or case reports exist to support
the benefits of olanzapine, clozapine, quetiapine, ziprasidone, and paliperidone.
head-to-head comparison RCT of risperidone and haloperidol in children with
autistic disorder showed risperidone to be significantly more effective than
haloperidol at reducing aberrant behavior and symptoms of PDD.
comparing risperidone, haloperidol, and placebo for the treatment of aggression in
adults with ID showed all three treatment arms to decrease aggression, though no
significant difference between any of the three treatments.
Two RCTs of similar size (n = 30
) looked at valproate versus placebo
in children and adolescents with ASD and irritability/aggression with somewhat
conflicting results. Hellings et al.
found no significant difference in improvement of
irritability or aggression (including ABC-I and CGI-I) between valproate and
placebo after 8 weeks, whereas Hollander et al.,
36 after 12 weeks, showed valproate
to be significantly superior to placebo at improving CGI-I and the rate of
improvement of ABC-I. While in Hollander et al.,
36 no significant differences existed
in adverse events between valproate and placebo, in Hellings et al.,
significantly increased rate of endorsed appetite increase in the valproate group, and
two individuals in the valproate group developed elevated ammonia levels, one with
clinically associated symptoms. Both studies had target blood valproate levels (at
Additional medications with either limited RCT data, open-label studies, or case
reports to support its use for irritability in individuals with ASD include buspirone,
clomipramine, clonidine, levetiracetam, memantine, mirtazapine, pioglitazone,
topiramate (when added to risperidone), riluzole, sertraline, and trazodone,
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 irritability.
with the addition of risperidone, which is now at 4 mg/day.
antipsychotics. You make the following recommendation.
Although risperidone and aripiprazole are not necessarily interchangeable, both
are indicated for the treatment of irritability in children with ASD, and aripiprazole
may convey less of a risk for weight gain than risperidone. This potential benefit may
outweigh the potential risk of aripiprazole being less clinically efficacious than
risperidone in some patients. In this context, you may recommend for the prescriber
to decrease risperidone by 1 mg every other week, while starting aripiprazole 2
mg/day for 7 days followed by an increase to 5 mg daily. Additional 5 mg dose
increases can be made weekly up to a maximum of 15 mg/day. C.Y. should be
monitored for tolerability during both the cross-taper/titration period and beyond.
Numerous different types of medications have been studied for the treatment of
repetitive behaviors in individuals with ASD. Selective serotonin reuptake inhibitors
(SSRIs) and TCAs have been studied likely due to perceived similarities between
the repetitive behaviors and compulsions exhibited in children with obsessive–
compulsive disorder, as well as the clinical observation that repetitive behaviors
may increase in children with PDD due to underlying anxiety. However, the literature
is mixed to support the use of SSRIs or TCAs for this indication.
Selective Serotonin Reuptake Inhibitors
Two RCTs looking at SSRIs for children with ASD and repetitive behavior
demonstrate conflicting results. Hollander et al.’s
78 crossover trial (n = 39, mean age,
8.2 years) showed that low-dose liquid fluoxetine was superior to placebo for
treating repetitive behaviors, as measured by the Children’s Yale-Brown Obsessive
Compulsive Scale (CY-BOCS) compulsion subscale, with a medium to large effect
size (0.76), though did not separate from placebo for improvements in other aspects
of global autism severity. In King et al.’s
large study of citalopram (n = 73) versus
placebo (n = 76) to target repetitive behaviors in children with ASD, there were no
statistically significant differences between citalopram and placebo in improvements
(n = 15 each group), however, did show fluvoxamine to be significantly superior to
placebo for improving repetitive thoughts and behavior.
anxiety/depression for more details on SSRI prescribing in children with ASD].
Clomipramine was studied in Gordon et al.’s
55 RCT, in which it was shown to be
significantly superior to both placebo and desipramine for the treatment of repetitive
behavior in children with ASD as shown by the Modified CPRS OCD subscale, the
modified National Institute of Mental Health (NIMH) OCD Scale, and the modified
NIMH Global OCD and Anxiety scales. The mean final week daily dose of
clomipramine was 152 mg; the mean final week clomipramine blood level was 235
ng/mL and desmethyl clomipramine level was 422 ng/mL. Overall adverse events
were relatively minor, though in those taking clomipramine, one person had a seizure,
and two had cardiac adverse events, one with a prolonged corrected QT interval
(0.45 seconds) and the other with severe tachycardia (160–170 beats/minute), both of
which resolved with reduction in dose. In Remington et al.’s
weeks each intervention) comparing clomipramine to haloperidol in children with
autistic disorder, the most striking finding was that only 37.5% of participants taking
clomipramine finished the study (compared to 69.7% haloperidol and 65.6% for
placebo), with adverse events contributing to discontinuation including behavioral
problems, fatigue or lethargy, tremors, tachycardia, insomnia, diaphoresis, nausea or
vomiting, and decreased appetite. The mean daily dose of clomipramine was 128.4
Overall, for the reduction of repetitive behaviors, SSRIs, specifically fluoxetine,
and TCAs, specifically clomipramine, may be helpful in children with ASD, though
adverse events may be particularly limiting for clomipramine. For adults with ASD,
SSRIs, specifically fluvoxamine, may be helpful in reducing repetitive behaviors.
Antipsychotics have shown the most robust evidence in reducing repetitive behaviors
in children with ASD. Nearly all of the data to support antipsychotics for this
purpose come from the same studies that targeted irritability. Both aripiprazole
32,33 were superior to placebo for reducing the score on the ABC
Stereotypy subscale. In McDougle et al.’s
81 secondary analysis of the 8-week RUPP
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
66 which found statistically significant reductions in the
modified version of the Y-BOCS (focusing only on repetitive behavior, not thoughts).
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.
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.
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.
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
83,84 one of which was statistically significant,
84 and statistically significant
66 Similar to studies in children with ASD, weight
gain and somnolence were markedly higher in children taking risperidone than
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.
reports and open-label studies have shown possible benefit for buspirone and
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
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.
Selective Serotonin Reuptake Inhibitors
Studies have found that individuals with PDDs are at high risk of comorbid anxiety
37,38 Due to the demonstrated benefits and relative safety of
SSRIs in typically developing children, SSRIs are very commonly prescribed 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.
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,
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
repetitive behaviors. In the crossover study (8 weeks each phase) of low-dose
fluoxetine by Hollander et al.
(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
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.
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.,
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.,
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%),
For citalopram, in the 12-week study by King et al.
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.
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.
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
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
78 of children with PDD was 9.9 mg, or 0.36 mg/kg. This is compared to
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
For citalopram, the mean daily dose in the King et al. study
and repetitive behavior was 16.5 mg. In studies of citalopram use in typically
developing children and adolescents with depression, citalopram was tolerated at
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
You get a call from N.W.’s mother 3 days after N.W. starts the new medication regimen. N.W.’s mother
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.
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.
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
; 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.
Additionally, it seems that adults with ASD with less social impairment (higher
social functioning) were more likely to be categorized as depressed.
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
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.
The medication with the strongest research backing for the treatment of sleep
disturbance in individuals with developmental disabilities is melatonin. Hollway and
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.
/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.
Adverse effects were mild and similar to placebo, and doses ranged from 4 to 64 mg.
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 Doses ranged from 25 to 150 mg.
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.
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.
studies were negative, one showed benefit, and none of them were specifically in
children with developmental disabilities.
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 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
Comments
Post a Comment
اكتب تعليق حول الموضوع