REVIEW

CURRENT
OPINION Pharmacotherapy for mental health problems
in people with intellectual disability
Na Young Ji a,b and Robert L. Findling a,b

Purpose of review
Psychotropic medications are commonly prescribed to people with intellectual disability. We reviewed
current evidence-based pharmacotherapy options and recent updates to guide clinicians in their
medication management plans.
Recent findings
Antipsychotics, particularly risperidone, appear to be effective in reducing problem behaviors in children
with intellectual disability. Evidence in adults is inconclusive. Methylphenidate appears to be effective,
and a-agonists appear promising in reducing attention-deficit hyperactivity disorder symptoms. Lithium
might be effective in reducing aggression. Evidence is limited to support the use of antiepileptic drugs,
anxiolytics, and naltrexone for management of problem behaviors. Antidepressants may be poorly
tolerated and might not be effective in reducing repetitive/stereotypic behaviors.
In recent trials, glutamatergic and GABAergic agents for fragile X syndrome, and acetylcholinesterase
inhibitors for Down’s syndrome, failed to show efficacy. Growth hormone treatment might improve
cognition and behavior in Prader–Willi syndrome population. Results from oxytocin trials on social
behaviors are inconclusive albeit promising. Melatonin appears to improve sleep. Most trials of dietary
supplements did not show benefits.
Summary
Evidence-based pharmacotherapy options in people with intellectual disability are limited, and many
agents can cause substantial adverse events. For this reason, clinicians should consider pharmacotherapy
as only a part of comprehensive treatment, and regularly assess drug effects, adverse events, and the
feasibility of decreasing dose or withdrawing medications.
Keywords
intellectual disability, pharmacotherapy, problem behaviors

INTRODUCTION CURRENT EVIDENCE AND PERTINENT

Mental health and behavioral problems, such as
aggression, self-injurious behavior (SIB), attentional
problems, depression, and anxiety are common in
people with intellectual disability (PWID) [1]. Psy-
chotropic medications are often prescribed to treat
these problems, and concerns of overuse and high
rates of polypharmacy in this population have been
&&
raised [2 ,3]. These concerns are further compli-
cated by the challenges in obtaining informed
consent for PWID. Furthermore, PWID tend to
experience adverse events more frequently than
the general population when prescribed psycho-
&
tropic medications [4,5 ]. Therefore, it is important
for clinicians to understand current evidence of
pharmacologic interventions, whereas carefully
weighing the risk/benefit ratio and alternatives
when considering pharmacotherapy.
UPDATES
We primarily focused on randomized placebo-
controlled trials (RPCTs) with a sample size of
10 or more within the entire study. We also included
genetic and other syndromes commonly associated
with PWID. We did not include studies conducted
exclusively in an autism spectrum disorder (ASD)
population, as we reviewed most of these studies
a
Kennedy Krieger Institute and bDepartment of Psychiatry and Behavioral
Sciences, Division of Child and Adolescent Psychiatry, Johns Hopkins
University School of Medicine, Baltimore, Maryland, USA
Correspondence to Na Young Ji, Kennedy Krieger School Programs,
3825 Greenspring Ave, Baltimore, MD 21231, USA. Tel: +1 443 923
7793; fax: +1 443 923 7788; e-mail: ji@kennedykrieger.org
Curr Opin Psychiatry 2016, 29:103–125
DOI:10.1097/YCO.0000000000000233

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Neurodevelopmental disorders
KEY POINTS
 Antipsychotics, particularly risperidone, appear to be
effective in reducing problem behaviors associated with
intellectual disability.
 For ADHD symptoms, methylphenidate has been shown
to be effective, and atomoxetine and a-agonists might
be beneficial.
 Lithium might be effective in reducing aggression.
Evidence for the use of antiepileptic drugs, anxiolytics,
and naltrexone for management of problem behaviors
is insufficient to draw conclusions.
 Antidepressants are often poorly tolerated and do not
appear to be effective in decreasing repetitive or
stereotypic behaviors associated with
intellectual disability.
 Melatonin appears to improve sleep in people with
intellectual disability.
in our previous article [6]. We limited our search
to studies that targeted mental health problems,
and excluded studies exclusively focused on other
medical problems (i.e., seizures, cancers, and
growth). Except for risperidone and aripiprazole
for treatment of irritability associated with ASD,
no other medications are approved specifically for
PWID by the US Food and Drug Administration.
Antipsychotics
Antipsychotics are the most commonly prescribed
&
psychotropic medications in PWID [7 ,8]. The target
symptoms are not limited to psychotic symptoms,
and often include problem behaviors, such as
aggression, SIB, severe stereotypies, hyperactivity
and severe temper tantrums [9].
Overall, there appears to be good evidence to
support the use of antipsychotics, particularly ris-
peridone, in children with intellectual disability
(CWID) [10–30] (Table 1). Two large acute RPCTs
of risperidone were conducted in children with
subaverage intelligence and disruptive behavior dis-
orders [14,16]. Aman et al. reported that a separation
from placebo in behavioral changes occurred as
early as the first week of treatment [16]. Snyder
et al. noted that intelligent quotient (IQ) or sedation
did not moderate the drug effects [14]. Somnolence,
headaches, appetite increase, weight gain, prolactin
increases, and extrapyramidal symptoms (EPS) were
commonly reported adverse events. The longer-
term efficacy and safety of risperidone were
described in subsequent open-label extension stud-
ies of these clinical trials that lasted up to a year
104 www.co-psychiatry.com
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[15,17]. In long-term studies of risperidone, initial
prolactin elevation seems to often reduce over time,
and sedation did not appear to result in decline in
cognitive functioning [15,17,31].
Results from the studies of antipsychotics in
adults with intellectual disability (AWID) are equiv-
ocal. Three RPCTs showed risperidone was effica-
cious in improving problem behaviors [10,18,19].
However, a more recent large-scale study with
three arms showed no significant difference in the
outcomes between risperidone, haloperidol, and
placebo groups [20]. Furthermore, a recent study
showed that controlled discontinuation of antipsy-
chotics prescribed for problem behaviors in PWID
resulted in improved behavioral functioning [32].
Efficacy and safety of aripiprazole in reducing
problem behaviors in children with ASD has
been well supported by large RPCTs [33–35]. How-
ever, no RPCT of aripiprazole was found in PWID
without ASD.
An RPCT of olanzapine in children with ASD
(seven out of 11 were CWID) reported efficacy in
improving clinical global impression, but resulted in
significant weight gain [36].
Two RPCTs of haloperidol in PWID suggest some
benefit in reducing problem behaviors [21,22]. EPS
were commonly reported.
A small randomized placebo-controlled cross-
over (RPCCO) study showed that body rocking
was significantly suppressed, but other problem
behaviors were not influenced by chlorpromazine
treatment. Chlorpromazine caused noticeable
drowsiness in all patients [37].
For thioridazine, some RPCTs showed only min-
imal improvement or worsening of problem behav-
iors [23,25,26] and another suggested efficacy in
improving some problem behaviors [24]. Neverthe-
less, the use is limited because of the potential for
proarrythmic cardiotoxicity including Torsades
de pointes.
Recent randomized placebo-controlled with-
drawal studies showed that zuclopenthixol (not
marketed in the United States) was superior to
placebo in maintaining improved problem behav-
iors in PWID [27,28,30]. Sedation, fatigue, and EPS
were common adverse events.
Stimulants and other medications for
attention deficit hyperactivity disorder
symptoms
Many RPCTs have reported the efficacy of methyl-
phenidate for treatment of attention deficit
hyperactivity disorder (ADHD) symptoms in CWID
&
(Table 2) [5 ,38–53]. However, the response rates in
&
CWID (40–60%) [5 ,44] are lower than what are
Volume 29  Number 2  March 2016
 Table 1. Selected randomized, placebo-controlled trials of antipsychotics for mental health problems in people with intellectual disability
Participants’
Study design  intellectual Target Noteworthy adverse
Medication Publication duration Dose N; age (years) disability range symptoms Comments events

Risperidone Vanden Borre (1993) RPCCO  7 weeks Add-on 4–10 mg/day 37; 15–58 Mild-profound PBs Separation from placebo in Sedation, drowsiness,
[10] improving PBs and and hypotension.
clinical global No difference in EPS
impression was observed
Zarcone (2001) [13] RPCCO  22 weeks; 6 Low dose: 1.5–3mg 20; 6–65 (9 adults) Mild to profound PBs Separation from placebo in Weight gain, sedation
months follow-up High dose (mean): improving PBs
1.8 mg/day for
children 2 mg/day
for adults
Van Bellinghen (2001) RPCT  4 weeks Mean 1.2 mg/day 13; 6–14 Borderline; IQ 66–85 PBs Separation from placebo in No clinically significant
[11] improving PBs and differences;
global clinical increased heart rate,
impression somnolence
Buitelaar (2001) [12] RPCT  6 weeks 0.5–5 mg bid; mean 38; 12–18 Subaverage IQ; IQ PBs Separation from placebo in Parkinsonism
2.9 mg/day 60–90 improving PBs and
clinical global
impression
Snyder (2002) [14] RPCT  6 weeks 0.4–3.8 mg/day; 110; 5–12 Borderline to PBs Separation from placebo in Somnolence,
mean 0.98 mg/day moderate; mean IQ decreasing conduct headaches, appetite
65.7–68.2; all with problems and clinical increase, weight
a DBD; no ASD global impression gain, dyspepsia,
prolactin increase
Turgay (2002) [15] Open-label extension 0.02–0.06 mg/kg/ 77; 5–12 Borderline to PBs Improvement was Somnolence,
of Snyder (2002) day; mean moderate; all with a maintained over 48- headache, weight
[14]  48 weeks 1.38 mg/day DBD; no ASD week extension period gain, prolactin

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decreased over time
Aman (2002) [16] RPCT  6 weeks 0.02–0.06 mg/kg/ 118; 5–12 Borderline to PBs Separation from placebo in Somnolence,
day; mean moderate; IQ 36– improving PBs and headaches,
1.16 mg/day 84; all with a DBD; clinical global vomiting, dyspepsia,
no ASD impression weight increase,
elevated serum
prolactin, increased
appetite
Findling (2004) [17] Open-label extension Mean 1.5 mg/day 107; 5–12 Borderline to PBs Improvement was Somnolence,
of Aman (2002) moderate; all with a maintained during long- headaches, rhinitis,
[16]  48 weeks DBD; no ASD term treatment weight gain,
prolactin decreased
over time
Gagiano (2005) [18] RPCT  4 weeks; 1–4 mg/day; mean 77; 18–59 Borderline to PBs Separation from placebo Somnolence,
Open-label  48 1.45 mg/day moderate; IQ 35– in improving PBs and headaches,
weeks 83 global clinical hyperprolactinemia,
impression. A further weight gain,
improvement during headaches
open-label follow-up

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Hellings (2006) [19] RPCCO  22 weeks; Low: 1 mg/day for 40; 8–56 (19 adults) Mild to profound; PBs Separation from placebo in Sedation,
Open-label youths, 2 mg/day IQ < 70; 36 with improving PBs. Low gastrointestinal
extension  24 for adults; high: ASD doses were equally complaints, all

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weeks 0.05 mg/kg/day effective but better increased appetite,
tolerated than high and weight gain
doses

(Continued )
Pharmacotherapy for mental health problems Ji and Findling

105
 106
Table 1 (Continued)
Participants’
Study design  intellectual Target Noteworthy adverse
Medication Publication duration Dose N; age (years) disability range symptoms Comments events

Risperidone Tyrer (2008) [20] RPCT, 3 arms  26 Risperidone: 0.5– 86; 26–75 Borderline to severe; PBs Neither drug showed No significant group
Haloperidol weeks 2 mg/day; five with ASD separation from placebo differences
Haloperidol: 1.25– in aggression, aberrant
5 mg/day placebo behavior, quality of life,
and general
improvement measures
Neurodevelopmental disorders

Haloperidol Burk (1968) [21] RPCT  8 weeks 0.2–7.8 mg/day 50; 5–21; mean age Moderate PBs The authors concluded that EPS (subsided with

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13.7 the active drug group reduction of drug
had a significantly dosage)
greater probability of
improvement in
hyperactivity,
assaultiveness,
impulsivity, and SIB
Aman (1989) [22] RPCCO  9 weeks Low: 0.025 mg/kg/ 20; 12–35 IQ 8–48 PBs The high-dose group No noteworthy
day, High: separated from placebo changes in seizure
0.05 mg/kg/day, in reducing strategic frequency or blood
placebo for 3 weeks behavior, and pressure and heart
each increasing movement rate measures were
and decreasing observed
inactivity
Thioridazine Singh (1981) [23] RPCCO  14 weeks Individualized dose: 20; mean age 15.79 IQ untestable-30 PBs Separation from placebo Weight gain (more
1.28–17.54 mg/ only in reducing pronounced during
kg/day (Mean hyperactivity and the individualized
5.23 mg/kg/day); stereotypy. No does treatment)
Standards dose: separation between two
2.5 mg/kg/day dose conditions
Heistad (1982) [24] RPCCO  8 weeks 30–800 mg/day; 106; 18–65 All with intellectual PBs Separation from placebo in None noteworthy
mean 235 mg/day disability; more than improving PBs.
50% profound
Aman (1988) [25] RPCT crossover  12 Previous dose, Low: 11; age unspecified Moderate to profound; PBs No separation from Lethargy, social
weeks 1.25 mg/kg/day, IQ 10–48 placebo in improving withdrawal
High: 2.5 mg/kg/ PBs. The high-dose
day then placebo group separated from
for 3 weeks each the low-dose group in
reducing hyperactivity
and SIB
Thioridazine SCH- Elie (1980) [26] RPCT, 3 arms  4 Thioridazine 50 mg/ 51; 32.9  2.59 IQ 33.2  3.29 PBs No separation from Sedation,
12679 weeks day, SCH-12679 placebo in improving gastrointestinal
100 mg/day PBs. Thioridazine group disturbances,
placebo had worse violence, anorexia, mydriasis

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provocativeness, and
anger at week 4

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 Pharmacotherapy for mental health problems Ji and Findling

ASD, autism spectrum disorder; DBD, disruptive behavior disorders; EPS, extrapyramidal symptoms; IQ, intelligent quotient; PBs, problem behaviors; RPCCO, randomized placebo-controlled crossover; RPCT, randomized
expected for typically developing children

abnormal behavior
(70–80%) [54,55]. CWID are also more susceptible

aggression, and

None noteworthy
to adverse events, including sleep difficulties and
Separation from placebo in Fatigue, EPS,
poor appetite. Unlike previous reports, a recent
Separation from placebo in Sedation

larger RPCT found IQ did not affect treatment effi-

Separation from placebo in EPS

&
cacy within CWID [5 ].
There is an RPCCO study in four children with

for the entire withdrawal

responders remaining

responders remaining
long-term treatment fetal alcohol spectrum disorder, which showed
improving PBs and

maintained during

methylphenidate was effective in reducing ADHD

the proportion of

the proportion of
clinical global

symptoms [56]. An RPCCO study in children with

The effects were
assessment

velocardiofacial syndrome suggested that methyl-

period
phenidate might improve cognition and ADHD
symptoms [45].
A small RPCCO study with methylphenidate,
dextroamphetamine, and placebo suggested that
Aggression

Aggression

Aggression

methylphenidate might be more effective and

safer than dextroamphetamine in boys with
PBs

fragile X syndrome (FXS) [46]. Apart from another

intellectual disability;

study which described that dextroamphetamine

intellectual disability

reduced hyperactivity compared with placebo in

Borderline IQ to

Borderline IQ to

a boy with mild intellectual disability [57], we

Mild to severe

IQ 30–70

IQ 30–84
Borderline to
moderate;

found no other studies of amphetamine-based

agents.
Atomoxetine was effective in reducing ADHD
symptoms in children with ASD with/without intel-
lectual disability in recent RPCTs [58,59]. Somno-
lence, fatigue, anorexia, nausea, and irritability were
common adverse events.
52; 22–60

49; 18–50

39; 24–54

39; 8–17

A small RPCCO study showed clonidine was

placebo-controlled trial; RPCWD, randomized placebo-controlled withdrawal; SIB, self-injurious behavior.

effective in reducing both inattentive and hyper-

active/impulsive ADHD symptoms in CWID [51].
Drowsiness, dry mouth, and anorexia were common
adverse events.
Open-label  6 weeks; 2–20 mg/day

2–20 mg/day

4–20 mg/day

A small RPCCO of guanfacine in children with

Open-label  6 weeks; 10 mg/day

developmental disabilities showed benefits in

improving hyperactivity and global functioning
[52]. A recent large RPCT in children with ASD
RPCWD  12 weeks

RPCWD  12 weeks

(63% were with IQ<70) showed that extended-

of Haessler (2007)
Open-label extension

RPCWD  12 weeks

release guanfacine was effective in reducing hyper-

[28]  2 years

activity/impulsivity and inattention with a large

effect size (1.67) [53]. Drowsiness, fatigue,
emotional fragility, and irritability were common
adverse events.
Haessler (2007) [28]

Haessler (2011) [29]

Haessler (2014) [30]

Singh (1992) [27]

Mood stabilizers and antiepileptic drugs

&&
Despite the common clinical use [2 ,8], evidence
for the efficacy of mood stabilizers and AEDs in
PWID is sparse, particularly outside the studies of
lithium (Table 3) [60–67].
A number of RPCTs showed lithium was effica-
cious for management of problem behaviors,
Zuclopenthixol

particularly aggression, in PWID [60–63,68]. How-

ever, most of these studies used nonvalidated out-
come measures. Nausea, diarrhea, headaches and
tremors were common adverse events [69].

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 108
Table 2. Selected randomized placebo-controlled trials of stimulants and other medications for attention deficit hyperactivity disorder symptoms in people with intellectual
disability
Participants’
Study design  N; age intellectual Noteworthy adverse
Medication Publication duration Dose (years) disability range Target symptoms Comments events

Stimulants
MPH Handen (1990) [38] RPCCO  6 weeks 0.3 and 0.6 mg/kg 12; 6–9 IQ 50–74 ADHD symptoms Separation from Increased staring,
BID behavioral measures placebo in drowsiness, social
improving ADHD withdrawal
symptoms (75%
responded to MPH),
work output, on-task
Neurodevelopmental disorders

behavior, and

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attentional skill; but
not in improvement
in learning
Handen (1991) [39] RPCCO  6 weeks 0.3 and 0.6 mg/kg 27; 6–12 IQ 48–74 Side-effects monitoring Separation from 22% discontinued
BID placebo in because of
decreasing intolerable AEs,
irritability, anxiety, including motor tics
moodiness, and and severe social
activity level. 67% withdrawal
responded to MPH
Handen (1992) [40] RPCCO  6 weeks 0.3 and 0.6 mg/kg 14; 6–12 IQ 48–74 ADHD symptoms, Separation from 4 patients discontinued
BID learning, social placebo in reducing because of
interactions ADHD symptoms intolerable adverse
(64% responded to events
MPH) and on-task
behavior. No
separation from
placebo in learning
or social interactions
Handen (1994) [41] RPCCO  6 weeks 0.3 and 0.6 mg/kg 47; 6–12 IQ 48–77 Predicting factors for Higher rating in Not reported
BID MPH response impulsivity, activity
level inattention, and
conduct problems at
baseline. Patients
who were men,
Whites and of high
socioeconomic level
were associated
with better
responses, but none
were statistically
significant
Handen (1999) [42] RPCCO  4 weeks 0.3 and 0.6 mg/kg 11; 4–5 IQ 40–78 ADHD symptoms Separation from Five patients
QAM to BID placebo in reducing experienced

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ADHD symptoms. significant AEs
67% responded to (social withdrawal,
MPH increased crying,
irritability)

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 Pearson (2003) [43] RPCCO  4 weeks 0.15, 0.30, and 24; 8–13 IQ 46–67 ADHD symptoms Separation from Sleep problems and
0.60 mg/kg BID placebo in reducing poor appetite were
ADHD symptoms. significantly more
The most significant frequent with
improvements 0.60 mg/kg dose
occurred at 0.60
mg/kg dose. No
separation from
placebo with
0.15 mg/kg dose
Aman (2003) [44] Three aggregated 0.40 mg/kg/day 90; 4–17 IQ untestable to 90; ADHD symptoms Separation from Slight heart rate
RPCTs 2–4 mean IQ placebo in increase
weeks 58.5  16.1 improving attention,
overactivity and
conduct problems. In
total, 44% of
patients showed at
least a 30%
reduction in teacher
ratings
Green (2011) [45] RPCT, single-dose; 0.5 mg/kg  single 34; 5–20 Velocardiofacial Prefrontal cognitive Separation from Increase in pulse rate
Open-label dose; 0.5 mg/kg/ syndrome; mean performance, ADHD placebo in and blood pressure
follow-up  6 day thereafter IQ 82.8  10.5 symptoms improvement in after single-dose
months cognitive Poor appetite,
performance after headache, and
single-dose MPH. In stomachache after 6
total, 40% reduction months
in severity of ADHD
after 6 months
No intolerable AEs,

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psychosis or manic/
hypomanic
exacerbations
&
Simonoff (2013) [5 ] RPCT  16 weeks Titrated from 0.5 to 122; 7–15 IQ 30–69; 32 with a ADHD symptoms Separation from Sleep difficulties,
1.5 mg/kg/day SCQ score over a placebo in improving decreased appetite
cutoff for ASD ADHD symptoms.
No subgroup
difference according
to autistic symptoms
or IQ
MPH Dextro- Hagerman (1988) [46] RPCCO  3 weeks MPH: 0.3 mg/kg BID; 15; 3–10 FXS boys; IQ 29–77 ADHD symptoms Both active drug Mood lability and
amphetamine Dextroamphetamine: treatments separated irritability were more
0.2 mg/kg/day from placebo in common with
improving only dextroamphetamine
teachers’ ADHD
ratings. MPH but not
dextroamphetamine
separated from
placebo in

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improving attention
and social skills

(Continued )

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Pharmacotherapy for mental health problems Ji and Findling

109
 110
Table 2 (Continued)
Participants’
Study design  N; age intellectual Noteworthy adverse
Medication Publication duration Dose (years) disability range Target symptoms Comments events

MPH Fenfluramine Aman (1993) [47] RPCCO  12 MPH: 0.4 mg/kg/day 28; 5–13 IQ untestable to 78; Cognitive function, Neither drug separated MPH increased heart
weeks QAM; Fenfluramine: mean 61 ADHD symptoms from placebo in rate and blood
Titrated from 0.5 to improving attention. pressure
1.5 mg/kg/day MPH separated from
divided BID placebo in reducing
commission errors,
Neurodevelopmental disorders

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whereas
fenfluramine
separated from
placebo on the
memory task
MPH Fenfluramine Aman (1997) [48] RPCCO  10 MPH: 0.4 mg/kg/day; 30; 5–14 IQ  84 Cognitive function, Both drugs separated Most side-effects
weeks Fenfluramine: 1.0, ADHD symptoms from placebo in (drowsiness,
1.5, or 2.0 mg/kg/ different areas of dizziness, anorexia)
day cognitive measures, occurred with
but not all. In total, fenfluramine
14% with IQs below
50 were regarded
as MPH responders,
48% with IQs of 50
or above were
responders (was not
statistically
significant, however)
MPH Thioridazine Aman (1991) [49] RPCCO  9 weeks MPH: 0.40 mg/kg/ 30; 4–16 IQ untestable to 90; ADHD symptoms, Both drugs separated Depressive affect,
day Thioridazine: mean measured IQ conduct problem from placebo in insomnia, diarrhea
1.75 mg/kg/day 52.3  20.4 some ADHD
divided BID measures but clinical
response to
thioridazine was
substantially less
than the response to
MPH. In total, 37%
considered MPH
responders; 27%
considered
thioridazine
responders
Fenfluramine Selikowitz (1990) [50] RPCCO  14 10–40 mg TID 15; 5–27 PWS; 14 with mild to Weight, food related Separation from None noteworthy
weeks depending on age moderate behavior placebo in weight
loss, improvement in

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food-related
behavior, decrease
in aggressive
behavior directed
toward others, but
not in self-mutilation

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 a-Agonists
Clonidine Agarwal (2001) [51] RPCCO  12 4, 6, 8 mg/kg/day 10; 6–15 IQ 30–69 ADHD symptoms Separation from Drowsiness, dry mouth,
weeks divided BID or TID placebo in anorexia
improving
hyperactivity/
impulsivity and
inattention. The
effect on
hyperactivity/
impulsivity was dose-
related from 4–
8 mg/kg/day,
whereas inattention
did not improve
further beyond
6 mg/kg/day
Guanfacine Handen (2008) [52] RPCCO  6 weeks Titrated to 2.5–3 mg/ 11; 5–9 10 with subaverage Behavior, ADHD Separation from Drowsiness, lethargy,
day divided TID IQ to severe; 7 symptoms placebo in irritability
with ASD improving
hyperactivity and
global impression,
but not in other
behavioral
measures. 45%
responded to
guanfacine

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Guanfacine Scahill (2015) [53] RPCT  8 weeks 1–4 mg/day 62; 5–14 All with ASD; 63% ADHD symptoms Separation from Drowsiness, fatigue,
extended-release with IQ < 70 placebo in reducing emotional fragility,
hyperactivity (effect tearfulness,
size ¼ 1.67), irritability, sinus
impulsivity, and bradycardia; one
inattention, but not patient was
in working memory hospitalized with
or motor planning aggression and
measures. In total, pressured speech
50% positively
responded to
extended-release
guanfacine

ADHD, attention-deficit hyperactivity disorder; AEs, adverse events; ASD, autism spectrum disorder; BID, twice daily; FXS, fragile X syndrome; IQ, intelligent quotient; MPH, methylphenidate; QAM, daily in the morning;
RPCCO, randomized placebo-controlled crossover; RPCT, randomized placebo-controlled trial; SCQ, social communication questionnaire.

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Pharmacotherapy for mental health problems Ji and Findling

111
 112
Table 3. Selected randomized placebo-controlled trials of mood stabilizers and antidepressants for mental health problems in people with intellectual disability
Participants’
Study design  N; age intellectual Target Noteworthy adverse
Medication Publication duration Dose (years) disability range symptoms Comments events

Mood stabilizers and antiepileptic drugs

Lithium Naylor (1974) [60] RPCT  2 years Level 0.6–1.0 mEq/l 14; 19–58 Mild-profound; all with Affective and Separation from placebo in None noteworthy
affective symptoms behavioral reducing mean number of
changes weeks ill
Tyrer (1984) [61] RPCCO  5 months Level 0.5–0.8 mmol/l 26; 14–50 (mean 27) ‘Mentally handicapped’ PBs Separation from placebo in None noteworthy;
reducing stereotypy but 1 patient with
not other PBs. 17 of the epilepsy showed
25 patients showed increase in seizures
improvement during the
Neurodevelopmental disorders

lithium phase compared

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with placebo
Craft (1987) [62] RPCT  4 months Level 0.7–1.2 mmol/l 42; 19–65 ‘Mentally handicapped’ Aggression Separation from placebo in Thirst, polyuria,
reducing aggression. In incoordination,
total, 73% showed tremors, drowsiness,
improvement on lithium and vomiting
compared with 30% on
placebo
Tyrer (1993) [63] RPCCO  4 months Add on level 0.5– 52; age unspecified ‘Mentally handicapped’ PBs Separation from placebo in None noteworthy
0.8 mmol/l reducing physical
aggression. On lithium
compared with placebo,
56% showed
improvement, 44%
showed no improvement,
and 10% had an increase
in aggression
Carbamazepine Reid (1981) [64] RPCCO  7 months Add-on level 25– 12; 14–50 (10 adults) Severe to profound; five Overactivity No separation from placebo None noteworthy
42 mmol/l with epilepsy in improving PBs. Some
improvements in
overactivity in the group
with overactivity without
other PBs
Antidepressants
Imipramine Aman (1986) [65] RPCCO  9 weeks 3 mg/kg/day 10; 8–25 Profound; IQ 9–19 Depressive symptoms Significantly worse irritability, Increased heart rate
and PBs hyperactivity, and lethargy
symptoms with imipramine
Clomipramine Lewis (1995) [66] Single-blind RPCT  2 Titrated up to 225 mg/ 10; 18–42 Intellectual disability Stereotypy, repetitive Separation from placebo in Poor appetite,
weeks; double-blind day SIB, and improving body and constipation,
RPCT  7 weeks; compulsive object stereotypy increased salivation,
RPCCO  10 weeks behavior and dizziness; 3/10
dropped out because
of seizure, ataxia,
flushing, worsening
mood with agitation,
and aggression

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Lewis (1996) [67] Single-blind RPCT  2 Up to 3 mg/kg/day 8; 21–39 Severe to profound; no SIB No separation from placebo 2/8 dropped out
weeks; double-blind ASD in SIB measures. 6/8 because of seizure,
RPCT  7 weeks; showed 50% or more tachycardia, and
RPCCO  10 weeks reduction in SIB with agitation
clomipramine

ASD, autism spectrum disorder; IQ, intelligent quotient; PBs, problem behaviors; RPCCO, randomized placebo-controlled crossover; SIB, self-injurious behavior.

Volume 29  Number 2  March 2016


The results from RPCTs of valproate in ASD
populations are mixed [70–72]), and no RPCT in
PWID without ASD was found. Evidence from open-
label studies suggested valproate might be effective
in improving problem behaviors and affective symp-
toms in PWID [73,74]. An open-label study in boys
with FXS suggested that valproate might be effective
in reducing ADHD symptoms [75]. A small RPCT
showed that carbamazepine was effective in reduc-
ing problem behaviors in AWID [64].
Antidepressants
The evidence for antidepressant use in PWID is
sparse, and overall is discouraging with generally
low response rates and high rates of adverse events
(Table 3) [60–67].
An RPCCO study in AWID showed worsening of
problem behaviors with imipramine treatment
compared with placebo, irrespective of depressive
symptoms [65]. An RPCCO study of clomipramine
in AWID showed efficacy in improving stereotypy
[66], whereas another RPCCO study did not show
efficacy in reducing repetitive SIB [67]. Both clo-
mipramine studies showed high dropout rates
(around 30%), because of intolerable adverse events,
including seizure, agitation, and aggression.
We found no RPCT of selective serotonin
reuptake inhibitors (SSRIs) in PWID without ASD
(selected RPCTs in pediatric ASD populations were
reviewed in our previous article [6]). Open-label
studies of fluoxetine for treatment of problem
behaviors, including repetitive and obsessive-com-
pulsive behaviors in PWID, showed mixed results
[76–78]. Their response rates ranged from 11–60%.
Deterioration of symptoms and intolerable adverse
events, such as irritability, increased aggression, and
sleep difficulties commonly occurred. Open-label
studies of paroxetine and citalopram in PWID that
targeted depressive symptoms reported slightly bet-
ter response rates and tolerability [79,80]. Studies in
ASD populations suggested that SSRIs might be bet-
&
ter tolerated in adults than in children [81 ]. How-
ever, most studies of SSRIs in PWID included both
adults and children, and age specific data were sel-
dom reported, therefore, we could not discern
whether the tolerability might be age related in this
population or not.
Anxiolytics
Although anxiolytics are often used in PWID for
treatment of anxiety symptoms and problem behav-
&&
iors [2 ], evidence to support their use is sparse.
Benzodiazepines may worsen problem behav-
iors in some PWID [82], and their long-term use
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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Pharmacotherapy for mental health problems Ji and Findling
can increase the risk of developing tolerance and
withdrawal, as well as potentially negative effects on
cognition, which are often documented in elderly
with cognitive decline [83]. Results from uncon-
trolled studies of buspirone for treatment of prob-
lem behaviors in AWID are mixed, some reporting
improvements [84–86] while another describing no
improvement [87]. Open-label studies suggested
that b-blockers might be effective in reducing
aggression and SIB in PWID [88–90].
Glutamatergic and g-aminobutyric acidergic
agents
Several glutamatergic and g-aminobutyric acidergic
(GABAergic) agents have been investigated in PWID
associated with genetic syndromes, in hopes of
modulating a hypothesized excitatory-inhibitory
imbalance in the brain. However, the results from
RPCTs of these agents have been rather disappoint-
&
ing (Table 4) [91,92,93 ,94–110].
Results from RPCTs of targeted treatments for
FXS with a number of mGluR5 antagonists, ampa-
kine (CX516) [91], mavoglurant (AFQ056; fraxa.org)
&
[92,93 ], and basimglurant (RO4917525; fragilex.
&
org.uk) [93 ] have failed to show efficacy in primary
outcome measures.
RPCTs of piracetam and memantine (glutamate
receptor modulators) showed mixed results. Pirace-
tam did not show efficacy in improving cognition in
Down’s syndrome children [94]. For memantine,
two RPCTs in Down’s syndrome adults did not show
efficacy in improving cognitive measures [95,96],
whereas an RPCT in adults with fragile X-associated
tremor/ataxia syndrome demonstrated efficacy in
improving verbal memory [97].
Despite the previous study suggesting benefits
in reducing social avoidance in people with FXS
[98], results from two subsequent large RPCTs of
arbaclofen (GABAB receptor agonist) did not show
efficacy in primary outcome measures [99].
Cholinergic agents
Agents that increase cholinergic effects, such as
acetylcholinesterase inhibitors and L-carnitine/
L-acetylcarnitine [111], have been investigated for
enhancement of cognition in PWID, but they pro-
&
duced mixed results (Table 4) [91,92,93 ,94–110].
In RPCTs in people with Down’s syndrome,
and in an RPCT in boys with FXS, donepezil (an
acetylcholinesterase inhibitors) failed to separate
from placebo in primary cognitive and behavioral
outcome measures [100,102–104,106]. Posthoc
analyses in these studies, and results from a small
RPCT in a Down’s syndrome population, suggested
www.co-psychiatry.com 113
 Table 4. Selected randomized placebo-controlled trials of glutamatergic, GABAergic, and cholinergic agents for mental health problems in people with intellectual disability

114
Study design  Participants’ intellec- Noteworthy adverse
Medication Publication duration Dose N; age (years) tual disability range Target symptoms Comments events

Glutamatergic and GABAergic agents

Ampakine (CX516) Berry-Kravis (2006) RPCT  4 weeks 600–900 mg 49; 18–49 FXS; 25 with ASD; IQ Cognitive (memory) No separation from 12.5% developed
[91] 36–75 and behavioral placebo in measures allergic rash, mild
outcomes of memory, elevation of hepatic
language, attention/ enzyme
executive
functioning, or
behavior
Mavoglurant Jacquemont (2011) RPCCO  4 weeks Titrated from 50 to 30; 18–35 FXS; IQ unspecified Behavioral symptoms No separation from Fatigue, headache
(AFQ056) [92] 150 mg BID placebo in
Neurodevelopmental disorders

www.co-psychiatry.com
improving primary
behavioral
measures. Posthoc
analysis showed
separation from
placebo in
improving behavior
only in fully
methylated group
NCT01357239 RPCT  12 weeks 25, 50, or 100 mg BID 139; 12–17 FXS; IQ unspecified Behavioral symptoms No separation from Unpublished
&
[93 ] placebo in
improving primary
behavioral measures
NCT01253629 RPCT  12weeks 25, 50, or 100 mg BID 175; 18–45 FXS; IQ unspecified Behavioral symptoms No separation from Unpublished
&
[93 ] placebo in
improving primary
behavioral measures
Basimglurant (RO NCT01517698 RPCT  12 weeks 0.5 or 1.5 mg/day 185; 14–50 FXS; IQ unspecified Behavioral symptoms No separation from Unpublished
&
4917523) [93 ] placebo in
improving primary
behavioral measures
NCT01750957 RPCT  12 weeks Only specified as 47; 5–13 FXS; IQ unspecified Behavioral symptoms No separation from Unpublished
&
[93 ] doses A and B in placebo in
clinicaltrials.gov improving primary
behavioral measures
Piracetam Lobaugh (2001) RPCCO  8 months 80–100 mg/kg/day 25; 6–13 Down’s syndrome; IQ Cognitive function No separation from CNS stimulatory effects
[94] unspecified placebo in cognitive (aggression,
performance or agitation, sexual
behavioral measures arousal, poor sleep,
and decreased
appetite) in 7/18
completed
Memantine Hanney (2012) RPCT  52 weeks 5 mg/day titrated to 173; > 40; mean 51 Down’s syndrome with, Cognition and No separation from None noteworthy
[95] 10 mg/day without dementia adaptive function placebo in any

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

cognitive measures
irrespective of
presence of a
dementia diagnosis
Boada (2012) RPCT  16 weeks 5 mg/day titrated to 40; 18–32 Down’s syndrome; Memory and other No separation from Anxiety, transient
[96] 10 mg BID average mental age cognitive function placebo in primary dizziness, echolalia,
7.6 (drug), 6.1 outcomes of memory hair loss
(placebo) assessments

Volume 29  Number 2  March 2016

 Yang (2014) [97] RPCT  52 weeks 5 mg/day titrated to 41; 62.1  2.5 (drug), FXTAS; IQ unspecified Verbal memory Separation from None noteworthy
10 mg BID 64.7  8.5 placebo in
(placebo) improving verbal
memory.
Improvement in
verbal memory was
positively correlated
with improvement in
event-related brain
potential studies
Arbaclofen (STX209) Berry-Kravis (2012) RPCCO  9 weeks Up to 10 mg BID for 63; 6–39 (17 adults) FXS; 37 with ASD; IQ Neurobehavioral No separation from Upper gastrointestinal
[98] Then follow-up  4 < 12 years, 10 mg 46  8 function, irritability, placebo on primary symptoms, sedation,
weeks TID for  12 years social avoidance outcome measures fatigue and
of irritability. Post headache
hoc analysis showed
separation in
improving social
avoidance
Berry-Kravis (2014) RPCT  8 weeks Flexible dosing 125; 12–50 FXS; IQ unspecified Social avoidance, PBs No separation from Headache, vomiting,
[99] (CNS meeting) placebo on any nausea, irritability/
behavioral measures agitation, anxiety,
hyperactivity,
decreased appetite,
and infections
Berry-Kravis (2014) RPCT, 4 arms  8 5 mg BID, 10 mg BID, 172; 5–11 FXS; IQ unspecified Social avoidance, PBs No separation from
[99] (CNS meeting) weeks 10 mg TID or placebo except for
placebo improving irritability
with 10 mg TID dose
Cholinergic agents
Donepezil Prasher (2002) RPCT  24 weeks 5–10 mg/day 30; 40–69 Down’s syndrome; mild Global functioning, No separation from Diarrhea, insomnia,
[100] to severe; all with cognitive function, placebo on any fatigue, and nausea
mild to moderate PBs outcomes. There was

0951-7367 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
dementia a tendency for
benefit with
donepezil in global,
cognitive and
adaptive functioning
Prasher (2003) Open-label extension 5–10 mg/day 25; 51.0  8.9 Down’s syndrome; mild Global functioning, Less deterioration in None noteworthy
[101] of Prasher (2002) to severe; all with cognitive function, global functioning
[100]  80 weeks mild to moderate PBs and adaptive
dementia behavior in
participants treated
with donepezil
compared to a
matched nontreated
group over a 2-year
period
Johnson (2003) RPCT  12 weeks 5–10 mg/day 19; 17–50 Down’s syndrome; no Cognitive function, No separation in One participant
[102] dementia behavior cognitive or experienced
behavioral measures increased irritability
except for language and agitation and

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scores withdrew from the
study

(Continued )

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Pharmacotherapy for mental health problems Ji and Findling

115
 Table 4 (Continued)

116
Study design  Participants’ intellec- Noteworthy adverse
Medication Publication duration Dose N; age (years) tual disability range Target symptoms Comments events

Kishnani (2009) RPCT  12 weeks 5–10 mg/day 123; 18–35 Down’s syndrome; no Cognitive and adoptive No separation from Abdominal pain,
[103] dementia functioning placebo in cognitive nausea, vomiting,
impairment and insomnia
measures.
Separation from
placebo in
improving adaptive
functioning
Kishnani (2010) RPCT  10 weeks 2.5–10 mg/day 129; 10–17 Down’s syndrome; mild Adaptive functioning No separation from Diarrhea, vomiting,
[104] to moderate placebo in upper respiratory
Neurodevelopmental disorders

improving adaptive tract infection

www.co-psychiatry.com
functioning
Kondoh (2011) RPCT  24 weeks 3 mg/day 21; women 32–58 Down’s syndrome; IQ Mental and physical Separation from Soft stool and skin rash
[105] 6–35 functioning placebo in
improving mental
and physical
functioning
Sahu (2013) RPCT  12 weeks 2.5–5 mg/day 20; boys 6–15 FXS; mean IQ Cognitive and No separation from Diminished appetite,
[106] 42  11.5 (drug) behavioral functions placebo in changes sluggishness,
48.3  9.5 in cognitive somnolence, and
(placebo) functions or daytime enuresis
behavioral measures
L-carnitine Ellaway (1999) PRCCO  24 weeks 100 mg/kg/day 35; 4–35 Rett syndrome; IQ Motor behavior, well- No separation from Loose bowel actions,
[107] divided TID unspecified being index placebo in motor fishy body or urine
behavior measures. odor
Separation from
placebo in well-
being in parent
reports
L-acetylcarnitine Torrioli (1999) RPCT  12 months 50 mg/kg BID 20; boys 6–13 FXS; IQ < 30–69 Hyperactivity Separation from None noteworthy
[108] placebo in reducing
hyperactivity in
parent reports but
not in teacher
reports
Pueschel (2006) RPCT  9 months 10 mg/kg/day 40; 19–23 Down’s syndrome; IQ Intelligence, behavior No separation from None noteworthy
[109] increased to 30 unspecified placebo in any
mg/kg/day divided cognitive or
TID behavioral measures
Torrioli (2008) RPCT  12 months 500 mg BID 63; boys 6–13 FXS; average IQ ADHD symptoms Separation from Mild headache,
[110] 46.45 (drug), 45.62 placebo in reducing nausea, vomiting,
(placebo) ADHD symptoms and diarrhea
and improving
social behavior

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ADHD, attention-deficit hyperactivity disorder; ASD, autism spectrum disorder; BID, twice daily; CNS, Child Neurology Society; FXS, fragile X syndrome; FXTAX, fragile X-associated tremor/ataxia syndrome; IQ,
intelligent quotient; PBs, problem behaviors; RPCCO, randomized placebo-controlled crossover; TID, three times daily.

Volume 29  Number 2  March 2016


donepezil might improve language and adaptive
functions [102,103,105]. Donepezil was generally
well tolerated [101].
RPCTs of L-carnitine and L-acetylcarnitine
suggested efficacy in reducing ADHD symptoms
in boys with FXS [108,110], but did not show effi-
cacy in improving cognitive or behavioral functions
in Rett syndrome or Down’s syndrome populations
[107,109].
Endocrinologic agents
Results from recently completed RPCTs of oxytocin
on social behavior in ASD population have been
mixed, and it appears single-dose administration
might be more effective than continuous treatment
&
in improving social behavior [112 ]. Currently,
about a dozen clinical trials of oxytocin in ASD
&
populations are underway [93 ].
In PWID populations (Table 5) [113–125], an
RPCT showed that single-dose oxytocin adminis-
tration increased eye gaze in 10 men with FXS (with
adaptive functioning 3–5 standard deviations below
the norm) [114]. In an RPCT, in adults with Prader–
Willi syndrome (PWS), single-dose oxytocin admin-
istration improved measures of trust in others, prob-
lem behaviors, and sadness tendency [113].
However, 8-week treatment of oxytocin did not
improve cognitive or behavioral functions in an
RPCCO study in a PWS population [115].
Growth hormone deficiency is common in
people with PWS, and some RPCTs suggested that
growth hormone therapy might improve cognitive
and behavioral functions in this population (Table
5) [113–125]. One recently published study showed
that open-label growth hormone therapy for up to
7 years in children with PWS was well tolerated, and
reduced delays in adaptive skills and motor develop-
ment, even though the drug effects were not
detected after 1–2 years of treatment during the
RPCT phase [122].
In RPCTs, melatonin appears to be effective in
reducing sleep problems in PWID, and was well
tolerated [123,124]. A large RPCT in neonates with
Down’s syndrome suggested that thyroxine might
have improved motor and mental development
[125]; however, its follow-up study at age 10.7 years
did not show benefits in motor or mental develop-
ment from the early treatment [126].
Opioid antagonists and other agents
Results from RPCTs of naltrexone in PWID are
mixed (Table 6) [127–138]. Some reported rather
robust effects [127,129], whereas others reported no
separation from placebo in reducing SIB [130], or
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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Pharmacotherapy for mental health problems Ji and Findling
deleterious effects on motor development and Rett
syndrome progression [128]. Appetite decrease,
nausea, tiredness, and sedation were reported
adverse events.
Most RPCTs of methylation promoting dietary
supplements such as folate and betadine failed to
show efficacy in improving cognitive, adaptive, or
behavioral functions (Table 6) [127–138]. A recent
RPCT in boys with FXS reported that minocycline
was effective in improving problem behaviors
associated with ADHD and anxiety [131].
CONCLUSION
Despite the fact that psychotropic medications are
commonly prescribed in PWID, evidence to support
their use is very limited.
Antipsychotics, particularly risperidone, have
shown to be effective in reducing problem behaviors
in CWID. Evidence of their use in AWID is incon-
sistent. The risk of adverse events, including EPS and
metabolic adverse events associated with long-term
antipsychotics use is concerning, and needs to be
reserved for severely impairing problem behaviors.
Methylphenidate appears effective in reducing
ADHD symptoms in PWID. Adverse events, includ-
ing irritability, appetite suppression, and sleep dif-
ficulties are common. Atomoxetine might be
effective also, inferring from the evidence in ASD
populations. a-Agonists, particularly extended-
release guanfacine, appear promising but need more
studies to draw a conclusion.
Lithium might be effective in reducing problem
behaviors in PWID, but many of the studies are
outdated and lack methodological rigor. There is
insufficient evidence to support use of valproate
or anxiolytics, including b-blockers for manage-
ment of problem behaviors, anxiety, and/or mood
symptoms in PWID. Antidepressants are often
poorly tolerated in PWID, and evidence to support
their use for management of repetitive/stereotypic
behaviors or other problem behaviors is weak.
Despite more promising preclinical data, tar-
geted treatment for people with genetic syndromes,
including glutamate receptor modulators and arba-
clofen for FXS, and donepezil for Down’s syndrome,
have failed to show consistent efficacy in recent
RPCTs. Growth hormone treatment in people with
PWS might have benefits in improving cognition
and behavior.
Results from RPCTs of oxytocin on social behav-
iors are mixed, but many more studies are currently
underway. Melatonin appears to reduce sleep diffi-
culties in PWID. It seems there might be a subgroup
of PWID that responds favorably to naltrexone with
reduced SIB, but predictors are unknown. Most
www.co-psychiatry.com 117
 118
Table 5. Selected randomized placebo-controlled trials of endocrinologic agents for mental health problems in people with intellectual disability
Participants’
Study design  intellectual Noteworthy adverse
Medication Publication duration Dose N; age (years) disability range Target symptoms Comments events

Oxytocin Tauber (2011) [113] RPCT  single dose Intranasal 24 IU 24; 18–43 PWS; IQ 45–75 Trust in others, Separation from None noteworthy
disruptive behavior placebo in
increasing trust in
others and
decreasing
disruptive behavior
and sadness
tendency, two days
after the
Neurodevelopmental disorders

administration of

www.co-psychiatry.com
oxytocin
Hall (2012) [114] RPCT  single dose Intranasal 24 IU and 10; men 13–28 FXS; adaptive Symptoms of social Separation from One participant
48 IU functioning 3–5 anxiety placebo in developed Bell’s
standard deviations increasing eye gaze palsy
below norm frequency and
salivary cortisol
levels
Einfeld (2014) [115] RPCCO  18 weeks 24 increased to 40 IU 30; 12–30 PWS; mental age Physical, behavioral No separation from None noteworthy
BID for > 16 years based on WASI (IQ) and cognitive placebo in
18 increased to 10–27 aspects development or
32 IU BID for 13–15 behavioral
years measures. Increase
in temper outbursts
with higher dose of
oxytocin compared
to placebo
Growth hormone Whitman (2002) [116] RPCCO  2 years 1 mg/m2/day 54; 4–16 PWS; IQ unspecified Psychiatric and No separation from 31% reported negative
behavioral placebo in side effects, all were
symptoms psychiatric symptom physical not
measures behavioral and were
not reported in the
paper
Höybye (2005) [117] RPCT  6 months; then 1.6 IU/day (0.53 mg/ 19; adults median PWS; IQ 40–90 Cognitive, emotional, Separation from None noteworthy
open-label follow- day) age 25 and social status placebo in
up  12 months improving mental
speed and flexibility,
and motor
performance
Myers (2007) [118] RPCT  1 year then 1 mg/m2/day 25; 4–37 months PWS; IQ unspecified Anthropometry, motor, Separation from One patient
the placebo group language and placebo in experienced
received 1.5 mg/ cognitive improving language scoliosis progression
m2/day for the developments and cognitive
second year development

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Festen (2008) [119] RPCT  12 months 1 mg/m2/day 43; 0.5–3 PWS; median mental Development Separation from None noteworthy
age 1.5 (drug), 1.2 placebo in infant
(placebo) mental and motor
development
measures

Volume 29  Number 2  March 2016

 Siemensma (2012) RPCT  2 years; open- 1 mg/m2/day 50; mean age PWS; mean IQ 66 Cognitive functioning Appeared to prevent None noteworthy
[120] labeled follow- 7.4  2.4 deterioration of
up  4 years certain cognitive
skills during the
RPCT but no
separation from
placebo. Abstract
reasoning and
visuospatial skills
improved during the
4 years of growth
hormone treatment
Böhm (2015) [121] RPCT  1 year then the 0.033 mg/kg/day or 19; 3–11 PWS; IQ  55–108; Cognition and No separation from None noteworthy
placebo group 0.066 mg/kg/day median IQ 64 behavior placebo in cognitive
received double measures during the
dose for the second RPCT. PBs worsened
year after discontinuation
of growth hormone
at the end of 2
years
Lo (2015) [122] RPCT  1 year for 1 mg/m2/day 75; 1–7 PWS; IQ 61–85 in Adaptive and cognitive No separation from None noteworthy
infants, 2 years for prepubertal children development placebo in the
prepubertal children; measures of
open-label follow-up development during
for up to 7 years the RPCT. During the
long-term follow-up,
reduction in delays
in communication,
living skills,
socialization, and
motor skills
development were
observed

0951-7367 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Melatonin Niederhofre (2003) RPCCO  9 week 0.1 and 3 mg 30 min 20; 14–18 IQ < 70 Insomnia Separation from None noteworthy
[123] before bed placebo (all doses of
melatonin) in
improving sleep
efficiency
Wirojanan (2009) RPCCO  4 weeks 3 mg 12; 2–15 ASD and/or FXS; 8 Sleep disturbances Separation from None noteworthy
[124] with ASD; IQ placebo in
unspecified increasing sleep
duration and
shortening sleep
onset latency
Thyroxine Trotsenburg (2005) RPCT  2 years 8 mg/kg 196; neonates Down’s syndrome; IQ Motor and mental Separation from Five children in the
[125] unspecified development and placebo in reducing thyroxine group
growth motor developmental were diagnosed
age delay. Mental with ‘other central
developmental age nervous system
delay was reduced disease’, which was
also, but lacked not specified in the
statistical paper
significance

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ASD, autism spectrum disorder; BID, twice daily; FXS, fragile X syndrome; IU, international unit; IQ, intelligent quotient; PBs, problem behaviors; PWS, Prader–Willi syndrome; RPCCO, randomized placebo-controlled

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crossover; WASI, Wechsler Abbreviated Scale of Intelligence.
Pharmacotherapy for mental health problems Ji and Findling

119
 120
Table 6. Selected randomized placebo-controlled trials of opioid antagonist and other agents for mental health problems in people with intellectual disability
Participants’
Study design  intellectual Noteworthy adverse
Medication Publication duration Dose N; age (years) disability range Target symptoms Comments events

Opioid antagonist
Naltrexone Sandman (1993) RPCCO  10 weeks 0.5, 1.0, and 2 mg/ 24; 13–67, mean Moderate to profound; SIB, stereotypy, activity Separation from None noteworthy
[127] kg/day 33.7, 23 adults five with ASD level, learning placebo in reduction
of SIB. No
separation in
activity, stereotypy,
involuntary
movement, and
neurological
Neurodevelopmental disorders

www.co-psychiatry.com
measures
Percy (1994) [128] RPCCO  9 months 1 mg/kg/day 25; 2–15 (placebo) Rett syndrome; Development, motor- Separation from Not reported
developmental age behavior analysis placebo in declines
1–13 months in motor
development and
more rapid
progression of the
disorder (deleterious
effect)
Gibson (1995) [129] RPCCO  10 weeks 0.5, 1.0, and 2.0 mg/ 24; 14–67 Moderate to profound SIB, motivation 65% had 25% Not recorded
kg/day assessment reduction in SIB with
2.0 mg/kg/day. SIB
with a motivation
related to sensory
consequences did
not influence the
drug response
Willemsen-Swinkels RPCCO  15 weeks 50 and 150 mg/day 33; 18–46 Mild to profound; 23 SIB, ASD symptoms No separation from Sedation, nausea,
(1995) [130] with ASD placebo in tiredness. One
therapeutic effects patient had
on SIB or symptoms worsening SIB and
of autism. Stereotypy withdrew from the
was worse with study
naltrexone treatment
Other agents
Minocycline Leigh (2013) [131] RPCT  6 months 25–100 mg/day 66; 3–16 FXS; mean IQ Global functioning, Separation from None noteworthy
depending on 58.8  20.7 (drug), severity of PBs placebo in clinical
weight 52.2  11.0 global impression,
(placebo) but not in severity of
target behaviors
Creatine Freilinger (2011) RPCCO  13 months 200 mg/kg/day 18; women 3–25 Rett syndrome; IQ Global DNA Separation from None noteworthy
[132] unspecified methylation, motor placebo in
behavior symptoms increasing global
DNA methylation.

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No separation from
placebo in motor
and behavioral
measures
Folate and betaine Glaze (2009) [133] RPCT  12 months Folic acid 15 mg QD. 73; women 1–28 Rett syndrome; IQ Clinical symptoms, No separation from None noteworthy
Betaine 2 g TID or unspecified motor/behavioral placebo in clinical
3 g QID depending function or behavioral
on weight measures

Volume 29  Number 2  March 2016

 Peters (2010) [134] RPCT  12 months Folic acid 15 mg QD, 48; 0.5–14 Angelman syndrome; Clinical symptoms, No separation from None noteworthy
betaine 2 g TID to IQ unspecified development placebo in clinical
3 g QID or developmental
parameters
Betaine, metafolin, Bird (2011) [135] RPCT  12 months Betaine 100–200 mg/ 90; 0–5 Angelman syndrome; Cognitive, motor, and No separation from 7 withdrew from the
creatine, and kg/day, metafolin mean Bayley language placebo in study because of
vitamin B12 0.5 mg/kg/day, developmental index development, DNA developmental worsening of
creatine 200 mg/ 31.5  14.0 (drugs), methylation performances or site- seizures, onset or
kg/day, vitamin 33.8  14.4 specific DNA worsening of sleep
B12 1mg/day (placebo) methylation problems,
constipation, or
anorexia
Folic acid Hagerman (1986) RPCCO  12 months 10 mg/day 25; men 1–31 FXS; IQ < 10–86 Cognition, language, No separation from None noteworthy
[136] behavior placebo in
psychological testing
and behavioral
measures
Strom (1992) [137] RPCCO  6 months 15 mg/day 21; men 2–22, mean FXS; IQ unspecified Laboratory test, No separation from Diarrhea, sleep delay
8.3 adaptive and placebo in and ‘mood swings’,
cognitive functions, laboratory or facial edema
behavior cognitive behavioral
measures

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Folinic acid Ellis (2008) [138] RPCT, 4 arms Antioxidants (selenium 156; < 7 months Down’s syndrome; Psychomotor and No separation from Vomiting or distress
Antioxidants (antioxidants only, 10 mg, zinc 5 mg, mean developmental language placebo in with antioxidants
folinic acid only, vitamin A 0.9 mg, quotient 56.1–58.7 development developmental or
antioxidants and vitamin E 100 mg, biochemical
folinic acid vitamin C 50 mg) measures
combined, and Folinic acid 0.1 mg/
placebo)  18 day
months

ASD, autism spectrum disorder; FXS, fragile X syndrome; IQ, intelligent quotient; PBs, problem behaviors, PWS, Prader–Willi syndrome; QD, once daily; QID, four times daily; RPCCO, randomized placebo-controlled
crossover; RPCT, randomized placebo-controlled trials; SIB, self-injurious behavior; TID, three times daily.

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Pharmacotherapy for mental health problems Ji and Findling

121
Neurodevelopmental disorders
RPCTs of dietary supplements did not show benefits
on development or behavioral measures.
Even with the medications that have evidence for
efficacy, safety, and tolerability are generally poorer
in PWID relative to those in the general population.
Therefore, more pharmacotherapy options for
severely impairing symptoms are urgently needed.
However, similar to the challenges in ASD popu-
lations discussed in our previous review [6], the wide
range of phenotypic and genotypic heterogeneity of
intellectual disability, and difficulty measuring drug
effects on cognition and mental development,
particularly after a short-term treatment, greatly hin-
der the development of effective drugs.
Continued research in genetic disorders associ-
ated with intellectual disability, such as FXS, Down’s
syndrome, and PWS might further expand our
understanding of pathophysiology, and thus help
identify endophenotypes of intellectual disability.
These types of advances could one day bring more
targeted and individualized treatments for PWID.
Clinical guidelines
With the paucity of evidence for pharmacotherapy
options for mental health problems in PWID, the
following clinical guidelines are recommended:
(1) Intellectual disability is a lifelong disorder, and
pharmacotherapy should be considered only as
a part of comprehensive multidisciplinary treat-
ment plan (behavioral therapy, special edu-
cation, living and social skills training, etc.).
(2) Clinicians should consider nonpharmacological
interventions, including functional behavior
analysis, behavioral management, and environ-
mental modifications before considering
pharmacotherapy.
(3) Pharmacotherapy should be reserved for impair-
ing symptoms where the risks of adverse events
are justified.
(4) Appropriate informed consent, with thorough
discussions of the risk-benefit ratio and altern-
atives, should be obtained.
(5) Target symptoms should be identified for each
medication, and treatment efficacy should be
tracked regularly with objective outcomes (fre-
quency, duration and severity of the symptoms,
and rating scales)
(6) ‘Start low and go slow’ to minimize adverse
events and increase tolerability.
(7) Monitor adverse events actively and regularly
(utilize questionnaires or scales)
(8) Minimize polypharmacy to decrease the like-
lihood of drug–drug interactions, adverse
events, and medication noncompliance.
122 www.co-psychiatry.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
(9) Aim to use the lowest effective dose and con-
sider lowering dose or withdrawing the medi-
cation after an extended period of stability
(6–12 months).
Acknowledgements
The authors would like to thank Dr James Harris for his
insightful feedback on our manuscript, and Katherine
Kendrick, BS for her help in organizing tables and refer-
ences.
Financial support and sponsorship
None.
Conflicts of interest
N.J. has no conflicts of interest. R.L.F. receives or has
received research support, acted as a consultant and/or
served on a speaker’s bureau for Alcobra, American
Academy of Child & Adolescent Psychiatry, American
Physician Institute, American Psychiatric Press, Astra-
Zeneca, Bracket, Bristol-Myers Squibb, CogCubed, Cog-
nition Group, Coronado Biosciences, Dana Foundation,
Elsevier, Forest, GlaxoSmithKline, Guilford Press, Johns
Hopkins University Press, Johnson & Johnson, Jubilant
Clinsys, KemPharm, Lilly, Lundbeck, Merck, NIH, Neu-
rim, Novartis, Noven, Otsuka, Oxford University Press,
Pfizer, Physicians Postgraduate Press, Purdue, Rhodes
Pharmaceuticals, Roche, Sage, Shire, Sunovion, Supernus
Pharmaceuticals, Transcept Pharmaceuticals, Validus,
and WebMD.
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