MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES
RESEARCH REVIEWS 10: 42–48 (2004)
PSYCHOPHARMACOLOGY IN FRAGILE X
SYNDROME—PRESENT AND FUTURE
Elizabeth Berry-Kravis* and Kristina Potanos
Department of Pediatrics, Neurology, and Biochemistry, RUSH-University Medical Center, Chicago, Illinois
In addition to cognitive disability, fragile X syndrome (FXS) is associ-
ated with behavioral problems that are often functionally limiting. There are
few controlled trials to guide treatment; however, available information
does suggest that medications can be quite helpful for a number of cate-
gories of behavioral disturbance in FXS. Specifically, stimulants appear to be
quite useful for management of distractibility, hyperactivity, and impulsive
behavior; antidepressants help with anxiety, obsessive-compulsive behav-
iors and mood dysregulation; and antipsychotics can reduce aggression.
These medications are supportive and help minimize dysfunctional behav-
iors and maximize functioning. As more is learned about the neural func-
tions of FMRP, medications in the future will be expected to target specific
synaptic mechanisms dysregulated in FXS brain and thus ameliorate the
cognitive deficit with resultant behavioral improvements. This article sum-
marizes knowledge about effectiveness and approaches to management of
currently available psychopharmacology for behavior in FXS and discusses
early leads to future treatments for cognition. © 2004 Wiley-Liss, Inc.
MRDD Research Reviews 2004;10:42– 48.
Key Words: fragile X syndrome; psychopharmacology; medications;
FMR1; synaptic plasticity; ampakine
CURRENT PSYCHOPHARMACOLOGY IN
FRAGILE X SYNDROME
General Strategy for Treatment
T
reatment strategies for individuals with fragile X syn-
drome (FXS) are at this point supportive strategies de-
signed to maximize functioning, as no treatments in
current clinical use are directed specifically at the underlying
neuronal defect due to absence of FMRP. As behavior in FXS
can significantly impact functionality, symptom-based treatment
of the most problematic behaviors in the individual with FXS
can be quite helpful.
Behavioral dysregulation occurs in over 50% of patients
with cognitive disability in general. This is a multifactorial
problem and at least in part stems from cognitive and executive
dysfunction, language deficits and difficulty communicating,
immature regulation of arousal and emotional state, and misin-
terpretation of the environment. Behavioral difficulties are par-
ticularly prevalent in FXS, out-of-proportion to cognitive level,
and can be grouped into commonly seen symptom clusters,
including (1) Attention Deficit/Hyperactivity Disorder-
(ADHD) like symptoms of hyperactivity, distractibility, impul-
sivity, and overarousal; (2) anxiety-related symptoms, including
OCD-like and perseverative behaviors; (3) emotional lability;
and (4) aggressive and self-aggressive behaviors.
© 2004 Wiley-Liss, Inc.
There are numerous reasons to use medications to support
behavior in FXS. The individual may be engaging in dangerous
or dysfunctional behaviors, or there may be a sense that the
individual could accomplish tasks or participate more success-
fully if a specific behavior is reduced. Medication may be used to
optimize functioning in a setting where there are no serious
detrimental behaviors and may significantly increase the ability
to attend or participate. In FXS, medication is virtually always an
adjunct to behavioral, therapeutic, and specific educational in-
terventions.
Although medication management for behavior in FXS
has been observed to effect improvement in the clinical setting,
there is a paucity of controlled studies to formally evaluate effects
of these medications in the FXS population and guide treatment.
A double-blind placebo-controlled crossover trial of high-dose
folic acid demonstrated some improvement in behavioral and
apparent cognitive functioning in a group of 8 prepubertal males
with FXS [Hagerman et al., 1986] although a similar trial of
folinic acid treatment resulted in no statistically significant gains
in a group of 19 children with FXS [Strom et al., 1992]. In a
double-blind placebo-controlled crossover study of 15 boys
with FXS, Hagerman et al. [1988] showed methylphenidate
(Ritalin) to be effective for attention and behavior in two-thirds
of boys with FXS. A recent double-blind placebo-controlled
trial of L-acetylcarnitine indicated there was some improvement
in hyperactive behavior [Calvani et al., 2001]. Interpretation of
these studies to guide treatment is heavily limited by the small
numbers of subjects evaluated.
Medication choice is thus best based on clinical identifi-
cation of the most problematic group or groups of symptoms,
followed by targeting of these problem areas with appropriate
class(es) of medications. As there are often problems in several
symptom areas, careful titration of medication is necessary as
medications may help with some behaviors but aggravate others.
Typically medication should be started at a low dose and titrated
up every week or two until, at maximum dose, effectiveness for
the target behaviors is observed or side effects occur. Reasonable
medications for the target behavior should be tried sequentially
*Correspondence to: Elizabeth Berry-Kravis, Department of Pediatrics, Neurology,
and Biochemistry, RUSH-University Medical Center, 1725 West Harrison, Suite 718,
Chicago, IL 60612. E-mail: elizabeth m berry-kravis@rush.edu
Received 12 March 2003; Accepted 10 May 2003
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/mrdd.20007
 Table 1.
Males 5–17 (%)
Number of Chicago
medications n ⫽ 83
0 32
1 37
2 31b
3 or more
a
Data from the Denver cohort were obtained from Amaria et al. [2001]. Data are expressed as the percentage of the cohort treated with the indicated number of medications.
b
Data represent those treated with two or more medications for comparison purposes as this corresponds to data presentation in Amaria et al. [2001].
and systematically to determine best re-
sponsiveness. Several medications in
combination may be necessary to target
different problematic symptom classes.
Effects and Management of
Common Medications for Behavior
in FXS
A chart review of records from a
Chicago FXS clinic was conducted to
determine numbers of individuals with
FXS treated with medication, medica-
tion classes used, and the percentage re-
port of a positive response for the tar-
geted symptom. The clinic population
consisted of 176 patients with FXS (136
males: 16 ages 0 –5, 83 ages 5–17, and 37
ages 18⫹; and 40 females: 8 ages 0 –5, 22
ages 5–17, and 10 ages 18⫹) of which
120 (99 males and 21 females) were
treated with one or more medications at
some point for management of behav-
ioral issues. Data pertaining to medica-
tion use in patients with FXS 5 years and
older were compared with those of a
similar survey of a large Denver-based
FXS clinic population [Amaria et al.,
2001]. Table 1 compares percentages of
patients with FXS treated with one or
multiple medications in the two popula-
tions surveyed.
Medication use was generally
higher in the Denver cohort, probably
related to differences in characteristics of
the cohorts. It is clear, however, that a
substantial fraction of both populations
was using medication combinations to
address dysfunction in different symptom
clusters. The pattern of medication use
was very similar between the two co-
horts, with stimulants being most com-
monly used in boys with FXS and a shift
to use of predominantly antidepressants
in adult males and females with FXS
(Fig. 1).
In the Chicago cohort, stimulants
were targeted to symptoms of distracti-
bility, hyperactivity, and impulsivity;
␣2-agonists were targeted to hyperactiv-
MRDD RESEARCH REVIEWS
Number of Medications Used by Males and Females with FXS:
Comparison of Two Cohortsa
Females 5–17 (%)
Denver Chicago Denver
n ⫽ 140 n ⫽ 22 n ⫽ 38
9 50 19
24 41 35
67b 9 43
0 3
ity, impulsivity, mild aggression, and hy-
perarousal and hypersensory behaviors.
Selective serotonin reuptake inhibitors
(SSRIs) and other antidepressants were
targeted to anxiety, perseverative and
OCD behaviors, and mood lability. An-
tipsychotics (predominantly risperidone)
targeted aggression and other more se-
vere aberrant behaviors. Response rates
in this cohort were determined for all
medications tried and grouped by age
and sex, based on the age at which the
medication was used. Because some of
the groups were quite small (n ⬍ 5), very
high and low response rates in these
groups are likely not reflective of pre-
dicted response in the general FXS pop-
ulation and should be interpreted as an-
ecdotal. Even in groups with higher
numbers the data are retrospective and
clinically based and therefore subject to
bias but serve as a guide that approxi-
mates results that may be expected based
on prior clinical experience.
Stimulants
In the Chicago FXS cohort, stim-
ulants were the most frequently used
(Fig. 1) and most frequently helpful (Fig.
2) class of medication in boys with FXS.
Amaria et al. [2001] (Fig. 1) also showed
stimulants to be the most frequently used
class of medications in boys with FXS
[Amaria et al., 2001]. Stimulants gave a
response rate for hyperactivity and atten-
tional symptoms of about 75% in chil-
dren with FXS (Fig. 2), which is similar
to the response rate of 67% seen with
methylphenidate in the one controlled
study [Hagerman et al., 1988] and that
reported previously in a portion of the
Chicago cohort [Berry-Kravis et al.,
2002]. Response rate is somewhat lower
in adult males with FXS (Fig. 2), who
tend to be less overactive but more anx-
ious and shift toward use of antidepres-
sants (Fig. 1). Nonetheless, some individ-
uals are helped substantially by use of
stimulants, even into their thirties or for-
● PSYCHOPHARMACOLOGY IN FRAGILE X SYNDROME
Males 18⫹ (%) Females 18⫹ (%)
Chicago Denver Chicago Denver
n ⫽ 37 n ⫽ 55 n ⫽ 10 n ⫽ 29
39 16 30 48
37 38 60 31
21 35 10 14
3 11 0 7
ties. Roberts et al. [2002] recently re-
ported that boys with FXS on stimulants
had better attention, lower motor activity
levels, and higher academic test scores on
medicated days versus unmedicated days,
although levels of physiological arousal
were unaffected by stimulant treatment.
Electrodermal studies measuring an en-
hanced sweat response to stimuli in chil-
dren with FXS did show a decrease in
response toward normal after stimulant
treatment [Hagerman et al., 2002].
Taken together, currently available infor-
mation suggests that stimulants are quite
helpful in managing distractibility and
hyperactivity symptoms in a subgroup of
boys and girls with FXS presenting with
prominent difficulty in these behavioral
domains.
In some individuals with FXS,
stimulants exacerbate anxiety, mood la-
bility, or aggressive tendencies and must
be abandoned. Stimulants (Adderall and
methylphenidate) now come in many
different long-acting forms that may be
quite useful in eliminating swings in
mood and behavior seen during the day
on multiple-dose regimens of fast-acting
preparations. Stimulants may also induce
excessive side effects or may not be ef-
fective in children with FXS who are
younger than 5 or 6 years old, although
they may be quite effective if reintro-
duced at an older age. Further, in popu-
lations with nonspecific mental retarda-
tion, stimulants have been shown to be
more effective in individuals with a
higher intelligence quotient (IQ),
whereas side effects are more problematic
in those with a lower IQ [Aman et al.,
1991; Handen et al., 1997]. Because
there is a wide range of functioning in
FXS, and outpatient clinic populations
are likely biased toward higher func-
tioning individuals (lower functioning
individuals may be institutionalized or
home-bound), stimulant response rates
presented here (Fig. 2) accurately reflect a
clinic population, but may be somewhat
● BERRY-KRAVIS AND POTANOS 43
high for the general population of males
with FXS.
Benefits to be expected from stim-
ulants include decreased distractibility,
longer attention span, decreased fidgeting
and motor overactivity, and decreased
impulsive behaviors. Side effects to be
monitored include appetite suppression,
insomnia (less if no late-day dose), a le-
thargic “drugged” appearance, moodi-
ness as the dose wears off, increased gen-
eral aggressiveness or irritability, picking
behaviors, tics, and aggravation of anxi-
ety or perseveration. Occasionally stut-
tering, decreased talking, or increased
seizures may be seen. Fortunately, with
the wide variety of stimulant preparations
currently available, a preparation and
regimen that minimizes side effects can
often be found for individuals showing a
clinical benefit of treatment. Some chil-
dren with FXS may do substantially bet-
ter on either methylphenidate or Adder-
all/dextroamphetamine, suggesting that
both classes of stimulant should be tried
before determining that stimulant treat-
ment has failed. Atomoxetine, a selective
norepinephrine reuptake inhibitor, has
recently been released for treatment of
ADHD symptoms. Although no data are
yet available regarding treatment in FXS,
it appears not to aggravate mood and
anxiety symptoms and may be an option
for individuals with FXS who cannot
tolerate stimulants because of this side Fig. 1. Distribution of medication use in two FXS cohorts. Data represent the number of patients
effect. on given subclasses of medication expressed as a percent of total patients treated with medication
at the time they were last seen. Total numbers of patients on medication are given in the legends.
Stimulants included methylphenidate preparations, Adderall, and dextroamphetamine prepara-
␣2-Adrenergic Agonists tions. Alpha2-agonists included clonidine and guanfacine (Tenex). Other antidepressants included
tricyclics (imipramine and amitriptyline), venlafaxine (Effexor), bupropion (Wellbutrin), trazodone
The ␣2-agonists clonidine and and nefazodone (Serzone). SSRIs included fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Lu-
guanfacine (Tenex) are thought to vox), paroxetine (Paxil), citalopram (Celexa), l-citalopram (Lexapro). Antipsychotics included risperi-
dampen sensory input perceived by the done (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon). Data from
brain and show about 70% efficacy (Fig. the Denver cohort were obtained and adapted from Amaria et al., 2001.
2) in treating hyperactive, hyperaroused,
hypersensitive, impulsive, and aggressive
behaviors (often due to overarousal) in
young boys with FXS. ␣2-Agonists were problems although sedation can also be a al., 1999]. In the Chicago cohort, re-
used in about 20% of boys with FXS in problematic side effect. sponse rate to antidepressants (SSRIs and
both the cohorts presented in Figure 1. other antidepressants) was about 50%–
Additional support for effectiveness of Antidepressants 60% (Fig. 2) for anxiety, mood, or com-
␣2-agonists in FXS comes from a parent Anxiety, compulsive and perse- pulsive/perseverative symptoms. This is
survey that suggested that clonidine is verative behaviors, and mood symptoms consistent with a 60%–70% response rate
helpful for hyperarousal and hyperactiv- can be managed with antidepressants, to fluoxetine in an open-label trial for
ity in about 80% of treated children with particularly selective SSRIs. In the FXS subjects with autistic disorder or mental
FXS [Hagerman et al., 1995]. This is cohorts presented here (Fig. 1) antide- retardation [Cook et al., 1992] and a 53%
consistent with the substantial improve- pressants were used in just under 50% of response rate to fluvoxamine in a place-
ment in hyperactivity and impulsivity boys with FXS and well over 50% of girls bo-controlled trial for subjects with au-
seen in a double-blind placebo-con- and adult males and females with FXS. tistic disorder [McDougle et al., 1996]. A
trolled crossover trial of clonidine in hy- SSRIs appear to be particularly helpful self-report survey of effects of fluoxetine
peractive children with nonspecific men- for social anxiety and withdrawal seen in in adults with FXS revealed improve-
tal retardation [Agarwal et al., 2001]. ␣2- females and high-functioning males and ments in anxiety, tantrums, or aggression
Agonists may be particularly effective in adult males with FXS, and fluoxetine in about 70% of treated individuals [Hag-
children younger than 5 years of age who (Prozac) has been reported to be success- erman et al., 1994]. A recent unblinded
do not tolerate or respond to stimulants. ful for selective mutism in females with prospective study of effects of sertraline
Clonidine can be quite helpful for sleep FXS and extreme shyness [Hagerman et in 12 children with FXS [Cohen et al.,
44 MRDD RESEARCH REVIEWS ● PSYCHOPHARMACOLOGY IN FRAGILE X SYNDROME ● BERRY-KRAVIS AND POTANOS

Fig. 2. Response rates to various classes of medications in a Chicago FXS cohort. Response was
determined by feedback from parents, teachers, and therapists, regarding target behaviors. Total
possible respondents (number of individuals treated) are given at the top of each bar and response
rates are given as a fraction of the total possible respondents. Response rates are grouped by age
according to the age at which the medication was utilized. Classes of medications are defined as in
the legend to Fig. 1.
2002] showed improvement in emo-
tional and behavioral parameters on the
BASC and ABC after starting sertraline
(Zoloft), although no changes were
noted in speech fluency or pragmatics,
failing to confirm previous anecdotal re-
ports regarding improvement in language
following treatment with SSRIs. Some
children had to discontinue treatment
due to disinhibition with increased im-
pulsivity. Taken together, available stud-
ies suggest that SSRIs can be useful for
management of anxiety and behavioral/
emotional symptoms in individuals with
FXS.
Specific benefits to be expected
from SSRIs in the individual with FXS
would include fewer fixations and com-
pulsive behaviors, easier transitions, less
irritability, less pacing and picking, in-
creased ability to tolerate things in the
environment, and increased comfort in
social settings. Side effects to be moni-
tored include activation with an increase
in hyperactivity and disinhibited behav-
iors, changes in appetite, insomnia, nau-
sea, and decreased sexual drive or impo-
tence. There are currently six different
SSRIs available with somewhat different
side effect and activity profiles. Fluox-
etine is more activating and seems to be
best for nonhyperactive patients with
shyness and social anxiety or withdrawal.
Less activating SSRIs may be better in
MRDD RESEARCH REVIEWS ● PSYCHOPHARMACOLOGY
individuals with FXS and higher levels of
hyperactivity and impulsive behavior.
For individuals who are too disin-
hibited on SSRIs, venlafaxine (Effexor)
or tricyclic antidepressants, which de-
crease reuptake of a mix of serotonin and
norepinephrine, may be useful to target
both anxiety and attention problems.
Tricyclic antidepressants can also work
well for bedwetting and sleep dysregula-
tion [Hilton et al., 1991] although EKGs
must be monitored as sudden death, pre-
sumed to be because of cardiac dysryth-
mias, has been described in some individ-
uals with FXS, albeit rarely. Bupropion
(Wellbutrin), which increases dopamine
levels more than other antidepressants,
can help with both focusing and mood/
anxiety issues and is not usually activat-
ing. We have followed several teenagers
with FXS who have done quite well with
bupropion to target both of these symp-
tom areas. Bupropion can precipitate sei-
zures in at-risk individuals and therefore
should not be used in individuals with
FXS and active seizures. Trazodone can
help with sleep dysregulation and anxiety
and has been found helpful for managing
aggression in children with severe behav-
ioral disturbance [Zubieta and Alessi;
1992]. Buspirone has been helpful for
treatment of anxiety, aggressive behavior,
and self-injurious behavior in adults with
nonspecific mental retardation [Ratey et
IN FRAGILE X SYNDROME
al., 1991; Verhoeven and Tuinier, 1996]
and has been anecdotally effective for
anxiety in individuals with FXS, but has
not been studied in FXS in a systematic
fashion.
Anticonvulsants
Anticonvulsants (valproic acid, car-
bamazepine, lamotrigine, gabapentin,
and topiramate) may be needed to treat
seizures, which occur in about 13%–18%
of individuals with FXS [Musumeci et
al., 2000; Berry-Kravis; 2002]. Many an-
ticonvulsants are also effective in bipolar
disease and may stabilize mood swings in
some individuals with FXS. Side effects
can affect functioning and include seda-
tion, cognitive slowing, and aggravation
of hypotonia and clumsiness. Valproate
and carbamazepine may induce weight
gain, whereas topiramate may cause
weight loss. Valproate may induce de-
pressive symptoms; disinhibition can be
seen with gabapentin; and topiramate can
specifically impair verbal functioning.
Our experience with individuals with
FXS treated with anticonvulsants for sei-
zures has suggested that anticonvulsants
can be quite helpful for sleep disturbance
but side effects, especially cognitive sup-
pression and disinhibition, have been
much more prevalent than behavioral
improvement. Carbamazepine and val-
proic acid require periodic blood work to
monitor liver functions and blood
counts.
Antipsychotics
Risperidone (Risperdal) is effective
clinically in FXS with high response rates
for aggressive behavior and other aber-
rant and undesired behaviors (Fig. 2), but
may result in intolerable weight gain, es-
pecially at higher doses. Risperidone has
also been found safe and effective for
aggressive and aberrant behaviors in a
double-blind placebo-controlled trial in
individuals with autism [McCracken et
al., 2002]. Antipsychotics are reserved for
individuals with FXS who exhibit more
extreme behaviors and use rates are much
lower than for stimulants and antidepres-
sants (Fig. 1). Other more recently de-
veloped atypical antipsychotics such as
quetiapine (Seroquel), ziprasidone (Ge-
odon), and aripiprazole (Abilify) have less
effect on weight and may be also be
helpful for aggressive behavior if there
are problems with weight gain on risperi-
done. Reports indicate that aggressive
and stereotypical behaviors are amelio-
rated by propanolol, a beta-blocker, in a
man with FXS [Cohen et al., 1991]. In
clinical practice, however, beta-blockers
● BERRY-KRAVIS AND POTANOS 45
seem to have a relatively low response
rate in FXS.
Benefits of antipsychotics can in-
clude diminished anxiety, agitation, and
perseveration and aggression and im-
proved sleep. Side effects of antipsychot-
ics include sedation, nausea, constipation,
dystonic and parkinsonian (extrapyrami-
dal) reactions, tardive dyskinesia, gyneco-
mastia, and big problems with weight
gain. The newer atypical antipsychotics
(risperidone, olanzapine, quetiapine, zi-
prasidone, and aripiprazole) are less sedat-
ing and have a much more favorable
motor side effect profile than older com-
monly used medications like haloperidol
and thioridazine.
Problems with sleep regulation are
common in FXS, particularly in young
children, and may aggravate behavior.
Sleep problems may respond to melato-
nin and, if not, clonidine, antidepressants,
or newer antipsychotics can be helpful.
Future Psychopharmacology of
Fragile X Syndrome
Current therapy in FXS is all sup-
portive or symptom-based and no ther-
apy exists that is specifically directed at
improving cognitive ability in FXS.
FMRP is known to be associated with
dendritic ribosomes and is thought to
regulate dendritic protein synthesis in re-
sponse to stimuli [Greenough et al.,
2001; Zalfa et al., 2003]. As information
regarding the specific dendritic functions
of FMRP becomes available, more di-
rected pharmacological interventions will
be designed to address specific neuro-
chemical and synaptic deficits generated
by the absence of FMRP. Pharmacology
directed at synaptic deficits in FXS will
be expected to target cognitive deficits
with secondary improvements in behav-
ior.
Abnormal dendritic morphology
in humans with FXS and the FMR1
knockout mouse has suggested abnor-
malities of strength of neural connections
and synaptic plasticity [Greenough et al.,
2001], presumably because of dysregula-
tion of dendritic translation. More recent
studies have begun to focus on synaptic
plasticity in FMR1 knockout mouse
brain, including assessment of cortical
and hippocampal synaptic strengthening
(long-term potentiation; LTP) and
weakening (long-term depression; LTD).
␣-Amino-3-hydroxy-5-methyl-4-isox-
azole propionic acid (AMPA) receptors
mediate rapid excitatory synaptic trans-
mission, are required for LTP, and play
an important role in defining synaptic
strength. Synaptic activation through
N-methyl-D-aspartate receptors causes
46 MRDD RESEARCH REVIEWS
AMPA receptors to move to the synapse
to give LTP. AMPA receptors are elim-
inated from the synapse in LTD (for re-
views see Luscher and Frerking, 2001;
Malinow and Malenka, 2002].
Huber et al. [2002] have recently
demonstrated that FMR1 knockout mice
show excessive hippocampal LTD, the
type of LTD that is regulated by
mGluR5 receptor activation and depen-
dent on protein synthesis. This exagger-
ation of LTD is associated with an exces-
sive reduction in AMPA receptor activity
because of a presumed lack of the normal
feedback inhibition by FMRP of
mGluR5-induced dendritic translation
and resultant persistence of AMPA re-
ceptor internalization [Snyder et al.,
2001]. Reduction in AMPA receptor
number and activity in the FMR1
As information regarding
the specific dendritic
functions of FMRP
becomes available, more
directed pharmacological
interventions will be
designed to address
specific neurochemical
and synaptic deficits
generated by the absence
of FMRP.
knockout has been confirmed in addi-
tional laboratories [Li et al., 2002; Laut-
erborn et al., 2002], along with corre-
sponding reduction in cortical LTP.
Thus, exaggerated synaptic weakening
and defects in strengthening seen in
FMR1 knockout mouse brain are both
associated with decreased AMPA recep-
tors. Despite reduction in AMPA re-
ceptors, ampakine-induced activation of
brain-derived neurotrophic factor (BDNF)
occurs in FMR1 knockout hippocampal
slices although does not persist as long as in
the wild-type [Lauterborn et al., 2002].
This new information has suggested that
deficiencies in glutaminergic synapses
and synaptic strength may be a factor in
the cognitive deficits in FXS. Thus,
treatment with mGluR5 antagonists to at
least partially block mGluR5-mediated
dendritic translation and/or AMPA-re-
● PSYCHOPHARMACOLOGY IN FRAGILE X SYNDROME
ceptor activators to enhance activity at
the deficient AMPA receptors might be
useful for cognitive enhancement di-
rected at a specific synaptic deficit in FXS
(Fig. 3).
Positive AMPA-receptor modula-
tors, called ampakines, which enhance
AMPA receptor activity only after syn-
aptic activation [Arai et al., 2002; Lynch
2002] are in development as cognitive
and memory enhancers. These com-
pounds are expected to be “experience-
dependent” enhancers of synaptic
strength. Indeed, there is a large body of
literature showing that ampakines en-
hance spatial learning, speed of perfor-
mance on spatial tasks, memory of sen-
sory tasks, fear learning, and memory of
previously learned spatial tasks in both
young and middle-aged rats (for a review
see [Lynch, 2002]; for representative ref-
erences see [Granger et al., 1996; Hamp-
son et al., 1998; Rogan et al., 1997;
Staubli et al., 1994]). Ampakines also de-
crease susceptibility to interfering influ-
ences during spatial memory tasks and
decrease metamphetamine-induced hy-
peractivity [Larson et al., 1996]. There
are significant carryover effects after
treatment. Most ampakines increase lev-
els of central nervous system (CNS)
brain-derived neurotrophic factor to
varying degrees, which itself may be as-
sociated with improvement in rodent
models of hyperactivity.
A single ampakine molecule,
CX516, has been moved into clinical
trials in humans and improved perfor-
mance on memory tasks such as delayed
recall of nonsense syllables in the young
and elderly has been shown, as well as
enhanced encoding of visual associations,
odor recognition, learning of a spatial
maze, and memorization of card place-
ment [Ingyar et al., 1997; Lynch et al.,
1997; Lynch, 2002]. Phase II trials study-
ing Alzheimer’s disease and schizophre-
nia have been encouraging, particularly
refractory schizophrenia, in which im-
provements in both behavioral and cog-
nitive measures were seen [Goff et al.,
2001; Lynch, 2002]. The first trial of an
AMPA-receptor positive modulator
(ampakine, CX516) in adults with FXS
and autism is currently in progress. This
is a 2-year double-blind placebo-con-
trolled study designed to assess safety and
determine whether 4 weeks of treatment
with CX516 improves any of a variety of
measures of memory and cognitive func-
tioning in 100 adults with FXS or autism.
Because learning and cognition develop
over time, however, it may be that the
full effects of AMPA-receptor activators
● BERRY-KRAVIS AND POTANOS

Fig. 3. Mechanism for exaggerated LTD in the absence of FMRP. Lack of normal feedback
inhibition of mGluR5-induced dendritic translation by FMRP leads to excessive internalization of
AMPA receptors and weaker, immature synapses. Arrows with open arrowheads indicate potential
targets for pharmacological intervention to normalize dendritic functioning in FXS.
will not be known until longer treatment
trials can be performed.
Studies are ongoing to see if mat-
uration of dendritic spines can be seen
after chronic treatment of the KO mouse
with ampakines and whether ampakines
ameliorate phenotypes such as hyperac-
tivity in the FMRP knockout mouse.
Ampakine molecules, which are more
potent AMPA receptor activators or in-
crease BDNF at lower doses, and have
low toxicity, are under development for
future clinical trials. Other types of pos-
itive allosteric AMPA receptor modula-
tors [Quirk and Nisenbaum; 2002] have
been developed and might potentially be
helpful. Partial antagonists of mGluR5
receptors would be expected to normal-
ize the exaggerated LTD in the FMRP
knockout. These compounds are not
available for human use at this point, but
are currently in testing to see if they can
reverse synaptic deficits and behavioral
phenotypes observed in the FMRP
knockout mouse. Thus, agents that target
cognitive functioning in FXS by revers-
ing neural deficits in the absence of
FMRP are on the horizon and it is ex-
pected that more such treatments will be
developed as additional synaptic mecha-
nisms related to absence of FMRP are
discovered. f
ACKNOWLEDGMENT
This work was supported in part by
a grant from the FRAXA Research
Foundation. The authors thank Dean
Kravis for assistance with graphics.
REFERENCES
Agarwal V, Sitholey P. Kumar S, et al. 2001.
Double-blind, placebo-controlled trial of
clonidine in hyperactive children with mental
retardation. Ment Retard 39:259 –267.
Aman MG, Marks RE, Turbott SH, et al. 1991.
The clinical effects of methylphenidate and
thioridazine in intellectually subaverage chil-
MRDD RESEARCH REVIEWS ● PSYCHOPHARMACOLOGY
dren. J Am Acad Child Adolesc Pysch 30:
246 –256.
Amaria RN, Billeisen LL, Hagerman RJ. 2001.
Medication use in fragile X syndrome. Mental
Health Asp Dev Dis 4:89 –93.
Arai AC, Xia YF, Rogers G, et al. 2002. Benz-
amide-type AMPA receptor modulators form
two subfamilies with distinct modes of action.
J Pharmacol Exp Ther 303:1075–1085.
Berry-Kravis E. 2002. Epilepsy in fragile X syn-
drome. Dev Med Child Neurol 44:724 –728.
Berry-Kravis E, Grossman AW, Crnic LS, et al.
2002. Fragile X syndrome. Curr Pediatr
2:316 –324.
Calvani M, Iddio S, De Gaetano A, et al. 2001.
L-acetylcarnitine treatment on fragile X pa-
tient hyperactive behaviour. Rev Neurol
Suppl 1:S65–S70.
Cohen IL, Tsiouris JA, Pfadt A. 1991. Effects of
long-acting propanolol on agonistic and ste-
riotyped behaviors in a man with pervasive
developmental disorder and fragile X syn-
drome: A double-blind placebo-controlled
study. J Clin Psychopharmacol 11:398 –399.
Cohen J, Kerr K, Iacono T, et al. 2002. Measuring
emotion, behavior change and speech in in-
dividuals with fragile X syndrome whilst tak-
ing sertraline: A pilot of tools. Procedings of
the 8th International Fragile X Conference,
Chicago.
Cook EH, Jr., Rowlett R, Jaselskis C, et al. 1992.
Fluoxetine treatment of children and adults
with autistic disorder and metal retardation.
J Am Acad Child Adolesc Psychiatry 31:739 –
745.
Granger R, Deadwyler S, Davis M, et al. 1996.
Facilitation of glutamate receptors reverses an
age-associated memory impairment in rats.
Synapse 22:332–337.
Greenough WT, Klintsova AY, Irwin SA, et al.
2001. Synaptic regulation of protein synthesis
and the fragile X protein. Proc Natl Acad Sci
USA 98:7101–7106.
Goff DC, Leahy L, Berman I, et al. 2001. A pla-
cebo-controlled pilot study of the ampakine
CX516 added to clozapine in schizophrenia.
J Clin Psychopharmacol 21:484 – 487.
Hagerman RJ, Jackson AW, Levitas A, et al. 1986.
Oral folic acid versus placebo in the treatment
of males with the fragile X syndrome. Am J
Med Genet 23:241–262.
Hagerman RJ, Murphy MA, Wittenberger MD.
1988. A controlled trial of stimulant medica-
tion in children with the fragile X syndrome.
Am J Med Genet 30:377–392.
IN FRAGILE X SYNDROME ● BERRY-KRAVIS
Hagerman RJ, Fulton MJ, Leaman A, et al. 1994.
Fluoxetine therapy in fragile X syndrome.
Dev Brain Dys 7:155–164.
Hagerman RJ, Riddle JE, Roberts LS, et al. 1995.
A survey of the efficacy of clonidine in fragile
X syndrome. Dev Brain Dys 8:336 –344.
Hagerman RJ, Hills J, Scharfnaker S, et al. 1999.
Fragile X syndrome and selective mutism.
Am J Med Genet 83:313–317.
Hagerman RJ, Miller LJ, McGrath-Clarke J, et al.
2002. Influence of stimulants on electroder-
mal studies in Fragile X syndrome. Microsc
Res Tech 57:68 –73.
Hampson RE, Rogers G, Lynch G, et al. 1998.
Facilitative effects of the ampakine CX516 on
short term memory in rats: enhancement of
delayed-nonmatch-to-sample performance.
J Neurosci 18:2740 –2747.
Handen BL, Janosky J, McAuliffe S. 1997. Long-
term follow up of children with mental retar-
dation/borderline intellectual functioning and
ADHD. J Abnorm Child Psychol 25:287–
295.
Hilton DK, Martin CA, Heffron WM, et al. 1991.
Imipramine treatment of ADHD in a fragile
X child. J Am Acad Child Adolesc Psychiatry
30:831– 834.
Huber KM, Gallagher SM, Warren ST, et al. 2002.
Altered synaptic plasticity in a mouse model
of fragile X mental retardation. Proc Natl
Acad Sci USA 99:7746 –7750.
Ingvar M, Ambros-Ingerson J, Davis M, et al. 1997.
Enhancement by an ampakine of memory
encoding in humans. Exper Neurol 146:553–
559.
Larson J, Quach CN, LeDuc BQ, et al. 1996.
Effects of an AMPA receptor modulator on
methamphetamine-induced hyperactivity in
rats. Brain Res 738:353–356.
Lauterborn JC, Baudry M, Gall CM. 2002. Ampa-
kines increase BDNF expression in FMR1
knockout mice despite lower glutamate re-
ceptor levels. Procedings of the 8th Interna-
tional Fragile X Conference, Chicago.
Li J, Pelletier MR, Perez Velazquez JL, et al. 2002.
Reduced cortical synaptic plasticity and
GluR1 expression associated with fragile X
mental retardation protein deficiency. Mol
Cell Neurosci 19:138 –151.
Luscher C, Frerking M. 2001. Restless AMPA re-
ceptors: implications for synaptic transmission
and plasticity. Trends Neurosci 24:665– 670.
Lynch G, Granger R, Ambros-Ingerson J, et al.
1997. Evidence that a positive modulator of
AMPA-type glutamate receptors improves
delayed recall in aged humans. Exper Neurol
145:89 –92.
Lynch G. 2002. Memory enhancement: the search
for mechanism-based drugs. Nat Neurosci 5S:
1035–1038.
Malinow R, Malenka RC. 2002. AMPA receptor
trafficking and synaptic plasticity. Annu Rev
Neurosci 25:103–126.
McCracken JT, McGough J, Shah B, et al. 2002.
Risperidone in children with autism and se-
rious behavioral problems. N Engl J Med
347:314 –321.
McDougle CJ, Naylor ST, Cohen DJ, et al. 1996.
A double-blind placebo-controlled study of
fluvoxamine in adults wit autistic disorder.
Arch Gen Psychiatry 53:1001–1008.
Musumeci SA, Hagerman RJ, Ferri R, et al. 1999.
Epilepsy and EEG findings in males with frag-
ile X syndrome. Epilepsia 40:1092–1099.
Quirk JC, Nisenbaum ES. 2002. LY404187: A
novel positive allosteric modulator of AMPA
receptors. CNS Drug Rev 8:255–282.
Ratey J, Sovner R, Parks A, et al. 1991. Buspirone
treatment of aggression and anxiety in men-
AND POTANOS 47
 tally retarded patients: A multiple-baseline
placebo lead-in study. J Clin Psychiatry 52:
159 –162.
Roberts JE, Bailey DB, Boccia ML. 2002. Psycho-
physiological measures of arousal: documen-
tation of treatment effects and impact of dis-
ability. Proceedings of the 8th International
Fragile X Conference, Chicago.
Rogan MT, Staubli UV, LeDoux JE. 1997. AMPA
receptor facilitation accelerates fear learning
without altering the level of conditioned fear
acquired. J Neurosci 17:5928 –5935.
Snyder EM, Philpot BD, Huber KM, et al. 2001.
Internalization of ionotropic glutamate recep-
48 MRDD RESEARCH REVIEWS
tors in response to mGluR activation. Nat
Neurosci 4:1079 –1085.
Staubli U, Rogers G, Lynch G. 1994. Facilitation
of glutamate receptors enhances memory.
Proc Natl Acad Sci USA 91:777–781.
Strom CM, Brusca RM, Pizzi WJ. 1992. Double-
blind placebo-controlled crossover study of
folinic acid (Leukovorin) for the treatment of
fragile X syndrome. Am J Med Genet 44:
676 – 682.
Torroli MG, Vernacotola S, Mariotti P, et al. 1999.
Double-blind placebo-controlled study of l-
acetylcarnitine for the treatment of hyperac-
tive behavior in fragile X syndrome. Am J
Med Genet 87:366 –368.
● PSYCHOPHARMACOLOGY IN FRAGILE X SYNDROME
Verhoeven WM, Tuinier S. 1996. The effect of
buspirone on challenging behaviour in men-
tally retarded patients: An open label prospec-
tive multiple-case study. J Intellect Disabil
Res 40:502–508.
Zalfa F, Giorgi M, Primerano B, et al. 2003. The
fragile X syndrome protein FMRP associates
with BC1 RNA and regulates translation of
specific mRNAs at synapses. Cell 112:317–
327.
Zubieta JK, Alessi NE. 1992. Acute and chronic
administration of trazodone in the treat-
ment of disruptive behavior disorders in
children. J Clin Psychopharmacol 12:346 –
351.
● BERRY-KRAVIS AND POTANOS