Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence

Figures & data

Figure 1. PRISMA flow diagram.

Table 1. Summary of studies included in final narrative review (n = 16).

Author	Year	Intervention	Population	Study Design	Outcome measures	Results
Hagerman et al. [10], United States	1986	Folic acid	N = 25 Sex: All male; Age range: 1–31 years (y)	Double-blind, crossover study. Computer randomization, switch at 6 months.	Peabody Picture Vocabulary Test (PPVT) [11], Test of Language Development (TOLD) and an apraxia battery [12]. Yale Revised Developmental Schedules, Stanford-Binet [13], or the Leiter International Scale [14]. Autism Behavior Checklist (ABC) [15], Autism Screening Instrument for Educational Planning (ASIEP) [16], and the Childhood Autism Rating Scale (CARS) [17].	Standardized testing did not show statistically significant changes. Psychological testing demonstrated statistically significant and clinically relevant improvement in IQ for the 8 pre-pubertal males who completed testing.
Hagerman et al. [18]	1988	Methylphenidate and Dextroamphetamine	N = 15 Sex: 13 male, 2 female. Further details: Cytogenic and clinical diagnoses, plus observed attention problems.	Double-blind, Randomized, crossover design, 3 weeks duration	Behavioral Checklists: the Comers Abbreviated Parent-Teacher Questionnaire [19], ADD-H: Comprehensive Teacher Rating Scale (AcTeRs) [20].	Improvement was seen with methylphenidate in socialization skills aid attention span according to teacher checklists. Ten children were clinically considered responders and treatment was continued after the study.
Strom et al. [21]	1992	Folinic acid	N = 21 Sex: All male; Age range: 2–22 y (mean 8.3 y); Further details: Caucasian participants, including one sibling pair	Randomized, double-blind, placebo-controlled crossover study. Two treatment intervals of 12 week each	Vineland Adaptive Behavioral (VAB) Scales [22], PPVT-Revised; the Conners Parent and Teacher Rating Scales; ACTeRS; and a questionnaire designed by the investigators.	No statistically significant differences between the treatment and placebo phases with any instrument. No significant side effects have been noted from long-term folic acid therapy.
Berry-Kravis et al. [23]	2006	CX516	N = 49 Sex: 38 male, 11 female; Age range: 18-50y; Further details: FXS diagnosis by DNA analysis; cognitive impairment with measured IQ 20 to 85; normal hearing and normal or corrected vision; stable medication regimen, negative pregnancy test	Phase II, 4-week randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and efficacy.	Clinical Global Impression Scale-Improvement (CGI-I) [24], Visual Analogue Scale (VAS), Swanson, Nolan, and Pelham Questionnaire IV (SNAP-IV) [25].	No significant difference between the placebo and C×516groups in safety parameters, or any of the cognitive and behavioral outcome measures.
Torrioli et al. [26]	2008	L-acetylcarnitine (LAC)	N = 63 Sex: All males; Age range: 6–13 y; Further details: Participants had co-occurring ADHD	Phase II, randomized, double- blind, placebo-controlled, parallel, multicenter study.	CGI-P; CGI-T; VAB Composite, and Vineland Socialization domain.	A stronger reduction of hyperactivity and improvement of social behavior in patients treated with LAC, compared with the placebo group.
Wirojanan et al. [27]	2009	Melatonin	N = 18 Sex: 16 male, 2 female; Age range: 2–15 y (mean 6 y, standard deviation [SD] 3.5 y); Further details: Participants had co-occurring reported sleep problems.	Randomized, double blind, placebo-controlled, 4-week crossover design.	Sleep variables: sleep-onset time, total night sleep duration, sleep-onset latency time, and the number of night awakenings.	Melatonin was associated with modest but significant improvement in mean night sleep duration, mean sleep-onset latency was shorter, and mean sleep-onset time was earlier.
Sahu et al. [28]	2012	Donepezil	N = 20 Sex: All males; Age range: 6–15 y; Further details: Cytogenic diagnosis of FXS, stable treatment for 8 weeks.	12-week, randomized, double-blind, placebo-controlled, parallel-group study.	Stanford-Binet Intelligence Scale, Conners 3 Parent Rating Scale (Short) and CARS.	No significant difference with placebo.
Leigh et al. [29]	2013	Minocycline	N = 66^2 Sex: male 47, female 8; age range: 3.5–16y (mean 9.2 y, SD 3.6 y); Further details: FXS confirmed by FMR1 DNA testing; stable regimen of pharmacological treatment.	Randomized, double-blind, placebo-controlled, crossover trial.	CGI-I and VAS 1 score (severity of target behavior 1).	Minocycline treatment for 3 months was associated with modest but significant benefits in global functioning when compared with placebo.
Berry-Kravis et al. [30]	2016	Mavoglurant	N = 314 Sex: 288; female 26. Age range 12–45 y; Further details: Cytogenic diagnosis of FXS, CGI-S score of ≥4, ABC-C score of >20, and an IQ score during screening that was lower than 2 SDs below the median	Two phase 2b, randomized, double-blind, placebo- controlled, parallel-group trials of mavoglurant in adult (18–45 y) and adolescent patients (12–17 y) with FXS 12 weeks.	Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX) [31,32]; CGI-I scale.	No significant difference with placebo in primary outcomes measures in either study.
Hess et al. [33]	2016	Sertraline	N = 57 Sex: male 48, female 9; Age range: 2–6 y	Randomized, double-blind, placebo-controlled trial	MSEL expressive language raw score, MSEL expressive language standard score [34], and CGI-I.	No difference between placebo and sertraline for primary outcome measures.
Berry-Kravis et al. [35]	2017	Arbaclofen	N = 278 (N = 119 adult/adolescent group, N = 159 child group) Sex: 243 male, 41 female (adult adolescent group, 99 male, 26 female; child group, 144 male, 15 female); age range: 5–50 y (12–50 y adolescent/adult group, 5–11 y child group); Further details: DNA-confirmed FMR1 full mutation	Two phase 3 placebo-controlled trials were conducted, flexible dosing.	Social Avoidance subscale of the ABC-CFX. Secondary outcomes included other ABC-CFX subscale scores, CGI-I, CGI-Severity, and VAB, Second Edition (Vineland-II) Socialization domain score.	No significant difference to placebo in adolescent/adult group. In the child group, highest dose group improved on irritability (p = 0.03) and parenting stress Index (p = 0.03).
Youssef et al. [36]	2017	Basimglurant	N = 183 Sex: 149 male, 34 female; age range: 14–50 y (mean 23.4 y)	Phase 2, double-blind, randomized, placebo-controlled, 12-week study.	ADAMS total score [37], a 28-item caregiver-completed instrument assessing aspects of anxiety, social interaction, compulsiveness, communication, concentration, depression, and mood.	No improvement over placebo.
Bruno et al. [38]	2019	Donepezil	N = 41 Sex: 26 male, 15 female; age range: 12–29 y (mean 19.6 y); Further details: cytogenic diagnosis of FXS; Verbal IQ 50 to 75 Tanner pubertal development stage 3 or higher	Randomized placebo-controlled trial study; 12 weeks.	Executive functioning: Contingency Naming Task (CNT) [39] ABC, neural processing assessed using functional MRI.	No significant difference to placebo on any outcome measure.
Berry-Kravis et al. [40]	2020	Trofinetide	N = 70 Sex: All males Age range: 12-41y (mean 23.5y)	Phase 2, multi-center, double-blind, placebo-controlled, parallel group study.	Investigator developed the fragile X syndrome rating scale (FXSRS) and the fragile X syndrome domain-specific concerns (FXSDSC), VAS, CGI-I, ABC-CFX.	Trofinetide at the 70 mg/kg dose level demonstrated no worsening of symptoms. A trend toward improvement in cores symptoms of FXS.
Berry-Kravis et al. [41]	2021	BPN14770	N = 30 Sex: all males Age range: 18–41 y	Phase II, 24-week randomized, placebo-controlled, two-way crossover study.	National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition, Picture, Cognition Crystallized Composite score, visual analogue caregiver rating scale [42].	Significant improvement across cognitive domains with collaborating caregiver rating on VAS.
Berry-Kravis et al. [43]	2022	Transdermal gel Cannabidiol (ZYN002)	N = 212 Sex: 159 male, 53 female; Age range: 3–<18 y (mean 9.7 y); further details: 79.7% more than 90% methylation of the FMR1 promotor and full mutation of FMR1; body mass index of 12–30 kg/m^2	Double‐blind, randomized phase 3 trial assessing efficacy and safety of ZYN002.	Change in social avoidance (SA) measured by the ABC‐CFXS SA subscale.	No significant difference for overall cohort. For those with over 90% methylation of the FMR1 promotor significant improvements in primary outcome plus isolation, irritability, disruptive behaviors and social interactions.

1. 63 participants were enrolled; 7 patients dropped out, 56 completed the one-year treatment, and 51 were included in the statistical analysis.

2. 66 randomized; 55 completed first period, 48 completed full trial.

Table 2. Evidence base for treatment considerations by domain in FXS [6].

Behavioral Phenotype	1. mGluR5 antagonists. 2.Ampakines (CX516) 3. Lithium
ADHD	1. Stimulants (methylphenidate). 2. ά-Adrenergic receptor agonists-Clonidine/Guanfacine-(profile: more severe phenotype, younger children, unable to tolerate stimulants). 3. L-acetyl-carnitine
Anxiety	SSRIs-Fluoxetine, Sertraline
BtC	Antipsychotic’s (second generation) – Aripiprazole, Risperidone

(Aggression,/SIB/mood dysregulation).

*Please note that these treatment considerations are aligned to the current limited evidence base. This includes evidence that does not meet the criteria for the review. These associations are not treatment recommendations, and many of these options and may not be available to clinicians. Treatment should be person centered and overseen by a clinician with relevant expertise.

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