Fragile X syndrome (FXS) is associated with behavior that limits functioning, including distractibility, hyperactivity, impulsivity, hyperarousal, anxiety, mood dysregulation, and aggression. Medication response and side effect data were reviewed retrospectively for 257 patients (age
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, with a frequency of about 1/4000 [
Behavioral problems are often substantial in FXS, out of proportion to level of cognitive impairment [
Although medication management for behavior in FXS is thought to affect improvement in the clinical setting, there is a paucity of information available regarding the effects of psychopharmacology in populations with FXS, with which to guide treatment. A double-blind placebo-controlled crossover study [
Surveys of a large clinic population with FXS in Colorado [
Chart review was conducted regularly for all patients with FXS seen at the RUSH University Medical Center Fragile X Clinic in the years from 1991 through 2005. The patient cohort comprised the full range of functional level for FXS, ranging from nonverbal individuals with FXS to individuals (predominantly female) with IQ in the normal range. Patients were referred to the fragile X clinic for a variety of reasons including discussion of clinical expectation for patients newly diagnosed, families desiring follow up in a fragile X specialty setting, assistance with educational or vocational recommendations, genetic issues, and seizure management; however, the most frequent reason for referral and ongoing follow-up was management of behavioral problems. Behavioral management recommended was typically a combination of approaches, including psychotherapy, structured behavioral training, and optimization of the environment and curriculum. When these interventions were only partially successful or unsuccessful and significant dysfunction persisted, medication was also implemented. An FXS psychopharmacology database was utilized as a tool for clinical management to allow easy tracking of patient responses to different medications. Medications used for treatment of behavior, age at treatment, response of targeted symptoms to each medication used, and reason for failure of unsuccessful medications were entered into an FXS psychopharmacology database on a continual basis. For this study, information in the database was analyzed to generate cohort data on medication usage, response rates, and side effects in the FXS cohort. The database was locked for analysis at the end of 2005 since many of the patients followed up at the clinic began to enter clinical trials of targeted treatments, requiring changes in data collection and making it more difficult to analyze responses in a “pure” clinic setting.
Each medication was chosen for use based on clinical identification of a target problem behavior producing significant dysfunction in the individual with FXS. Stimulants were targeted to symptoms of distractibility, hyperactivity, and impulsivity; alpha2-agonists were targeted to hyperactivity, impulsivity, mild aggression, and hyperarousal and hypersensory behaviors; SSRIs (selective serotonin reuptake inhibitors) and other antidepressants were targeted to anxiety, perseverative and OCD-like behaviors, and mood lability; antipsychotics targeted outbursts, aggression, severe irritability, and other more severe aberrant behaviors. Response rates in this cohort were determined for all medications tried and grouped by gender and age for males (adults age 18 or more, and boys < 18 years), based on the age at which the medication was used. As all of the patients in the cohort were managed by only one physician, a consistent approach to medication choice, initial dose, dose titration, and assessment was utilized throughout the cohort. Follow-up regarding medication effects was obtained by phone and email communications 2–4 weeks after initiating medication and then 2 weeks after any further dose adjustments. Patients were seen for follow-up and medication review every 6–12 months (depending on distance). Response for each medication in each patient was determined as in clinical practice, with systematic questioning of parents and reports from teachers and therapists or, for older individuals, group home coordinators or job/workshop supervisors, regarding amount of improvement in targeted behaviors. Assessment was based on individualized descriptive and semi-quantitative (e.g., number of outbursts per day at school) feedback regarding the target symptom(s) from at least two sources that typically included the parents or caregivers and personnel from a school or vocational program. These reports were reviewed by the physician combined with data from interactions at clinic visits to give an impression of whether the patient was improved, unchanged, worse, or had side effects. Doses were adjusted based on this feedback. Medications were not continued if they did not produce benefit for the target symptom(s) at maximally tolerated doses. When patients were treated with multiple medications, these were always added or weaned sequentially so as to be able to ascertain the effect of each individual medication. If patients had already been on medications at the initial visit to the FXS clinic, data on medication response history was used only if specific information regarding the effects of the medication could be obtained. A positive response to each medication used was defined as documented clinical report of improvement in the behavior(s) being targeted in 2 settings, improvement sustained over at least a 6-month period on the medication, and no major side effect requiring discontinuance of the medication. Although determination of response relied ultimately on the clinical judgment of a single physician reviewing all information, this is not different from currently accepted standard of care in clinical practice.
Classes of psychopharmacologic medications analyzed included the following specific agents: stimulants included all (both short-acting and sustained release) methylphenidate preparations, mixed amphetamine salts preparations (Adderall), and dextroamphetamine preparations. Alpha2-agonists included clonidine and guanfacine (Tenex). Selective serotonin reuptake inhibitors (SSRIs) included fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro). Other antidepressants included tricyclics (imipramine and amitriptyline), venlafaxine (Effexor), bupropion (Wellbutrin), trazodone (Desyrel), and nefazodone (Serzone). Trazodone and nefazodone were used for behavior or for a combination of behavior and sleep problems. Antipsychotics included risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify). Although there were a handful of individuals treated with agents not covered by this classification system, including buspirone (Buspar), anticonvulsants for mood cycling, and lithium, the number of individuals treated with these agents was too small for analysis. Furthermore, the vast majority of individuals on anticonvulsants were taking these for seizure control and behavioral responses were not being monitored.
Data from 257 total individuals in this FXS cohort was available for analysis, including 203 males and 54 females ranging from one to sixty years of age. Figure
Age and gender demographics of the FXS cohort in this study.
For stimulants, antidepressants, and antipsychotics, there are lower response rates for both males and females when response is analyzed based on success of individual trials of medication in the drug class than when response is analyzed based on successful treatment of patients with any medication within the drug class (Figure
Response rate for major classes of psychopharmacological agents utilized. Response rate for “trials” indicates percent of positive responses for individual trials of medications within the class. Response rate for “patients” indicates percent of patients who responded positively to any medication within the class. Only the trial response rate is shown for alpha2-agonists because virtually all of these treatments were with clonidine and there were no patients with trials of two different medications in this class, thus the patient response rate is the same as the trial response rate for this medication class. No response data is shown for alpha2-agonists in females because no females were treated; the fraction of responders is zero for alpha2-agonists in males > 18.
In total, 93/208 stimulant trials (45%) failed, 107/230 antidepressant trials (47%) failed, 20 alpha2-agonist trials (38%) failed, and 46/100 antipsychotic trials (46%) failed. The majority of failures for all medication classes were because the treatment was not helpful (Figure
Reason for failure of various classes of medications during treatment trials. Green areas of charts indicate percent of individuals for whom no follow-up information was available, Red areas indicate failure due to medication ineffectiveness, and Blue sections of charts represent individuals failing due to a side effect that limited treatment. For antidepressants and antipsychotics data is presented separately for children and adolescents less than 18 and adults 18 and over to compare rates of intolerable side effects in these age groups. For alpha2-agonists and stimulants, only 1 and 5 individuals, respectively, aged 18 or over failed treatment, all due to medication ineffectiveness. Therefore, age groups were not presented separately for these medication classes.
Side effects most commonly observed with stimulants included appetite suppression with occasional weight loss, stomach discomfort, lethargy, suppression of exuberance, reduced speech output, and aggravation of anxiety, perseverative, irritable, and aggressive behaviors. Stimulants were virtually never discontinued because of appetite problems, and in fact, in many cases, this was viewed as a beneficial side effect. The most common side effect resulting in stimulant discontinuance for individuals with FXS was aggravation of anxiety/perseveration/irritability. The most common side effects observed with antidepressants were nausea, diarrhea, sedation, and aggravation of impulsive and disinhibited behavior. For the most part, gastrointestinal side effects and lethargy were mild and often manageable with dose or timing modifications. The side effect that resulted in the most antidepressant discontinuances in the FXS cohort, particularly for SSRIs but also observed for other antidepressants, was severe disinhibited behavior. Aggravation of sleep problems was not commonly observed in this FXS cohort with either stimulants or antidepressants. The most common side effects observed for antipsychotics were nausea, vomiting, lethargy, and weight gain. The most common side effect resulting in antipsychotic discontinuance for individuals with FXS was problematic weight gain. Four instances of extrapyramidal side effects were observed with antipsychotic treatment, and these involved parkinsonian symptoms including bradykinesia, mild rigidity, problems with initiation of movement including swallowing, and aggravation of baseline coordination deficits. These effects occurred at very high doses of olanzapine (one patient) and aripiprazole (one patient) but were seen at doses as low as 0.5 mg of risperidone for the other two patients. Resting tremor was also observed in relation to high-dose aripiprazole treatment in the patient described above, despite excellent behavioral response. Tardive dyskinesia was never observed in any individual with FXS, even with antipsychotic treatment for as long as 10 years. The only side effect requiring discontinuance of an alpha2-agonist in this FXS cohort was persistent sedation that did not abate over the first weeks of treatment.
Data on treatment and response to different types of stimulants was analyzed in an attempt to determine whether there was an advantage to treatment with either MPH (methylphenidate) preparations (MPH, includes generics, Ritalin, Ritalin SR, Ritalin LA, Metadate, Metadate CD, Methylin, Concerta, Focalin, and Focalin XR) or APH (amphetamine) preparations (APH, includes Adderall, Adderall XR, Dextrostat, and Dexedrine) in the FXS population. Overall a larger percentage of individuals, both males and females, were treated with MPH preparations (2.6% adult males, 76.8% males
In total, 63 of 112 trials of MPH (56%) and 52 of 96 trials of APH (54%) were successful (Figure
Response rates in patients with FXS to trials of different types of stimulants, fractionated by age and gender. Numbers above bars represent total number of patients in the indicated category treated with the stimulant type.
Reasons for failing treatment trials with MPH or APH showed nearly identical patterns. The majority (61% for APH, 60% for MPH) of failures for both stimulant types were because the treatment was not helpful (no change from baseline ADHD-like behavior), while the remainder failed treatment primarily because of side effects (including worsening of irritability and hyperactivity).
The outcome of independent trials of MPH and APH was assessed for those individuals with FXS who had trials of both stimulant types at different times (Figure
Results of sequential stimulant trials for the subgroup of individuals with FXS who had trials of both APH and MPH preparations
It should be noted that 6 trials of atomoxetine with starting dose typically about 0.5 mg/kg/day were carried out in this FXS cohort (data not shown, 4 males, 2 females) and all of these were unsuccessful, with the majority failing due to aggravation of irritable, moody, and aggressive behaviors.
Fluoxetine, sertraline, and citalopram were the most commonly used antidepressants (Figure
Response rates to different antidepressants, fractionated by age and gender. For bars with an asterisk, there were <5 trials of the indicated medication for the patient group represented by the bar.
Multiple atypical antipsychotics were used with risperidone and aripiprazole being most frequently used (Figure
Response rates to different antipsychotics, fractionated by age and gender. Numbers above bars represent total number of patients in the indicated category treated with the antipsychotic agent.
Because aripiprazole is a reasonably new agent and data were limited in the 1999–2005 cohort, responses to aripiprazole were analyzed in additional patients with FXS receiving this treatment through July of 2006. High response rates were confirmed in the larger series (Figure
Response and failure rates in patients with FXS treated with aripiprazole, fractionated by age. This figure includes response data for aripiprazole from 7 additional patients with FXS started on this treatment between the end of December of 2005 and July of 2006.
This paper presents a retrospective analysis of clinically assessed results of psychopharmacological treatment for a large cohort of males and females with fragile X syndrome (FXS). From the data presented here we can conclude that males with FXS under the age of 18 years most commonly exhibit ADHD-like symptoms that are treated with stimulants and males over 18 years and females with FXS most commonly exhibit mood and anxiety symptoms dictating treatment with antidepressants. This is consistent with the patterns of medication usage observed in smaller FXS cohorts presented previously [
Successful treatment of targeted behaviors in FXS ranged from 53 to 62% for trials of different classes of psychoactive medications. The rate of success, however, improved with sequential trials of medications within a class such that ultimately targeted behaviors were perceived as improved for about 73–77% of individuals with FXS. These response rates to the studied medication classes are similar to those presented in a smaller FXS cohort previously [
Stimulants were helpful in a clinical setting to target distractibility, hyperactivity, and impulsive behavior in this study as 73% of individuals with FXS responded without major side effects to some preparation of stimulant. This is similar to the 67% response rate seen with methylphenidate in the one controlled study [
In some individuals with FXS, stimulants exacerbate anxiety, irritability, or aggressive tendencies and must be abandoned. Indeed in this study 40% of failed stimulant trials occurred because of side effects, which mostly consisted of aggravation of anxiety/irritability/aggressiveness. Stimulants now come in many different long-acting forms that may be quite useful in eliminating swings in mood and behavior during the day seen on multiple-dose regimens of fast-acting preparations. Stimulants are thought to induce excessive side effects or may not be effective in children with FXS less than five or six years old, although they may be quite effective if reintroduced at an older age. The number of patients less than 5 years of age treated in our series is too low to clarify this issue (data not shown). In populations with nonspecific mental retardation, stimulants have been shown to be more effective in individuals with higher IQ, while side effects are more problematic in those with lower IQ [
Data from this study show that MPH and APH preparations have about the same overall response rates and the same profile of reasons for failure, although adults with FXS may be more likely to respond to APH. It also appears that distinct groups of patients with FXS respond to or have side effects on only one of APH or MPH, suggesting that sequential trials of both will raise overall response rate and are indicated before abandoning treatment. Further, if an adolescent or adult with prominent attention problems is no longer responding well to an MPH preparation, it would be reasonable to try switching to APH before using another category of medication.
Antidepressants were helpful in a clinical setting to target anxiety, compulsive and perseverative behaviors, and mood symptoms in this study as 77% of individuals with FXS responded without major side effects limiting treatment to at least one antidepressant. SSRIs were most commonly utilized and were the most common form of treatment for females and adults with FXS. SSRIs appear to be particularly helpful for social anxiety and withdrawal in females with FXS, and fluoxetine has been previously reported to be successful for selective mutism in females with FXS and extreme shyness [
The predominant side effect of SSRIs observed in this FXS cohort was activation with an increase in hyperactivity and disinhibited behaviors, which may be more pronounced with fluoxetine. Less activating SSRIs, such as sertraline or escitalopram, may be better in individuals with FXS and higher levels of hyperactivity and impulsive behavior. For individuals who are too disinhibited on SSRIs, other antidepressants may be successful treatments that do not produce the disinhibited behavior and, in this study, had similar response rates when compared to the SSRIs. Tricyclic antidepressants can also work well for bedwetting and sleep dysregulation [
Antipsychotics are generally reserved for individuals with FXS who exhibit more extreme behaviors and use rates are thus lower than for stimulants and antidepressants. Antipsychotics were helpful in a clinical setting to target irritability, aggression, and perseverative behaviors in this study, as 76% of individuals with FXS responded to at least one antipsychotic, without side effects requiring withdrawal. Risperidone was effective clinically in FXS with high response rates for aggressive behavior in older males with FXS and other aberrant and undesired behaviors in young boys with FXS and autistic traits. This is consistent with the finding that risperidone is safe and effective for aggressive and aberrant behaviors in a double-blind placebo-controlled trial in individuals with autism [
Alpha2-agonists, clonidine and guanfacine, showed about 62% efficacy in a clinic setting in treating hyperactive, hyperaroused, hypersensitive, impulsive, and aggressive behaviors due to overarousal in young boys with FXS, consistent with a survey study showing an 80% response rate for management of hyperarousal and hyperactivity. The results in studies of FXS are consistent with substantial improvement in hyperactivity and impulsivity seen in a double-blind placebo-controlled crossover trial of clonidine in hyperactive children with nonspecific mental retardation [
This study is clearly limited by its retrospective nature, lack of objective valid/reliable outcome measures, and lack of tracking of dosing information. Although care was taken to try to get documentation of medication effects from at least two persons working with the individual with FXS, there is likely to be placebo effect and response rates are probably somewhat high. Also this study cohort was treated over a period of 15 years during which pharmacological treatment evolved with more options available. Thus, there may have been less opportunity to identify a successful regimen for patients for whom treatment was attempted earlier in the time period. Although this clinic population contained patients with a broad range of functional level, it is likely somewhat biased toward higher functioning patients with FXS who are able to get into clinic, are not institutionalized, and are expected to be more treatable, thus raising response rates. There are a number of medications, including anticonvulsants, buspirone, and propanolol, that have been anecdotally used for behavior in, but they were not included in this analysis as very few patients were treated with these medications for behavior in this fragile X patient cohort.
Current therapy in FXS is predominantly supportive or symptom based, and no therapy currently exists that has been shown to improve cognitive ability in FXS. As information regarding the specific neural functions of FMRP has become available, more directed pharmacological interventions have been explored, potentially acting on GABA [
This work was supported by a grant from the Spastic Paralysis and Allied Diseases of the Central Nervous System Research Foundation of the Illinois-Eastern Iowa District Kiwanis International to EBK.