Managing maladaptive behaviors in fragile X patients
Psychotropics can improve hyperactivity, anxiety, and aggression.
L-acetylcarnitine—a carnitine derivative required for neuronal use and transport of fatty acids—is being investigated to treat hyperactivity in FXS. Hyperactive symptoms improved significantly with L-acetylcarnitine, as measured by the Conners’ Abbreviated Parent-Teacher Questionnaire, in a 1-year, placebo-controlled trial of 20 boys (mean age 9.2) with FXS.17
Discussion. Supporting evidence is limited, but clinicians are treating ADHD-like symptoms with stimulants and alpha-2 agonists in many FXS patients. Preliminary data indicate that stimulants may be more effective and better tolerated in individuals with FXS than in those with PDD.
Trying a stimulant or alpha-2 agonist for inattention or hyperactivity symptoms in a child or adolescent with FXS appears clinically appropriate, given the available evidence. Additional data based on placebo-controlled and standardized measures of treatment response are needed to help guide treatment.
We start Mike on methylphenidate, 5 mg in the morning, for inattention and hyperactivity. He tolerates this well, and after 2 weeks we increase the dosage to 5 mg bid. Several weeks into treatment, his teacher comments that he is beginning to stay in his seat and attends to some assigned tasks in the classroom.
Mike continued to tolerate methylphenidate over the next 4 years. We gradually increased the dosage as he grew and when he periodically developed breakthrough interfering symptoms in the classroom.
Anxiety symptoms
In grade school, Mike became increasingly nervous around schoolmates, teachers, and friends. His teachers commented that he repeated phrases when he appeared anxious. Other children in his special education class began to shun him; they found his perseveration odd and sometimes threatening.
Now that Mike is age 10 and in fifth grade, his parents decide that his anxiety, particularly in social settings, is interfering with his life.
Anxiety symptoms—including generalized nervousness and OCD-like obsessions and perseverations—are common psychotropic targets in FXS. Boys may be the FXS patients most often prescribed drugs for inattention and hyperactivity, but they are the least likely to receive antidepressants for anxiety symptoms.1,2
Efficacy. More than 50% of female patients and men with FXS are prescribed SSRIs for anxiety (Table 2), and the reported response rate of 50% to 60%1 is similar to that seen with SSRIs in autism and related disorders.18 In autism, a developmental approach is warranted, as SSRIs tend to be less effective and cause more side effects in children and adolescents than in adults.18
Adverse effects reported with SSRIs in FXS include behavioral activation, appetite changes, insomnia, and nausea.1 In a study of fluoxetine for FXS symptoms, 10 of 35 patients (29%) had persistent side effects, most commonly weight loss and weight gain.19 One patient with pre-existing suicidal ideation worsened.
Watch for emergence or worsening of suicidal thoughts in all children and adolescents receiving antidepressants, whatever their target symptoms.
Mike is taking methylphenidate, 15 mg bid, for comorbid ADHD, and we add fluoxetine, 10 mg/d, for anxiety. This regimen is well-tolerated, so we increase fluoxetine to 20 mg/d at his 4-week follow-up appointment. After about 8 weeks, Mike’s parents report that his anxiety-associated symptoms are less severe.
Mike still appears nervous sometimes, but he uses markedly fewer perseverative phrases. This allows him to interact more meaningfully with peers and contributes to his social development.
Table 2
Target symptoms and treatment options for fragile X syndrome
| Medication class | Target symptom cluster | Evidence for use of drug class in FXS |
|---|---|---|
| Stimulants | Inattention, hyperactivity | One placebo-controlled trial, two large clinic surveys |
| Alpha-2 agonists | Inattention, hyperactivity | One parent-interview report, two large clinic surveys |
| SSRIs | Anxiety-related symptoms | One mailed survey, two large clinic surveys |
| Atypical antipsychotics | Aggression, self-injury | Two large clinic surveys, several controlled trials in PDDs |
| FXS: fragile X syndrome | ||
| SSRIs: selective serotonin reuptake inhibitors | ||
| PDDs: pervasive developmental disorders. | ||
Aggression and self-injury
Mike, now age 20 and participating daily in a vocational workshop, begins yelling profanities at coworkers. At his group home, he has been hitting staff at least twice a week when redirected.
He is no longer taking stimulants, having been weaned from methylphenidate several years ago, but he continues to take fluoxetine, 40 mg/d.
Fluoxetine19 and clonidine15 can decrease irritability in FXS, but atypical antipsychotics are most commonly used for aggression and SIB.1,2 SGAs are prescribed to 10% to 20% of FXS patients who are taking medication1,2—particularly to men—and have produced response rates of 60% to 100% when used for aggression and SIB.1
Risperidone. No published reports have addressed using specific SGAs in FXS. In the PDD literature, most controlled data concerns risperidone.20
The largest randomized, placebo-controlled trial enrolled 101 children ages 5 to 17 with autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior. Among the 49 children taking risperidone, 0.5 to 3.5 mg/d for 8 weeks, 34 (69%) were judged as treatment responders with significantly reduced irritable behavior, compared with 6 of 52 (12%) taking placebo.21 Risperidone therapy was associated with average weight gain of 2.7±2.9 kg, compared with 0.8±2.2 kg with placebo.
