Evidence-Based Reviews

Managing maladaptive behaviors in fragile X patients

Author and Disclosure Information

Psychotropics can improve hyperactivity, anxiety, and aggression.


 

References

Psychotropics1,2 are used to manage maladaptive and interfering behaviors in 70% of patients with fragile X syndrome (FXS), the leading cause of hereditary mental retardation. Treatment tends to follow a developmental course:

  • In children, stimulants and alpha-2 agonists are used for attention-deficit/hyperactivity disorder (ADHD)-like symptoms.
  • In adolescents and adults, selective serotonin reuptake inhibitors (SSRIs) are used for anxiety/repetitive phenomena and second-generation antipsychotics (SGAs) for irritability.

This course—which is often effective—is based primarily on anecdotal descriptions and on rationales borrowed from studies of ADHD, obsessive-compulsive disorder (OCD), and autistic disorder/related pervasive developmental disorders (PDDs).3 Disease-modifying agents to target the underlying brain dysregulation inherent in FXS (Box)1,4-10 are being investigated. For now, psychotropics can help you manage three common FXS symptom clusters: inattention and hyperactivity, anxiety, and aggression and self-injurious behavior (SIB).

Box

Fragile X syndrome’s genetic and behavioral features

The term “fragile X” describes how the X chromosome of affected individuals fractures in a folate-deprived medium. This most common form of inherited mental retardation affects 1 in 2,000 to 4,000 males and 1 in 4,000 to 8,000 females.4 One in four individuals with fragile X syndrome (FXS) also meets diagnostic criteria for autistic disorder (Table 1), with social skill and communication delays and interfering repetitive behaviors.5

Genetic profile. FXS results from a triplet repeat expansion in the fragile X mental retardation-1 gene.6 This mutation causes underproduction of fragile X mental retardation protein (FMRP), an inhibitor of the metabotropic glutamate receptor (mGluR). In theory, insufficient FMRP allows exaggerated group 1 mGluR activity and leads to the FXS neurobehavioral phenotype: mental retardation, increased seizure risk, behavioral symptoms, and stereotypic movements.7,8

Behavioral difficulties cluster in three categories: attention-deficit/hyperactivity disorder-like symptoms, anxiety symptoms, and aggression and self-injurious behaviors.1,4,9 These are thought to be more prevalent in persons with FXS than would be expected from the degree of cognitive delay alone.1 Potential differences in the behavioral phenotypes of FXS patients with and without comorbid autism continue to be defined.10

Table 1

Clinical characteristics of patients with fragile X syndrome

Physical features (seen in some males)Long, narrow face
High, arched palate
Narrow inter-eye distance
Enlarged ears
Macro-orchidism
Behavioral symptomsInattention
Hyperactivity
Anxiety
Repetitive behaviors
Aggression and self-injurious behaviors (increased in adolescence and adulthood)
ComorbiditiesMental retardation (mean IQ for affected males in moderate range)
Comorbid autism (25% of affected individuals)
Frequent seizures (10% to 20% of affected males)
Hypersensitivity to sensory Stimuli

Inattention and hyperactivity

Mike, age 6, has fragile X syndrome. He has been attending first grade for 4 months, and his teacher reports he does not sit still, runs throughout the classroom, and cannot focus on class work. Mike’s hyperactivity has been evident for 2 years but did not cause problems until first grade, his parents report.

Psychostimulants are the most frequently prescribed agents for inattention and hyperactivity in FXS, particularly in boys and male adolescents.1 Among FXS patients prescribed ≥ 1 psychotropic, approximately 70% are taking a stimulant.1,2

Efficacy. A clinical chart review found a 75% response rate in FXS children and adolescents who were given a stimulant for inattention and/or hyperactivity.1 This is higher than the 25% to 49% stimulant response rate reported in patients with PDDs.11,12

A 3-week, placebo-controlled, crossover trial of methylphenidate and dextroamphetamine noted a statistically significant response only to methylphenidate, with a positive response reported in 10 of 15 children (67%).13

Side effects. To date, limited information has described the rate of intolerable side effects associated with stimulant use in FXS,14 but in patients with PDD:

  • 154 of 268 (57.5%) patient trials in a retrospective naturalistic study showed significant adverse effects with stimulant use.11
  • 13 of 72 (18%) subjects in a controlled trial discontinued methylphenidate because of adverse events (most commonly irritability).12
Based on these observations, possible side effects that deserve close monitoring include mood lability, exacerbation of anxiety, increased social withdrawal, irritability, insomnia, decreased appetite, and increased repetitive movements.

Antiadrenergics. The alpha-2 agonists clonidine and guanfacine are the second most-used class of agents for inattention and hyperactivity in FXS. As with stimulants, boys and male adolescents are most likely to receive alpha-2 agonists, with administration rates of 10% to 20%.1,2

Efficacy. In one survey, nearly two-thirds (63%) of parents described clonidine as “very beneficial” to 35 children (mean age 6.6) with FXS.15 This is similar to a 70% response rate described for these alpha-2 agonists in a chart review.1 These rates are much higher than the 24% response rate reported with guanfacine in a retrospective chart review of 80 children and adolescents with a PDD.16 In that review, guanfacine use was associated with reduced hyperactivity, insomnia, and tics, and increased attention.15

Side effects associated with alpha-2 agonists include lowered blood pressure and sedation.

Pages

Recommended Reading

PDA Screener Helps Enrich Adolescent Visit
MDedge Psychiatry
Head Trauma Precedes Confusional Migraine
MDedge Psychiatry
Brief Scale Assesses Core Symptoms of Autism
MDedge Psychiatry
Autism Symptoms at 18 Months Predict Dx at Age 3
MDedge Psychiatry
Access to Specialists More Likely to Elude Children With Autism
MDedge Psychiatry
Thoughts of High School Faze Boys
MDedge Psychiatry
Foreign Adoptees Close Development Gap
MDedge Psychiatry
Restless Legs Often Present, Rarely Diagnosed
MDedge Psychiatry
Source of Aggression Should Determine Treatment : It may be helpful to consider aggressive behavior in the context of a child's other traits.
MDedge Psychiatry
Diabetes Control May Suffer in Children Who Are Bullied
MDedge Psychiatry