Managing maladaptive behaviors in fragile X patients
Psychotropics can improve hyperactivity, anxiety, and aggression.
Besides weight gain, other significant side effects associated with risperidone include sedation and elevated serum prolactin. These effects often are more pronounced in children and adolescents than in adults with PDDs.20
Other antipsychotics. Future use of SGAs in FXS will likely mirror the pattern seen in PDDs, where clinicians are moving towards weight-neutral antipsychotics such as ziprasidone and aripiprazole. In a preliminary report, aripiprazole reduced irritability in 5 youths with PDD.22 Our group is conducting a double-blind, placebo-controlled trial of aripiprazole in autism, targeting aggression, SIB, and irritability.
Discussion. SGAs are used most often in FXS to treat aggression and SIB, based on data from studies on treating similar symptoms in PDDs. Closely monitor patients for sedation, weight gain, and lipid, glucose, and prolactin elevations when using SGAs (Table 3). Be especially vigilant when children gain weight rapidly or show hyperprolactinemia signs while taking these drugs.
After being suspended from the vocational workshop, Mike is treated at a local mental health center for aggressive behaviors. He tolerates an initial dosage of aripiprazole,2.5 mg/d, which is titrated in 2.5-mg increments biweekly to 10 mg/d. At this dosage, he stops hitting staff members and his yelling of profanities is greatly reduced. Over several months, Mike returns to his vocational workshop and maintains residence at his group home.
Table 3
Medication side effects and recommended monitoring
| Medication class | Side effects | Medication monitoring |
|---|---|---|
| Stimulants | Anorexia, insomnia, agitation, exacerbation of tics | Observe closely when starting treatment and increasing dosage |
| Alpha-2 agonists | Lowered blood pressure, sedation, dizziness | Observe closely when starting treatment and increasing dosage |
| Check blood pressure with all dosage changes and at all clinic visits | ||
| SSRIs | Irritability, mood lability, nausea, sleep and appetite disturbances, suicidality | Observe closely when starting treatment and increasing dosage |
| Atypical antipsychotics | Sedation, weight gain, hyperglycemia, hyperlipidemia, hyperprolactinemia, EPS, NMS, tardive dyskinesia | Obtain metabolic profile, including fasting lipids, glucose, and prolactin levels |
| Monitor for weight gain and signs of EPS | ||
| EPS: extrapyramidal symptoms | ||
| NMS: neuroleptic malignant syndrome | ||
| SSRIs: selective serotonin reuptake inhibitors | ||
Genetic-related treatments
Studies are needed to investigate the use of stimulants, SSRIs, and antipsychotics in patients with FXS unaccompanied by generalized anxiety disorder, OCD, ADHD, or PDDs. How FXS patients without those comorbidities will respond to drug treatment is unknown. Also, little also is known about possible side effects associated with combining drug treatments in individuals with FXS.
Future drug treatment in FXS will likely focus on agents that target the underlying neurochemical dysregulation associated with the FXS genotype. This approach might reduce interfering behaviors and alter the course of cognitive dysfunction—including mental retardation—associated with FXS.
Past attempts to correct FXS’ neurochemical abnormalities focused on using folic acid. The term “fragile X” describes how the X chromosome of individuals with FXS fractures in a folate-deprived medium. Many controlled trials of folic acid in FXS did not support earlier positive reports, however.4
Greater understanding of fragile X mental retardation protein (FMRP) function has led to the metabotropic glutamate receptor (mGluR) theory.7 It holds that FMRP underproduction allows exaggerated group 1 mGluR activity and leads to the FXS neurobehavioral phenotype. Researchers now are attempting to reverse the neurochemical impact of insufficient FMRP with two medication classes:
- selective group 1 mGluR receptor antagonists (mGluR5 antagonists, in particular). The mGluR5 receptor antagonist MPEP has shown the ability to rescue normal behaviors in animal models of FXS. MPEP and lithium have reversed behaviors associated with FXS and—at the microscopic level—rescued synaptic plasticity.23,24 In the drosophila fly model of FXS, lithium reduced activity in the mGluR cascade, thus compensating for lack of FMRP.23
- positive AMPA receptor modulators (ampakines) that promote activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.9 Excessive mGluR activity appears to impair AMPA receptors’ ability to promote cortical development, memory, and learning.7 Reduced AMPA receptors have been shown in the FXS mouse model,25 and an ampakine is being investigated in a study of men with FXS and autism.1
- FRAXA: The Fragile X Research Foundation. Founded by parents of children with fragile X syndrome to increase funding for research toward effective treatments. www.fraxa.org.
- The National Fragile X Foundation. Provides educational and emotional support for fragile X families and promotes public and professional awareness. www.fragilex.org.
- Hagerman RJ, Hagerman PJ, eds. Fragile X syndrome: diagnosis, treatment, and research, 3rd ed. Baltimore, MD: The Johns Hopkins University Press; 2002.
- Aripiprazole • Abilify
- Clonidine • Catapres
- Dextroamphetamine • Dexedrine
- Fluoxetine • Prozac
- Guanfacine • Tenex
- Lithium • Eskalith, Lithobid
- Methylphenidate • Ritalin
- Risperidone • Risperdal
- Ziprasidone • Geodon
Dr. Erickson reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Stigler receives grant/research support from Bristol-Myers Squibb Co. and Janssen Pharmaceutica.
