CP_1006_Erickson.FinalREV3 9/21/06 8:59 AM Page 80 Current p SYCHIATRY Managing maladaptive behaviors in fragile X patients Psychotropics can improve hyperactivity, anxiety, and aggression Craig A. Erickson, MD Fellow, child and adolescent psychiatry ® Dowden Health Media Kimberly A. Stigler, MD Copyright Assistant professor For personalDavid use J. Posey, only MD Associate professor Christopher J. McDougle, MD Albert E. Sterne Professor and chairman Department of psychiatry Indiana University School of Medicine Christian Sarkine Autism Treatment Center James Whitcomb Riley Hospital for Children Indianapolis sychotropics1,2 are used to manage mal- P adaptive 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 sero- tonin reuptake inhibitors (SSRIs) are used for anxiety/repetitive phenomena and second-generation antipsychotics (SGAs) for irritability. © images.com / Veer 80 VOL. 5, NO. 10 / OCTOBER 2006 For mass reproduction, content licensing and permissions contact Dowden Health Media. CP_1006_Erickson.FinalREV2 9/20/06 2:44 PM Page 81 Current p SYCHIATRY This course—which is often effective—is Box based primarily on anecdotal descriptions and on Fragile X syndrome’s genetic rationales borrowed from studies of ADHD, and behavioral features obsessive-compulsive disorder (OCD), and autis- tic disorder/related pervasive developmental dis- The term “fragile X” describes how the 3 orders (PDDs). Disease-modifying agents to tar- X chromosome of affected individuals get the underlying brain dysregulation inherent fractures in a folate-deprived medium. This 1,4-10 in FXS (Box) are being investigated. For now, most common form of inherited mental psychotropics can help you manage three com- retardation affects 1 in 2,000 to 4,000 males mon FXS symptom clusters: inattention and and 1 in 4,000 to 8,000 females.4 One in four hyperactivity, anxiety, and aggression and self- individuals with fragile X syndrome (FXS) injurious behavior (SIB). also meets diagnostic criteria for autistic disorder (Table 1, page 82 ), with social skill INATTENTION AND HYPERACTIVITY and communication delays and interfering Mike, age 6, has fragile X syndrome. He has been repetitive behaviors.5 attending first grade for 4 months, and his teacher Genetic profile. FXS results from a triplet reports he does not sit still, runs throughout the repeat expansion in the fragile X mental classroom, and cannot focus on class work. retardation-1 gene.6 This mutation causes Mike’s hyperactivity has been evident for 2 years underproduction of fragile X mental but did not cause problems until first grade, his retardation protein (FMRP), an inhibitor of the parents report. metabotropic glutamate receptor (mGluR). In theory, insufficient FMRP allows exaggerated Psychostimulants are the most frequently pre- group 1 mGluR activity and leads to the scribed agents for inattention and hyperactivity in FXS neurobehavioral phenotype: mental FXS, particularly in boys and male adolescents.1 retardation, increased seizure risk, behavioral Among FXS patients prescribed ≥ 1 psychotropic, symptoms, and stereotypic movements.7,8 1,2 approximately 70% are taking a stimulant. Behavioral difficulties cluster in three Efficacy. A clinical chart review found a 75% categories: attention-deficit/hyperactivity response rate in FXS children and adolescents who disorder-like symptoms, anxiety symptoms, were given a stimulant for inattention and/or and aggression and self-injurious behaviors.1,4,9 1 hyperactivity. This is higher than the 25% to 49% These are thought to be more prevalent in stimulant response rate reported in patients with persons with FXS than would be expected PDDs.11,12 from the degree of cognitive delay alone.1 A 3-week, placebo-controlled, crossover trial Potential differences in the behavioral of methylphenidate and dextroamphetamine phenotypes of FXS patients with and without noted a statistically significant response only to comorbid autism continue to be defined.10 methylphenidate, with a positive response report- ed in 10 of 15 children (67%).13 Side effects. To date, limited information has described the rate of intolerable side effects asso- • 154 of 268 (57.5%) patient trials in a retro- ciated with stimulant use in FXS,14 but in spective naturalistic study showed signifi- patients with PDD: cant adverse effects with stimulant use.11 continued VOL. 5, NO. 10 / OCTOBER 2006 81 CP_1006_Erickson.FinalREV 9/20/06 10:56 AM Page 82 Fragile X Table 1 eficial” to 35 children (mean age 6.6) Clinical characteristics with FXS.15 This is similar to a 70% of patients with fragile X syndrome response rate described for these alpha-2 agonists in a chart review.1 Physical features Long, narrow face These rates are much higher than the (seen in some males) High, arched palate Narrow inter-eye distance 24% response rate reported with Enlarged ears guanfacine in a retrospective chart Macro-orchidism review of 80 children and adolescents with a PDD.16 In that review, guan- Behavioral symptoms Inattention Hyperactivity facine use was associated with Anxiety reduced hyperactivity, insomnia, and Repetitive behaviors tics, and increased attention.15 Aggression and self-injurious Side effects associated with behaviors (increased in alpha-2 agonists include lowered adolescence and adulthood) blood pressure and sedation. Comorbidities Mental retardation (mean L-acetylcarnitine—a carnitine deriva- IQ for affected males in tive required for neuronal use and moderate range) transport of fatty acids—is being inves- Comorbid autism (25% tigated to treat hyperactivity in FXS. of affected individuals) Hyperactive symptoms improved sig- Frequent seizures (10% to 20% of affected males) nificantly with L-acetylcarnitine, as Hypersensitivity to sensory measured by the Conners’ Abbreviated stimuli Parent-Teacher Questionnaire, in a 1- year, placebo-controlled trial of 20 boys (mean age 9.2) with FXS.17 Discussion. Supporting evidence is • 13 of 72 (18%) subjects in a controlled trial limited, but clinicians are treating ADHD-like discontinued methylphenidate because of symptoms with stimulants and alpha-2 agonists adverse events (most commonly irritability).12 in many FXS patients. Preliminary data indicate Based on these observations, possible side that stimulants may be more effective and better effects that deserve close monitoring include tolerated in individuals with FXS than in those mood lability, exacerbation of anxiety, increased with PDD. social withdrawal, irritability, insomnia, decreased Trying a stimulant or alpha-2 agonist for appetite, and increased repetitive movements. inattention or hyperactivity symptoms in a child Antiadrenergics. The alpha-2 agonists clonidine or adolescent with FXS appears clinically appro- and guanfacine are the second most-used class of priate, given the available evidence. Additional agents for inattention and hyperactivity in FXS. As data based on placebo-controlled and standard- with stimulants, boys and male adolescents are ized measures of treatment response are needed most likely to receive alpha-2 agonists, with to help guide treatment. administration rates of 10% to 20%.1,2 Efficacy. In one survey, nearly two-thirds We start Mike on methylphenidate, 5 mg in the morn- (63%) of parents described clonidine as “very ben- ing, for inattention and hyperactivity. He tolerates continued on page 86 82 Current VOL. 5, NO. 10 / OCTOBER 2006 p SYCHIATRY CP_1006_Erickson.Final 9/19/06 11:24 AM Page 86 Fragile X continued from page 82 Table 2 Target symptoms and treatment options for fragile X syndrome Evidence for use Medication class Target symptom cluster 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. this well, and after 2 weeks we increase the Anxiety symptoms—including generalized ner- dosage to 5 mg bid. Several weeks into treatment, vousness and OCD-like obsessions and persever- his teacher comments that he is beginning to stay ations—are common psychotropic targets in in his seat and attends to some assigned tasks in FXS. Boys may be the FXS patients most often the classroom. prescribed drugs for inattention and hyperactivity, Mike continued to tolerate methylphenidate but they are the least likely to over the next 4 years. We gradually receive antidepressants for increased the dosage as he grew anxiety symptoms.1,2 and when he periodically devel- Stimulants may be Efficacy. More than 50% of female oped breakthrough interfering patients and men with FXS are pre- more effective, better symptoms in the classroom. scribed SSRIs for anxiety (Table 2), and tolerated in fragile X the reported response rate of 50% to 60%1 ANXIETY SYMPTOMS patients than in is similar to that seen with SSRIs in In grade school, Mike became those with PDD autism and related disorders.18 In autism, increasingly nervous around school- a developmental approach