Ajmr_109_401.301_309.tp

VOLUME 109, NUMBER 4: 301–309 ͦ JULY 2004 Effects of Topiramate in Adults With
Prader-Willi Syndrome
Nathan A. Shapira, Mary C. Lessig, Mark H. Lewis, Wayne K. Goodman, and
Daniel J. Driscoll
University of Florida
Abstract
Prader-Willi syndrome is a multisystem neurogenetic obesity disorder with behavioral man-
ifestations, including hyperphagia, compulsive behavior, self-injury, and mild to moderate
mental retardation. In an 8-week open-label study, we evaluated adjunctive therapy with
the anticonvulsant topiramate in 8 adults with Prader-Willi syndrome. Appetite was mea-
sured by a 1-hour access to food four times throughout the study and quantified with a
visual analogue scale. Topiramate did not significantly change calories consumed, Body
Mass Index, or increase self-reported appetite. In addition, there were no significant changes
in compulsions. Surprisingly, topiramate treatment resulted in a clinically significant im-
provement in the self-injury (i.e., skin-picking) that is characteristic of this syndrome. Po-
tential benefits of topiramate for self-injury should be evaluated further in controlled trials.
Prader-Willi syndrome is a multisystem neu- drome (Inoue, 1995; Itoh, Koeda, Ohno, & Tak- rogenetic disorder characterized by neonatal fail- eshita, 1995; Inui et al., 1997). Although opiate ure-to-thrive, hypogonadism, dysmorphic fea- antagonists have been reported to be helpful in tures, mild to moderate mental retardation, severe obese and bulimic patients (de Zwaan & Mitchell, hyperphagia, and childhood-onset obesity (Prader, 1992), naloxone failed to alter food intake in in- Labhart, & Willi, 1956; A. Martin et al., 1998).
dividuals with Prader-Willi syndrome (Zipf & Also common in this population are behavioral/ psychiatric manifestations, including self-injury, Small open-label studies have demonstrated explosive outbursts, obsessive ruminations, and that selective serotonin reuptake inhibitors (SSRIs) can be helpful for self-injurious, aggressive, affec- Limited use of appetite suppressants and an- tive, and compulsive behaviors in these individ- orectic agents have been reported in the literature uals (A. Martin et al., 1998). Unfortunately, SSRIs for individuals with Prader-Willi syndrome. Seli- can exacerbate these behaviors during the initia- kowitz, Sunman, Pendergast, and Wright (1990) tion/titration phases (A. Martin et al., 1998). An- reported on the use of fenfluramine, which re- tiepileptic and antipsychotic medications are sulted in significant weight loss, an improvement sometimes helpful in individuals with Prader-Willi in behaviors associated with the exposure to food, syndrome for targeting impulsive and psychotic and a decrease in aggressive impulses in 15 indi- behavior, although these agents can increase viduals with the syndrome. Due to cardiovascular weight (Durst, Rubin-Jabotinsky, Raskin, Katz, & consequences, however, fenfluramine is currently Zislin, 2000; A. Martin et al., 1998; Stein, Keeting, not available for use. In three reports of the an- Zar, & Hollander, 1994). Recently, Durst et al.
orectic mazindol, available in Japan, researchers (2000) reported on the benefits of the use of the demonstrated its benefit for appetite and weight atypical antipsychotic risperidone for behavioral control in 5 individuals with Prader-Willi syn- management without significant increases in ᭧ American Association on Mental Retardation VOLUME 109, NUMBER 4: 301–309 ͦ JULY 2004 Topiramate effects
weight. Classically, atypical antipsychotics have and safety of open-label topiramate in adults with been reported to induce weight gain, although it Prader-Willi syndrome as an appetite-regulating is recognized that the risk of weight gain with ris- medication. Following previous observations by peridone therapy is not as great as other neuro- the authors of the effects of topiramate in binge- leptics, for example, clozapine or olanzapine eating disorder and, subsequently, antipsychotic- (Baptista, Kin, Beaulieu, & de Baptista, 2002).
induced weight gain, we hypothesized that topi- Only small case reports (1 to 3 subjects) on ramate would decrease appetite and manage the use of antiepileptic medications for behavioral weight in individuals with Prader-Willi syndrome management have previously been reported in the (Lessig, Shapira, & Murphy 2001; McElroy et al., literature (Gupta, Fish, & Yerevanian, 1987; Je- 2003; Shapira et al., 2000). In addition, we eval- rome 1993; A. Martin et al., 1998; Tu, Hartridge, uated whether topiramate would also affect other & Izawa, 1992). However, Smathers, Wilson, and behaviors associated with this syndrome. Changes Nigro (2003) reported on the successful use of the in appetite were quantified in terms of appetite antiepileptic topiramate in 8 children and adoles- regulatory effects; these effects were identified as cents with Prader-Willi syndrome to control a decrease in the number of consumed calories as weight and behavior. Topiramate is a novel anti- directly measured and incidences of active food epileptic agent associated with appetite suppres- sion and weight loss (Privitera, 1997). Further-more, this medication has been reported to be helpful in the treatment of binge-eating disorder(McElroy et al., 2003; Shapira, Goldsmith, & McElroy, 2000) and may have mood-stabilizing The 9 participants enrolled in this 8-week open-label trial of topiramate, described in Table Individuals with Prader-Willi syndrome often 1, were residents of local group homes specializing live in controlled and behaviorally monitored en- in the care of persons with Prader-Willi syndrome.
vironments, such as group homes, where their ac- Participants were confirmed as having Prader-Willi cess to food is limited. Even when in a controlled environment, some individuals with Prader-Willi lecular analyses (Glenn et al., 1996). Participants syndrome continue to forage and hoard food, were recruited through a letter approved by the making it difficult to place them in programs out- Institutional Review Board of the University of side of these controlled settings (Hoffman, Ault- Florida Health Science Center. This recruitment man, & Pipes, 1992; Page, Stanley, Richman, letter was sent to their parents prior to participa- Deal, & Iwata 1983). We evaluated the efficacy tion to inform them of the study and its goals; Table 1. Participant Demographics
aInitiated sertraline therapy during study interventions. bParticipant 6 was not included in analysis due to exclusion fromstudy interventions. cUniparental disomy. dBody Mass Index.
᭧ American Association on Mental Retardation VOLUME 109, NUMBER 4: 301–309 ͦ JULY 2004 Topiramate effects
included with the letter was a copy of the in- of standardized rating measurements, the Aber- formed consent document, which was not to be rant Behavior Checklist (Aman, Singh, Stewart, & signed. Full written informed consent was ob- Field, 1985); the Repetitive Behavior Scale, in- tained from participants and witnessed by either cluding the Self-Injury and Self-Restraint Check- a parent or group home operator. One participant list (Bodfish, Symons, & Lewis, 1999; Bodfish, Sy- during screening was excluded due to behavioral mons, Parker, & Lewis, 2000; Powell, Bodfish, outbursts that met exclusion criteria; however, Parker, Crawford, & Lewis, 1996), the Yale-Brown these outbursts would not have ruled the potential Obsessive-Compulsive Scale Checklist (Goodman participant out for clinical treatment with topira- et al., 1989), and the Clinical Global Impression mate. Eight participants initiated and completed Scale. Problems with verbal fluency and a decrease the study (5 female, 3 male; 6 deletion, 2 unipa- in attention have been noted in healthy volunteer rental disomy; mean age ϭ 29.5 years, standard adults taking topiramate (R. Martin et al., 1999).
Thus, we assessed verbal fluency and attention us-ing the Controlled Oral Word Association Test (Lezak, 1996), the Semantic Category Naming Participants began topiramate following a 1- Test (Lezak, 1996), and the Vigilance and Delay week screening phase that involved laboratory Task of the Gordon Diagnostic System (Gordon, evaluations and a medical/psychiatric history, in- 1983). Participants completed the Yale-Brown Ob- cluding the Structured Clinical Interview for the sessive-Compulsive Scale checklist, Controlled Diagnostic and Statistical Manual for Mental Dis- Oral Word Association Test, Semantic Category orders, Fourth Revision DSM-IV Patient Ver- Naming Test, and Gordon Diagnostic System task sion (American Psychiatric Association, 2000).
with the aid of the research assistant. Group home Group home operators and staff members main- operators completed the Aberrant Behavior tained detailed records of behavioral outbursts, Checklist and Repetitive Behavior Scale.
weight, and daily activities. We were granted ac- While in the study, the daily activities of the cess to these records during the screening process participants were not altered nor was their pre- for review as well as during participation for mon- scribed caloric intake altered. Participants exer- itoring purposes after the Informed Consent Doc- cised an average of 45 minutes daily and con- ument and a medical record release were signed.
sumed between 900 and 1,200 baseline calories Topiramate therapy was begun at a dose of 25 per day. Based on a token system already in place mg orally at bedtime at baseline and increased in these facilities, additional food could be earned weekly by a dose of 25 mg at bedtime. We deter- for completing tasks and exhibiting appropriate mined whether to increase participants’ medica- behavior (Dykens & Hodapp, 1997; Lowenstein, tion dose based on side effect profile (e.g., pres- ence of parasthesias or significant sedation) and Appetite was assessed during one hour of free response (e.g., loss of weight). Following the ben- access to food (low-calorie) at the baseline visit eficial finding that topiramate positively affected and Weeks 2, 4, and 8 (Holland et al., 1993). Test skin-picking behavior (observed initially in the food was presented in the form of sandwich quar- first participant), attenuation of self-injury was ters that were, on average, 273 kcal and comprised also factored into whether to increase their study of low-calorie bread (40 kcal), luncheon meat (9 medication dose or maintain the dose until the kcal), and cheese (30 kcal) with no condiments.
next week, although the primary indicators for in- Sandwiches were prepared in 3 forms: cheese only creasing the dose were the presence of side effects (275 kcal), luncheon meat only (245 kcal), and and topiramate’s effect on appetite and related be- cheese and luncheon meat (298 kcal). The num- haviors. Conventional dosing regimens warrant a ber of sandwich quarters consumed was recorded twice a day dosing schedule. Due to our clinical per 15-minute interval of the 1-hour free access experience, a single dosing schedule of prescribed period for the type of sandwich quarter chosen.
topiramate was initiated to minimize daytime se- Totals were calculated for the types and total cal- dation and other side effects. In addition, in order ories consumed. Water was available to the par- to further minimize the side effect profile, we ti- ticipants throughout the hour, and they were per- trated doses in a slow, linear fashion of approxi- mitted to stop eating at any time during the free mately 25 to 50 mg weekly increases.
access period. Participants were monitored closely Baseline and weekly visits included a battery for signs of discomfort and distress due to an oc- ᭧ American Association on Mental Retardation VOLUME 109, NUMBER 4: 301–309 ͦ JULY 2004 Topiramate effects
clusion from rapid eating because individuals withPrader-Willi syndrome may have a limited gag re-flex and inability to vomit. The start and stoptime was recorded for each discrete session.
Appetite was quantified utilizing a ‘‘Feelings of Hunger’’ visual analogue (0 to 5) scale devel- Figure 1. Feelings of Hunger Scale.
oped by the investigators. The scale was similar toa 10-cm visual analogue scale described by Hol-land, Treasure, Coskeran, and Dallow (1995). Ourscale consisted of pictorial representations of fig- fects, including parathesias, irritability, sedation, ures with full or empty stomachs, numbers, or and cognitive delays, were mild overall, and to- brackets that could be used to endorse hunger.
piramate was generally well-tolerated. Side effects Pictorial representations were included to aid the were determined by interviews with the partici- participant in selecting the appropriate level of pant and group home operators each week and hunger (Figure 1). We described hunger to each during phone interviews at intermittent times participant in terms of ‘‘how full his or her belly throughout their participation. All 8 participants felt’’ at the time of questioning (e.g., a rating of a completed the 8 weeks of treatment. As shown in 0 on the scale indicated that the participant was Table 2, topiramate did not alter appetite as mea- full and would not continue to eat the presented sured by calories during the free access to food low-calorie food). Participants self-reported their period or significantly decrease body mass index appetite prior to beginning the free access to low- (BMI). Reported appetite as measured by the Feel- calorie food testing period and following the test- ings of Hunger visual analogue scale actually in- ing period. They were not encouraged or rewarded creased. Furthermore, there were no significant with extra sandwiches following endorsement of changes in the Yale-Brown Obsessive-Compulsive Scale checklist or Clinical Global Impression-Se- verity Scale (see Table 3). Although no participant changes in behavior as follows. The group home got worse, only 2 displayed much or very much operators were asked to endorse the occurrence or improvement by Week 8 on the Clinical Global nonoccurrence of behaviors on the Aberrant Be- havior Checklist each week (Aman et al., 1985).
In contrast to appetite and weight, there was The overall number of endorsed behaviors was significant improvement in behavior as demon- calculated for each session. Group home operators strated by the total number of items endorsed on endorsed obsessive and compulsive behaviors us- the Aberrant Behavior Checklist, t(7) ϭ Ϫ2.72, p ing the Yale-Brown Obsessive-Compulsive Scale ϭ .03, and reduced self-injury as demonstrated by checklist at each visit. Self-injury was assessed by the Self-Injury Restraint Checklist, t(7) ϭ Ϫ3.83, endorsement of items on the Self-Injury and Self- p ϭ .006 (see Figure 2 and Table 3). Subscales of Restraint Checklist, a subscale of the Repetitive the Aberrant Behavior Checklist showed a de- Behavior Scale developed by Bodfish et al. (1999).
crease in the overall number of endorsed behav- Symptom severity was also assessed by the Clini- iors; however, these decreases were not significant.
cal Global Impression, which was completed by While taking topiramate, 7 of 8 individuals who the primary investigator and research assistant.
engaged in self-injurious behavior (SIB) showed The Clinical Global Impression rating was based improvement of symptomology, which included on changes in appetite, weight, behavior, and the attenuation of these behaviors and apparent improved healing of self-inflicted wounds. At the Data were analyzed by t test conducted to test time of participation, the seventh participant to the hypothesis that the slope of the dependent engage in SIB was not identified by the investi- variables measured over 8 weeks was significantly gators. However, we became aware of his SIB ret- rospectively. During follow-up conversations, thisindividual’s parent reported that the subject’s nail-biting and ripping of his cuticles had significantly improved throughout the study period and had Topiramate was titrated to an average dose of continued during follow-up, to the point that it 162.5 mg at bedtime (SD ϭ 23.15 mg). Side ef- had decreased to almost an indistinguishable lev- ᭧ American Association on Mental Retardation VOLUME 109, NUMBER 4: 301–309 ͦ JULY 2004 Topiramate effects
Table 2. Measures of Appetite Regulation in Adults With Prader-Willi Syndrome During an 8-Week
Open-Label Trial of Topiramate (N ϭ 8)
a7-point scale.
*p Ͻ .05.
el. Overall, for the 6 Prader-Willi syndrome indi- Discussion
viduals who were known to engage in SIB at thetime of the study (particularly skin-picking), there This study represents the largest reported in- was a clinically noticeable decrease in the size of vestigation of anticonvulsant medication use for most primary lesions and number of lesions (from appetite and behavior control in adults with Prad- a mean of 2.5 to a mean of 1 based on report of er-Willi syndrome. We found that topiramate did group home operators). A case report of 3 of the not help appetite control or weight for these in- participants in this study can be found in Shapira, dividuals, as measured by calorie consumption Lessig, Murphy, Driscoll, and Goodman (2002).
during free access to food, visual analogue scale, Comparable observations were noted in the 3 sub- or BMI. This result is contrary to our hypothesis sequent participants in addition to the 3 reported and inconsistent with the positive response to to- piramate that has been noted in individuals with In terms of possible cognitive effects reported obesity as a result of binge-eating disorder and in the literature, there were no significant changes from the administration of weight-increasing med- on the Controlled Oral Word Association Test or ications (Lessig et al., 2001; McElory et al., 2003; the Vigilance Task, but there was an unexpected improvement in the Semantic Category Naming These negative findings on appetite control Test, t(7) ϭ 2.51, p ϭ .04, and a trend towards could be the result of a number of factors, in- improvement in the Delay Task, t(7) ϭ 2.28, p ϭ cluding small sample size, concomitant psycho- tropic medications, or short duration of this open- Table 3. Other Measures of Interest
aY-BOCS ϭ Yale-Brown Obsessive-Compulsive Scale Checklist: GDS ϭ Gordon Diagnostic System; COWAT ϭ Con- trolled Oral Word Association Test; SCNT ϭ Semantic Category Naming Test; ABC ϭ Aberrant Behavior Checklist- Modified. SIB-C ϭ Self-Injury and Self-Restraint Checklist.
*p Ͻ .05. **p Ͻ .01.
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crease in food intake (Stanley, Ha, Spears, & Dee,1993; Stanley, Willett, Donias, Ha, & Spears,1993), and researchers have hypothesized that to-piramate’s positive effects in binge-eating disorderrelates to its kainate/AMPA glutamate receptor an-tagonism (McElroy et al., 2003; Shapira et al.,2000). Within the deleted region of chromosome15 are proteins that synthesize the production ofthree GABA receptor subunits, beta-3, alpha-5,and gamma-3. The lack of these receptor subunitsmay be responsible for our finding that topira- Figure 2. Average number of endorsed behaviors
mate did not have an effect on appetite.
on the Aberrant Behavior Checklist (ABC) and Conversely, we were surprised by the signifi- Self-Injury and Self-Restraint Checklist (SIB-C).
cant improvements in behavior observed follow-ing drug treatment, particularly skin-picking. Inaddition to its effect on behaviors, topiramate also label study. The addition of topiramate to several appeared to improve wound healing and, thus, psychotropic medications was consistent with the was a factor in the healing of skin lesions. As not- Federal Drug Administration and pharmaceutical ed above, our research group reported on 3 of the manufacturer’s recommendation of the use of to- 6 individuals included in this review of the effect piramate as an adjunctive therapy in epilepsy; of topiramate on skin-picking (Shapira et al., however, the use of topiramate as a monotherapy 2002). These individuals continued to maintain may have produced different results. Two partic- positive changes throughout their follow-up peri- ipants were medication free at enrollment, one od, although 1 subject voluntarily elected to be participant was started on sertraline, and the other taken off the medication approximately 8 months maintained medication-free status throughout par- after completing the trial. This trial was not sys- ticipation. The medication-free participant expe- tematically designed to evaluate topiramate’s ef- rienced a significant reduction in skin-picking and fects on SIB. Therefore, these apparent improve- a modest weight loss (1.47 kg). Few researchers ments should be viewed cautiously. In order to have looked at the efficacy of topiramate as a address this issue, we are currently conducting fol- monotherapy (Conner, 2002; Cross, 2002). Fur- low-up studies in a blinded, cross-over manner thermore, topiramate may have been underdosed; based on our observations with topiramate for doses have been reported from 25 mg to 1600 mg wound healing and SIB, with direct observation (Ortho-McNeil Pharmaceuticals, 2000; Shapira et of lesion improvement in individuals with Prader- al., 2000). In addition, our participants were all in well-controlled group-home settings and although Topiramate did not have an overtly positive obese, they may have been closer to goal weights effect on compulsive behaviors in these 8 individ- than nonsupervised individuals with Prader-Willi uals. To date, in other clinical populations that exhibit symptoms of compulsions, the use of to- On the other hand, it is possible that these piramate has not been fully evaluated. Overall, in findings demonstrate that the genetic makeup of terms of Prader-Willi syndrome, Feurer et al.
Prader-Willi syndrome alters the expected re- (1998) reported on administration of the Com- sponse to topiramate. Several possible mecha- pulsive Behavior Checklist to 75 individuals to nisms of action have been identified for this med- evaluate the 25 endorsable items. Of these items, ication (Privatera, 1997): (a) state-dependent skin-picking did not load on the general factor blockade of voltage-activated Naϩ channels, (b) fa- and should be considered as a separate behavior cilitation of GABAergic activity at a nonbenzo- or unique item when evaluating these individuals.
diazepine site on ␥-aminobutyric acid (GABA ) This finding is consistent with our findings of a receptors, and (c) antagonism of kainate/AMPA differential response to topiramate for SIB and type glutamate receptors. Interestingly, stimula- tion in rats of the lateral hypothalamus by gluta- mate agonists, including kainite/AMPA agonists, chose to continue on topiramate after the trial.
causes a rapid and intense dose-dependent in- One participant stopped due to lack of weight/ ᭧ American Association on Mental Retardation VOLUME 109, NUMBER 4: 301–309 ͦ JULY 2004 Topiramate effects
appetite control after 5 months and one requested treatment effects. American Journal of Mental to stop the medication, although not for clinical purposes, after 8 months. She was benefiting in Baptista, T., Kin, N. M. K. N. Y., Beaulieu, S., & terms of self-injury and other behaviors but decid- de Baptista, E. A. (2002). Obesity and related ed she did not want to take the medicine any- metabolic abnormalities during antipsychotic more. Thus, she was titrated off the medication slowly and, consequently, her symptoms began to ment and research perspectives. Pharmapsy- return. She had gained approximately 0.4 kg dur- ing the 8 months on topiramate. Individuals in Bodfish, J. W., Symons, F. J., & Lewis, M. H.
these specialized group homes without any med- (1999). The Repetitive Behavior Scale (Western ication augmentation typically lose weight at a Carolina Center Research Reports). Morgan- steady pace, approximately .227 kg per week (M.
Lister, personal communication, August 20, Bodfish, J. W., Symons, F. J., Parker, D. E., & 2002). The 6 other participants continued taking Lewis, M. H. (2000). Varieties of repetitive be- topiramate (8.17 months, SD ϭ 4.53), with a de- havior in autism. Journal of Autism and Devel- crease in weight of approximately 50% of what opmental Disabilities, 30, 237–243.
might be expected for that time period (3.68 kg, Conner, G. S. (2002). A double-blind placebo SD ϭ 1.35). However, they did experience contin- controlled trial of topiramate treatment for es- ued improvement in terms of behavior and self- sential tremor. Neurology, 59, 132–134.
Cross, J. (2002). Topiramate monotherapy for Topiramate resulted in a decrease in total Ab- childhood absence seizures: An open-label pi- errant Behavior Checklist scores, although a time- lot study. Seizure, 11, 406–410.
dependent change in individual subscales was not de Zwaan, M., & Mitchell, J. E. (1992). Opiate significant. This outcome represents a change in antagonists and eating behavior in humans: A the number of items endorsed on the Aberrant review. Journal of Clinical Pharmacology, 321, Behavior Checklist and not severity. By collapsing the rating measurement from a 4-point rating of Durst, R., Rubin-Jabotinsky, K., Raskin, S., Katz, severity to simply endorsement of behavior, we G., & Zislin, J. (2000). Risperidone in treating limited the sensitivity of the rating measurement.
behavioural disturbances of Prader-Willi syn- Had we asked the group home operators to also drome. Acta Psychiatrica Scandanavica, 102, rate the severity of the behaviors reported on the Aberrant Behavior Checklist, a more sensitive es- Dykens, E. M., Cassidy, S. B., & King, B. H.
timate of treatment outcome might have been ap- (1999). Maladaptive behavior differences in Prader-Willi syndrome due to paternal dele- Skin-picking is a very serious problem in the tion versus maternal uniparental disomy.
Prader-Willi syndrome population (Dykens, Cas- American Journal on Mental Retardation, 104, sidy, & King, 1999) and may lead to serious con- sequences, such as cellulitus and osteomylitus. To Dykens, E. M., & Hodapp, R. M. (1997). Treat- date, there have been no medications or effective ment issues in genetic mental retardation syn- behavior modification strategies to alleviate this dromes. Professional Psychology: Research and problem. Thus, the positive preliminary findings reported in this study and by Smathers et al.
Feurer, I. D., Dimitropoulos, A., Stone, W. L., (2003) warrant follow-up with a more extensive, Roof, E., Butler, M. G., & Thompson, T.
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Editor-in-charge: Elisabeth M. Dykens G., II. (1993). Lateral hypothalamic injectionsof glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid or This project was supported by grants from the N-methyl-D-aspartic acid rapidly elicit intense Prader-Willi Syndrome Association (USA) and the transient eating in rats. Brain Research, 613, College Incentive Fund of the University of Flor- ida (Nathan Shapira) as well as National Institute Stanley, B. G., Willett, V. L., III, Donias, H. W., Ha, L. H., & Spears, L. C. (1993). The lateral hypothalamus: A primary site mediating ex- citatory amino acid-elicited eating. Brain Re- Driscoll).The authors gratefully acknowledge Mark Yang for statistical support and analysis and Stein, D. J., Keeting, J., Zar, H. J., & Hollander, Mark Gold for his valuable suggestions. The au- thors also thank the ARC of Alachua County. Re- and pharmacotherapy of compulsive and im- quests for reprints should be sent to Nathan A.
pulsive-aggressive symptoms in Prader-Willi Shapira, College of Medicine, PO Box 100256, syndrome. Journal of Neuropsychiatry and Clin- University of Florida, Gainesville, FL 32610.
ical Neuroscience, 6, 23–29.
᭧ American Association on Mental Retardation

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