Vocabulary comprehension in adults with fragile X syndrome (FXS).

BACKGROUND: Receptive and expressive vocabulary in adult and adolescent males with fragile X syndrome (FXS) have been shown as significantly lower than their chronological age; however, receptive vocabulary has been considered a strength relative to mental age. This has not been formally examined, however, and data are needed to compare receptive vocabulary with other language skills and with mental age in individuals with FXS. This is especially important as vocabulary measures are sometimes used as a proxy to estimate language ability. METHODS: This preliminary study examined receptive vocabulary, global language, and cognitive skills in 42 adults (33 males and 9 females) with FXS as a portion of the baseline evaluation prior to randomization in a clinical trial of ampakine CX516. The battery of standardized tests addressed receptive vocabulary with the Peabody Picture Vocabulary Test, Third Edition (PPVT-III), receptive and expressive language (termed henceforth as global language) via the Preschool Language Scale, Fourth Edition or the Clinical Evaluation of Language Fundamentals, Third Edition, and non-verbal cognition via the Stanford-Binet Intelligence Scales, Fourth Edition (SB-IV). RESULTS: Results showed (1) significantly higher receptive vocabulary than global language, (2) significantly better receptive vocabulary than non-verbal cognition, (3) equivalent non-verbal cognition and global language, and (4) severity of autism symptomatology was not correlated to receptive vocabulary or global language once non-verbal cognition was removed as factor. The scores from the PPVT-III did not represent the global language skills in our sample of adults with FXS. CONCLUSIONS: Findings from this investigation strongly suggest that the PPVT-III should not be used as a screening tool for language levels or cognitive function in clinical studies since the scores from the PPVT-III were not representative of global language or non-verbal cognitive skills in adults with intellectual disabilities. This finding is critical in order to understand how to evaluate, as well as to treat, language in individuals with FXS. Development of efficient and appropriate tools to measure language, cognition, and behavior in individuals with FXS is essential.

5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism.

OBJECTIVE: The serotonin transporter gene (SLC6A4) is a strong autism candidate gene because of its association with anxiety, aggression and attention, and the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating certain behavioral symptoms. In families with individuals with autism, several reports of biased transmission of both alleles (short, long) at the serotonin transporter gene promotor polymorphism (5-HTTLPR) locus of SLC6A4 now exist. The heterogeneity in these reports may be due to clinical heterogeneity. The authors hypothesized that 5-HTTLPR genotypes would be related to variation in specific symptoms in children with autism. METHOD: The authors explored whether variants of two functional polymorphisms of SLC6A4 (5-HTTLPR, intron 2 variable number tandem repeat [2 VNTR]) were related to behavioral characteristics measured by the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Subjects (N=73, age 3-19 years old) met diagnostic criteria for autistic disorder based on both measures. RESULTS: Evidence of genotype-phenotype interactions on the Autism Diagnostic Interview-Revised was found with the 5-HTTLPR short group of HTTLPR (S/L or S/S genotypes) being rated as more severe on the subdomain "failure to use nonverbal communication to regulate social interaction," and the long group (L/L genotype) being more severe on the subdomain "stereotyped and repetitive motor mannerisms" and on an aggression measure. In contrast, on the Autism Diagnostic Observation Schedule, the long group was associated with greater severity on directed facial expressions and unusual sensory interests. There were no significant relationships between the intron 2 VNTR genotypes and subdomains or domains of symptoms on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. CONCLUSIONS: These findings provide initial support for genotype-specific phenotypes for 5-HTTLPR in autism based on ratings from the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule.

A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders.

BACKGROUND: This pilot study examined the effectiveness of memantine hydrochloride in improving cognitive functioning and behavioral symptoms in children with pervasive developmental disorders (PDDs). METHOD: Subjects aged 3-12 years inclusive were enrolled in this 8-week, open-label study. Expressive and receptive language, nonverbal IQ, and nonverbal memory measures were administered at baseline and after 8 weeks of treatment with 0.4 mg/kg of memantine hydrochloride. Throughout the study, the Aberrant Behavior Checklist (ABC) was sent in weekly by parents as a measure of behavioral change. RESULTS: Twelve of 14 subjects completed the study. Significant improvement from baseline was noted on the memory test (Children's Memory Scale Dot Learning Subtest). There were no significant differences from baseline on measures of expressive or receptive language or nonverbal IQ. There were significant improvements on a number of ABC subscales, including hyperactivity, lethargy, and irritability. There were no overall significant statistical differences from baseline on the Clinical Global Improvement-Severity (CGI-S) scale. On the Clinical Global Improvement-Improvement (CGI-I), 4 of 14 subjects showed minimal improvement, and none was deemed "much-improved" or "very much improved." CONCLUSIONS: This small, prospective, open-label study suggests that memantine may be useful in the treatment of memory functioning and some behavioral symptoms in PDDs. The investigators did not see the same degree of change as endorsed by caretakers. Controlled studies are needed to substantiate and clarify these preliminary findings.

Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial.

A Phase II, 4-week randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and efficacy of the Ampakine compound CX516 as a potential treatment for the underlying disorder in fragile X syndrome (FXS). After baseline screening, subjects with FXS (n = 49) underwent a 1-week placebo lead-in and then were randomized to study drug or placebo for a 4-week period. Cognitive and behavioral outcome measures were administered prior to treatment, at the end of treatment, and 2 weeks posttreatment. There were minimal side effects, no significant changes in safety parameters, and no serious adverse events. There was a 12.5% frequency of allergic rash in the CX516 group and 1 subject developed a substantial rash. There was also no significant improvement in memory, the primary outcome measure, or in secondary measures of language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo. This study did demonstrate that many outcome measures were reproducible in this test-retest setting for the FXS population, yet some were too difficult or variable. Adult subjects with FXS were able to complete an intensive clinical trial, and some valid outcome measures were identified for future FXS trial design. Problems with potency of CX516 in other studies have suggested dosing may have been inadequate for therapeutic effect and thus it remains unclear whether modulation of AMPA-mediated neurotransmission is a viable therapeutic strategy for the treatment of FXS.

An open-label trial of escitalopram in pervasive developmental disorders.

OBJECTIVE: To assess the effect of escitalopram in the treatment of pervasive developmental disorders (PDDs). METHOD: This 10-week study had a forced titration, open-label design. Twenty-eight subjects (mean age 125.1 +/- 33.5 months) with a PDD received escitalopram at a dose that increased weekly to a maximum dose of 20 mg as tolerated. The Aberrant Behavior Checklist-Community Version (ABC-CV) and the Clinical Global Impression scale (CGI) were used to assess outcome. RESULTS: There was significant improvement in ABC-CV Irritability Subscale Scores (baseline mean 20.5 +/- 5.9 to final mean 10.9 +/- 7.2; p < or = .001) and in the other ABC-CV Subscales. Improvement on Clinical Global Improvement Scale severity rating was also significant (baseline mean 5.2 +/- 1.0 to final mean 4.6 +/- 1.2; p < or = .001). Twenty-five percent of the subjects responded at a dose less than 10 mg and did not tolerate the 10-mg dose, and an additional 36% responded at a dose greater than or equal to 10 mg. Final dose was unrelated to weight and only weakly correlated with age. CONCLUSIONS: This open-label study found escitalopram to be useful in treating some difficulties common in PDDs. A wide variability in dose was found that could not be accounted for by weight and only partially by age. The study provides information useful for the design of double-blind, placebo-controlled studies of escitalopram in PDDs.

The Scottish Centre for autism preschool treatment programme. II: The results of a controlled treatment outcome study.

This article evaluates the effectiveness of a developmentally based early intervention programme. Two groups of children were compared, a treatment group and a no-treatment control group. Standardized assessments were administered before and after the intervention period by an independent clinician. Pre-treatment comparisons revealed that the control group had a significantly higher pre-treatment IQ; but the two groups were comparable for age, mental age, socioeconomic status and number of hours of non-experimental therapy. Results demonstrated that children in the treatment group improved significantly more than those in the control group on measures of joint attention, social interaction, imitation, daily living skills, motor skills and an adaptive behaviour composite. A measure of requesting behaviour fell short of statistical significance. The total stress index reduced for treatment group parents and increased for the control group parents (but not significantly). The results of the study are considered to support the efficacy of this treatment approach.

A pharmacogenetic study of escitalopram in autism spectrum disorders.

OBJECTIVE: To determine the effect of serotonin transporter polymorphism promoter region (5-HTTPLR) genotypic variation (low, intermediate, and high expression groups) on response to escitalopram treatment of children and adolescents with autism spectrum disorders (ASDs). METHOD: The study used a forced titration, open label design, with genotype blind until study completion. Participants were children and adolescents aged 4-17 years of age with a confirmed ASD (autistic disorder, Asperger's disorder, or pervasive developmental disorder, not otherwise specified). RESULTS: There was an interaction between genotype group and time on the Aberrant Behavior Checklist (ABC) Irritability Subscale (primary outcome variable) (linear maximum marginal likelihood estimation=-4.84, Z=-2.89, SE=1.67, P=0.004). Examination of baseline to last visit revealed that a genotype grouping based on a previous study of platelet 5-HT uptake revealed less response in the genotype group that had S/S genotype for 5-HTTLPR and did not have a diplotype in intron 1 previously shown to be associated with increased platelet 5-HT uptake. CONCLUSION: This genotype-blind, prospective pharmacogenetic study found the group of subjects with associated with the lowest platelet 5-HT uptake from previous study had the smallest reduction in ABC-Irritability scores after open label treatment with escitalopram. Replication is necessary to confirm these findings.

Factors affecting GUM clinic attenders decisions and intentions to seek HIV testing.

OBJECTIVES: To evaluate factors that predict HIV testing using the model of health care utilisation as its conceptual framework and to analyse some of the factors that encourage or inhibit seeking an HIV test in this population. METHOD: A cross sectional questionnaire study in two Genito-Urinary Medicine (GUM) clinics in central Scotland. A final sample of 195 represented a 91% response rate. Participants were categorised by their HIV testing status (already tested, planning to be tested, no intention to seek testing). RESULTS: The 'already tested' and 'planning to be tested' groups were combined as there were no significant differences on reported risk behaviours. Analysis therefore compared two groups those 'testing' (n = 66) and 'not testing' (n = 129). 67% of those not tested for HIV reported at least one HIV risk factor. Perceived risk was the strongest predictor of HIV testing using our model. Perception of risk and actual risk were not correlated. Those not seeking testing endorsed less benefits of testing and more denial of the need to be tested. Same day testing and testing without an appointment were endorsed as factors to promote testing. CONCLUSION: To encourage people who have high risk factors to access HIV testing, programmes should: (1) highlight the benefits of testing which would be lost if people do not test, eg. effective drug treatments (2) increase the range of HIV testing services available (eg. same day testing). Furthermore, studies to determine the main predictors of perceived risk are needed if we are to increase testing in relevant populations.