William Chaplin

A Placebo Controlled Crossover Trial of Liquid Fluoxetine on Repetitive Behaviors in Childhood and Adolescent Autism

Repetitive behaviors are a core symptom domain in autism that has been linked to alterations in the serotonin system. While the selective serotonin-receptive inhibitor fluvoxamine has been shown to be effective in adults with autism, as yet no published placebo controlled trials with these agents document safety and efficacy in children with autism. This study examines the selective serotonin reuptake inhibitor liquid fluoxetine in the treatment of repetitive behaviors in childhood and adolescent autism spectrum disorders (ASDs). In total, 45 child or adolescent patients with ASD were randomized into two acute 8-week phases in a double-blind placebo-controlled crossover study of liquid fluoxetine. Study design included two randomized 8-week fluoxetine and placebo phases separated by a 4-week washout phase. Outcome measures included measures of repetitive behaviors and global improvement. Low-dose liquid fluoxetine (mean final dose: 9.9±4.35 mg/day) was superior to placebo in the treatment of repetitive behaviors by CY-BOCS compulsion scale. The effect size was in the moderate to large range, and the doses used were low. Liquid fluoxetine was only slightly, and not significantly, superior to placebo on CGI autism score partially due to a phase order effect. However, fluoxetine was marginally superior to placebo on a composite measure of global effectiveness. Liquid fluoxetine did not significantly differ from placebo on treatment emergent side effects. Liquid fluoxetine in low doses is more effective than placebo in the treatment of repetitive behaviors in childhood autism. Limitations include small sample size and the crossover design of the study. Further replication and long-term maintenance trials are needed.

A Double-Blind Placebo-Controlled Trial of Fluoxetine for Repetitive Behaviors and Global Severity in Adult Autism Spectrum Disorders

OBJECTIVE The effects of fluoxetine and placebo on repetitive behaviors and global severity were compared in adults with autism spectrum disorders (ASDs). METHOD Adults with ASDs were enrolled in a 12-week double-blind placebo-controlled fluoxetine trial. Thirty-seven were randomly assigned to fluoxetine (N=22) or placebo (N=15). Dosage followed a fixed schedule, starting at 10 mg/day and increasing as tolerated up to 80 mg/day. Repetitive behaviors were measured with the compulsion subscale of the Yale-Brown Obsessive Compulsive Scale; the Clinical Global Impression (CGI) improvement scale was used to rate improvement in obsessive-compulsive symptoms and overall severity. RESULTS There was a significant treatment-by-time interaction indicating a significantly greater reduction in repetitive behaviors across time for fluoxetine than for placebo. With overall response defined as a CGI global improvement score of 2 or less, there were significantly more responders at week 12 in the fluoxetine group than in the placebo group. The risk ratio was 1.5 for CGI global improvement (responders: fluoxetine, 35%; placebo, 0%) and 1.8 for CGI-rated improvement in obsessive-compulsive symptoms (responders: fluoxetine, 50%; placebo, 8%). Only mild and moderate side effects were observed. CONCLUSIONS Fluoxetine treatment, compared to placebo, resulted in significantly greater improvement in repetitive behaviors, according to both the Yale-Brown compulsion subscale and CGI rating of obsessive-compulsive symptoms, as well as on the CGI overall improvement rating. Fluoxetine appeared to be well tolerated. These findings stand in contrast to findings in a trial of citalopram for childhood autism.

Prenatal Detection of Embryo Resorption in Osteopontin-Deficient Mice Using Serial Noninvasive Magnetic Resonance Microscopy

Appropriate temporal and spatial expression of osteopontin (OPN) in the female genital tract may be critical for successful embryo implantation and maintenance of gestation. Traditionally, experimental assessments of reproductive success have been limited to ex vivo dissection at a single time point to determine embryo number and size and are inadequate for ongoing study of the effect(s) of genetic manipulation on any individual gestation. To investigate the role of OPN in the maintenance of gestation, we developed a noninvasive, in vivo method of pregnancy surveillance suitable for murine application using magnetic resonance microscopy (MRM). Gravid wild-type mice (n =7) and mice with targeted disruption of one or both OPN alleles (OPN−/−, n = 9; OPN+/−, n = 3) underwent MRM on postcoital days 10.5, 15.5, and 19.5. Prenatal MRM images were used to determine embryo numbers and sizes. There were no significant differences in embryo numbers determined independently by two blinded observers (mean difference between observers = 0.04 embryos; p = 0.87). There was a significant effect of genotype on embryo size, with OPN−/− embryos significantly smaller at all gestational ages. However, targeted disruption of one or more OPN alleles had no effect on embryo number at any gestational age. Thus, MRM may be a powerful noninvasive method for in vivo prenatal developmental study of genetically engineered mice.

FDG-PET study in pathological gamblers. 1. Lithium increases orbitofrontal, dorsolateral and cingulate metabolism.

Background: Pathological gambling affects 1–3% of the adult population, and has high comorbidity. Although mood stabilizers and serotonin reuptake inhibitors have shown some efficacy in the treatment of this condition, there is little known about how these pharmacological interventions work. Methods: Twenty-one patients with pathological gambling, who met lifetime comorbid bipolar spectrum diagnoses, received baseline PET scans. Sixteen of these patients were entered into a randomized double-blind placebo-controlled parallel group design trial of lithium, and received follow-up PET scans at 10 weeks. A comparison group of 32 age- and sex-matched controls was also available. Anatomical MRIs were obtained as a structural template. Results: In patients with pathological gambling, relative glucose metabolic rates (rGMR) in the orbitofrontal cortex and medial frontal cortex were significantly increased at baseline compared to normal controls. Lithium increased rGMR further in the orbitofrontal cortex, heightening normal/patient differences, but it also increased the rGMR of the posterior cingulate and the dorsolateral frontal cortex normalizing the metabolic rate in these regions. Conclusion: Cortical areas implicated in impulse control disorders show increased rGMR in pathological gambling at baseline. Lithium treatment, while alleviating the symptoms, further increases rGMR in these areas.

Race/ethnicity moderates the relationship between chronic life stress and quality of life in type 2 diabetes.

AIMS To determine whether chronic life stress is differentially associated with quality of life (QoL) for Blacks vs. Hispanics with type 2 diabetes. METHODS We assessed self-reported chronic stress and QoL in 125 patients with type 2 diabetes who self-identified as either non-Hispanic Black or Hispanic. Separate cross-sectional two-way interaction models (stress × race/ethnicity) with physical and mental health as outcomes were examined. RESULTS The two-way interaction predicted mental (b=3.12, P=.04) but not physical health. Simple slopes analyses indicated that under conditions of high stress, Blacks (b=-4.4, P<.001), but not Hispanics, experienced significantly lower levels of mental health. In exploratory analyses, we examined a three-way interaction (stress × race/ethnicity × social support) with physical and mental health as outcomes. Results indicated the three-way interaction predicted mental (b=.62, P=.01) but not physical health. Simple slopes analyses indicated that under conditions of high stress, high levels of social support improved mental health for Hispanics (b=1.2, P<.001), but not for Blacks. CONCLUSIONS Black patients with type 2 diabetes may be particularly vulnerable to the deleterious effects of high chronic stress. Social support buffers effects of stress on mental health in Hispanics but not Blacks, which suggests differences in the use and/or quality of social support between Hispanics and Blacks. Longitudinal investigations that examine race/ethnicity, stress, social support, and QoL should help clarify the processes that underlie these observed relations.