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BACKGROUND: Rigidity contributes to severity and functional impairment in autism spectrum disorder (ASD). There is an unmet need for a valid, reliable, and sensitive outcome measure to assess rigidity in ASD. OBJECTIVE: To develop and validate the Montefiore-Einstein Rigidity Scale-Revised (MERS-R) to assess the Behavioral Rigidity Domain (BRD), Cognitive Rigidity Domain (CRD), and Protest Domain (PD). MATERIALS AND METHODS: The MERS-R was administered to 93 individuals with ASD (children and adults, high and low IQ) at baseline, Week 2, and Week 12. Internal consistency was assessed for domain scores, Total Rigidity Composite (TRC = BRD + CRD), and Total Composite (TC = BRD + CRD + PD) with Cronbach's α. Intraclass correlation coefficients (ICCs) assessed test-retest reliability from baseline to weeks 2 and 12. Pearson's correlations assessed the relationship between the MERS-R and age, sex, and IQ. Convergent validity assessed the correlation of MERS-R scores to the Children's Yale-Brown Obsessive-Compulsive Scale-ASD (CY-BOCS-ASD). RESULTS: Good internal consistency was demonstrated for the BRD, PD, TRC and TC (Cronbach's α = 0.83, 0.88, 0.82, and 0.89, respectively) and adequate internal consistency for the CRD (α = .72). Good or excellent test-test reliability was demonstrated over two weeks (ICC: 0.66─.79), and fair or good reliability over 12 weeks (ICC: 0.56-66). MERS-R scores did not differ by age, sex, or IQ (p: 0.16─.99) with the exception that higher PD scores were associated with younger age (correlation = -0.25, p = 0.01). Significant convergent validity was demonstrated between all MERS-R scores and the CY-BOCS-ASD (p < 0.0001). DISCUSSION: The MERS-R demonstrated internal consistency, test-retest reliability, convergent validity and applicability to autistic children and adults of different sexes and IQ levels. It is a valid, sensitive, and reliable instrument to measure behavioral and cognitive rigidity in ASD.

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Autism Spectrum Disorder (ASD) is a developmental disorder marked by deficits in social communication and social interaction, together with restricted and/or repetitive patterns of behaviours, activities or interests. As more adults are being diagnosed with ASD, and more diagnosed children are aging into adulthood, the need for effective treatments and support services for autistic adults is quickly growing. As such, clinical research targeting autistic adults has emerged in recent years. Currently, caregiver ratings are commonly used as outcome measures in child treatment studies, but these scales present challenges when utilised to assess the autistic adult population. In this commentary, we seek to unveil the difficulties and obstacles in assessing change in clinical treatment trials for autistic adults. Specifically, this article uses case examples to explore the limitations of rating scales. Steps for improving the accuracy of ratings, and for developing novel self-rating scales for autistic adults are discussed. It is hoped that in exploring these difficulties in more depth, clinical research with adult ASD populations will continue to improve and that reliable, valid and sensitive outcome measures will be developed to ensure the highest quality treatments emerge.

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OBJECTIVE: The effects of intranasal oxytocin and placebo on hyperphagia and repetitive behaviors were compared in children and adolescents with Prader Willi Syndrome (PWS). METHODS: Children and adolescents with PWS were enrolled in an 8-week double-blind placebo-controlled intranasal oxytocin randomized trial. Twenty-three (23) subjects were assigned to oxytocin (N = 11) or placebo (N = 12). Hyperphagia was measured with the Hyperphagia Questionnaire (HQ), and repetitive behavior was measured with Repetitive Behavior Scale- Revised (RBS-R). RESULTS: There were modest significant treatment by-time interactions indicating reduction in hyperphagia and repetitive behaviors across time for placebo but no reduction for oxytocin. Total HQ score showed a greater average reduction of 1.81 points/week for the placebo group vs. oxytocin, with maximum reduction at week 4. There were also greater reductions on HQ-Drive and HQ-Behavior subscales on placebo vs. oxytocin. RBS-R subscales followed similar patterns to the HQ, with a significantly greater reduction in sameness subscale behaviors (average 0.825 points/week) in the placebo group compared to the oxytocin group. Oxytocin was well tolerated, and the only adverse event that was both more common and possibly related to oxytocin vs. placebo was nocturia (n = 1 vs 0). CONCLUSION: Placebo was associated with modest improvement in hyperphagia and repetitive behaviors in childhood PWS whereas intranasal oxytocin was not associated with improvement in these domains. More work is needed to understand the meaning and mechanism of these findings on hyperphagia and repetitive behaviors in PWS.

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Objectives: Inflammatory mechanisms are implicated in the aetiology of autism spectrum disorder (ASD), and use of the immunomodulator Trichuris suis Ova (TSO) is a novel treatment approach. This pilot study determined the effect sizes for TSO versus placebo on repetitive behaviours, irritability and global functioning in adults with ASD.Methods: A 28-week double-blind, randomised two-period crossover study of TSO versus placebo in ten ASD adults, aged 17-35, was completed, with a 4-week washout between each 12-week period at Montefiore Medical Center, Albert Einstein College of Medicine. Subjects with ASD, history of seasonal, medication or food allergies, Y-BOCS ≥6 and IQ ≥70 received 2,500 TSO ova or matching placebo every 2 weeks of each 12-week period.Results: Large effect sizes for improvement in repetitive behaviours (d = 1.0), restricted interests (d = 0.82), rigidity (d = 0.79) and irritability (d = 0.78) were observed after 12 weeks of treatment. No changes were observed in the social-communication domain. Differences between treatment groups did not reach statistical significance. TSO had only minimal, non-serious side effects.Conclusions: This proof-of-concept study demonstrates the feasibility of TSO for the treatment of ASD, including a favourable safety profile, and moderate to large effect sizes for reducing repetitive behaviours and irritability.Clinicaltrials.gov: NCT01040221.

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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.

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Studies suggest that neuropsychological measures may provide prognostic information regarding SSRI treatment response, yet it is unclear which specific cognitive domains are the most effectual predictors. The aim of this study was to characterize the cognitive profile associated with SSRI nonresponse using a comprehensive set of neuropsychological tests. Participants (N = 32) met criteria for current major depressive episode. Assessment followed pre-treatment medication washout. Clinical response was measured after 3-month open-label SSRI treatment. Groups did not differ by demographic characteristics, intelligence or depression severity. Responders outperformed nonresponders across all cognitive domains, with the largest differences observed in executive, language and working memory functions. Results indicate poorer global cognitive functioning is predictive of treatment nonresponse. Deficits were most pronounced in tests demanding greater mental search and manipulation rather than speeded motor output. Cognitive slowing may mediate the working memory and executive function deficits found in nonresponders. These findings can inform exploration for pharmacogenetic endophenotypes.

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OBJECTIVE: This study examined the utility of baseline psychomotor speed, measured with neuropsychological tests, to predict fluoxetine response in moderately depressed outpatients. The authors hypothesized that since psychomotor slowing in depressed patients has been linked to reduced dopaminergic neurotransmission, patients with slowing would be unresponsive to fluoxetine, a selective serotonin reuptake inhibitor. METHOD: After baseline neuropsychological testing, patients were treated openly with fluoxetine for 12 weeks. Thirty-seven patients completed the trial. RESULTS: Compared to the 25 patients who responded, the 12 patients who did not respond to fluoxetine exhibited significantly poorer performance in verbal fluency on the Controlled Oral Word Association Test FAS and in color naming on the Stroop Color and Word Test. In addition, the nonresponders tended to perform worse than the responders on the Stroop Color and Word Test reading subtest and the WAIS-III digit symbol subtest. Differential treatment response was specific to psychomotor speed because responders and nonresponders did not perform differently on tasks of executive functioning, attention, visuospatial functioning, or verbal intelligence. CONCLUSIONS: Psychomotor slowing may identify a subgroup of depressed patients who have a dopaminergic deficit that is unresponsive to fluoxetine monotherapy and who should therefore receive an alternative treatment.

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OBJECTIVE: This effectiveness study assessed remission rates in patients who had the opportunity to receive up to 3 antidepressant trials if unresponsive. METHOD: One hundred seventy-one consecutive outpatients entered 1 of 3 studies for the treatment of major depressive disorder (DSM-IV criteria) from January 1999 through December 2001. This group primarily received fluoxetine as a first treatment in trials lasting 6 to 12 weeks (a small number received gepirone). If unimproved, patients received a second or third trial (primarily clinician's choice). A standard criterion to determine remission-a score of 7 or less on the 17-item Hamilton Rating Scale for Depression-was used. In order to contrast remission rates with first-generation antidepressants, patients' outcomes in a previously published study that compared placebo, phenelzine, and imipramine were also examined (N = 420). RESULTS: In an intent-to-treat analysis, 66% (113/171) of patients who were treated with second-generation antidepressants and 65% (275/420) of patients who were treated with first-generation antidepressants eventually achieved remission. CONCLUSIONS: Remission rates in the effectiveness study are approximately 20% higher than the rates usually cited, a result of our choice to examine outcome following 3 treatment trials. This choice is dictated by good clinical practice. The usual procedure when comparing treatment modalities is to assess outcome after a single anti-depressant trial. The cumulative high remission rates suggest antidepressants are effective and should encourage more patients to seek treatment and physicians to develop techniques to improve patient adherence.

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OBJECTIVE: The study examined a large data set to determine whether patients' sex affected the outcome of antidepressant treatment. METHOD: Data for 1,746 patients aged 18-65 years who had been treated with tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), fluoxetine, or placebo were examined in a retrospective analysis to determine whether men and women differed in their responses to antidepressants. To examine the effect of menopausal status in the absence of data on individual patients' menopausal status, results for female patients younger or older than age 50, 52, 54, and 56 were compared. RESULTS: Men and women both younger and older than age 50 had equivalent response rates to tricyclics and fluoxetine. Women had a statistically superior response to MAOIs. Placebo response was equivalent across all groups. CONCLUSIONS: Neither sex nor menopausal status may be relevant in antidepressant treatment of adult depressed patients up to 65 years of age. Although women had a statistically superior response to MAOIs, this difference may not be clinically relevant.

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