Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial.

BACKGROUND: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults. METHODS: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. FUNDING: F Hoffmann-La Roche.

Safe Medication Administration in Patients with Communication Disorders: A Simulation-Enhanced Interprofessional Education Approach.

Medications and their associated side effects impact systems treated by speech-language pathologists and audiologists, such as speech, language, voice, swallowing, hearing, tinnitus, and balance. However, students in these disciplines receive limited training in pharmacology, while nursing students receive training in pharmacology but limited training in communication disorders. In this interprofessional simulation experience to increase understanding of the impact of medications on communication, swallowing, and balance, audiology, nursing, and speech-language pathology students worked together to interview standardized patients (SPs) about their medications and symptoms in a simulated clinical setting. Goals were for students to understand professional roles, identify high-risk medications with potential communication implications, provide patient education, and evaluate interdisciplinary collaboration. The SPs demonstrated symptoms patients may have as they take high-risk medications. Students (n = 101) completed a knowledge pretest, online training, simulation, debriefing facilitated by faculty experts, and posttest and impressions survey. Results indicated high satisfaction with teamwork and interprofessional interactions. Student knowledge of high-risk medications was improved as a result of this exercise, with nursing and speech-language pathology students demonstrating statistically significant improvements in posttest results. While knowledge deficits of some high-risk medications were evident across student groups, the overall effects demonstrated benefits of the simulation-enhanced interprofessional education experience.

Language impairment in Alzheimer's disease and benefits of acetylcholinesterase inhibitors.

Alzheimer's disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer's disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer's disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer's disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important.

Cognition and communication dysfunctions in early-onset schizophrenia: effect of risperidone.

BACKGROUND: Cognitive impairment and formal thought disorder, also referred to as communication disturbances, are considered the core symptoms of schizophrenia, strongly affecting social functioning and long-term outcome. Several studies in adult patients suggest improvement of both functions after the treatment with atypical antipsychotic drugs. Such medications are also used as first line treatment in early-onset schizophrenia, however their efficacy in cognitive and communication domains in this population have not been systematically assessed. AIM OF THE STUDY: Evaluation of risperidone efficacy at psychopathological symptoms, cognitive impairment and formal thought disorder in adolescents with schizophrenia spectrum diagnosis. MATERIAL AND METHOD: Psychopathological symptoms, cognitive functioning and formal thought disorder were evaluated in 32 hospitalized adolescent patients with schizophrenia spectrum diagnosis at the beginning of risperidone treatment and after clinical improvement and compared to the results of matched healthy control group. RESULTS: Risperidone treatment was associated with reduction of symptom severity and moderate improvement of formal thought disorder and some aspects of executive functions. Working memory and verbal fluency were not improved. There were few correlations between psychopathological symptoms and results of cognitive tests, mainly between negative symptoms and executive functions. DISCUSSION: In early-onset schizophrenia spectrum disorders atypical antipsychotic treatment is associated with alleviation of symptoms and only selective and moderate cognitive and communication improvement.

Developing drugs for core social and communication impairment in autism.

There are many challenges to studying drug effects on core social and language impairment in autism. Drugs such as fenfluramine, naltrexone, and secretin do not appear to be efficacious for these core symptoms. Risperidone has led to improvement in some aspects of social relatedness when used to treat irritability in autism. More research is needed on the utility of selective serotonin reuptake inhibitors, cholinergic drugs, glutamatergic drugs, and oxytocin for core autistic symptoms.

Effect of galantamine on verbal repetition in AD: a secondary analysis of the VISTA trial.

OBJECTIVES: To understand how commonly diminution of verbal repetition was a goal of treatment in patients with Alzheimer disease (AD), how commonly that goal was achieved, whether goal attainment might be attributable to galantamine treatment, and whether change in verbal repetition is a marker of the overall treatment response. METHODS: This is a secondary analysis of the Video-Imaging Synthesis of Treating Alzheimer's Disease study, a 4-month, double-blind, randomized, placebo-controlled trial of galantamine in 130 community-dwelling patients with mild to moderate AD. The primary outcome was Goal Attainment Scaling, in which individualized problems identified by patients/caregivers and treating physicians were assessed bimonthly. RESULTS: Reduction of verbal repetition was set as a treatment goal in 44% (n = 57) of randomized patients. More patients/caregivers (32%) set repetition goals than did physicians (18%). After 4 months, more galantamine-treated patients showed diminution of verbal repetition (58%) than did placebo-treated patients (24%; p < 0.01). Reduction of verbal repetition correlated with improvement in clinical measures, but not in standardized ones. CONCLUSIONS: Reduction of verbal repetition is a common goal of Alzheimer disease treatment. After 4 months, patients treated with galantamine were more likely to experience a reduction of verbal repetition than those treated with placebo. Diminution of verbal repetition was associated with other improvements, suggesting it might be a clinical marker of a positive treatment response.

Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology.

OBJECTIVE: Risperidone has been found efficacious for decreasing severe tantrums, aggression, and self-injurious behavior in children and adolescents with autistic disorder (autism). The authors report on whether risperidone improves the core symptoms of autism, social and communication impairment and repetitive and stereotyped behavior. METHOD: The database from an 8-week double-blind, placebo-controlled trial (N=101) and 16-week open-label continuation study (N=63) of risperidone for children and adolescents with autism was used to test for drug effects on secondary outcome measures: scores on the Ritvo-Freeman Real Life Rating Scale, the Children's Yale-Brown Obsessive Compulsive Scale, and the maladaptive behavior domain of the Vineland Adaptive Behavior Scales. RESULTS: Compared to placebo, risperidone led to a significantly greater reduction in the overall score on the Ritvo-Freeman Real Life Rating Scale, as well as the scores on the subscales for sensory motor behaviors (subscale I), affectual reactions (subscale III), and sensory responses (subscale IV). No statistically significant difference was observed, however, on the subscale for social relatedness (subscale II) or language (subscale V). Risperidone also resulted in significantly greater reductions in scores on the Children's Yale-Brown Obsessive Compulsive Scale and Vineland maladaptive behavior domain. This pattern of treatment response was maintained for 6 months. CONCLUSIONS: Risperidone led to significant improvements in the restricted, repetitive, and stereotyped patterns of behavior, interests, and activities of autistic children but did not significantly change their deficit in social interaction and communication. Further research is necessary to develop effective treatments for the core social and communicative impairments of autism.

Open-label study of olanzapine in children with pervasive developmental disorder.

The effects of olanzapine on the symptomatology of children with pervasive developmental disorder with emphasis on problems of communication and the safety of the drug were investigated in a 3-month open-label, open-dosage study. Participating in the study were 25 children age 6 to 16 years with a diagnosis of either autistic disorder or pervasive developmental disorder not otherwise specified. Psychometric measures included the Clinical Global Impression of Severity/Improvement, the Aberrant Behavior Checklist, and the TARGET (a checklist of five target symptoms). Communication skills were assessed during behavioral analysis of a playroom session. Safety measures included clinical chemistry variables, electrocardiography, the SimpsonAngus Neurological Rating Scale, the Barnes Akathisia Scale, and vital signs. Twenty-three children completed the study and showed significant improvement on three subscales of the Aberrant Behavior Checklist (Irritability, Hyperactivity, and Excessive Speech) and the TARGET. The final mean dose was 10.7 mg/day. Several aspects of communication were also improved after olanzapine treatment. However, only three children were considered responders in terms of the Clinical Global Impression of Severity/Improvement scores. The most important adverse events were weight gain, increased appetite, and loss of strength. Three children showed extrapyramidal symptoms that disappeared after the dose was lowered. Thus, while olanzapine was a relatively safe medication in children, its clinical relevance in children with pervasive developmental disorder may be limited.