Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism

Autism Spectrum Disorders (ASD) include Autistic disorder, Asperger's syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). These are developmental disorders beginning prior to three years of age. Recent Centers for Disease Control (CDC) estimates suggest that ASD affects up to 1 in 100 individuals and up to 1 in 50 boys. There are very substantial costs associated with caring for patients with ASD, and ASD has the highest Caregiver Burden Scores of any condition. There are three core symptom domains of ASD, including social deficits, repetitive behaviors and language deficits. Patients can also have associated symptoms of attentional deficits, disruptive behaviors and intellectual disability. There is currently no Food and Drug administration (FDA) approved treatment for the core symptoms of autism, but risperidone and aripiprazole have FDA approval for disruptive behaviors associated with autism.

This is a 12 week randomized double blind placebo controlled trial of Milnacipran in adults with ASD or Aspergers Syndrome. Milnacipran is said to play a role in the activation and normalization of the locus coeruleus-noradrenergic system, of which is hypothesized to play a role in behavior adaptations and performance.

Study Overview

• Status: Completed
• Conditions: Autism Spectrum Disorder; Asperger Syndrome; Aspergers Syndrome
• Intervention / Treatment: Drug: Milnacipran; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center, Albert Einstein College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and Female patients
• Aged 18-50 years
• Diagnosis of Autism Spectrum Disorder
• intelligence quotient greater than 70

Exclusion Criteria:

• Pregnant subjects
• Patients deemed by comprehensive psychiatric interview to have a significant risk of suicide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
EXPERIMENTAL: Milnacipran	Drug: Milnacipran; Patients will receive a titrated dose of milnacipran increasing to a maximum of 100mg a day over the 12 week study period. Dosing will be based on a fixed schedule that will be monitored using a side effect profile.; Other Names: Savella

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale	Change will be measured in each subject's score on the Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale from baseline through study end (week 12).Higher values represent a worse outcome. The raw scores are converted to T-scores for each scale and sub-scale which are then compared against the mean. Higher values represent a worse outcome. A T-score of 50 is the mean of a relevant reference population. A T-score above 65 indicates a moderate to severe problem. For example, Row 1 is the mean of baseline T-scores for the Inattention/ Memory subscale and Row 2 is the mean of week 12 T-scores for the Inattention/ Memory subscale. The difference between these two means is used to measure the change from baseline through week 12 for both the groups.	Baseline and Week 12 scores
Change in Hyperactivity as Measured by Aberrant Behavior Checklist - Hyperactivity Scale	The Aberrant Behavior Checklist is an informant-based questionnaire consisting of 58 items subdivided amongst 5 scales: irritability, lethargy and social withdrawal, stereotypic behavior, hyperactivity/non-compliance, and inappropriate speech [34]. A score for each item ranges from 0 indicating "no problem" to 3 indicating "severe problem". Scale scores are calculated by summing the items within that scale. Higher scores indicate greater impairment.Reported Data is for change in ABC-H from baseline to endpoint (week 0 to week 12).This data is specifically looking at the hyperactivity scale which is 16 items with each item ranging from 0-3 making total scores 0-48.	Baseline to Endpoint - 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Autism Severity Levels Based on the Clinical Global Impressions Scale	The CGI-I reflects the rater's impression of the subject's current autism severity on a 7-point scale ranging from Much Improved (1) to Much worse (5).	screening, baseline, weeks 2,4,6,8,10,12
Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale	This scale has been shown to be a sensitive outcome measure in autism trials of repetitive behaviors. Data for secondary outcome not analyzed due to lack of significance in primary outcomes measured.; scale range: 0 - 40 total, 0 - 7 subclinical, 8-15 mild, 16 - 23 moderate, 24 - 31 severe, 32 - 40 extreme; score interpretation: Higher overall scores reflect increasing symptom severity.	baseline, weeks 2,4,6,8,10,12
Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF)	This scale is shown to be sensitive to change in adults with autism, and related to amygdala function. Higher scores mean a better outcome.A clinical tool measuring emotion recognition through facial expression, voice and posture.; Child faces 2 (range 0 - 100, higher values reflecting higher % of errors); Adult faces 2 (range 0 - 100, higher values reflecting higher % of errors); Child paralanguage 2 (range 0 - 100, higher values reflecting higher % of errors); Adult paralanguage 2 (range 0 - 100, higher values reflecting higher % of errors) Errors are counted and organized by pre-determined affect and intensity. Subtests considered separately.	baseline, weeks 2,4,6,8,10,12

Collaborators and Investigators

• Sponsor: Montefiore Medical Center
• Collaborators: Forest Laboratories

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: December 27, 2010
• First Submitted That Met QC Criteria: April 18, 2011
• First Posted (ESTIMATE): April 19, 2011

Study Record Updates

• Last Update Posted (ACTUAL): February 27, 2020
• Last Update Submitted That Met QC Criteria: February 13, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: ASD; Autism; Autism Spectrum Disorder; PDD; Asperger Syndrome; PDD-NOS; Asperger
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Syndrome; Autistic Disorder; Autism Spectrum Disorder; Asperger Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Milnacipran; Levomilnacipran
• Other Study ID Numbers: 10-09-299