Brain Response to Serotonergic Medications in ASD

Can Brain Activation and Connectivity Predict Treatment Response to Two Serotonergic Medications (Citalopram and Tianeptine) in Subjects With Autism Spectrum Disorders (ASD)?

This study investigates brain response to single acute dose of citalopram, tianeptine, and placebo in males with and without autism spectrum disorder.

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Citalopram; Drug: Tianeptine

Detailed Description

There is increasing evidence that the serotonin (5-HT) system is implicated in autism spectrum disorder (ASD), with the standard treatment for depression and anxiety in both the general population and ASD includes targeting the 5-HT system with selective serotonin reuptake inhibitors (SSRIs) citalopram. Some individuals with ASD have a good treatment response but others do not. Tianeptine, which has a different mechanism of action to SSRIs, is also an effective antidepressant. As it is unlikely that all individuals with ASD will respond to the same treatment, the investigators aim to conduct a pharmacological magnetic resonance imaging (phMRI) investigation to elucidate the neural mechanisms underlying the response to citalopram and tianeptine in ASD. The investigators are inviting 50 male adults with ASD and 50 male adults without ASD. Each participant receives each drug once (20 mg citalopram, 12.5 mg tianeptine, or placebo) and MRI is used to obtain measures of brain biochemistry, activity, and connectivity. The investigators also acquire data from questionnaires, electroencephalography, neurocognitive tests and blood samples.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nichol Wong, PhD; Phone Number: +44 (0)2078480124; Email: nichol.wong@kcl.ac.uk
• Study Contact Backup: Name: Grainne McAlonan, PhD; Phone Number: +44 (0)2078480831; Email: grainne.mcalonan@kcl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 8AF
    • Recruiting
    • King's College London
    • Contact: Nichol Wong, PhD; Phone Number: +44 (0)2078480124; Email: nichol.wong@kcl.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Intelligence Quotient (IQ) above 70
• Has capacity and is capable of giving written informed consent
• Able to read, comprehend and record information written in English
• Bodyweight of <120 kg and BMI within the range 18.5 - 33 kg/m2 (inclusive).
• Not taking medication directly affecting gamma-aminobutyric acid (GABA) neurotransmission for at least the past 4 weeks
• Not taking medication directly affecting the serotonergic system for at least the past 4 weeks
• ASD only: Diagnosis of Autism Spectrum Disorder (ICD 10-R criteria, confirmed using the Autism Diagnostic Interview (ADI) and/or ADOS) including atypical autism
• ASD only: Being recommended drug therapy for symptoms of depression and/or anxiety
• Controls only: No diagnosis of Autism Spectrum Disorder (ICD 10-R criteria, confirmed using the ADI and/or ADOS)
• Controls only: No diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or ICD 10.

Exclusion Criteria:

• Current risk of self-harm
• Acute risk of suicidality (e.g., current suicidal ideations)
• Age < 18 years or > 60 years old.
• Taking medication directly affecting the serotonergic system (e.g. SSRIs, Tricyclic antidepressants)
• Taking medication directly affecting GABA neurotransmission (e.g. antiepileptic drugs, and benzodiazepines)
• Taking antipsychotic medication or medication for attention deficit hyperactivity disorder (ADHD) for the past 4 weeks
• History of dependence to alcohol or substances of abuse (excluding nicotine)
• Major mental illness (e.g. psychosis), or a learning disability (mental retardation)
• Needle phobia
• Medical/genetic disorder associated with ASD
• Diagnosed and treated for hyperkinesis or Tourette's syndrome
• Allergy to food colouring

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo, Citalopram, Tianeptine; Dose order: Placebo, Citalopram, Tianeptine	Drug: Placebo; Two oral doses of placebo.; Drug: Citalopram; Single oral dose of citalopram (20mg) and single oral dose of placebo.; Drug: Tianeptine; Single oral dose of tianeptine (12.5mg) and single oral dose of placebo.
Experimental: Placebo, Tianeptine, Citalopram; Dose order: Placebo, Tianeptine, Citalopram	Drug: Placebo; Two oral doses of placebo.; Drug: Citalopram; Single oral dose of citalopram (20mg) and single oral dose of placebo.; Drug: Tianeptine; Single oral dose of tianeptine (12.5mg) and single oral dose of placebo.
Experimental: Citalopram, Placebo, Tianeptine; Dose order: Citalopram, Placebo, Tianeptine	Drug: Placebo; Two oral doses of placebo.; Drug: Citalopram; Single oral dose of citalopram (20mg) and single oral dose of placebo.; Drug: Tianeptine; Single oral dose of tianeptine (12.5mg) and single oral dose of placebo.
Experimental: Citalopram, Tianeptine, Placebo; Dose order: Citalopram, Tianeptine, Placebo	Drug: Placebo; Two oral doses of placebo.; Drug: Citalopram; Single oral dose of citalopram (20mg) and single oral dose of placebo.; Drug: Tianeptine; Single oral dose of tianeptine (12.5mg) and single oral dose of placebo.
Experimental: Tianeptine, Placebo, Citalopram; Dose order: Tianeptine, Placebo, Citalopram	Drug: Placebo; Two oral doses of placebo.; Drug: Citalopram; Single oral dose of citalopram (20mg) and single oral dose of placebo.; Drug: Tianeptine; Single oral dose of tianeptine (12.5mg) and single oral dose of placebo.
Experimental: Tianeptine, Citalopram, Placebo; Dose order: Tianeptine, Citalopram, Placebo	Drug: Placebo; Two oral doses of placebo.; Drug: Citalopram; Single oral dose of citalopram (20mg) and single oral dose of placebo.; Drug: Tianeptine; Single oral dose of tianeptine (12.5mg) and single oral dose of placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain excitation and inhibition response to pharmacological stimulation as assessed by magnetic resonance spectroscopy	The measure of brain excitation and inhibition response to placebo, citalopram, and tianeptine includes the following: Assessment of the ratio of brain excitation and inhibition (measured as the balance of excitatory and inhibitory neurotransmitters) using proton magnetic resonance spectroscopy.	In the months 1-2 following the last day of scanning
Brain activation response to pharmacological stimulation as assessed by functional magnetic resonance imaging	The measure of brain activation response to placebo, citalopram, and tianeptine includes the following: Assessment of the blood-oxygen-level-dependent activation during tasks using functional magnetic resonance imaging.	In the months 3-4 following the last day of scanning
Brain connectivity response to pharmacological stimulation as assessed by resting-state functional magnetic resonance imaging	The measure of brain connectivity response to placebo, citalopram, and tianeptine includes the following: Assessment of the regional homogeneity during resting-state using functional magnetic resonance imaging.	In the months 5-6 following the last day of scanning

Collaborators and Investigators

• Sponsor: King's College London
• Investigators: Principal Investigator: Grainne McAlonan, PhD, King's College London; Study Chair: Declan Murphy, PhD, King's College London

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2014
• Primary Completion (Anticipated): February 1, 2023
• Study Completion (Anticipated): May 31, 2023

Study Registration Dates

• First Submitted: October 25, 2019
• First Submitted That Met QC Criteria: October 28, 2019
• First Posted (Actual): October 30, 2019

Study Record Updates

• Last Update Posted (Actual): April 15, 2022
• Last Update Submitted That Met QC Criteria: April 14, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: pharmacological imaging; citalopram; tianeptine
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Citalopram; Tianeptine
• Other Study ID Numbers: 14/LO/0663

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No