Enhancement of Learning Associated Neural Plasticity by Selective Serotonin Reuptake Inhibitors

Background:

Conclusive evidence states that the serotonergic system mediates neuroplasticity from early embryonic development until brain maturation in adulthood. This study aims to demonstrate that selective serotonin reuptake inhibitors (SSRIs) enhance learning-dependent neuroplasticity in vivo, hereby contributing to the investigators understanding of the mechanism of action of therapy with SSRIs.

Objectives:

1. To prove a positive influence of SSRIs on structural remodeling during learning, reflected by enhancements of gray and white matter microstructure, connectivity and functionality in brain regions involved in learning processes.
2. To show that this effect is topologically specific, i.e. that enhancements of plasticity markers are found in different regions depending on their involvement during the performance of specific learning tasks.

Study design:

Randomized, double-blind, placebo-controlled, longitudinal mono-center study. 80 healthy subjects will undergo three MRI scanning sessions: 1. baseline, at study entry, 2. after 3 weeks of facial/emotional (n=40) or Chinese character-meaning learning (n=40) and 3. after 3 weeks learning of new associations under administration of an SSRI or placebo.

Methods:

MRI measurements will be performed on a 3 Tesla PRISMA MAGNETOM MR scanner. Changes in gray matter microstructure will be assessed using high-resolution structural MRI and analyzed with voxel-based morphometry (VBM). Diffusion tensor imaging (DTI) enables non-invasive investigation of neuroplasticity in the human brain based on the reduction in mean diffusivity associated with swelling of astrocytes after increased synaptic activity. Resting-state functional MRI (fMRI) will allow for the measurement of changes in functional coupling between brain regions, and fMRI during tasks will assess differential activity in brain regions during learning.

Relevance and implications:

This study aims to provide evidence that SSRIs facilitate cytoarchitectonical restructuring. In addition to expanding the investigators current knowledge on the trophic effects of SSRIs, the results of this study will also elucidate interactions between the serotonergic system and changes to neuronal networks during learning as well as their behavioral consequences. By probing the neurobiological correlates of the antidepressant and anti-anxiety effects of SSRIs, this study will provide a rationale for targeted interventions that harness the neuroplasticity enhancing properties of SSRIs to facilitate therapeutic processes.

Study Overview

• Status: Unknown
• Conditions: Neuronal Plasticity; Ssri
• Intervention / Treatment: Drug: Escitalopram; Other: 3xMR scan (fMRI, DTI, strucutral MRI); Behavioral: Association learning paradigm; Behavioral: Association re-learning paradigm; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Department of Psychiatry and Psychotherapy, Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• General health based on medical history, physical examination and structured clinical interview for DSM-IV (SCID)
• Willingness and competence to sign the informed consent form
• Right-handedness
• Non-smoker, and non-alcohol drinker

Exclusion Criteria:

• Any medical, psychiatric or neurological illness
• Current or former substance abuse
• Any implant or stainless steel graft or any other contraindications for MRI
• First degree relatives with a history of psychiatric illness or substance abuse
• Color blindness, any Chinese language skills
• Failure to comply with the study protocol or to follow the instructions of the investigating team
• Lifetime use of SSRIs or related psychotropic agents
• Non-Caucasian

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SSRI treatment; Subjects will receive 21 days of 10mg escitalopram treatment while performing learning paradigms.	Drug: Escitalopram; Tablet 10mg, 21 days; Other: 3xMR scan (fMRI, DTI, strucutral MRI); 3 Tesla PRISMA MAGNETOM MR scanner; performed at baseline, after 21 days of performing learning paradigms and after 21 days of drug/placebo treatment and re-learning paradigms; Behavioral: Association learning paradigm; 21 daily internet-based sessions (20min) of learning associations (pairs) of stimuli; Behavioral: Association re-learning paradigm; 21 daily internet-based sessions (20min) of learning new associations (pairs) of stimuli performed during escitalopram/placebo treatment
Placebo Comparator: Placebo treatment; Subjects will receive 21 days of placebo treatment while performing learning paradigms.	Other: 3xMR scan (fMRI, DTI, strucutral MRI); 3 Tesla PRISMA MAGNETOM MR scanner; performed at baseline, after 21 days of performing learning paradigms and after 21 days of drug/placebo treatment and re-learning paradigms; Behavioral: Association learning paradigm; 21 daily internet-based sessions (20min) of learning associations (pairs) of stimuli; Behavioral: Association re-learning paradigm; 21 daily internet-based sessions (20min) of learning new associations (pairs) of stimuli performed during escitalopram/placebo treatment; Drug: Placebo; Tablet, 21 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gray matter volume	voxel based morphometry (T1 weighted MPRAGE sequence)	21 days
Mean diffusivity	diffusion tensor imaging	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BOLD signal	functional MRI (learning paradigms)	21 days

Collaborators and Investigators

• Sponsor: Medical University of Vienna

Publications and helpful links

General Publications

• Vanicek T, Reed MB, Unterholzner J, Klobl M, Godbersen GM, Handschuh PA, Spurny-Dworak B, Ritter V, Gryglewski G, Kraus C, Winkler D, Lanzenberger R, Seiger R. Escitalopram administration, relearning, and neuroplastic effects: A diffusion tensor imaging study in healthy individuals. J Affect Disord. 2022 Mar 15;301:426-432. doi: 10.1016/j.jad.2021.12.135. Epub 2022 Jan 10.

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Anticipated): August 1, 2019

Study Registration Dates

• First Submitted: April 21, 2016
• First Submitted That Met QC Criteria: April 25, 2016
• First Posted (Estimate): April 28, 2016

Study Record Updates

• Last Update Posted (Estimate): April 28, 2016
• Last Update Submitted That Met QC Criteria: April 25, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: 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; Citalopram
• Other Study ID Numbers: 21042016