Serotonergic Modulation of Cognition, Emotion and Brain Activation in Healthy Volunteers

NCT04239339 | Completed Phase 4

• 1 other identifier: H-18038352
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this project is:

• To apply a pharmacological tool of selective serotonin (5-hydroxytryptamine, 5-HT system) reuptake inhibition in healthy humans. Specifically:
• To investigate how sub-chronic administration of 20 mg of escitalopram affects cognitive performance ('cold' cognition) and social-emotional functioning ('hot' cognition) compared with placebo; and
• To investigate how sub-chronic administration of 20 mg of escitalopram affects functional brain activation during a paradigm of reinforcement learning following drug administration compared with placebo, and how activation relates to cognitive performance and social-emotional functioning.

Conditions

Healthy

Keywords

Serotonin; Cognition; Emotion; Neural Activation

Outcome Measures

Primary Outcomes (16)

• Learning Primary Outcome 1: Mean errors Stage 1 (Learning) - Probability Reversal Learning.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 years

• Learning Primary Outcome 2: Mean errors Stage 2 (Reversal) - Probability Reversal Learning.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Learning Primary Outcome 3: Learning Rate in Reward Trial - Reinforcement Learning.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Learning Primary Outcome 4: Learning Rate in Punishment Trials - Reinforcement Learning.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Inhibition Primary Outcome 1: Stop Signal Reaction Time - Interleaved Stop Signal Task/Go-NoGo.

  Outcome variables have been grouped a priori into carefully defined cognitive domains.

  3 Years

• Executive Function Primary Outcome 1: Extra Dimensional Set Errors -3Dimensional Intra/Extra Dimensional Shift.

  Outcome variables have been grouped a priori into carefully defined cognitive domains.

  3 Years

• Reinforcement Behaviour Model

  A model comparison will be conducted to determine the winning model of reinforcement behaviour using one, a combination of, or all these parameters. The winning model will be a single outcome model. 1. Reward Learning Rate 2. Punishment Learning Rate 3. Reinforcement Sensitivity 4. Stimulus Stickiness

  3 Years

• Social Cognition Primary Outcome 1: Proportion of offers accepted - Ultimatum Game

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Social Cognition Primary Outcome 2: Agent Guilt Score - Moral Emotions Task.

  3\. Agent Shame Score ---------- Moral Emotions Task Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Social Cognition Primary Outcome 3: Agent Shame Score - Moral Emotions Task.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Emotion Recognition Primary Outcome 1: Affective bias in decreasing condition - EMOTICOM Intensity Morphing.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Emotion Recognition Primary Outcome 2: Affective bias for D' - EMOTICOM Emotion Recognition Task.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Emotion Recognition Primary Outcome 3: Detection threshold decreasing - EMOTICOM Intensity Morphing.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Emotion Recognition Primary Outcome 4: D'Prime for Emotion Recognition - EMOTICOM Emotion Recognition Task.

  Outcome variables have been grouped a priori into carefully defined cognitive domains. FDR correction, for multiple comparisons, using the Benjamin Hochberg procedure will be applied to the outcomes within each cognitive domain.

  3 Years

• Biofluids: Serum Escitalopram levels

  3 Years

• PET Imaging: Cerebral (particularly hippocampal) presynaptic density, as measured with 11 C-UCB-J-PET.

  Collected in a sub-sample of participants.

  3 Years

Secondary Outcomes (44)

• Learning Secondary Outcome 1: Stage 1 Reward-Stay/Lose-Shift behaviour - Probability Reversal Learning.

  3 Years

• Learning Secondary Outcome 2: Stage 2 Reward-Stay/ Lose-Shift behaviour - Probability Reversal Learning.

  3 Years

• Learning Secondary Outcome 3: Pre Extra Dimension Set Errors - 3Dimensional Intra/Extra Dimensional Shift.

  3 Years

• Learning Secondary Outcome 4: Proportion of Stays - Sequential Model-Based/Model-Free.

  3 Years

• Inhibition Secondary Outcome 1: Go reaction time - Interleaved Stop Signal Task/Go-NoGo.

  3 Years

Other Outcomes (32)

• Emotion Recognition Other Outcome 1: Detection threshold decreasing Happy - Intensity Morphing

  3 Years

• Emotion Recognition Other Outcome 2: Detection threshold decreasing Sad - Intensity Morphing

  3 Years

• Emotion Recognition Other Outcome 3: Detection threshold decreasing Anger - Intensity Morphing

  3 Years

Study Arms (2)

Control Group

PLACEBO COMPARATOR

The placebo control group will be administered the exact same procedure as the intervention group, the only difference being that this group will be administered a placebo pill.

Drug: Placebo

Intervention Group

EXPERIMENTAL

The intervention group will be administered 20mg of Escitalopram daily for approximately 3 weeks.

Drug: Escitalopram 20 mg

Interventions

Escitalopram 20 mg DRUG

20mg daily for approximately 3 weeks.

Intervention Group

Placebo DRUG

Placebo daily for approximately 3 weeks.

Control Group

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy volunteer (male or female) between 18 and 45 years.

You may not qualify if:

• Current or former primary psychiatric disorder (DSM IV Axis I or WHO ICD-10 diagnostic classification).
• Current or previous neurological disease, severe somatic disease, or the consumption of drugs likely to influence the test results.
• Non- fluent in Danish or pronounced visual or auditory impairments.
• Current or past learning disability.
• Pregnancy (females).
• Lactation (females).
• Contraindications for MRI (pacemaker, metal implants, etc.).
• Allergy to the ingredients in the administered drug.
• Abnormal ECG (e.g. prolonged QT syndrome).
• Dizzy when changing from supine to upright position (e.g. postural orthostatic tachycardia syndrome).
• Mild hypotension (blood pressure below 100/70 mmHg) or hypertension (blood pressure above 140/90 mmHg).
• Head injury or concussion resulting in loss of consciousness for more than 2 min.
• Alcohol or drug abuse.
• Drug use other than tobacco and alcohol within the last 30 days.
• Hash \> 50 x lifetime.

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• University of Cambridge: collaborator
• Lundbeck Foundation: collaborator

Study Sites (1)

Neurobiology Research Unit

Copenhagen, DK-2100, Denmark

Location

Related Publications (10)

• Homberg JR. Serotonin and decision making processes. Neurosci Biobehav Rev. 2012 Jan;36(1):218-36. doi: 10.1016/j.neubiorev.2011.06.001. Epub 2011 Jun 12.

  PMID: 21693132 BACKGROUND

• Meneses A. Are 5-HT(1B/1D) and 5-HT(2A/2B/2C) receptors involved in learning and memory processes? IDrugs. 1999 Aug;2(8):796-801.

  PMID: 16127655 BACKGROUND

• Worbe Y, Savulich G, Voon V, Fernandez-Egea E, Robbins TW. Serotonin depletion induces 'waiting impulsivity' on the human four-choice serial reaction time task: cross-species translational significance. Neuropsychopharmacology. 2014 May;39(6):1519-26. doi: 10.1038/npp.2013.351. Epub 2014 Jan 2.

  PMID: 24385133 BACKGROUND

• Worbe Y, Savulich G, de Wit S, Fernandez-Egea E, Robbins TW. Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans. Int J Neuropsychopharmacol. 2015 Feb 5;18(10):pyv013. doi: 10.1093/ijnp/pyv013.

  PMID: 25663044 BACKGROUND

• Worbe Y, Palminteri S, Savulich G, Daw ND, Fernandez-Egea E, Robbins TW, Voon V. Valence-dependent influence of serotonin depletion on model-based choice strategy. Mol Psychiatry. 2016 May;21(5):624-9. doi: 10.1038/mp.2015.46. Epub 2015 Apr 14.

  PMID: 25869808 BACKGROUND

• Park SB, Coull JT, McShane RH, Young AH, Sahakian BJ, Robbins TW, Cowen PJ. Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology. 1994 Mar-Apr;33(3-4):575-88. doi: 10.1016/0028-3908(94)90089-2.

  PMID: 7984295 BACKGROUND

• Sahakian BJ, Morris RG, Evenden JL, Heald A, Levy R, Philpot M, Robbins TW. A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson's disease. Brain. 1988 Jun;111 ( Pt 3):695-718. doi: 10.1093/brain/111.3.695.

  PMID: 3382917 BACKGROUND

• Bland AR, Roiser JP, Mehta MA, Schei T, Boland H, Campbell-Meiklejohn DK, Emsley RA, Munafo MR, Penton-Voak IS, Seara-Cardoso A, Viding E, Voon V, Sahakian BJ, Robbins TW, Elliott R. EMOTICOM: A Neuropsychological Test Battery to Evaluate Emotion, Motivation, Impulsivity, and Social Cognition. Front Behav Neurosci. 2016 Feb 24;10:25. doi: 10.3389/fnbeh.2016.00025. eCollection 2016.

  PMID: 26941628 BACKGROUND

• Armand S, Langley C, Johansen A, Ozenne B, Overgaard-Hansen O, Larsen K, Jensen PS, Knudsen GM, Sahakian BJ, Stenbaek DS, Fisher PM. Functional brain responses to emotional faces after three to five weeks of intake of escitalopram in healthy individuals: a double-blind, placebo-controlled randomised study. Sci Rep. 2024 Feb 7;14(1):3149. doi: 10.1038/s41598-024-51448-2.

  PMID: 38326352 DERIVED

• Langley C, Armand S, Luo Q, Savulich G, Segerberg T, Sondergaard A, Pedersen EB, Svart N, Overgaard-Hansen O, Johansen A, Borgsted C, Cardinal RN, Robbins TW, Stenbaek DS, Knudsen GM, Sahakian BJ. Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study. Neuropsychopharmacology. 2023 Mar;48(4):664-670. doi: 10.1038/s41386-022-01523-x. Epub 2023 Jan 23.

  PMID: 36683090 DERIVED

MeSH Terms

Interventions

Escitalopram

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 13, 2020
• First Posted: January 27, 2020
• Study Start: April 28, 2020
• Primary Completion: October 30, 2022
• Study Completion: October 30, 2022
• Last Updated: November 18, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: Upon Compeletion of the Study.
• Access Criteria: Researchers may apply for access to the data.

Locations

DK (1)