Neurobehavioral Correlates of Caffeine on Anxiety, Avoidance and Interoception in Healthy Individuals and Panic Disorder. (BINCAP)

Adenosine Receptors From Genes to Behavior: Neurobehavioral Correlates of Caffeine on Anxiety, Avoidance, Decision-Making and Interoception in Healthy Individuals and Panic Disorder.

The current study is a placebo-controlled, double-blind, randomized controlled study using a cross-over design, including Healthy Controls (HC) and participants with Panic Disorder (PD).

The primary aim of the study is to investigate the neural correlates and behavioral effects of caffeine (versus placebo), and its impact on emotional reactivity, decision-making, and interoception, and compare the effects in individuals with PD vs HCs. Subjective anxiety and the occurrence of panic attacks will also be measured. Multimodal neuroimaging methods, such as structural and functional MRI, will be used to address the aims of the study.

Emotional reactivity, emotional decision-making and interoception will be measured with experimental tasks in a 7 Tesla (7T) magnetic resonance (MR) scanner, jointly with measures of skin conductance, heart rate, respiratory rate, and self-reported ratings of anxiety and interoception.

Emotional reactivity will be assessed using emotional and neutral faces. Emotional decision-making will be assessed with an approach-avoidance conflict task. Changes in interoception (bodily sensation, such as pulse and respiration) will be explored using a task in which participants are asked to focus on their breathing or an external stimulus. Caffeine effects on brain resting-state activity will also be assessed. All tasks will be conducted while in the 7T MR scanner.

A secondary aim of the study is to examine the impact of genetic variability in the adenosine A2A receptor (ADORA2A) genotype (e.g., rs5751876 T/T) on the effects of caffeine (vs placebo), as ADORA2A genotype has previously been associated with elevated caffeine-induced anxiety.

Study Overview

• Status: Completed
• Conditions: Healthy; Panic Disorder
• Intervention / Treatment: Drug: Placebo; Dietary supplement: Caffeine

Detailed Description

Given the novelty of the intended study and the lack of previous neuroimaging and emotion-related behavioral studies on caffeine effects in HCs and PD, analyses will be exploratory without directed hypotheses.

It is intended to conduct between-group analyses (HCs vs PD) in the two conditions (caffeine versus placebo), as well as within-group analyses in HCs and PD separately. Between-group analyses will also be conducted between individuals with different ADORA2A genotypes.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Lund, Sweden
    • National 7T Facility - Lunds universitet
  • Uppsala, Sweden, 75185
    • Uppsala University, Department of Medical Sciences, Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Panic Disorder group (PD): Primary diagnosis of Panic Disorder.
• Healthy control group (HCs): No current or history of psychiatric disorders.
• All participants (PD and HCs): Weekly caffeine consumption ≤ 300 mg.

Exclusion Criteria:

• Weekly caffeine consumption ≥ 300 mg.
• Thoracic or head surgery, or any other surgery or metallic implanted devices not compatible with the safety standards for 7T MR scanner.
• History of severe psychiatric disorder (e.g., schizophrenia).
• Somatic or neurological conditions (e.g., hypertension and heart condition).
• Ongoing treatment with psychotropic medication or treatment with psychotropic medication which has been discontinued within 2 months.
• Other ongoing treatments that may confound the results.
• Current drug or alcohol abuse/dependency.
• Habitual nicotine use.
• Uncorrected visual or hearing impairment.
• Pregnancy.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Panic Disorder; Participants will be randomized to start with either the caffeine condition or the placebo condition. Participants will complete session 2 with the other condition (condition not allocated to in session 1).	Drug: Placebo; Placebo capsule, oral intake; Dietary supplement: Caffeine; Caffeine capsule 250 mg, oral intake
Other: Healthy controls; Participants will be randomized to start with either the caffeine condition or the placebo condition. Participants will complete session 2 with the other condition (condition not allocated to in session 1).	Drug: Placebo; Placebo capsule, oral intake; Dietary supplement: Caffeine; Caffeine capsule 250 mg, oral intake

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Task-related BOLD fMRI signal	Task-related BOLD (blood-oxygen-level-dependent) fMRI (functional magnetic resonance imaging) signal will be collected through a 7T MR scanner, starting approximately 30 minutes after oral intake of caffeine or placebo pill. Tasks: Emotional reactivity, Approach-Avoidance Conflict Task, Interoception, Resting-state fMRI.	Session 1 (day 1)
Task-related BOLD fMRI signal	Task-related BOLD (blood-oxygen-level-dependent) fMRI (functional magnetic resonance imaging) signal will be collected through a 7T MR scanner, starting approximately 30 minutes after oral intake of caffeine or placebo pill. Tasks: Emotional reactivity, Approach-Avoidance Conflict Task, Interoception, Resting-state fMRI.	Session 2 (day 2; minimum of 36 hours after session/day 1)
Self-reported anxiety	Anxiety will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task measured with self-reported ratings, on a scale from 0-100 (0= no anxiety - 100= extreme anxiety).	Session 1 (day 1)
Self-reported anxiety	Anxiety will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task measured with self-reported ratings, on a scale from 0-100 (0= no anxiety - 100= extreme anxiety).	Session 2 (day 2; minimum of 36 hours after session/day 1)
Self-reported interoceptive awareness	Interoceptive awareness will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task in the MR scanner, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no awareness - 100= extreme awareness).	Session 1 (day 1)
Self-reported interoceptive awareness	Interoceptive awareness will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task in the MR scanner, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no awareness - 100= extreme awareness).	Session 2 (day 2; minimum of 36 hours after session/day 1)
Self-reported interoceptive functional impairment	Interoceptive functional impairment will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no impairment - 100= extreme impairment).	Session 1 (day 1)
Self-reported interoceptive functional impairment	Interoceptive functional impairment will be assessed before capsule intake (either caffeine or placebo), 20 minutes after intake, after each task, and during the interoception task, measured with self-reported ratings on a scale from 0-100 (0= no impairment - 100= extreme impairment).	Session 2 (day 2; minimum of 36 hours after session/day 1)
Skin conductance responses (SCR)	Skin conductance responses will be used to assess emotional reactivity at the physiological level to emotional stimuli vs neutral stimuli (faces).	Session 1 (day 1)
Skin conductance responses (SCR)	Skin conductance responses will be used to assess emotional reactivity at the physiological level to emotional stimuli vs neutral stimuli (faces).	Session 2 (day 2; minimum of 36 hours after session/day 1)
Occurrence of panic attacks	The occurrence of panic attacks will be assessed according to the Diagnostic Statistical Manual (DSM-5) criteria for panic attacks and will be coded dichotomous as "present" or "not present".	Session 1 (day 1)
Occurrence of panic attacks	The occurrence of panic attacks will be assessed according to the Diagnostic Statistical Manual (DSM-5) criteria for panic attacks and will be coded dichotomous as "present" or "not present".	Session 2 (day 2; minimum of 36 hours after session/day 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Structural brain data, T1-w sMRI	Structural brain changes will be analyzed through T1-weighted sMRI (structural magnetic resonance imaging).	Session 1 (day 1)
Structural brain data, T1-w sMRI	Structural brain changes will be analyzed through T1-weighted sMRI (structural magnetic resonance imaging).	Session 2 (day 2; minimum of 36 hours after session/day 1)
Heart rate variability	Heart rate variability (HRV) will be assessed by using a 7T MR-compatible heart rate band, during the whole MR scanner time.	Session 1 (day 1)
Heart rate variability	Heart rate variability (HRV) will be assessed by using a 7T MR-compatible heart rate band, during the whole MR scanner time.	Session 2 (day 2; minimum of 36 hours after session/day 1)
Respiratory rate	Respiratory or breathing rates will be assessed during the whole MR scanner time.	Session 1 (day 1)
Respiratory rate	Respiratory or breathing rates will be assessed during the whole MR scanner time.	Session 2 (day 2; minimum of 36 hours after session/day 1)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expectancy ratings	Participants will be asked to report if they believed they received placebo or caffeine and how certain they are on a scale from 0-100% before capsule intake and after completing the MR-session.	Session 1 (day 1)
Expectancy ratings	Participants will be asked to report if they believed they received placebo or caffeine and how certain they are on a scale from 0-100% before capsule intake and after completing the MR-session.	Session 2 (day 2; minimum of 36 hours after session/day 1)
Panic Disorder Severity Scale (PDSS)	PDSS is a self-reported questionnaire that assesses the severity of Panic Disorder; range 0-28, higher scores indicating more severe symptoms.	1-7 days prior to session 1 (internet)
Body Sensations Questionnaire (BSQ)	BSQ assesses body sensations present during aversive situations; range 17-85, higher scores indicating higher levels of body sensations.	1-7 days prior to session 1 (internet)
Multidimensional Assessment of Interoceptive Awareness (MAIA-2)	MAIA-2 is an 8-scale state-trait questionnaire with 37 items to measure multiple dimensions of interoception by self- report. The score of each scale is the the average of the items on each scale. Higher mean scores indicate higher levels of the measured dimensions (Noticing, Not-Distracting, Not-Worrying, Attention Regulation, Emotional Awareness,Self-Regulation, Body Listening, and Trust) on a scale from 0-5 (0=never- 5=always), respectively.	1-7 days prior to session 1 (internet)
Anxiety Sensitivity Index (ASI)	ASI assesses anxiety sensitivity; range 0-64, higher scores indicating higher anxiety sensitivity.	1-7 days prior to session 1 (internet)
Spielberger State-Trait Anxiety Inventory (STAI-T)	STAI-T is a self-rated questionnaire assessing trait anxiety; range 20-80, higher scores represent higher levels of trait anxiety.	1-7 days prior to session 1 (internet)
Caffeine Expectancy Questionnaire (CaffEQ)	CaffEQ is a self-rated questionnaire that assesses expected effect of caffeine intake.	1-7 days prior to session 1 (internet)

Collaborators and Investigators

• Sponsor: Uppsala University
• Investigators: Principal Investigator: Andreas Frick, PhD, Uppsala University, Department of Medical Sciences, Psychiatry

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2024
• Primary Completion (Actual): May 15, 2025
• Study Completion (Actual): May 15, 2025

Study Registration Dates

• First Submitted: November 17, 2023
• First Submitted That Met QC Criteria: November 17, 2023
• First Posted (Actual): November 24, 2023

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders; Panic Disorder; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Purinones; Purines; Xanthines; Caffeine
• Other Study ID Numbers: 2023-02915-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No