The current study is a placebo-controlled, double-blind, randomized controlled study using a cross-over design, including participants with Panic disorder and healthy controls.

The study's primary aim is to investigate the effects of caffeine (vs placebo) on self-reported anxiety and its impact on emotional reactivity and goal-directed behavior in individuals with Panic disorder (vs healthy controls). Emotional reactivity will be measured with self-reported emotions and skin conductance responses. Caffeine-induced effects on goal-directed behavior will be assessed using an approach-avoidance conflict paradigm and an effort-allocation task. The occurrence of panic attacks and panic-related symptoms will also be measured. Furthermore, the link between a genotype of ADORA2A (rs5751876 T/T) previously associated with caffeine-induced anxiety, and the anxiogenic effects of caffeine will also be explored. In addition, caffeine-induced changes in attention to interoceptive stimuli (bodily sensation such as pulse and respiration) and anxiety elicited by attention to interoceptive stimuli will be explored. A secondary aim is to examine the potential caffeine-induced effects and the impact of genetic variation in healthy participants (caffeine vs placebo).

Hypotheses

Self-reported anxiety during resting state

• Participants with Panic disorder will report higher resting-state levels of anxiety and negative emotions during the caffeine condition vs the placebo condition.
• Participants with Panic disorder will report higher resting-state levels of caffeine-induced (caffeine > placebo) anxiety and negative emotions compared to healthy subjects.

Panic attacks

• The occurrence of panic attacks and panic-related symptoms will be higher among participants with Panic disorder than in healthy controls in both conditions (caffeine and placebo).

Genetic variation

• Carriers of adenosine A2A receptor (i.e., ADORA2A) polymorphism (rs5751876 T/T) will report higher levels of caffeine-induced (caffeine >placebo) anxiety and negative emotions, in both individuals with Panic disorder and healthy participants.

Attention to interoceptive stimuli and associated anxiety

• Participants with Panic disorder will report higher levels of attention towards interoceptive stimuli in the caffeine condition (vs placebo).
• Participants with Panic disorder will report higher levels of self-reported anxiety associated with experiencing interoceptive stimuli during the caffeine condition (vs placebo).
• Participants with Panic disorder will report higher levels of self-reported attention to interoceptive stimuli and anxiety associated with experiencing interoceptive stimuli compared to healthy participants, both in general (placebo condition) and after caffeine intake (caffeine vs placebo).

Exploratory research questions

Analyses of emotional reactivity, the approach-avoidance conflict task, and the effort-allocation task will be exploratory without directed hypotheses, due to lack of previous research on the effects of caffeine in patients with Panic disorder on these tasks. We will also conduct exploratory analyses to explore if 150 mg of caffeine (vs placebo) affect self-reported levels of positive emotions in patients with Panic disorder and healthy controls.

Inclusion Criteria:

Panic disorder group: Primary diagnosis of panic disorder.

Healthy control group: No current or history of psychiatric disorders.

All participants (Panic disorder and healthy): Weekly caffeine consumption ≤ 300 mg.

Exclusion Criteria:

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.

Double blind