Aetiology

A combination of factors is likely to predispose people to panic disorders.

  • Genetic factors: the risk of panic disorder increases fivefold among first-degree relatives.[22] The concordance rates for monozygotic and dizygotic twins are approximately 23% and 6%, respectively, with meta-analytic findings attributing an estimated 30% to 50% of the variance to shared genetic liability.[22][23][24] Although identification of panic-specific genes has yielded inconclusive findings, it is likely that multiple genetic variants of small effect interact with each other and contribute to the panic disorder risk.[24][25] One meta-analysis of candidate genes showed an association of panic disorder with TMEM132D gene variants.[26] One genome wide association study (GWAS) found that a polymorphism in the GLRB gene may predispose to panic disorder by increasing startle response and agoraphobic thoughts.[27] Epigenetic mechanisms are also believed to contribute to panic disorder predisposition, possibly by mediating gene-environment interactions.[28]

  • Environmental factors: panic attacks, by definition, initially occur unexpectedly. However, they do happen in context, and thus certain features of the environment may become triggers that elicit intense anxiety symptoms. Significant histories of unpredictable and uncontrollable life stressors and trauma are common.[29][30] Prior to the onset of panic attacks, up to 80% of patients report one or more major negative life events.[29] Asthma severity appears to be associated with an incremental risk for panic disorder.[5] Respiratory variability may also increase risk factor for later onset panic disorder.[31] Nicotine use and dependence are disproportionately high among patients with panic disorder, and may be temporally related to elevated risk for developing panic disorder.[6]

  • Psychological factors: cognitive behavioural models of panic assume that repeated, unpleasant experiences with external (e.g., crowds) and internal (e.g., rapid heartbeat) triggers lead to selective attention and hypervigilance. In turn, individuals learn to catastrophically misinterpret normal physical symptoms as dangerous.[32] Across all anxiety disorders, there may be a perturbed threat response with abnormalities in the circuitry involved in attention, emotion, learning and memory.[33] Activation of the fight or flight response to perceived danger further amplifies the panic response, and attempts to manage the panic through escape, avoidance, and safety behaviours provide short-term relief but lead to increasing functional impairments across time.[34] Temperamental factors, such as behavioural inhibition, may contribute to panic risk in adulthood.[35][36] Anxiety sensitivity, or a tendency to catastrophically misinterpret physical symptoms as dangerous, is viewed as a psychological risk factor for the development of panic disorder.[37][38]

Pathophysiology

Neuroimaging studies of panic suggest involvement of the central nuclei of the amygdala, including activation of other fear centres of the brain, such as the thalamus, hypothalamus, and hippocampus, which may dysregulate respiratory control in the brainstem.[39][40] One study found decreased grey matter volume across the medial temporal, prefrontal cortex, and cingulate regions of the brain in panic disorder.[41]

Other pathophysiological models suggest that exaggerated hypothalamic-pituitary-adrenal axis reactivity to environmental stimuli may be involved in panic disorder.[42] Functional magnetic resonance imaging studies demonstrate abnormalities in attention and threat response.[43][44]

In patients with panic disorder, cognitive behavioural therapy has shown significant reductions in the activation of the left interior frontal gyrus region, with reduced activity correlated with reduced agoraphobic symptoms.[45] One study indicated that pre-treatment activation of the bilateral insula and left dorsolateral prefrontal cortex during threat processing is associated with rapid response to cognitive behavioural therapy.[46]

Classification

Diagnostic and statistical manual of mental disorders: 5th edition, text revision (DSM-5-TR)[1]

Panic disorder:

  • The experience of recurrent, unexpected panic attacks

  • At least one of the attacks has been followed by a period of at least 1 month of one or both of the following: persistent concern or worry about additional panic attacks or their consequences (e.g., heart attack); a significant maladaptive change in behaviour related to the attacks (e.g., avoidance of exercise or unfamiliar situations)

  • Panic symptoms must not be attributable to substance-related effects (e.g., a drug of misuse, a medication), other medical conditions (e.g., hyperthyroidism, cardiopulmonary disorders), or other psychiatric disorders (e.g., social anxiety disorder, specific phobias, obsessive compulsive disorder, post-traumatic stress disorder, separation anxiety disorder).

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