Neuroanatomical hypothesis of panic disorder, revised

Am J Psychiatry. 2000 Apr;157(4):493-505. doi: 10.1176/appi.ajp.157.4.493.


Objective: In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance.

Method: The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals.

Results: There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder.

Conclusions: Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adult
  • Amygdala / drug effects
  • Amygdala / physiopathology
  • Animals
  • Behavior, Animal / physiology
  • Brain / drug effects
  • Brain / physiopathology*
  • Brain Stem / drug effects
  • Brain Stem / physiopathology
  • Cognition / physiology
  • Cognitive Behavioral Therapy
  • Conditioning, Psychological / physiology
  • Disease Models, Animal
  • Diseases in Twins / genetics
  • Family
  • Fear / physiology
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • Humans
  • Life Change Events
  • Models, Neurological*
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Panic Disorder / etiology*
  • Panic Disorder / physiopathology
  • Panic Disorder / therapy
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Serotonin / physiology
  • Twin Studies as Topic


  • Serotonin Uptake Inhibitors
  • Serotonin