Emerging Evidence of the Neurobiology of Panic Disorder : Emerging Evidence of the Neurobiology of Panic Disorder
Objectives : Objectives Describe stimuli and factors potentially contributing to development of panic disorder Review the neuroanatomical components of the anxiety response associated with panic disorder Review the neurochemical components of the anxiety response associated with panic disorder Discuss the various treatment approaches for panic disorder
Development of Panic Disorder : Development of Panic Disorder Adapted from Stein DJ. CNS Spectr . 2005;9(suppl 12):12-24. Predisposing Factors Genetics Family/environment Temperament Psychological issues Stimulus Somatic sensations Sensory information that triggers the alarm system Pharmacologic challenge Panic attacks Avoidance Anticipatory anxiety Somatic sensations
Anxiety Affects Brain and Body : Anxiety Affects Brain and Body Somatosensory/ Emotional Cardiovascular Increased sympathetic outflow ACTH Hypothalamus Amygdala Locus coeruleus Cortisol Cognitive Prefrontal cortex Epi, NE Respiratory Increased rate Bone ACTH=adrenocorticotropic hormone; Epi=epinephrine; NE=norepinephrine. Sternberg EM, Gold PW. In: The Hidden Mind . Sci Am . 2002:82-89.
Neuroanatomic Areas of Interest : Neuroanatomic Areas of Interest Adapted from Charney DS. Am J Psychiatry. 2004;161:195-216. Stahl SM. J Clin Psychiatry. 2002;63:854-855. Thalamus 1 Hippocampus 1 Hypothalamus 1 Prefrontal cortex 1 Locus coeruleus 1 Amygdala 1 Raphe nucleus 2
Amygdala1 Hub of the CNS Fear Network : CNS=central nervous system. Adapted from Charney DS. Am J Psychiatry . 2004;161:195-216. Bremner JD. Expert Rev Neurother . 2004;4:275-284. Davis M. In: Neuropsychopharmacology: The Fifth Generation of Progress . 2002:931-951. Kent JM, et al. In: Neurobiology of Mental Illness . 2nd ed. 2004:639-660. Amygdala 1 Hub of the CNS Fear Network Assesses threat level and assigns emotional valence 2 to stimuli entering the thalamus 3 Coordinates the autonomic and behavioral responses to anxiety-provoking stimuli 4 Amygdala
Thalamus1 Gateway to the Brain : Thalamus 1 Gateway to the Brain Filters sensory information to the amygdala 2 Disseminates sensory information to different brain regions associated with the response to stressful stimuli 3 Adapted from Charney DS. Am J Psychiatry . 2004;161:195-216. Gorman JM, et al. Am J Psychiatry . 2000;157:493-505. Kent JM, Rauch SL. In: Neurobiology of Mental Illness . 2nd ed. 2004:639-660. Thalamus
Hippocampus1 Memory Center : Hippocampus 1 Memory Center Stores contextual information 2 and conveys it directly to the amygdala 3 Creates cognitive connections with anxiety-producing events 4 Adapted from Charney DS. Am J Psychiatry . 2004;161:195-216. Kent JM, Rauch SL. In: Neurobiology of Mental Illness . 2nd ed. 2004:639-660. Gorman JM, et al. Am J Psychiatry . 2000;157:493-505. Charney DS, Deutch A. Crit Rev Neurobiol . 1996;10:419-446. Hippocampus
Prefrontal Cortex Information Processing Center : Prefrontal Cortex Information Processing Center Processes cognitive information related to the anxiety response 2 Inhibits activity of the amygdala, providing “top- down control” of the anxiety response 2,3 Adapted from Charney DS. Am J Psychiatry . 2004;161:195-216. Gorman JM, et al. Am J Psychiatry. 2000;157:493-505. Kent JM, Rauch SL. In: Neurobiology of Mental Illness . 2nd ed. 2004:639-660. Prefrontal cortex
Hypothalamus1 Autonomic Regulatory Center : Hypothalamus 1 Autonomic Regulatory Center Coordinates behavioral responses to emotions through the neuroendocrine and autonomic systems 2,3 Triggers release of excitatory neurochemicals 2 1. Adapted from Charney DS. Am J Psychiatry. 2004;161:195-216. 2. Gorman JM, et al. Am J Psychiatry. 2000;157:493-505. 3. Charney DS, Deutch A. Crit Rev Neurobiol. 1996;10:419-446. Hypothalamus
Anatomy of Anxiety : Hypothalamus Hippocampus Autonomic + Pituitary/ Adrenal Activation Anatomy of Anxiety Adapted from Kent JM, Rauch SL. In: Neurobiology of Mental Illness. 2nd ed. 2004:639-660. Adapted from Charney DS. Am J Psychiatry . 2004;161:195-216. Prefrontal Cortex Amygdala Sensory/ Visceral Stimuli S T e h n a s l o a r m y u s
Raphe Nucleus1 Headquarters of the Serotonin System : Raphe Nucleus 1 Headquarters of the Serotonin System Activity influences the cortical and limbic systems 2 Inhibits activity of the periaqueductal gray 3 region and locus coeruleus, 4 modulating the anxiety response 1. A dapted from Charney DS. Am J Psychiatry. 2004;161:195-216. 2. Amat J, et al. Nat Neurosci. 2005;8:365-371. 3. Gorman JM, et al. Am J Psychiatry . 2000;157:493-505. 4. Coplan JD, et al. Biol Psychiatry. 1998;44:1264-1276. Raphe nucleus
Locus Coeruleus1 Headquarters of the Norepinephrine System : Locus Coeruleus 1 Headquarters of the Norepinephrine System Initiates NE release 2 Contributes to behavioral and physiologic arousal 2 Contains the highest concentration of NE neurons in the brain 3 Directly modulated by the amygdala 1 Inhibited by 5-HT and GABA 4 5-HT=serotonin; GABA=gamma-aminobutyric acid. 1. Adapted from Charney DS. Am J Psychiatry. 2004;161:195-216. 2. Gorman JM, et al. Am J Psychiatry. 2000;157:493-505. 3. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications . 2nd ed. 2000:135-197. 4. Aston-Jones G, et al. J Neurosci . 2004;24:2313-2321. Locus coeruleus
Neurocircuitry of Anxiety1,2 : Raphe Nucleus 3,4 Peri- aqueductal Gray Region Defense/Escape Behaviors 3 Adapted from Kent JM, Rauch SL. In: Neurobiology of Mental Illness. 2nd ed. 2004:639-660. Adapted from Charney DS. Am J Psychiatry . 2004;161:195-216. Gorman JM, et al. Am J Psychiatry. 2000;157:493-505. Coplan JD, Lydiard RB. Biol Psychiatry. 1998;44:1264-1276. Neurocircuitry of Anxiety 1,2 Hippocampus Amygdala Prefrontal Cortex S T e h n a s l o a r m y u s Hypothalamus Sensory/ Visceral Stimuli Locus Coeruleus Behavioral/ Physiologic Arousal 3
Neurochemical Inputs Potentially Affecting the Anxiety Response : Raphe Nucleus Locus coeruleus 1 Periaqueductal gray region Defense/ Escape Behaviors 1 Behavioral/ Physiologic Arousal 1 Gorman JM, et al. Am J Psychiatry. 2000;157:493-505. Coplan JD, et al. Biol Psychiatry. 1998;44:1264-1276. Butler PD, et al. J Neurosci . 1990;10:176-183. – Neurochemical Inputs Potentially Affecting the Anxiety Response Amygdala GABA 2 – Inhibitory Stimulatory + + – + + Glutamate 5 + – CRF 2,3 + – Stress + + – 5-HT 2 Pharmacotherapy 4 + NE 2,3 + Charney DS, et al. Acta Psychiatr Scand. 2003;108(suppl 417):38-50. Charney DS. Am J Psychiatry. 2004;161:195-216.
Potential Therapeutic Targets for Treatment of Panic Disorder : Potential Therapeutic Targets for Treatment of Panic Disorder “Top-down control” Therapeutic approach Cognitive-behavioral therapy (CBT) Objective Use cognitive techniques to stop or prevent panic symptoms and avoidance behaviors Proposed mechanisms Increase activity of prefrontal cortex to inhibit amygdala Decondition phobic avoidance and decrease cognitive misattributions and exaggerated emotional reactions “Bottom-up control” Therapeutic approach Pharmacotherapy Objective Modulates neurochemical reactions that lead to panic attacks and avoidance Proposed mechanisms Decrease locus coeruleus and amygdala firing Gorman JM, et al. Am J Psychiatry . 2000;157:493-505.
Conclusions : Conclusions Symptoms of panic disorder may affect both the brain and the body and are theoretically mediated via the CNS fear network Evidence suggests that dysregulation of a number of different neurochemical systems may play a role in the pathogenesis of panic disorder Medications and psychotherapy are effective treatments and are thought to work to varying degrees at different, perhaps complementary, areas of the brain © 2006, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101 119182-01 June 2006