52 Consistent with a persistent breathing irregularity, panic disorder patients exhibit a chronically low end-tidal CO2 56-59 and a compensatory decrease in serum bicarbonate.2,59 Those who exhibit breathing irregularities may also be more likely to have respiratory symptoms during an attack.38,60 Symptom P450 inhibitor concentration cluster analyses have identified a subtype of panic disorder, in which respiratory symptoms appear to predominate.38,60 Interestingly, the respiratory subtype may be the most sensitive to CO2 38 and lactate.39 This subtype may also respond best to the antidepressant imipramine,60 and may be more likely

to be Inhibitors,research,lifescience,medical associated with a family history of panic disorder.38 Supporting a role for pH in panic pathophysiology, correcting blood gas abnormalities through breathing control or pharmacology has been suggested to produce clinical improvement.57,59 Endogenous lactate and pH abnormalities in panic disorder Lactate is a weak acid that can be an independent determinant of pH in biological systems.61 Several studies Inhibitors,research,lifescience,medical using 1H-magnetic resonance spectroscopy suggest endogenous lactate levels may

be elevated in panic disorder patients. Panic disorder patients had higher lactate levels than controls Inhibitors,research,lifescience,medical in response to visual cortex activation,62 following hyperventilation,63 and during lactate-induced panic.49 Fiberoptic biosensor measurements of pH in primates suggest that intravenous lactate infusion reduces brain pH.64 Phosphorus spectroscopy further suggests that the elevated brain lactate in panic disorder patients may change pH buffering capacity.65 It was suggested that a Inhibitors,research,lifescience,medical vascular or metabolic abnormality might be responsible for the lactate elevation.49,53,62 Consistent with this view, probands who had a family history of panic and an atypical CO2 ventilatory response were more likely to carry a polymorphism in a gene encoding

lactate dehydrogenase, which catalyzes the conversion of lactate to pyruvate.53 CNS chemosensitivity CO2 and acid chemosensitivity Inhibitors,research,lifescience,medical in the CNS The potential associations between panic disorder, the action of panicogens, and brain pH begs the question of how the brain Thiamine-diphosphate kinase normally senses and responds to pH change. The majority of research on chemosensitivity in the CNS has focused on respiratory control. Thus, understanding how pH regulates breathing could provide critical insights into panic disorder. Breathing rate and volume are exquisitely sensitive to CO2 in the blood, largely through interstitial pH and activation of pH-sensitive chemoreceptors.45,66 Although the precise sites of CO2-mediated ventilatory control are uncertain, they are thought to lie in the brain stem67 (medulla and pons). Neurons in multiple brain stem sites can be activated by CO2 and low pH, suggesting the relevant chemosensitivity might reside at multiple locations.