The study of the respiratory physiology in sufferers from panic disorder has received a lot of attention (Abelson et al., 2001, Cowley and Roy-Byrne, 1987, Nardi et al., 2009 and Niccolai et al., 2009). A substantial body of research, suggest the involvement of respiratory abnormalities in panic disorder, particularly hyperventilation (Grassi et al., 2013). Increased respiratory variability is a trait feature of panic disorder patients which is not reversed by effective treatment (Martinez et al., 2001). Looking at the temporal relationship, earlier carbon dioxide partial pressure (pCO2) levels predict later levels of anxiety sensitivity and respiratory rate, but not vice versa (Meuret et al., 2009). Moreover, raising end-tidal pCO2 by means of capnometry-assisted feedback is therapeutically beneficial for panic disorder patients (Meuret et al., 2008). The analysis of panic attack symptom dimensions, including “prominent respiratory symptoms” (Brigss et al., 1993) may be functionally meaningful (Meuret et al., 2006). Respiratory subtype panic disorder patients seem to be more sensitive to the CO2 inhalation challenge test and the hyperventilation test than non-respiratory subtype patients (Freire et al., 2008).
When tested under ambulatory conditions (which should minimize the stressful conditions of a laboratory setting), panic disorder patients present cardio-respiratory instability and elevated levels of end-tidal pCO2 during the hour preceding a panic attack (Meuret and Ritz, 2010). However, other ambulatory studies (with a substantial proportion of patients under medication) do not find baseline abnormalities in ventilatory function parameters such as respiratory volumes, frequency and variability (Pfaltz et al., 2009 and Pfaltz et al., 2010).
Hyperventilation, as might occur during panic attacks, induces a state of acute respiratory alkalosis characterized by a low pCO2 (hypocapnia) and elevated arterial pH (or decreased H+ concentration) and a variable reduction in plasma bicarbonate concentration (Gardner, 1996, Gorman et al., 1985, Knochel, 1977 and Rose and Post, 2001). Alkalemia triggers a compensatory response that involves two steps: rapid buffering, within 10 min (by H+ ions which are released from the protein, phosphate and hemoglobin buffers and then combine with HCO3−), and a later decrease in net renal acid excretion, completed within 24–28 h (Ueda et al., 2009). As a result of the time differential between these effects, the changes in acute and chronic respiratory alkalosis are different (Rose and Post, 2001 and Ueda et al., 2009). Some studies have shown hypocapnia, hypobicarbonatemia and a pH close to normal in subgroups of panic disorder patients at baseline, consistent with chronic hyperventilation (Gorman et al., 1985 and Gorman et al., 1986). Thus, venous pH, pCO2, and bicarbonate levels have been proposed as markers of treatment status in some patients with panic disorder who normalize these variables after successful pharmacological intervention (Gorman et al., 1985).
An additional finding in respiratory alkalosis is the reduction in the plasma phosphate concentration (measured as inorganic phosphorous), which reflects a rapid shift of phosphate from the extracellular fluid into the cells (Brautbar et al., 1983 and Knochel, 1977). The severity of alkalemia is ameliorated by buffer and renal responses that promote bicarbonate and phosphate (HPO42− and H2PO4−) excretion, deriving in diminished plasma bicarbonate concentrations and hypophosphatemia (Gardner, 1996 and Knochel, 1977). Over half a century ago, it was found that with hyperventilation “the urine became alkaline and showed an increase of phosphates after 8–10 min of overbreathing” (Ames, 1955, p. 482).
Although far from conclusive, an association between panic disorder and hypophosphatemia has been established in the laboratory setting. Thus, in baseline conditions, panic disorder patients show evidence of hyperventilation and have lower pCO2, bicarbonate and inorganic phosphate levels compared to healthy controls (Balon et al., 1988 and Kligler, 1999). Interestingly, among patients with panic disorder, low baseline phosphate levels can predict a panic attack subsequent to a lactate infusion, suggesting that low serum phosphate could be a state-marker of chronic hyperventilation (Gorman et al., 1986). Moreover, a case report with repeated measures from a panic disorder patient has shown an inverse correlation between phosphate levels and severity of panic symptoms (Roestel et al., 2004).
Although hypophosphatemia is not considered classically as a sign of clinical panic disorder (Roestel et al., 2004), a recent meta-analysis support the hypothesis that panic disorder patients show hyperventilation at baseline associated with lower pCO2, bicarbonate and phosphate levels (Grassi et al., 2013). Therefore, serum phosphate might be considered as a state-marker of chronic hyperventilation and indirectly of state-anxiety associated with panic disorder. Despite easy access to this laboratory measure in routine clinical practice, little attention has been paid to its potential usefulness for the assessment of the clinical condition of panic disorder patients.
The aim of the present study was to verify the feasibility of serum phosphate levels as a state marker for panic disorder, comparing a series of panic disorder patients, before and after effective treatment, with a healthy volunteer comparison group.
