¹²³I-Metaiodobenzylguanidine Myocardial Scintigraphy in Panic Disorder

MATERIALS AND METHODS

RESULTS

The scintigraphic results for the patients with panic disorder and the healthy control subjects are shown in Table 2. The ¹²³I-MIBG H/M ratios of the patients with panic disorder were 1.80 ± 0.16 for the early images and 1.86 ± 0.30 for the delayed images, which were significantly lower than those in the control subjects (2.15 ± 0.15 [P = 0.001] and 2.26 ± 0.21 [P = 0.009], respectively). The ¹²³I-MIBG WR from the heart in the patients with panic disorder (33.8% ± 6.9%) was significantly higher than that in the control subjects (27.8% ± 3.5%; P = 0.02). Scintigraphic examples of a patient with panic disorder (patient 3) and a healthy control subject are represented in Figure 1.

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FIGURE 1.

Myocardial ¹²³I-MIBG anterior planar images (30 min [early image, left] and 4 h [delayed image, right]) of 52-y-old healthy control subject, with early H/M ratio of 2.31, delayed H/M ratio of 2.51, and WR of 26.1% (A) and of 39-y-old man with panic disorder (patient 3), with early H/M ratio of 1.63, delayed H/M ratio of 1.61, and WR of 36.1% (B).

DISCUSSION

No definitive pathophysiologic mechanism for panic disorder has been found to date. On the basis of the cardinal features of the symptoms of panic attacks—including palpitations, tachycardia, sweating, shaking, shortness of breath, and chest pains—autonomic nervous system dysfunction has been suggested as a possible pathology of panic disorder, and a variety of studies have attempted to measure autonomic nervous system function in panic disorder. However, these studies have failed to show consistent differences in autonomic nervous system function between patients with panic disorder and healthy subjects.

Studies have focused on the heart rate, blood pressure, and measurements of plasma or urinary catecholamines or catecholamine metabolites from an early stage of the investigation into panic disorder. Nesse et al. reported that patients with panic disorder had elevated heart rate, and plasma epinephrine and norepinephrine levels at rest, indicating baseline hypersensitivity of the cardiovascular autonomic nervous system function in panic disorder (14). On the contrary, although the heart rate and blood pressure increase in panic attacks, there have been reports that they do not differ between patients with panic disorder and healthy subjects during control periods (15,16). Stein and Asmundson performed a variety of tests consisting of postural challenge, isometric exercise, cold pressor, and the Valsalva maneuver and found that patients with panic disorder did not differ from healthy control subjects in their heart rate and blood pressure (17). They also measured plasma norepinephrine and epinephrine levels and concluded that patients with panic disorder showed catecholaminergic responses similar to those of healthy control subjects. Some investigators have reported elevation the plasma norepinephrine level (14,18), and others have reported that patients with panic disorder show no difference in the plasma norepinephrine level from that of healthy subjects even during panic attacks or after autonomic stimuli (17,19,20). One of the main reasons for this inconsistency is that perhaps the plasma norepinephrine concentration in samples obtained from the peripheral vein has important limitations. For example, since antecubital venous concentrations of norepinephrine primarily reflect the activity in muscle and skin sympathetic nerves to the forearm, they are difficult to use as a global or cardiac index of sympathetic activity (21). Wilkinson et al. used infusion of radiolabeled epinephrine and norepinephrine with arterial catheterization and coronary sinus sampling and showed that cardiac epinephrine overspill is increased at rest and during panic attacks in panic disorder (21). The method, which can give selective cardiac functional measurement, is rather complicated and it is possible that anxiety about the equipment and invasive procedures influence the physiologic features of the patients.

Power spectral analysis of heart rate variability has recently been used in various clinical disorders. It consists of high-frequency, low-frequency, and very-low-frequency components. The experimental results have suggested that the high-frequency component is mediated by the cardiac parasympathetic tone, which depends on respiration, whereas the low-frequency component is mediated by both the cardiac sympathetic and the parasympathetic tones (22–24). Generally, this body of research has indicated reduced overall heart rate variability, diminished vagal tone, and relative sympathetic dominance in patients with panic disorder (25–28). However, there have been reports that sympathetic activity is depressed and the vagal tone is predominant in panic disorder by heart rate variability analysis (29,30). In addition, there is the argument that since heart rate variability depends on both the parasympathetic and the sympathetic systems, together with intact baroreflex loops, it is a rather indirect measure of sympathetic function (31). Collectively, various alterations of autonomic nervous system function in panic disorder have been reported. There is no consensual explanation in the literature for these discrepant findings, and the discrepancies may, in part, be due to differences in the anxiety of the subjects at the time of testing or differences in the disease severity or duration among patients included across studies.

In the present study, we used ¹²³I-MIBG as a direct approach for the assessment of cardiac sympathetic nervous function. It was demonstrated that the H/M ratio, as an index of myocardial ¹²³I-MIBG uptake, was lower and the WR, as an index of myocardial clearance, was higher in patients with panic disorder than those values in age-matched healthy control subjects. The mechanisms for the abnormal findings of ¹²³I-MIBG myocardial imaging, decreased H/M ratio, and increased WR are still under investigation. These phenomena are thought to indicate a derangement or imbalance in cardiac sympathetic nerve supply to the myocardium and are a common feature of damaged myocardium due to various diseases, such as heart failure, coronary artery disease, cardiomyopathies, and neurologic diseases (3–8). With respect to panic disorder, if the dramatic elevations in heart rate, blood pressure, and other alarming somatic symptoms generally observed in panic attacks are related to sympathetic activation, the recurrent surges of sympathetic overactivity by panic attacks could lead to depletion or exhaustion of the sympathetic efferent system, which can be depicted as an abnormality in ¹²³I-MIBG myocardial imaging. Although further investigation is required to validate this possibility, ¹²³I-MIBG myocardial imaging, which can be performed easily and noninvasively, would serve to explore the pathophysiology of panic disorder.

In addition to possibly contributing to the analysis of altered autonomic nervous system function in panic disorder, ¹²³I-MIBG myocardial imaging may yield important insights into cardiac comorbidity in panic disorder. There have been reports showing an association between panic disorder and various cardiac illnesses, such as cardiovascular diseases, cardiomyopathy, and supraventricular tachycardia (32–35). Since panic disorder and these cardiac diseases can occur together, it is important to examine whether abnormal findings in an ¹²³I-MIBG study are relevant to the development of cardiac illnesses in further investigations. In addition, since the study group in the present investigation was small and consisted of relatively advanced stages of panic disorder (stage 2 to stage 7; mean, stage 4.4), further studies with larger populations and various subgroups of disease severity are needed to clarify a more detailed role for ¹²³I-MIBG in investigating panic disorder.

CONCLUSION

Our data indicate that patients with panic disorder appear to have significant myocardial sympathetic nervous dysfunction, as was demonstrated by abnormal ¹²³I-MIBG imaging findings. The results suggest that ¹²³I-MIBG imaging could be a useful and noninvasive tool for analyzing the pathophysiology of panic disorder.