The platelet intracellular calcium response to serotonin and thrombin in patients with panic disorder

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Abstract

Serotonin is implicated in both the biology of depression and anxiety. The aim of this study was to examine the platelet intracellular calcium response to serotonin and thrombin using spectroflouromery in 14 patients with DSM-4 panic disorder compared to 14 matched controls. Patients did not show significantly higher baseline platelet intracellular calcium levels and serotonin stimulated levels of intracellular calcium than control subjects. There was a much smaller standard deviation in the control subjects than in the panic patients. The intracellular calcium response to thrombin activation was however greater in panic patients than in control subjects (P<0.001). The failure of this study to find enhanced sensitivity of 5-HT2 receptors in panic disorder is compatible with the findings of previous challenge studies that found no consistent dysregulation of serotonin in panic disorder. The enhanced thrombin sensitivity, nevertheless suggests some receptor mediated second messenger changes independent of serotonin in the disorder.

Introduction

Panic disorder (with or without phobic avoidance) is a common anxiety disorder, occurring in 2%–6% of the population (Myers et al., 1984). Panic disorder is a distinct syndrome characterised by the recurrence of spontaneous panic attacks that arise from a dysfunctional biological substrate and elicit additional symptomatic reactions.

Alterations in several measures of serotonergic function, including levels of serotonin metabolites, receptor binding, and uptake in platelets and endocrine responses have been linked to depression (Sheehan and Harnett-Sheehan, 1996). Serotonin is implicated in the biology of anxiety, and similar experimental evidence also links changes in serotonergic neurotransmission in panic disorder (Krystal et al., 1996). Three such studies compared the effect of serotonin precursors on neuroendocrine responses in healthy subjects and in patients with panic disorder. Two showed no differences in the prolactin release in response to the serotonin precursor tryptophan between patients and controls (Charney et al., 1988; Den Boer and Westenberg, 1990). A small study of the effects of fenfluramine, a serotonin-releasing agent, reported more anxiogenic responses and greater elevations in plasma cortisol and prolactin among nine panic disorder patients than in a group of healthy control subjects (Targum and Marshall, 1989). A study of the cortisol response to 5-hydroxytryptophan did not clearly differentiate panic patients from controls (van Vliet et al., 1996). Examination of post-synaptic serotonin receptor function in panic disorder with the mixed agonist–antagonist m-chlorophenylpiperizine has shown some evidence of serotinergic dysregulation (Charney et al., 1987; Khan et al., 1988; Khan and Wetzler, 1991). These neuroendocrine challenge studies do not robustly support the involvement of serotonin in panic disorder. Binding of [3-H] paroxetine to the serotonin transporter in panic disorder was not found to differ from controls or patients with social phobia (Stein et al., 1995).

Binding sites for serotonin (5HT) are present on platelet membranes. Serotonin binds to cell surface receptors and results directly or indirectly in a rise in the intracellular concentration of ionised calcium (Murray and Harper, 1988). The platelet intracellular calcium response to serotonin has been found to be abnormal in depression (Mikuni et al., 1991; Eckert et al., 1993), suggesting increased sensitivity of the 5-HT2 receptor. The aim of this study was to examine the platelet intracellular calcium response to serotonin and thrombin in patients with panic disorder to clarify whether the above mentioned dysfunction of the serotinergic system is found in panic disorder.

Section snippets

Method

Patients aged 18–65 who met DSM-IV criteria for panic disorder were selected for the study. A Hamilton Depression Rating Scale (HAMD) and a structured interview to confirm the clinical diagnosis were done. Exclusion criteria included the presence of another axis 1 diagnosis including major depression, a HAMD score of over 16, significant medical illness, concomitant psychotropic drug therapy except PRN benzodiazepines with a washout period of 2 weeks (5 weeks for fluoxetine); I, hypertension

Results

Patients have slightly higher platelet intracellular calcium levels than control subjects (Fig. 1). This difference is not statistically significant at any of the 5HT concentrations. Only at 50 nM and at 500 nM does the confidence interval approach significance: (P=0.089; n=14; S.D.=126) There is a much smaller standard deviation in the control subjects than in the panic patients. A wide standard deviation of intracellular calcium results in mood disorders is a consistent finding in the

Discussion

Second messenger involvement in panic disorder is suggested by an enhanced T cell CCK-4 stimulated intracellular calcium response (Akiyoshi et al., 1996). In this study there is a trend showing higher intracellular calcium levels in response to serotonin stimulation in panic patients compared to controls, although these levels do not reach statistical significance. There nevertheless is a significant statistical difference in the intracellular calcium response to thrombin activation. This

Acknowledgements

The authors wish to thank the University of the Witwatersrand Postgraduate Merit Award/Bursary Fund, the Department of Clinical and Experimental Pharmacology for financial support, Zane Wilson and the Anxiety Disorders Support group of South Africa for its assistance in the recruitment of volunteers and Professor Ivan Havlik for his support of this project.

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