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Serotonin function and panic disorder
256 cholecystokinin B receptor in anxiety. Proc. Natl. Acad. Sci. USA 88. 1130 1133. Vasar, E., Peuranen, E., O6pik, T., Harro, J. and Mfinnist6, P.T. (1993) Ondansetron. an antagonist of 5-HT3 receptors, antagonizes the anti-exploratory effect of caerulein, an agonist of CCK receptors, in the elevated plus-maze. Psychopharmacology 110, 213 218. Woodruff, G.N. and Hugues, J. (1991) Cholecystokinin antagonists. Annu. Rev. Pharmacol. Toxicol. 31,469 501.
Serotonin function and panic disorder
R.S. Kahn Department (![ Psychiatry, Utrecht University. Academic Hospital, 350~ GA Utrecht, The Nether/ands Key wor&v Panic disorder: Anxiety; Serotonin
Summary Increasing serotonin (5-hydroxytryptamine, 5HT) function is anxiogenic in animals and man. Patients with panic disorder appear hypersensitive to the anxiogenic effect of increasing 5HT function, possibly due to increased sensitivity of postsynaptic 5HTIc or 5HT3 receptors. Presynaptic (5HTla) function may be reduced in panic disorder patients. Both phenomena can be explained as the result of decreased production of 5HT in the presynaptic neuron. Introduction A substantial number of studies in animals indicate that 5HT and anxiety are related. Although animal anxiety models are hampered by their indirect measurements of anxiety, decreasing 5HT function (particularly by diminishing 5HT synthesis and by blocking 5HTlc and 5HT3 receptors) reduces anxiety in animals. Conversely, increasing 5HT function increases anxiety in animals (see Kahn and Moore, 1992). Although panic anxiety in humans may not be equivalent to the anxiety operationalized in animal anxiety paradigms, there are interesting parallels between the results of anxiety studies in animals and studies examining the role of 5HT in panic disorder. Treatment studies 5HT reuptake inhibitors are effective anti-panic agents. The potent, but non-selective, 5HT reuptake inhibitor, clomipramine, has been found effective in reducing panic attacks and agoraphobia. Similar results have been obtained using the selective 5HT reuptake inhibitor, fluvoxamine. Although suggestive of a role for 5HT in the treatment of panic anxiety, the efficacy of 5HT reuptake inhibitors does not indicate which of the 5HT receptor subtypes may be affected in panic disorder. Recent availability of agents selective for a particular subset of 5HT receptors, such as the 5HTla partial agonists buspirone, gepirone and ipsapirone, the 5HT2 antagonist ritanserin, and selective 5HT3 antagonists, may facilitate elucidation of possible involvement of these receptors in the pathogenesis of panic disorder. Only very few studies with such agents have been conducted to date. One study comparing the anti-panic effects of fluvoxamine to those of ritanserin (and placebo) found that the latter was not effective in reducing panic symptoms. Two studies examining the efficacy of buspirone in panic disorder found it to be ineffective (see Kahn and Moore, 1992 for review). The efficacy of 5HTlc and 5HT3 antagonists in panic anxiety has not yet been reported. Challenge studies Several 5HT agonists have been used as probes of 5HT receptor function in panic disorder, i.e., 5HT precursors, such as tryptophan and 5-hydroxytryptophan (5HTP); the 5HT releasing agent, fenfluramine: and the 5HT(lc) receptor agonist, mchlorophenylpiperazine (MCPP). MCPP when administered intravenously induces anxiety and panic attacks in healthy humans and patients with panic disorder alike (see Kahn and Moore, 1992). When MCPP is administered orally (0.5 mg/kg) it induces some anxiety, but no panic, in normal subjects (Murphy et al., 1989), but leads to panic attacks in 70% of patients with panic disorder (Klein et al., 1991). When a lower oral dose of MCPP is used (i.e., 0.25 mg/kg), it elicits anxiety and panic in patients with panic disorder but not in normal controls (see Kahn and Moore, 1992). Similarly, oral administration of 60
257 mg fenfluramine induced anxiety and panic in panic disorder patients but not in healthy controls nor in patients with major depression (Targum and Marshall, 1989). Thus, the threshold to experience anxiety and panic in response to 5HT agonist stimulation appears lowered in patients with panic disorder. Den Boer et al. (1990), however, using 5HTP as a challenge agent, found similar effects in panic disorder patients and normal controls. When another 5HT precursor, tryptophan, was used to challenge 5HT receptors, responses in panic disorder patients did not differ from normal controls, either (Charney and Heninger, 1986). Panic disorder: a presynaptic 5 H T deficit?
The data reviewed above can be explained by hypothesizing a presynaptic 5HT deficit in panic disorder. Impaired synthesis of 5HT is expected to lead - via decreased availability of 5HT in the synaptic cleft to adaptive increases in the sensitivity of the postsynaptic receptor. This increased sensitivity would explain the lowered threshold to the anxiogenic effects of enhancing 5HT activity (i.e., responses to MCPP and fenfluramine). It would also explain why tryptophan and 5HTP fail to produce anxiogenic responses. In the presence of a defect in the production of 5HT, administration of 5HT precursors would not be expected to lead to sufficient production of 5HT. Consequently, administration of 5HT precursors would (even at hypersensitive postsynaptic 5HT receptors) not induce anxiogenic responses. Indeed, the finding that fenfluramine did produce increased anxiety in panic disorder patients suggests that when adequate amounts of 5HT are released, responses in these patients are augmented. Finally, decreased 5HT synthesis and availability would be expected to lead to a compensatory reduction in the sensitivity of the (5HTla) autoreceptor (diminishing its inhibitory effect on 5HT release). Blunted responses to the 5HTIa agonist, ipsapirone, have indeed been found in patients with panic disorder, suggesting decreased 5HTla receptor responsivity in these patients (Lesch et al., 1992). In summary, a defect in the production of 5HT in the presynaptic neuron explains the lowered threshold to the anxiogenic effects of MCPP and fenfluramine (reflecting increased 5HT(Ic) receptor function), the blunted responses to ipsapirone (reflecting decreased 5HTla receptor function) and the failure to induce augmented responses by tryptophan and 5HTP (reflecting diminished presynaptic metabolism). References
Charney, D.S. and Heninger, G.R. (1986) Serotonergic function in panic disorders. Arch. Gen. Psychiatry 43, 1059 1065. Den Boer, J.A. and Westenberg, H.G.M. (1990) Behavioral, neuroendocrine and biochemical effects of 5-hydroxytryptophan administration in panic disorder. Psychiatry Res. 31,267 278. Kahn, R.S. and Moore, C. (1992) Serotonin function in anxiety. In: Hoehn-Saric (Ed.), Biology of Anxiety Disorders: Recent Developments. American Psychiatric Press, Chicago, IL. Klein, E., Zohar, J., Geraci, M.F., Murphy, D.L. and Uhde, T.W. (1991) Anxiogenic effects of mCPP in patients with panic disorder: comparison to caffeine's anxiogenic effects. Biol. Psychiatry 30, 973 984. Lesch, K.P., Wiesmann, M., Hoh, A., Muller, T., Disselkamp-Tietze, J., Osterheider, M. and Schulte, H.M. (1992) 5HTla receptor-effector system responsivity in panic disorder. Psychopharmacology 106, 111-117. Murphy, D.L., Mueller, E.A., Hill, J.L., Tolliver, T.J. and Jacobsen, F.M. (1989) Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers. Psychopharmacology 98, 275 282. Targum, S.D. and Marshall, L.E. (1989) Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry Res. 28, 95 306.
Serotonin function and panic disorder
R.S. Kahn Department (![ Psychiatry, Utrecht University. Academic Hospital, 350~ GA Utrecht, The Nether/ands Key wor&v Panic disorder: Anxiety; Serotonin
Summary Increasing serotonin (5-hydroxytryptamine, 5HT) function is anxiogenic in animals and man. Patients with panic disorder appear hypersensitive to the anxiogenic effect of increasing 5HT function, possibly due to increased sensitivity of postsynaptic 5HTIc or 5HT3 receptors. Presynaptic (5HTla) function may be reduced in panic disorder patients. Both phenomena can be explained as the result of decreased production of 5HT in the presynaptic neuron. Introduction A substantial number of studies in animals indicate that 5HT and anxiety are related. Although animal anxiety models are hampered by their indirect measurements of anxiety, decreasing 5HT function (particularly by diminishing 5HT synthesis and by blocking 5HTlc and 5HT3 receptors) reduces anxiety in animals. Conversely, increasing 5HT function increases anxiety in animals (see Kahn and Moore, 1992). Although panic anxiety in humans may not be equivalent to the anxiety operationalized in animal anxiety paradigms, there are interesting parallels between the results of anxiety studies in animals and studies examining the role of 5HT in panic disorder. Treatment studies 5HT reuptake inhibitors are effective anti-panic agents. The potent, but non-selective, 5HT reuptake inhibitor, clomipramine, has been found effective in reducing panic attacks and agoraphobia. Similar results have been obtained using the selective 5HT reuptake inhibitor, fluvoxamine. Although suggestive of a role for 5HT in the treatment of panic anxiety, the efficacy of 5HT reuptake inhibitors does not indicate which of the 5HT receptor subtypes may be affected in panic disorder. Recent availability of agents selective for a particular subset of 5HT receptors, such as the 5HTla partial agonists buspirone, gepirone and ipsapirone, the 5HT2 antagonist ritanserin, and selective 5HT3 antagonists, may facilitate elucidation of possible involvement of these receptors in the pathogenesis of panic disorder. Only very few studies with such agents have been conducted to date. One study comparing the anti-panic effects of fluvoxamine to those of ritanserin (and placebo) found that the latter was not effective in reducing panic symptoms. Two studies examining the efficacy of buspirone in panic disorder found it to be ineffective (see Kahn and Moore, 1992 for review). The efficacy of 5HTlc and 5HT3 antagonists in panic anxiety has not yet been reported. Challenge studies Several 5HT agonists have been used as probes of 5HT receptor function in panic disorder, i.e., 5HT precursors, such as tryptophan and 5-hydroxytryptophan (5HTP); the 5HT releasing agent, fenfluramine: and the 5HT(lc) receptor agonist, mchlorophenylpiperazine (MCPP). MCPP when administered intravenously induces anxiety and panic attacks in healthy humans and patients with panic disorder alike (see Kahn and Moore, 1992). When MCPP is administered orally (0.5 mg/kg) it induces some anxiety, but no panic, in normal subjects (Murphy et al., 1989), but leads to panic attacks in 70% of patients with panic disorder (Klein et al., 1991). When a lower oral dose of MCPP is used (i.e., 0.25 mg/kg), it elicits anxiety and panic in patients with panic disorder but not in normal controls (see Kahn and Moore, 1992). Similarly, oral administration of 60
257 mg fenfluramine induced anxiety and panic in panic disorder patients but not in healthy controls nor in patients with major depression (Targum and Marshall, 1989). Thus, the threshold to experience anxiety and panic in response to 5HT agonist stimulation appears lowered in patients with panic disorder. Den Boer et al. (1990), however, using 5HTP as a challenge agent, found similar effects in panic disorder patients and normal controls. When another 5HT precursor, tryptophan, was used to challenge 5HT receptors, responses in panic disorder patients did not differ from normal controls, either (Charney and Heninger, 1986). Panic disorder: a presynaptic 5 H T deficit?
The data reviewed above can be explained by hypothesizing a presynaptic 5HT deficit in panic disorder. Impaired synthesis of 5HT is expected to lead - via decreased availability of 5HT in the synaptic cleft to adaptive increases in the sensitivity of the postsynaptic receptor. This increased sensitivity would explain the lowered threshold to the anxiogenic effects of enhancing 5HT activity (i.e., responses to MCPP and fenfluramine). It would also explain why tryptophan and 5HTP fail to produce anxiogenic responses. In the presence of a defect in the production of 5HT, administration of 5HT precursors would not be expected to lead to sufficient production of 5HT. Consequently, administration of 5HT precursors would (even at hypersensitive postsynaptic 5HT receptors) not induce anxiogenic responses. Indeed, the finding that fenfluramine did produce increased anxiety in panic disorder patients suggests that when adequate amounts of 5HT are released, responses in these patients are augmented. Finally, decreased 5HT synthesis and availability would be expected to lead to a compensatory reduction in the sensitivity of the (5HTla) autoreceptor (diminishing its inhibitory effect on 5HT release). Blunted responses to the 5HTIa agonist, ipsapirone, have indeed been found in patients with panic disorder, suggesting decreased 5HTla receptor responsivity in these patients (Lesch et al., 1992). In summary, a defect in the production of 5HT in the presynaptic neuron explains the lowered threshold to the anxiogenic effects of MCPP and fenfluramine (reflecting increased 5HT(Ic) receptor function), the blunted responses to ipsapirone (reflecting decreased 5HTla receptor function) and the failure to induce augmented responses by tryptophan and 5HTP (reflecting diminished presynaptic metabolism). References
Charney, D.S. and Heninger, G.R. (1986) Serotonergic function in panic disorders. Arch. Gen. Psychiatry 43, 1059 1065. Den Boer, J.A. and Westenberg, H.G.M. (1990) Behavioral, neuroendocrine and biochemical effects of 5-hydroxytryptophan administration in panic disorder. Psychiatry Res. 31,267 278. Kahn, R.S. and Moore, C. (1992) Serotonin function in anxiety. In: Hoehn-Saric (Ed.), Biology of Anxiety Disorders: Recent Developments. American Psychiatric Press, Chicago, IL. Klein, E., Zohar, J., Geraci, M.F., Murphy, D.L. and Uhde, T.W. (1991) Anxiogenic effects of mCPP in patients with panic disorder: comparison to caffeine's anxiogenic effects. Biol. Psychiatry 30, 973 984. Lesch, K.P., Wiesmann, M., Hoh, A., Muller, T., Disselkamp-Tietze, J., Osterheider, M. and Schulte, H.M. (1992) 5HTla receptor-effector system responsivity in panic disorder. Psychopharmacology 106, 111-117. Murphy, D.L., Mueller, E.A., Hill, J.L., Tolliver, T.J. and Jacobsen, F.M. (1989) Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers. Psychopharmacology 98, 275 282. Targum, S.D. and Marshall, L.E. (1989) Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry Res. 28, 95 306.