We would like provisionally to name it serotonin, which indicates that its source is serum and its activity is one of causing constriction.
Rapport M, et al
The cardiovascular properties of serotonin (5-HT) have been known for some time—its name reflects its presence in serum and its action in increasing vascular tone. Serotonergic medications are routinely used to treat depressive and anxiety disorders, and the association of depression with cardiovascular disease has become well established.2 Recent studies have confirmed the colloquial wisdom that anxiety (especially panic) and hypertension are linked.
In this article, we examine the trinity of serotonin—serotonergic dysfunction, autonomic panic, and normal-weight essential hypertension— and the evidence that hypertensive individuals who experience panic with autonomic symptoms may be a group of patients in whom serotonergic dysfunction plays a key role. We discuss implications of this model, including the potential utility of SSRIs as antihypertensives in this cohort.
The role of serotonin
SSRIs are well established as first-line treatments of clinical anxiety disorders.3 Their wide availability, relative safety in overdose, limited adverse effects, and broad clinical effectiveness have contributed to their popularity. Indeed, their categorization as antidepressants seems increasingly inadequate because these agents have been found to be clinically useful in a range of psychiatric conditions.
In recent years, there has been much concern about emergent suicidality in adults and children treated with SSRIs. 
Such fears appear to have eroded clinical confidence in these medications, despite some methodological concerns.4-6 Sadly, a parallel decrease in prescribing of SSRIs appears to be associated with increased suicide rates—a powerful reminder of the need to closely monitor all patients for whom these powerful medicines are prescribed and the complex implications of health policy modification.7 Most authorities continue to advocate considered use of SSRIs and/or cognitive-behavioral therapy (CBT) in clinical anxiety states, although the evidence base supporting combination therapy over SSRIs alone is surprisingly sparse.8
Patients are commonly told that SSRIs work by “correcting” an abnormality in the 5-HT system, but only recently has evidence emerged to support this correlation with anxiety. One difficulty has been competing theories that patients with anxiety disorders have either too little or too much 5-HT in the synaptic cleft.9
The 5-HT deficit model proposes that 5-HT reuptake blockade leads to increased availability of 5-HT, which, in turn, rapidly leads to a decreased rate of firing of the raphe nucleus. The initial net result is little overall change in cortical 5-HT concentration. After a few weeks to months, however, the raphe firing rate recovers, and eventually 5-HT cerebral concentration reaches levels that are therapeutic. This model accounts for the delayed onset of antidepressant and anxiolytic action as well the initial transient increase in anticipatory anxiety.
An alternative (5-HT excess) model proposes that increased levels of 5-HT produce an increase in anticipatory anxiety initially; however, a gradual down-regulation of supersensitive postsynaptic receptors (or a decrease in presynaptic excitability) produces an anxiolytic effect.
1. Rapport M, Green A, Page I. Crystalline serotonin. Science. 1948;108:329-330.
2. Davies SJ, Hood SD, Christmas D, Nutt DJ. Psychiatric disorders and cardiovascular disease. Anxiety, depression and hypertension. In: Sher L, ed. Psychological Factors and Cardiovascular Disorders: The Role of Psychiatric Pathology and Maladaptive Personality Features. New York: Nova Science Publishers; 2008: chap 6.
3. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19:567-596.
4. Nutt DJ. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. J Psychopharmacol. 2003;17:355-364.
5. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63:332-339.
6. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry. 2007;164:1044-1049.
7. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164:1356-1363.
8. van Apeldoorn FJ, van Hout WJ, Mersch PP, et al. Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia. Acta Psychiatr Scand. 2008;117:260-270.
9. Hood SD, Argyropoulos SV, Nutt DJ. New directions in the treatment of anxiety disorders. Expert Opinion on Therapeutic Patents. 2003;13:401-423.
10. Hood SD, Bell C, Nutt DJ. Acute tryptophan depletion. Part I: rationale and methodology. Aust N Z J Psychiatry. 2005;39:558-564.
11. Nash JR, Sargent PA, Rabiner EA, et al. Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study. Br J Psychiatry. 2008;193:229-234.
12. Bell C, Hood SD, Nutt DJ. Acute tryptophan depletion. Part II: clinical effects and implications. Aust N Z J Psychiatry. 2005;39:565-574.
13. Lanzenberger RR, Mitterhauser M, Spindelegger C, et al. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry. 2007;61:1081-1089.
14. Descartes R. De Homine Figuris et Latinitate Donatus a Florentio Schuyl. Leyden, the Netherlands: P Leffen & F Moyardum; 1662.
15. Eaker ED, Sullivan LM, Kelly-Hayes M, et al. Tension and anxiety and the prediction of the 10-year inkcidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham Offspring Study. Psychosom Med. 2005;67:692-696.
16. Fleet RP, Beitman BD. Cardiovascular death from panic disorder and panic-like anxiety: a critical review of the literature. J Psychosom Res. 1998;44:71-80.
17. Lynch P, Galbraith KM. Panic in the emergency room. Can J Psychiatry. 2003;48:361-366.
18. Davies SJ, Ghahramani P, Jackson PR, et al. Association of panic disorder and panic attacks with hypertension. Am J Med. 1999;107:310-316.
19. Davies SJ, Jackson PR, Ramsay LE, et al. No evidence that panic attacks are associated with the white coat effect in hypertension. J Clin Hypertens (Greenwich ). 2003;5:145-152.
20. Esler M, Eikelis N, Schlaich M, et al. Chronic mental stress is a cause of essential hypertension: presence of biological markers of stress. Clin Exp Pharmacol Physiol. 2008;35:498-502.
21. Wilkinson DJ, Thompson JM, Lambert GW, et al. Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks. Arch Gen Psychiatry. 1998;55:511-520.
22. Davies SJ, Jackson PR, Lewis G, et al. Is the association of hypertension and panic disorder explained by clustering of autonomic panic symptoms in hypertensive patients? J Affect Disord. 2008;111: 344-350.
23. Glassman AH, O’Connor CM, Califf RM, et al; Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina [published correction appears in JAMA. 2002;288:1720]. JAMA. 2002;288:701-709.
24. Berkman LF, Blumenthal J, Burg M, et al; EnhancingRecovery in Coronary Heart Disease Patients (ENRICHD) Investigators. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA. 2003;289:3106-3116.
25. Johnson PL, Hollis JH, Moratalla R, et al.Acute hypercarbic gas exposure reveals functionally distinct subpopulations of serotonergic neurons in rats. J Psychopharmacol. 2005;19:327-341.
26. Davies SJ, Hood SD, Argyropoulos SV, et al. Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders. J Clin Psychopharmacol. 2006;26:414-418.
27. Bell C, Forshall S, Adrover M, et al. Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine. J Psychopharmacol. 2002;16:5-14.
28. Hood SD, Hince DA, Robinson H, et al. Serotonin regulation of the human stress response. Psychoneuroendocrinology. 2006;31:1087-1097.
29. Polyák J. How should we manage cardiovascular panic disorder accompanied by hypertension? J Hypertens. 2001;19(suppl 2):S64.
Evidence-Based References
Davies SJ, Hood SD, Argyropoulos SV, et al. Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders. J Clin Psychopharmacol. 2006;26: 414-418.
Davies SJ, Jackson PR, Lewis G, et al. Is the association of hypertension and panic disorder explained by clustering of autonomic panic symptoms in hypertensive patients? J Affect Disord. 2008;111:344- 350.
