Psychiatric Times.
No. 2
Special Report - Anxiety Disorders
SSRIs as Antihypertensives in Patients With Autonomic Panic Disorder
Is There a Link Between Panic Disorder and Hypertension?
By Sean Hood, MBBS, MSC |
February 1, 2009
Dr Hood is associate professor in Clinical Psychopharmacology at the School of Psychiatry and Clinical Neurosciences, University of Western Australia Queen Elizabeth II Medical Centre Nedlands, Perth, Australia, and he maintains an honorary appointment at the Psychopharmacology Unit of the University of Bristol in England. Dr Hood reports that he is on the advisory boards for Eli Lilly and GlaxoSmithKline (GSK); he is on the speakers’ bureau for Lundbeck, Eli Lilly, GSK, Astra-Zeneca, Janssen, Pfizer, Wyeth, and Bristol-Myers Squibb; and he has received educational and travel support from Lundbeck, Eli Lilly, GSK, AstraZeneca, Janssen, Pfizer, Wyeth, Bristol-Myers Squibb, Servier, Sanofi-Aventis, and Cephalon.
Autonomic dysfunction and serotonin
For many years, the majority of cases of hypertension were classified as “essential hypertension,” which simply means of unknown etiology. Because there is substantial evidence for autonomic dysfunction in both hypertension and panic, a parsimonious explanation for the association between these 2 conditions in at least some cases of essential hypertension is common autonomic dysfunction.21 Davies and colleagues22 tested this hypothesis by considering panic attack symptom profiles in people who had experienced a panic attack. Hypertensive participants (with resting blood pressure greater than 160/90 mm Hg) were more likely to report experiencing sweating (64.6% vs 46.2%) and flushing (54.9% vs 39.7%) during their worst attack than were normotensive patients. In addition, factor analysis revealed a 4-factor solution with a dominant autonomic symptom factor containing sweating, flushes, and shaking—and only this factor was significantly associated with hypertension. An explanation of these data may be that experiencing panic attacks with autonomic symptoms is a marker for a specific kind of hypertension in these people—one in which there is a dysregulated central 5-HT system. A range of diverse data relates to this assertion, including the clinical utility of SSRI antidepressant medications in patients with cardiovascular conditions. The Sertraline(Drug information on sertraline) Antidepressant Heart Attack Randomized Trial (SADHART) group reported that sertraline was a safe and somewhat effective antidepressant in subjects with ischemic heart disease and major depression, and a post hoc analysis hinted at an improvement in severe cardiac events.23 The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) investigators demonstrated a psychological benefit in post–myocardial infarction patients with cognitive therapy (plus sertraline for some patients) with no impact on cardiovascular morbidity or mortality.24 Depression rather than anxiety was examined in these studies and neither study reported a significant improvement in blood pressure. SSRI-induced inhibition of platelet 5-HT uptake is known to reduce platelet plug formation, which could be of additional benefit. Animal data also exist that support putative 5-HT (ie, sympathethic) anxiety circuits and provide a plausible preclinical biological model.25 Using the ATD procedure, we demonstrated that people with SSRI-remitted anxiety disorders—including panic disorder—show an increased cardiovascular (independent of anxiety measures) and psychological response to a disorder-specific stressor when depleted of tryptophan(Drug information on tryptophan) in comparison with a control (nondepleted) condition.10,12,26,27 Healthy volunteers, however, do not show an increased response to a single-breath 35% carbon dioxide stress challenge when they are tryptophan-depleted, which suggests that they have a more robust 5-HT system.28 The integrity of the 5-HT system in people with dysregulated blood pressure control, as determined by the ability to buffer the stress response under the tryptophan-depleted versus nondepleted condition, has yet to be assessed. SSRIs as antihypertensives
If patients with hypertension and autonomic symptoms of panic are susceptible to a pressor effect by acutely depleting central 5-HT, might not the addition of SSRIs improve their blood pressure control? We already have some intriguing early data that suggest that this may indeed be true. Polyák29 has presented the results of a study of 107 adults with both hypertension and anxiety who were taking a range of antihypertensive medications. Low-dose (mean, 39 mg/d) sertraline was added to their diverse antihypertensive regimens, and the effects on blood pressure was checked at 1 month and at 6 months. At both points, a significant improvement in systolic blood pressure of about 10 mm Hg and diastolic blood pressure of about 5 mm Hg were seen. Although this case series has not been replicated and subjects with autonomic panic were not specifically identified, these data cannot easily be ignored. We propose conducting a series of follow-up studies to explore the utility of SSRI therapy in people with hypertension and the related condition of prehypertension, and to evaluate the evidence for serotonergic dysfunction and altered blood pressure response to stress in people with prehypertension and panic attacks via serotonergic manipulation. Until such work is undertaken, this interesting therapeutic option will remain largely a research interest. Conclusions
An association between 5-HT, panic, and hypertension has long been noted and is now the subject of active research interests. Manipulating 5-HT may have clinical implications for blood pressure control in people with panic attacks and anxiety. Our data suggest that panic attacks comorbid with hypertension may be distinct from panic attacks uncomplicated by hypertension—and it may be that hypertension complicated by panic attacks has specific biological features compared with hypertension uncomplicated by panic. Serotonergic manipulation of hypertension has largely been ignored or dismissed since the isolation of serotonin in 1948; however, we believe that by focusing on patients with key autonomic panic symptoms such as sweating and flushing, we may clarify this issue with potential therapeutic benefits.
Also in this Special Report
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.
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