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VENLAFAXINE AND CARDIAC ILLNESSES
OVERVIEW
Depression is a common psychiatric disorder with potentially serious morbidity and mortality. Fortunately, it is very treatable with numerous antidepressant options as a component of a biopsychosocial treatment plan. This article addresses controversies and concerns regarding the use of venlafaxine in patients who have existing or potential comorbid medical conditions, especially cardiovascular disorders.
Venlafaxine is a prototypical serotonin-norepinephrine reuptake inhibitor (SNRI) that blocks reuptake of serotonin (5-HT) and norepinephrine (NE) receptors. It has minimal antagonism of dopamine receptors and no antagonism of alpha1-adrenergic, cholinergic, or histaminergic receptors.1 At dosages less than 225 mg/d, venlafaxine primarily inhibits serotonin reuptake; at dosages more than 225 mg/d, venlafaxine inhibits serotonin and norepinephrine reuptake.2,3
Venlafaxine is effective in treating major depression, treatment-resistant depression, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) and provides cognitive enhancement in attention-deficit/hyperactivity disorder.1,2,4,5 Venlafaxine also treats nonpsychiatric pain disorders, including postherpetic neuralgia, diabetic neuropathic pain, tension headaches, migraine headaches, rheumatoid arthritis, chronic low back pain, cancer, central poststroke pain, and fibromyalgia.3
Venlafaxine has greater efficacy than selective serotonin reuptake inhibitors (SSRIs) because of its broad-based receptor coverage and the pharmacologic synergy between serotonergic and noradrenergic antagonism.1,2,6 Accordingly, the American Psychiatric Association (APA) Practice Guidelines list venlafaxine, SSRIs, desipramine, nortriptyline, and bupropion as “likely to be optimal for most patients.”7 Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine recommends venlafaxine as useful in treating depression in the presence of comorbid cardiovascular disease because venlafaxine lacks any significant cytochrome P450 (CYP) inhibition and is not highly protein bound.8
CARDIAC MORBIDITY AND MORTALITY
The effect of venlafaxine in cardiac morbidity and mortality is a complex and controversial issue.
With venlafaxine and venlafaxine extended release (XR), patients’ pulse rates increased by an average of 4 beats per minute (bpm); with placebo, the average increase was 1 bpm. Tachycardia occurred in at least 2% of patients taking venlafaxine XR. Venlafaxine should be used with caution, particularly in dosages higher than 200 mg/d, patients with elevated pulse rates, and medical conditions causing elevated pulse rates (eg, hyperthyroidism, heart failure, myocardial infarctions) within the previous 6 months.4
In patients without preexisting cardiac disease, venlafaxine has few cardiovascular effects and no effects on ECGs;
Braunwald’s recognizes a dose-related increase in blood pressure (BP) and pulse rate.8 As venlafaxine has minimal, if any, adverse effects on cardiac function in medically healthy patients, it does not cause any significant ECG changes and is actually associated with a slightly decreased risk of acute myocardial infarction.10,11
With regard to cardiac dysrhythmias, no treatment-emergent cardiac conduction abnormalities (including QTc prolongation) were found in patients treated with venlafaxine IR or venlafaxine XR.4,9 Additionally, based upon a pooled analysis of 6670 patients, arrhythmias, extrasystoles, and bradycardia occurred infrequently (0.1-1%) in patients taking venlafaxine XR.4 Based upon this same analysis, first-degree atrioventricular (AV) block, bigeminy, bundle-branch block, and sinus arrhythmia occurred rarely (<0.1%) in patients taking venlafaxine XR.4 However, case reports describe the presence of cardiac arrhythmias (eg, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, ventricular extrasystoles, ventricular fibrillation, ventricular tachycardia [including torsade de pointes]) and ECG changes (ie, bundle-branch block, prolongation of QTc and QRS intervals) w!
ith venlafaxine IR and venlafaxine XR.4,9
Specific case studies also describe cardiac morbidity associated with the administration of venlafaxine. Venlafaxine was “strongly related” and attributed to 2 cases of heart failure and interstitial pneumonia.12 Another case report noted a 60-year-old patient with hypertension, mild dyspnea, and depression who was treated with venlafaxine and had a QTc interval of 582 milliseconds. Within a few days after discontinuing venlafaxine, her QTc interval returned to the reference range.13 Finally, one study underscores the importance of careful monitoring of patients during polypharmacy; when antipsychotics were combined with SSRIs or SNRIs, mean QTc intervals increased by 24 milliseconds, and significantly increased QTc intervals (to >450 milliseconds) were observed in 38% of patients taking antipsychotics plus antidepressants versus 7% of patients taking antipsychotics alone.14
GERIATRIC PATIENTS
One study of geriatric patients who had depression and were taking venlafaxine found few clinical or statistically significant changes in vital signs, ECG findings, or laboratory findings. These patients initially received dosages of 25 mg 2 or 3 times daily; dosages were titrated to 50-150 mg/d. No unexpected deaths occurred. Within 2 months, 67% of patients responded to venlafaxine. At the end of the 12-month study, 80% of patients reported feeling much or very much improved.15 On the other hand, a case report has noted that a geriatric woman with preexisting ischemic heart disease developed acute myocardial infarction within the first week of treatment.16
BLOOD PRESSURE CHANGES
Elevations in BP are consistent with a norepinephrine mechanism of action. For venlafaxine IR, BP elevations are dose-dependent and are rare at dosages less than 225 mg/d; the incidence is 3%, with 1% of patients discontinuing venlafaxine as a result of elevated BP.2 That 1% of patients experienced a modest diastolic BP increase of 10-15 mm Hg. Average BP elevations were 1 mm Hg for patients taking 75 mg/d, 2 mm Hg for 225 mg/d, and 7.5 mm Hg with 375 mg/d.2
Sustained hypertension means treatment-emergent elevations in diastolic BP higher than 89 mm Hg or more than 10 mm Hg above baseline for 3 visits. The incidence of sustained hypertension with venlafaxine is 3% in patients taking less than 101 mg/d, 5% in patients taking 101-200 mg/d, 7% in patients taking more than 200 mg/d, 13% in patients taking more than 300 mg/d, and 2% in patients taking placebo.4 BP elevations are independent of age, gender, baseline BP, and renal or hepatic status. Because elevated BP is a serious risk factor for morbidity and mortality, patients who exhibited sustained hypertension when taking venlafaxine were excluded from clinical studies. As a result, whether unstable hypertension is a risk factor for elevated BP with venlafaxine is unknown.9
Venlafaxine inhibits norepinephrine reuptake in the absence of alpha1-adrenergic blockade. As a result, the vasoconstrictive effects of norepinephrine are potentiated, thereby increasing BP. Risk factors for elevated BP as an adverse effect of venlafaxine are unknown, but preexisting mildly elevated BP is not such a risk factor.9 A 24-week pharmacovigilance study of 4320 patients taking venlafaxine XR found that patients with preexisting hypertension experienced significant decreases in systolic and diastolic BPs; in patients without preexisting elevated BP, systolic BP increased by an average of 0.3 mm Hg and diastolic BP increased by 0.1 mm Hg; these elevations are both within the reference range.17
During premarketing studies (8-12 wk in duration) of 2261 patients treated with venlafaxine XR for GAD, SAD, and PD, 0.5-1.4% sustained BP elevations between 7-19 mm Hg.4 In patients with depressive disorders, a 0.7% incidence of diastolic BP increases, averaging 12-16 mm Hg, occurred in those treated with venlafaxine XR.4 Although venlafaxine IR has a dose-dependent association with increased BP, any dose-dependent relationship is unknown for venlafaxine XR.4
Other special populations may be at higher risk for BP elevations with venlafaxine. Consider a case report of a 52-year-old Asian man with preexisting hypertension who was admitted for a depressive episode. He received venlafaxine 75 mg/d and an unreported dose of alprazolam. After his dosage of venlafaxine was increased to 150 mg/d, his systolic BP rose to 180 mm Hg. After the venlafaxine was discontinued, his BP normalized within 4 days.18 Because Asians and some Asian Americans are more sensitive to psychotropic medications, this case report underscores the importance of considering ethnicity when determining starting doses and titration rates of all psychotropic medications.
In short, clinicians should obtain baseline BPs and check BP regularly in patients taking any form of venlafaxine, particularly in those taking 225 mg/d or more. Increased BP occurs most commonly within the first 2 months of stabilization with venlafaxine.9 Before initiating treatment with venlafaxine, clinicians should treat any preexisting elevations in BP.9 Fortunately, venlafaxine does not adversely effect BP treatment.19 BP elevations are relatively easier to treat than are mood disorders, and detecting elevated BP is the overriding consideration. Therefore, with all things equal, patients who fail to respond to other antidepressants but experience BP elevations while taking venlafaxine should continue taking venlafaxine and have their BP elevations treated. Alternatives include a dosage reduction of venlafaxine or supplementation with another psychotropic medication, such as lithium.
THE ROLE OF THE ECG
As a key test in diagnosing acute and chronic cardiac conditions, the ECG is the most commonly used laboratory test for helping to diagnose cardiac disorders.8,20 Indications for obtaining an ECG include known cardiovascular disease, suspected cardiovascular disease, and high risk for cardiovascular disease.8,20,21 When patients with known cardiovascular disease are stable, annual ECGs are recommended. Risk factors for cardiovascular disease include smoking; diabetes; peripheral vascular disease; and family history of cardiovascular disorders, especially QT-interval prolongation and ventricular preexcitement. Other cardiovascular risk factors that warrant an ECG include preoperative workup for complex surgery, cardiac symptoms (eg, chest pain), cardiotoxic medication exposure (eg, digitalis, anti-arrhythmics, TCA overdose), and any treatment that causes ECG changes or adverse cardiac events. An important practice pattern to keep in mind is that age alon!
e is not an indication for obtaining an ECG.
ECGs can also help assess pacemaker functioning and diagnose ischemia; infarcts; arrhythmias; drug-induced, electrolyte, and metabolic abnormalities, especially hypocalcemia, hypercalcemia, kalemia, and magnesia; conduction delays (eg, bundle-branch blocks); prolonged QRS and QT intervals; repolarization abnormalities in ST-T waves; atrial abnormalities, including hypertrophy; ventricular hypertrophy; and preexcitation.8,20,21 ECGs are the best measure of the QTc interval, an electrical manifestation of ventricular depolarization and polarization. The QTc interval is a correction of the QT interval, which varies based on heart rate, heredity, other biological and technical factors, and intraobserver and interobserver variables. According to the European Agency for the Evaluation of Medicinal Products (EMEA) guidelines, a QTc interval change of less than 30 milliseconds is clinically insignificant, a change of 30-60 milliseconds suggests a drug effect and is cause !
for concern, and changes greater than 60 milliseconds raise the risk of arrhythmias.22 Average QTc changes associated with venlafaxine XR vary from 0 milliseconds to 4.7 milliseconds.4 No QTc interval changes are associated with venlafaxine IR.9
The limitations of ECGs also warrant discussion. According to Cecil, “a patient with heart disease may have a normal ECG, while a normal individual may have an abnormal ECG.”21 In other words, ECGs have relatively low sensitivity and specificity. Therefore, arbitrary or even universal testing with ECG and its use as the sole means of diagnosing cardiac pathology are improper; false-positive results may expose patients to further unnecessary tests and treatments, which may increase morbidity and mortality. Errors in interpreting ECGs can also create so-called iatrogenic heart disease. The most serious error is a failure to correlate ECG findings clinically; this is the most common cause of iatrogenic heart disease.20 Although computers have revolutionized medicine, electronic ECG interpretation remains imperfect. Programmers design algorithms based on a predetermined range of normality, which, as discussed above, is somewhat controversial. For instance, !
serial ECGs, 1 minute apart, resulted in ECG interpretations that varied 35% of the time.23 No major textbook of pharmacology, internal medicine, cardiology, or psychiatry recommends baseline ECGs in all venlafaxine candidates.
Because venlafaxine has minimal, if any, adverse cardiac conduction effects in medically healthy patients, it does not produce significant changes on ECG.10 Therefore, obtaining a baseline ECG is only necessary in some candidates for venlafaxine therapy. However, in patients who have (or are suspected to have) significant or suspected medical conditions, a baseline ECG is indicated. Hampton best described the role of the ECG as follows: “The key to the ECG is to use it as an adjunct to the patient’s history and physical examination. When in doubt, it’s better to depend on these than on the ECG, and it is always the patient who should be treated, not the ECG.”24
REFERENCES
1. Stahl SM. Essential psychopharmacology: Neuroscientific basis and practical applications. 2nd ed. New York, NY: Cambridge University Press; 2005.
2. Janicak PG, Davis JM. Preskorn SH, et al. Principles and Practice of Psychopharmacology. 4th ed. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2006.
3. Kasper DL, Braunwald E, Fauci AS, et al. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005.
4. Effexor XR (venlafaxine HCl) Extended-Release Capsules Product Overview. Wyeth Pharmaceuticals, Inc. Web site. Available at: http://www.wyeth.com/products/prescription?product=/wyeth_html/home/products/prescription/Effexor%20XR%C2%AE%20(venlafaxine%20HCl)%20Extended-Release%20Capsules/Effexor%20XR%C2%AE%20(venlafaxine%20HCl)%20Extended-Release%20Capsules_overview.html. Accessed November 1, 2006.
5. Rosenbaum JF, Arena GW, Hyman SE, et al. Handbook of psychiatric medication treatment. 5th ed. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2005.
6. Kennedy SH, Andersen HF, Lam RW. Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis.
J Psychiatry Neurosci. 2006;31(4);228.
7. American Psychiatric Association (APA). Practice Guidelines for the Treatment of Psychiatric Disorders. APA Web site. Available at: http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed November 1, 2006.
8. Zipes DP, Libby P, Bonow RO, Braunwald E. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, Pa: Elsevier Saunders;
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9. Effexor (venlafaxine hydrochloride) [package insert]. Philadelphia, Pa: Wyeth Pharmaceuticals, Inc.; 2006. Available at: http://www.wyeth.com/content/ShowLabeling.asp?id=99. Accessed November 1, 2006.
10. Beliles K, Stoudemire A. Psychopharmacologic treatment of depression in the medically ill.
Psychosomatics. 1998;39:S12-19.
11. Schlienger RG, Fischer LM, Jick H, Meier CR. Current use of selective serotonin reuptake inhibitors and risk of acute myocardial infarction.
Drug Saf. 2004;27(14):115-65.
12. Drent M, Singh S, Gorels AP, et al. Drug-induced pneumonitis and heart failure simultaneously associated with venlafaxine,
Am J Resp Crit Care Med. 2003;167(7):958-61.
13. Letsas K, Korantzopolous P, Pappas L, et al. QT interval prolongation associated with venlafaxine administration,
Int J Cardiol. 2006;109(1):116-7.
14. Sala M, Vicentini A, Brambilla P, et al. QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy.
Ann Gen Psychiatry. 2005;4(1)1.
15. Dierick M, An open-label evaluation of the long-term safety of oral venlafaxine in depressed elderly patients.
Ann Clin Psychiatry. 1996;8(3):169-78.
16. Reznik I, Rosen Y, Rosen B. An acute ischaemic event associated with the use of venlafaxine: a case report and proposed pathophysiological mechanisms.
J Psychopharmacol. 1999;13(2):193-5.
17. Baldomero EB, Enguiz SC, and Grupo de Estudio teso. Cardiovascular safety of venlafaxine retard in patients with depression. A pharmacovigilance study.
Psiquiatria Biologica 2005;12:33-8.
18. Bahk W-M, Pae C-U, Chae J-H, et al. Even lose-dose treatment of venlafaxine may provoke recurrent of hypertension in an Asian patient?
Gen Hosp Psychiatry. 2001;23:232-4.
19. Thase ME. Effects of venlafaxine on blood pressure: A meta-analysis of original data from 3744 depressed patients.
J Clin Psychiatry. 1998:59:502-8.
20. Alexander RW, Schlant RC, Foster V, O’Rourke RA. Hurst’s The Heart. 9th ed. New York, NY: McGraw-Hill: 1998.
21. Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia, Pa: Saunders; 2004.
22. Committee for Proprietary Medicinal Products (CPMP). Points to consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. The European Agency for the Evaluation of Medicinal Products. December 1997. Available at: http://www.coresearch.biz/regulations/cpmp.pdf. Accessed November 1, 2006.
23. Spodick DH, Bishop RL. Computer treason: Intraobserver variability of an electrocardiographic computer system.
Am J Cardiol. 1997;16:14-28.
24. Hampton, JR. The ECG in practice. 4th ed. Edinburgh, UK: Churchill-Livingstone; 2006.
FURTHER READING
Brunton LL, Lazo JS, Parker KL. Goodman and Gilman’s Pharmacologic Basis of Treatment. 11th ed. New York: McGraw-Hill; 2006.
Ciraulo DA, Shader RI, Greenblatt PJ, Creelman W. Drug Interactions in Psychiatry. 3d ed. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2006.
Hales RE, Yudofsky SC. APA Textbook of Clinical Psychiatry. 4th ed. Washington, DC: American Psychiatric Publishing; 2003.
Kaplan HI, Sadock BJ, eds. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Science, Clinical Psychiatry. 9th ed. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2003.
Pies RW. Handbook of Essential Psychopharmacology. 2nd ed. Washington, DC: American Psychiatric Association; 2005.
Schatzberg AF, Cole JO, DeBattista C. Manual of Clinical Psychopharmacology. 5th ed. Washington, DC: American Psychiatric Association; 2005.
Staab JP, Evans DL. Efficacy of venlafaxine in geriatric depression. Depress Anxiety. 2000;12 Suppl. 1:63-8.
Wells BG, Dipro JT, Schwinghammer TL, Hamilton CW. Pharmacotherapy Handbook. 6th ed. New York, NY: McGraw-Hill; 2005.
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