Advertisement

Impact of Depression and Antidepressant Treatment on Heart Rate Variability: A Review and Meta-Analysis

Published:February 08, 2010DOI:https://doi.org/10.1016/j.biopsych.2009.12.012

      Background

      Depression is associated with an increase in the likelihood of cardiac events; however, studies investigating the relationship between depression and heart rate variability (HRV) have generally focused on patients with cardiovascular disease (CVD). The objective of the current report is to examine with meta-analysis the impact of depression and antidepressant treatment on HRV in depressed patients without CVD.

      Methods

      Studies comparing 1) HRV in patients with major depressive disorder and healthy control subjects and 2) the HRV of patients with major depressive disorder before and after treatment were considered for meta-analysis.

      Results

      Meta-analyses were based on 18 articles that met inclusion criteria, comprising a total of 673 depressed participants and 407 healthy comparison participants. Participants with depression had lower HRV (time frequency: Hedges' g = −.301, p < .001; high frequency: Hedges' g = −.293, p < .001; nonlinear: Hedges' g = −1.955, p = .05; Valsalva ratio: Hedges' g = −.712, p < .001) than healthy control subjects, and depression severity was negatively correlated with HRV (r = −.354, p < .001). Tricyclic medication decreased HRV, although serotonin reuptake inhibitors, mirtazapine, and nefazodone had no significant impact on HRV despite patient response to treatment.

      Conclusions

      Depression without CVD is associated with reduced HRV, which decreases with increasing depression severity, most apparent with nonlinear measures of HRV. Critically, a variety of antidepressant treatments do not resolve these decreases despite resolution of symptoms, highlighting that antidepressant medications might not have HRV-mediated cardioprotective effects and the need to identify individuals at risk among patients in remission.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Andrade L.
        • Caraveo-Anduaga J.J.
        • Berglund P.
        • Bijl R.V.
        • De Graaf R.
        • Vollebergh W.
        • et al.
        The epidemiology of major depressive episodes: Results from the International Consortium of Psychiatric Epidemiology (ICPE) surveys.
        Int J Methods Psychiatr Res. 2003; 12: 3-21
        • Murray C.J.
        • Lopez A.D.
        Alternative projections of mortality and disability by cause 1990–2020: Global burden of disease study.
        Lancet. 1997; 349: 1498-1504
        • Carney R.M.
        • Rich M.W.
        • Tevelde A.
        • Saini J.
        • Clark K.
        • Jaffe A.S.
        Major depressive disorder in coronary artery disease.
        Am J Cardiol. 1987; 60: 1273-1275
        • Gonzalez M.B.
        • Snyderman T.B.
        • Colket J.T.
        • Arias R.M.
        • Jiang J.W.
        • O'Connor C.M.
        • et al.
        Depression in patients with coronary artery disease.
        Depression. 1996; 4: 57-62
        • Pratt L.A.
        • Ford D.E.
        • Crum R.M.
        • Armenian H.K.
        • Gallo J.J.
        • Eaton W.W.
        Depression, psychotropic medication, and risk of myocardial infarction.
        Circulation. 1996; 94: 3123-3129
        • Barefoot J.C.
        • Helms M.J.
        • Mark D.B.
        • Blumenthal J.A.
        • Califf R.M.
        • Haney T.L.
        • et al.
        Depression and long-term mortality risk in patients with coronary artery disease.
        Am J Cardiol. 1996; 78: 613-617
        • Penninx B.W.
        • Beekman A.T.
        • Honig A.
        • Deeg D.J.
        • Schoevers R.A.
        • van Eijk J.T.
        • et al.
        Depression and cardiac mortality: Results from a community-based longitudinal study.
        Arch Gen Psychiatry. 2001; 58: 221-227
        • Anda R.
        • Williamson D.
        • Jones D.
        • Macera C.
        • Eaker E.
        • Glassman A.
        • et al.
        Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of US adults.
        Epidemiology. 1993; 4: 285-294
        • Grippo A.J.
        • Johnson A.K.
        Biological mechanisms in the relationship between depression and heart disease.
        Neurosci Biobehav Rev. 2002; 26: 941-962
        • Sheffield D.
        • Krittayaphong R.
        • Cascio W.E.
        • Light K.C.
        • Golden R.N.
        • Finkel J.B.
        • et al.
        Heart rate variability at rest and during mental stress in patients with coronary artery disease: Differences in patients with high and low depression scores.
        Int J Behav Med. 1998; 5: 31-47
        • Cameron O.
        Depression increases post-mi mortality: How?.
        Psychosom Med. 1996; 58: 111-112
        • Thayer J.F.
        • Lane R.D.
        The role of vagal function in the risk for cardiovascular disease and mortality.
        Biol Psych. 2007; 74: 224-242
        • Carney R.
        • Blumenthal J.
        • Freedland K.
        • Stein P.
        • Howells W.
        • Berkman L.
        • et al.
        Low heart rate variability and the effect of depression on post-myocardial infarction mortality.
        Arch Intern Med. 2005; 165: 1486-1491
        • Huikuri H.
        • Raatikainen M.
        • Moerch-Joergensen R.
        • Hartikainen J.
        • Virtanen V.
        • Boland J.
        • et al.
        Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction.
        Eur Heart J. 2009; 30: 689
        • Bigger J.T.
        • Kleiger R.E.
        • Fleiss J.L.
        • Rolnitzky L.M.
        • Steinman R.C.
        • Miller J.P.
        Components of heart rate variability measured during healing of acute myocardial infarction.
        Am J Cardiol. 1988; 61: 208-215
        • Hughes J.W.
        • Stoney C.M.
        Depressed mood is related to high-frequency heart rate variability during stressors.
        Psychosom Med. 2000; 62: 796-803
        • Verrier R.L.
        • Lown B.
        Experimental studies of psychophysiological factors in sudden cardiac death.
        Acta Med Scand Suppl. 1982; 660: 57-68
        • La Rovere M.
        • Pinna G.
        • Maestri R.
        • Mortara A.
        • Capomolla S.
        • Febo O.
        • et al.
        Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients.
        Circulation. 2003; 107: 565
        • Berntson G.G.
        • Bigger J.T.
        • Eckberg D.L.
        • Grossman P.
        • Kaufmann P.G.
        • Malik M.
        • et al.
        Heart rate variability: Origins, methods, and interpretive caveats.
        Psychophysiology. 1997; 34: 623-648
        • Udupa K.
        • Sathyaprabha T.N.
        • Thirthalli J.
        • Kishore K.R.
        • Lavekar G.S.
        • Raju T.R.
        • et al.
        Alteration of cardiac autonomic functions in patients with major depression: A study using heart rate variability measures.
        J Affect Disord. 2007; 100: 137-141
        • van der Kooy K.G.
        • van Hout H.P.
        • van Marwijk H.W.
        • de Haan M.
        • Stehouwer C.D.
        • Beekman A.T.
        Differences in heart rate variability between depressed and non-depressed elderly.
        Int J Geriatr Psychiatry. 2006; 21: 147
        • Boettger S.
        • Hoyer D.
        • Falkenhahn K.
        • Kaatz M.
        • Yeragani V.K.
        • Bar K.
        Nonlinear broad band dynamics are less complex in major depression.
        Bipolar Disord. 2008; 10: 276-284
        • Yeragani V.K.
        • Rao K.A.
        • Smitha M.R.
        • Pohl R.B.
        • Balon R.
        • Srinivasan K.
        Diminished chaos of heart rate time series in patients with major depression.
        Biol Psychiatry. 2002; 51: 733-744
        • Nahshoni E.
        • Aravot D.
        • Aizenberg D.
        • Sigler M.
        • Zalsman G.
        • Strasberg B.
        • et al.
        Heart rate variability in patients with major depression.
        Psychosomatics. 2004; 45: 129-134
        • Yeragani V.
        • Radhakrishna Rao K.
        Nonlinear measures of QT interval series: Novel indices of cardiac repolarization lability: MEDqthr and LLEqthr.
        Psychiatry Res. 2003; 117: 177-190
        • Rajendra A.U.
        • Paul J.K.
        • Kannathal N.
        • Lim C.
        • Suri J.
        Heart rate variability: A review.
        Med Biol Eng Comput. 2006; 44: 1031-1051
        • Rottenberg J.
        Cardiac vagal control in depression: A critical analysis.
        Biol Psychol. 2007; 74: 200-211
        • Berntson G.
        • Lozano D.
        • Chen Y.
        Filter properties of root mean square successive difference (RMSSD) for heart rate.
        Psychophysiology. 2005; 42: 246-252
        • Agelink M.W.
        • Majewski T.
        • Wurthmann C.
        • Postert T.
        • Linka T.
        • Rotterdam S.
        • et al.
        Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone.
        J Affect Disord. 2001; 62: 187-198
        • Dawood T.
        • Lambert E.A.
        • Barton D.A.
        • Laude D.
        • Elghozi J.L.
        • Esler M.D.
        • et al.
        Specific serotonin reuptake inhibition in major depressive disorder adversely affects novel markers of cardiac risk.
        Hypertens Res. 2007; 30: 285-293
        • Volkers A.C.
        • Tulen J.H.
        • van den Broek W.W.
        • Bruijn J.A.
        • Passchier J.
        • Pepplinkhuizen L.
        Motor activity and autonomic cardiac functioning in major depressive disorder.
        J Affect Disord. 2003; 76: 23-30
        • Lehofer M.
        • Moser M.
        • Hoehn-Saric R.
        • McLeod D.
        • Liebmann P.
        • Drnovsek B.
        • et al.
        Major depression and cardiac autonomic control.
        Biol Psychiatry. 1997; 42: 914-919
        • Sayar K.
        • Gülec H.
        • Gökçe M.
        • Ak I.
        Heart rate variability in depressed patients.
        Bulletin Clin Psychopharmacol. 2002; 12: 130-133
        • Moser M.
        • Lehofer M.
        • Hoehn-Saric R.
        • McLeod D.R.
        • Hildebrandt G.
        • Steinbrenner B.
        • et al.
        Increased heart rate in depressed subjects in spite of unchanged autonomic balance?.
        J Affect Disord. 1998; 48: 115-124
        • Thayer J.F.
        • Smith M.
        • Rossy L.A.
        • Sollers J.J.
        • Friedman B.H.
        Heart period variability and depressive symptoms: gender differences.
        Biol Psychiatry. 1998; 44: 304-306
        • Licht C.M.M.
        • de Geus E.J.C.
        • Zitman F.G.
        • Hoogendijk W.J.G.
        • van Dyck R.
        • Penninx B.W.J.H.
        Association between major depressive disorder and heart rate variability in the Netherlands study of depression and anxiety (NESDA).
        Arch Gen Psychiatry. 2008; 65: 1358-1367
        • Yeragani V.
        • Pesce V.
        • Jayaraman A.
        • Roose S.
        Major depression with ischemic heart disease effects of paroxetine and nortriptyline on long-term heart rate variability measures.
        Biol Psychiatry. 2002; 52: 418-429
        • Lederbogen F.
        • Gernoth C.
        • Weber B.
        • Colla M.
        • Kniest A.
        • Heuser I.
        • et al.
        Antidepressive treatment with amitriptyline and paroxetine: Comparable effects on heart rate variability.
        J Clin Psychopharmacol. 2001; 21: 238-239
        • Tulen J.H.M.
        • Bruijn J.A.
        • de Man K.J.
        • Pepplinkhuizen L.
        • van den Meiracker A.H.
        • ‘t Man V.A.J.
        Cardiovascular variability in major depressive disorder and effects of imipramine or mirtazapine (orig 3770).
        J Clin Psychopharmacol. 1996; 16: 135
        • Richelson E.
        Pharmacology of antidepressants in use in the United States.
        J Clin Psychiatry. 1982; 43: 4
        • Jakobsen J.
        • Hauksson P.
        • Vestergaard P.
        Heart rate variation in patients treated with antidepressants.
        Psychopharmacology. 1984; 84: 544-548
        • Balogh S.
        • Fitzpatrick D.
        • Hendricks S.
        • Paige S.
        Increases in heart rate variability with successful treatment in patients with major depressive disorder.
        Psychopharmacol Bull. 1993; 29: 201
        • Sala M.
        • Lazzaretti M.
        • De Vidovich G.
        • Caverzasi E.
        • Barale F.
        • d'Allio G.
        • et al.
        Electrophysiological changes of cardiac function during antidepressant treatment.
        Ther Adv Cardiovasc Dis. 2009; 3: 29
        • Udupa K.
        • Sathyaprabha T.N.
        • Thirthalli J.
        • Kishore K.R.
        • Raju T.R.
        • Gangadhar B.N.
        Modulation of cardiac autonomic functions in patients with major depression treated with repetitive transcranial magnetic stimulation.
        J Affect Disord. 2007; 104: 231-236
        • Karavidas M.K.
        • Lehrer P.M.
        • Vaschillo E.
        • Vaschillo B.
        • Marin H.
        • Buyske S.
        • et al.
        Preliminary results of an open label study of heart rate variability biofeedback for the treatment of major depression.
        Appl Psychophysiol Biofeedback. 2007; 32: 19-30
        • Carney R.M.
        • Freedland K.E.
        • Stein P.K.
        • Skala J.A.
        • Hoffman P.
        • Jaffe A.S.
        Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease.
        Psychosom Med. 2000; 62: 639-647
        • Nahshoni E.
        • Aizenberg D.
        • Sigler M.
        • Zalsman G.
        • Strasberg B.
        • Imbar S.
        • Weizman A.
        Heart rate variability in elderly patients before and after electroconvulsive therapy.
        Am J Geriatr Psychiatry. 2001; 9: 255-260
        • van Zyl L.
        • Hasegawa T.
        • Nagata K.
        Effects of antidepressant treatment on heart rate variability in major depression: A quantitative review.
        Biospsychosoc Med. 2008; 2: 12
        • Richelson E.
        Synaptic effects of antidepressants.
        J Clin Psychopharmacol. 1996; 16: 1-7
        • Borenstien M.
        • Hedges L.V.
        • Higgins J.
        • Rothstein H.
        Comprehensive Meta-Analysis.
        Biostat, Englewood, New Jersey2000
        • Hedges L.V.
        • Olkin I.
        Statistical Methods for Meta-Analysis.
        Academic Press, Orlando1985
        • Cohen J.
        Set correlation and contingency tables.
        Appl Psych Meas. 1988; 12: 425
        • Shaddish W.R.
        • Haddock C.K.
        Combining estimates of effect size.
        in: Cooper H. Hedges L.V. The Handbook of Research Synthesis. Russel Sage Foundation, New York, NY1994: 261-285
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        • Higgins J.P.T.
        • Thompson S.G.
        • et al.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Egger M.
        • Smith G.D.
        Bias in location and selection of studies.
        BMJ. 1998; 316: 61-66
        • Bruce E.
        • Musselman D.
        Depression, alterations in platelet function, and ischemic heart disease.
        Psychosom Med. 2005; 67: 34-36
        • Agelink M.W.
        • Boz C.
        • Ullrich H.
        • Andrich J.
        Relationship between major depression and heart rate variability.
        Psychiatry Res. 2002; 113: 139-149
        • Davidson J.
        • Watkins L.
        • Owens M.
        • Krulewicz S.
        • Connor K.
        • Carpenter D.
        • et al.
        Effects of paroxetine and venlafaxine XR on heart rate variability in depression.
        J Clin Psychopharmacol. 2005; 25: 480-484
        • Khaykin Y.
        • Dorian P.
        • Baker B.
        • Shapiro C.
        • Sandor P.
        • Mironov D.
        • et al.
        Autonomic correlates of antidepressant treatment using heart-rate variability analysis.
        Can J Psychiatry. 1998; 43: 183-186
        • Post R.M.
        Transduction of psychosocial stress into the neurobiology of recurrent affective disorder.
        Am J Psychiatry. 1992; 149: 999-1010
        • Sauer W.H.
        • Berlin J.A.
        • Kimmel S.E.
        Selective serotonin reuptake inhibitors and myocardial infarction.
        Circulation. 2001; 104: 1894-1898
        • Rechlin T.
        • Claus D.
        • Weis M.
        Heart rate analysis in 24 patients treated with 150 mg amitriptyline per day.
        Psychopharmacology. 1994; 116: 110-114
        • Maestri R.
        • Pinna G.
        • Porta A.
        • Balocchi R.
        • Sassi R.
        • Signorini M.
        • et al.
        Assessing nonlinear properties of heart rate variability from short-term recordings: Are these measurements reliable?.
        Physiol Meas. 2007; 28: 1067-1077
        • de Jonge P.
        • Mangano D.
        • Whooley M.
        Differential association of cognitive and somatic depressive symptoms with heart rate variability in patients with stable coronary heart disease: Findings from the heart and soul study.
        Psychosom Med. 2007; 69: 735-739
        • Appelhans B.
        • Luecken L.
        Heart rate variability as an index of regulated emotional responding.
        Review Gen Psych. 2006; 10: 229-240
        • Porges S.
        The Polyvagal theory: Phylogenetic contributions to social behavior.
        Physiol Behav. 2003; 79: 503-513
        • Porges S.
        The polyvagal perspective.
        Biol Psych. 2007; 74: 116-143
        • Thayer J.
        • Siegle G.
        Neurovisceral integration in cardiac and emotional regulation.
        IEEE Eng Med Biol Mag. 2002; 21: 24-29
        • Shields Jr, R.
        Functional anatomy of the autonomic nervous system.
        J Clin Neurophysiol. 1993; 10: 2
        • Musselman D.
        • Marzec U.
        • Manatunga A.
        • Penna S.
        • Reemsnyder A.
        • Knight B.
        • et al.
        Platelet reactivity in depressed patients treated with paroxetine: Preliminary findings.
        Arch Gen Psychiatry. 2000; 57: 875-882
        • Roose S.
        • Laghrissi-Thode F.
        • Kennedy J.
        • Nelson J.
        • Bigger J.
        • Pollock B.
        • et al.
        Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease.
        JAMA. 1998; 279 (JT): 287-291
        • Markovitz J.
        • Shuster J.
        • Chitwood W.
        • May R.
        • Tolbert L.
        Platelet activation in depression and effects of sertraline treatment: An open-label study.
        Am J Psychiatry. 2000; 157: 1006-1008
        • Glassman A.
        • Bigger J.
        • Gaffney M.
        • Van Zyl L.
        Heart rate variability in acute coronary syndrome patients with major depression: Influence of sertraline and mood improvement.
        Arch Gen Psychiatry. 2007; 64: 1025
        • Watkins L.L.
        • Grossman P.
        • Krishnan R.
        • Blumenthal J.A.
        Anxiety reduces baroreflex cardiac control in older adults with major depression.
        Psychosom Med. 1999; 61: 334-340
        • Rottenberg J.
        • Wilhelm F.H.
        • Gross J.J.
        • Gotlib I.H.
        Respiratory sinus arrhythmia as a predictor of outcome in major depressive disorder.
        J Affect Disord. 2002; 71: 265-272

      Linked Article