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Resting vagal activity in schizophrenia: Meta-analysis of heart rate variability as a potential endophenotype

  • Annika Clamor (a1), Tania M. Lincoln (a1), Julian F. Thayer (a2) and Julian Koenig (a3)

Cardiac vagal tone, indexed by heart rate variability (HRV), is a proxy for the functional integrity of feedback mechanisms integrating central and peripheral physiology.


To quantify differences in HRV in individuals with schizophrenia compared with healthy controls.


Databases were systematically searched for studies eligible for inclusion. Random effect meta-analyses of standardised mean differences were calculated for vagal activity indicated by high-frequency HRV and the root mean square of successive R–R interval differences (RMSSD).


Thirty-four studies were included. Significant main effects were found for high-frequency HRV (P = 0.0008; Hedges' g =–0.98, 95% CI −1.56 to −0.41, k = 29) and RMSSD (P<0.0001; g =–0.91, 95% CI −1.19 to −0.62, k = 24), indicating lower vagal activity in individuals with schizophrenia than in healthy controls. Considerable heterogeneity was evident but effects were robust in subsequent sensitivity analyses.


Given the association between low HRV, threat processing, emotion regulation and executive functioning, reduced vagal tone may be an endophenotype for the development of psychotic symptoms.

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Corresponding author
Annika Clamor, University of Hamburg, Department of Clinical Psychology and Psychotherapy, Von-Melle-Park 5, 20146 Hamburg, Germany. Email:
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This work was supported by a scholarship from the German Academic Exchange Service (DAAD), granted to A.C. for studies at the Department of Psychology, Ohio State University.

Declaration of interest


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1 Nuechterlein, KH, Dawson, ME. A heuristic vulnerability/stress model of schizophrenic episodes. Schizophr Bull 1984; 10: 300–12.
2 Zubin, J, Spring, B. Vulnerability – a new view of schizophrenia. J Abnorm Psychol 1977; 86: 103126.
3 Van Os, J, Kenis, G, Rutten, BPF. The environment and schizophrenia. Nature 2010; 468: 203–12.
4 Thayer, JF, Ahs, F, Fredrikson, M, Sollers, JJ, Wager, TD. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health. Neurosci Biobehav Rev 2012; 36: 747–56.
5 Thayer, JF, Lane, RD. A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord 2000; 61: 201–16.
6 Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 1996; 17: 354–81.
7 Levy, MN. Neural control of cardiac function. Baillieres Clin Neurol 1997; 6: 227–44.
8 Hennekens, CH, Hennekens, AR, Hollar, D, Casey, DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J 2005; 150: 1115–21.
9 Neill, E, Rossell, SL. Executive functioning in schizophrenia: the result of impairments in lower order cognitive skills? Schizophr Res 2013; 150: 7680.
10 Thayer, JF, Hansen, AL, Saus-Rose, E, Johnsen, BH. Heart rate variability, prefrontal neural function, and cognitive performance: the neurovisceral integration perspective on self-regulation, adaptation, and health. Ann Behav Med 2009; 37: 141–53.
11 Hansen, AL, Johnsen, BH, Thayer, JF. Vagal influence on working memory and attention. Int J Psychophysiol 2003; 48: 263–74.
12 Lincoln, TM, Hartmann, M, Kother, U, Moritz, S. Do people with psychosis have specific difficulties regulating emotions? Clin Psychol Psychother 24 Sep 2014 (doi:10.1002/cpp.1923).
13 Jacobson McEwen, SC, Connolly, CG, Kelly, AMC, Kelleher, I, O'Hanlon, E, Clarke, M, et al. Resting-state connectivity deficits associated with impaired inhibitory control in non-treatment-seeking adolescents with psychotic symptoms. Acta Psychiatr Scand 2014; 129: 134–42.
14 Shepherd, AM, Laurens, KR, Matheson, SL, Carr, VJ, Green, MJ. Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia. Neurosci Biobehav Rev 2012; 36: 1342–56.
15 Williams, LM, Das, P, Harris, AWF, Liddell, BB, Brammer, MJ, Olivieri, G, et al. Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. Am J Psychiatry 2004; 161: 480–9.
16 Castro, MN, Vigo, DE, Weidema, H, Fahrer, RD, Chu, EM, de Achaval, D, et al. Heart rate variability response to mental arithmetic stress in patients with schizophrenia. Autonomic response to stress in schizophrenia. Schizophr Res 2008; 99: 294303.
17 Castro, MN, Vigo, DE, Chu, EM, Fahrer, RD, de Achaval, D, Costanzo, EY, et al. Heart rate variability response to mental arithmetic stress is abnormal in first-degree relatives of individuals with schizophrenia. Schizophr Res 2009; 109: 134–40.
18 Bar, KJ, Letzsch, A, Jochum, T, Wagner, G, Greiner, W, Sauer, H. Loss of efferent vagal activity in acute schizophrenia. J Psychiatr Res 2005; 39: 519–27.
19 Bar, KJ, Rachow, T, Schulz, S, Bassarab, K, Haufe, S, Berger, S, et al. The phrenic component of acute schizophrenia – a name and its physiological reality. PLoS One 2012; 7: e33459.
20 Kim, JH, Ann, JH, Lee, J. Relationship between heart rate variability and the severity of psychotic symptoms in schizophrenia. Acta Neuropsychiatr 2011; 23: 161–6.
21 Agelink, MW, Majewski, T, Wurthmann, C, Lukas, K, Ullrich, H, Linka, T, et al. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine. J Clin Psychopharmacol 2001; 21: 813.
22 Valkonen-Korhonen, M, Tarvainen, MP, Ranta-Aho, P, Karjalainen, PA, Partanen, J, Karhu, J, et al. Heart rate variability in acute psychosis. Psychophysiology 2003; 40: 716–26.
23 Zhang, J. Effect of age and sex on heart rate variability in healthy subjects. J Manipulative Physiol Ther 2007; 30: 374–9.
24 Bar, KJ, Wernich, K, Boettger, S, Cordes, J, Boettger, MK, Loffler, S, et al. Relationship between cardiovagal modulation and psychotic state in patients with paranoid schizophrenia. Psychiatry Res 2008; 157: 255–7.
25 Bar, KJ, Boettger, MK, Berger, S, Baier, V, Sauer, H, Yeragani, VK, et al. Decreased baroreflex sensitivity in acute schizophrenia. J Appl Physiol 2007; 102: 1051–6.
26 Lee, K, Park, J, Choi, J, Park, CG. Heart rate variability and metabolic syndrome in hospitalized patients with schizophrenia. J Korean Acad Nurs 2011; 41: 788–94.
27 Moher, D, Liberati, A, Tetzlaff, J, Altman, DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097.
28 Higgins, JPT, Green, S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Cochrane, 2011.
29 Higgins, JPT, Thompson, SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–58.
30 Knapp, G, Hartung, J. Improved tests for a random effects meta-regression with a single covariate. Stat Med 2003; 22: 2693–710.
31 Wallace, BC, Dahabreh, IJ, Trikalinos, TA, Lau, J, Trow, P, Schmid, CH. Closing the gap between methodologists and end-users: R as a computational back-end. J Stat Softw 2012; 49: 115.
32 Agelink, MW, Zeit, T, Baumann, B, Majewski, T, Lemmer, W, Postert, T, et al. In vivo cardiovascular effects of the new atypical neuroleptic sertindole. Int J Psychiatry Clin Pract 2001; 5: 3340.
33 Akar, SA, Kara, S, Latifoglu, F, Bilgic, V. Analysis of heart rate variability during auditory stimulation periods in patients with schizophrenia. J Clin Monit Comput 2015; 29: 153–62.
34 Berger, S, Boettger, MK, Tancer, M, Guinjoan, SM, Yeragani, VK, Bar, KJ. Reduced cardio-respiratory coupling indicates suppression of vagal activity in healthy relatives of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 406–11.
35 Chang, JS, Yoo, CS, Yi, SH, Hong, KH, Oh, HS, Hwang, JY, et al. Differential pattern of heart rate variability in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 991–5.
36 Chang, JS, Yoo, CS, Yi, SH, Hong, KH, Lee, YS, Oh, HS, et al. Changes in heart rate dynamics of patients with schizophrenia treated with risperidone. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 924–9.
37 Chung, MS, Yang, AC, Lin, YC, Lin, CN, Chang, FR, Shen, S, et al. Association of altered cardiac autonomic function with psychopathology and metabolic profiles in schizophrenia. Psychiatry Res 2013; 210: 710–5.
38 Clamor, A, Hartmann, MM, Kother, U, Otte, C, Moritz, S, Lincoln, TM. Altered autonomic arousal in psychosis: an analysis of vulnerability and specificity. Schizophr Res 2014; 154: 73–8.
39 Henry, BL, Minassian, A, Paulus, MP, Geyer, MA, Perry, W. Heart rate variability in bipolar mania and schizophrenia. J Psychiatr Res 2010; 44: 168–76.
40 Jindal, RD, Keshavan, MS, Eklund, K, Stevens, A, Montrose, DM, Yeragani, VK. Beat-to-beat heart rate and QT interval variability in first episode neuroleptic-naive psychosis. Schizophr Res 2009; 113: 176–80.
41 Kim, JH, Yi, SH, Yoo, CS, Yang, SA, Yoon, SC, Lee, KY, et al. Heart rate dynamics and their relationship to psychotic symptom severity in clozapine-treated schizophrenic subjects. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 371–8.
42 Moon, E, Lee, SH, Kim, DH, Hwang, B. Comparative study of heart rate variability in patients with schizophrenia, bipolar disorder, post-traumatic stress disorder, or major depressive disorder. Clin Psychopharmacol Neurosci 2013; 11: 137–43.
43 Mueck-Weymann, M, Rechlin, T, Ehrengut, F, Rauh, R, Acker, J, Dittmann, RW, et al. Effects of olanzapine and clozapine upon pulse rate variability. Depress Anxiety 2002; 16: 93–9.
44 Rachow, T, Berger, S, Boettger, MK, Schulz, S, Guinjoan, S, Yeragani, VK, et al. Nonlinear relationship between electrodermal activity and heart rate variability in patients with acute schizophrenia. Psychophysiology 2011; 48: 1323–32.
45 Boettger, S, Hoyer, D, Falkenhahn, K, Kaatz, M, Yeragani, VK, Bar, KJ. Altered diurnal autonomic variation and reduced vagal information flow in acute schizophrenia. Clin Neurophysiol 2006; 117: 2715–22.
46 Chang, LR, Lin, YH, Kuo, TBJ, Wu Chang, HC, Liu, CM, Liu, CC, et al. Autonomic modulation and health-related quality of life among schizophrenic patients treated with non-intensive case management. PLoS One 2011; 6: e26378.
47 Cohen, H, Loewenthal, U, Matar, M, Kotler, M. Association of autonomic dysfunction and clozapine: heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br J Psychiatry 2001; 179: 167–71.
48 Fujibayashi, M, Matsumoto, T, Kishida, I, Kimura, T, Ishii, C, Ishii, N, et al. Autonomic nervous system activity and psychiatric severity in schizophrenia. Psychiatry Clin Neurosci 2009; 63: 538–45.
49 Hempel, RJ, Tulen, JHM, van Beveren, NJM, Roder, CH, Hengeveld, MW. Cardiovascular variability during treatment with haloperidol, olanzapine or risperidone in recent-onset schizophrenia. J Psychopharmacol 2009; 23: 697707.
50 Ieda, M, Miyaoka, T, Wake, R, Liaury, K, Tsuchie, K, Fukushima, M, et al. Evaluation of autonomic nervous system by salivary alpha-amylase level and heart rate variability in patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci 2014; 264: 83–7.
51 Iwamoto, Y, Kawanishi, C, Kishida, I, Furuno, T, Fujibayashi, M, Ishii, C, et al. Dose-dependent effect of antipsychotic drugs on autonomic nervous system activity in schizophrenia. BMC Psychiatry 2012; 12: 199.
52 Jauregui, OI, Costanzo, EY, de Achaval, D, Villarreal, MF, Chu, E, Mora, MC, et al. Autonomic nervous system activation during social cognition tasks in patients with schizophrenia and their unaffected relatives. Cogn Behav Neurol 2011; 24: 194203.
53 Mathewson, KJ, Jetha, MK, Goldberg, JO, Schmidt, LA. Autonomic regulation predicts performance on Wisconsin Card Sorting Test (WCST) in adults with schizophrenia. Biol Psychol 2012; 91: 389–99.
54 Mujica-Parodi, LR, Yeragani, V, Malaspina, D. Nonlinear complexity and spectral analyses of heart rate variability in medicated and unmedicated patients with schizophrenia. Neuropsychobiology 2005; 51: 10–5.
55 Birkhofer, A, Geissendoerfer, J, Alger, P, Mueller, A, Rentrop, M, Strubel, T, et al. The deceleration capacity – a new measure of heart rate variability evaluated in patients with schizophrenia and antipsychotic treatment. Eur Psychiatry 2013; 28: 81–6.
56 Scholten, MRM, van Honk, J, Aleman, A, Kahn, RS. Behavioral inhibition system (BIS), behavioral activation system (BAS) and schizophrenia: relationship with psychopathology and physiology. J Psychiatr Res 2006; 40: 638–45.
57 Toichi, M, Kubota, Y, Murai, T, Kamio, Y, Sakihama, M, Toriuchi, T, et al. The influence of psychotic states on the autonomic nervous system in schizophrenia. Int J Psychophysiol 1999; 31: 147–54.
58 Pappens, M, Schroijen, M, Sutterlin, S, Smets, E, Van den Bergh, O, Thayer, JF, et al. Resting heart rate variability predicts safety learning and fear extinction in an interoceptive fear conditioning paradigm. PLoS One 2014; 9: e105054.
59 Chalmers, JA, Quintana, DS, Abbott, MJA, Kemp, AH. Anxiety disorders are associated with reduced heart rate variability: a meta-analysis. Front Psychiatry 2014; 5: 80.
60 Kemp, AH, Quintana, DS, Felmingham, KL, Matthews, S, Jelinek, HF. Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk. PLoS One 2012; 7:e30777.
61 Kemp, AH, Quintana, DS, Gray, MA, Felmingham, KL, Brown, K, Gatt, JM. Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis. Biol Psychiatry 2010; 67: 1067–74.
62 Kemp, AH, Quintana, DS. The relationship between mental and physical health: insights from the study of heart rate variability. Int J Psychophysiol 2013; 89: 288–96.
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Resting vagal activity in schizophrenia: Meta-analysis of heart rate variability as a potential endophenotype

  • Annika Clamor (a1), Tania M. Lincoln (a1), Julian F. Thayer (a2) and Julian Koenig (a3)
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