Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis

Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis

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J Psychiatry Neurosci 2016;41(2):89-104

Gail A. Alvares, PhD; Daniel S. Quintana, PhD; Ian B. Hickie, MBBS, FRANZCP; Adam J. Guastella, PhD


Background: Autonomic nervous system (ANS) dysfunction is a putative underlying mechanism for increased cardiovascular disease risk in individuals with psychiatric disorders. Previous studies suggest that this risk may be related to psychotropic medication use. In the present study we systematically reviewed and analyzed published studies of heart rate variability (HRV), measuring ANS output, to determine the effect of psychiatric illness and medication use.

Methods: We searched for studies comparing HRV in physically healthy adults with a diagnosed psychiatric disorder to controls and comparing HRV pre- and post-treatment with a psychotropic medication.

Results: In total, 140 case–control (mood, anxiety, psychosis, dependent disorders, k = 151) and 30 treatment (antidepressants, antipsychotics; k = 43) studies were included. We found that HRV was reduced in all patient groups compared to controls (Hedges g = –0.583) with a large effect for psychotic disorders (Hedges g = –0.948). Effect sizes remained highly significant for medication-free patients compared to controls across all disorders. Smaller and significant reductions in HRV were observed for specific antidepressants and antipsychotics.

Limitations: Study quality significantly moderated effect sizes in case–control analyses, underscoring the importance of assessing methodological quality when interpreting HRV findings.

Conclusion: Combined findings confirm substantial reductions in HRV across psychiatric disorders, and these effects remained significant even in medication-free individuals. Reductions in HRV may therefore represent a significant mechanism contributing to elevated cardiovascular risk in individuals with psychiatric disorders. The negative impact of specific medications on HRV suggest increased risk for cardiovascular disease in these groups, highlighting a need for treatment providers to consider modifiable cardiovascular risk factors to attenuate this risk.

Submitted Aug. 6, 2014; Revised June 6, 2015; Accepted June 24, 2015; Early-released Oct. 8, 2015

Acknowledgements: The authors thank Melissa Warshavsky for her assistance in data retrieval and quality assessment ratings, Anne Masi for statistical advice and Yu Sun Bin for critical assessment of the final manuscript. This work was supported by an Australian Research Council Linkage Grant (LP110100513) and a National Health and Medical Research Council Career Development Fellowship (1061922) to A.J. Guastella and an Australia Fellowship (494914) to I.B. Hickie. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Affiliations: From the Brain & Mind Centre, University of Sydney, Sydney, Australia (Alvares, Quintana, Hickie, Guastella); the Telethon Kids Institute, The University of Western Australia, Perth, Australia (Alvares); the NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (Quintana); and the Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (Quintana).

Competing interests:
I.B. Hickie is a Senior Principal Research Fellow of the Australian National Health & Medical Research Council (1046899). He is the executive director of the Brain and Mind Research Institute (BMRI) at the University of Sydney, which operates 2 early-intervention youth services under contract to headspace. He is a commissioner of the Australian National Mental Health commission and was previously the CEO of beyondblue: the national depression initiative and a director of headspace: the national youth mental health foundation until January 2012. Previously, he has led a range of community-based and pharmaceutical industrysupported depression awareness and education and training programs. He has led depression and other mental health research service evaluation or investigator-initiated research projects that have been supported by a variety of pharmaceutical partners. Current investigator-initiated studies are supported by Servier (manufacturers of agomelatine) and Pfizer. He has received honoraria for his contributions to professional educational seminars related to depression, youth mental health and circadian rhythms research. He has received travel support from Servier to attend scientific meetings related specifically to circadian-rhythm disorders. No other competing interests declared.

All authors designed the study. G. Alvares and D. Quintana acquired the data, which all authors analyzed. G. Alvares wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.140217

Correspondence to: A.J. Guastella, Brain & Mind Centre, University of Sydney, 94 Mallett St, Camperdown NSW Australia;