Heart rate variability and vagal tone in schizophrenia: A review

Journal of Psychiatric Research 69 (2015) 57e66

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Review

Heart rate variability and vagal tone in schizophrenia: A review Julian M. Montaquila, Benjamin J. Trachik, Jeffrey S. Bedwell* Department of Psychology, University of Central Florida, 4111 Pictor Lane, Orlando, FL, 32816, United States

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 December 2014 Received in revised form 14 July 2015 Accepted 23 July 2015

Recent heart rate variability (HRV) research has identified diminished levels of parasympathetic activity among schizophrenia patients. Over two dozen empirically-based studies have been published on this topic; primarily over the last decade. However, no theoretical review appears to have been published on this work. Further, only one empirical study has evaluated HRV research findings in the context of documented hypothalamic-pituitary-adrenal axis hyperactivity in schizophrenia. HRV research indicates that no abnormalities exist in the initial sympathetic stress response of schizophrenia patients. However, evidence has consistently demonstrated that patients exhibit a diminished capacity to recover from a stress response as a result of deficits in parasympathetic activity. Moreover, this diminished parasympathetic nervous system (PNS) response, also known as decreased vagal tone, has been found to relate to increased symptom severity. Although these findings may cause speculation that the observed vagal tone disruption merely results from anxiety produced by the presence of positive symptomology, additional studies have identified similar parasympathetic dysfunction among nonpsychotic relatives of individuals with schizophrenia. We posit that the resulting sympathovagal imbalance leads to an overall sympathetic dominance despite the fact that sympathetic nervous system activity is not abnormally elevated among patients. Implications are discussed within the context of the diathesis-stress/ vulnerability-stress model, including the potential for identifying a mechanism of action by which environmental stressors may contribute to triggering first-episode psychosis. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Heart rate variability Vagal tone Schizophrenia Autonomic nervous system Heritability Stress sensitivity

1. Introduction 1.1. Stress sensitivity and the HPA-axis The current consensus of the literature suggests that both stress sensitivity (i.e., typical reactivity to life stressors) and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity are commonly found among individuals with schizophrenia (Aiello et al., 2012; Walker et al., 2001, 2010, 2013). Some evidence has also surfaced identifying the presence of elevated stress sensitivity, elevated production of adrenocorticotropic hormone (ACTH; the hormone responsible for stimulating cortisol production), and altered neurological structures of the pituitary gland and hippocampus among relatives of schizophrenia patients (Aiello et al., 2012). It has also been hypothesized that disease onset may be catalyzed when individuals vulnerable to developing schizophrenia are placed under sufficient stress (Zubin and Steinhauer, 1981).

* Corresponding author. Department of Psychology, University of Central Florida, 4111 Pictor Lane, Orlando, FL, 32816-1390, USA. E-mail address: [email protected] (J.S. Bedwell). http://dx.doi.org/10.1016/j.jpsychires.2015.07.025 0022-3956/© 2015 Elsevier Ltd. All rights reserved.

Specifically, Walker et al. (2010, 2013) suggest that elevated cortisol secretion and stress sensitivity may be associated with subsequent development of schizophrenia following the prodromal phase of the illness. If environmental stress exposure is linked to illness onset, especially during key developmental periods (Walker et al., 2001, 2010), then central nervous system (CNS) HPA-axis dysfunction should be present in schizophrenia. In support of this HPA-axis dysfunction, for over 30 years, researchers have identified high concentrations of cortisol present in schizophrenia samples (Coppen et al., 1983; Tandon et al., 1991; Walker et al., 2013). These findings, coupled with documented evidence of diminished hippocampal volume, further highlight the mediating role of the HPAaxis functioning between environmental stressors and psychiatric illness (Stansbury and Gunnar, 1994; Walker and Diforio, 1997). Specifically, it appears that increases in cortisol may sensitize or increase dopaminergic activity in the mesolimbic pathway, leading to greater symptom severity in individuals with schizophrenia (Walker and Diforio, 1997; Walker et al., 2001, 2008). Furthermore, it appears that extremely stressful events such as prenatal complications, or chronically stressful events such as substance abuse (Dean and Murray, 2005), may disrupt the course of neural

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plasticity development of the HPA-axis (Aiello et al., 2012). However, more recent evidence suggests that HPA-axis abnormalities in severe mental illness may be independent of stressful life events (Mondelli et al., 2010) and instead serve as a unique indication of individuals on the path to psychosis (Aiello et al., 2012) or as a biomarker for psychosis conversion (Walker et al., 2013; Steen et al., 2011). 1.2. Cardiac autonomic control in schizophrenia Increased complexity in heart rate fluctuations is indicative of stronger cardiac adaptability (Bӓr, Boettger, Koschke et al., 2007; Chang et al., 2009; Mujica-Parodi et al., 2005). However, cardiac autonomic dysregulation and reduced complexity of heart rate modulation have been found in patients with schizophrenia (Bӓr, Boettger et al., 2008; Birkhofer et al., 2013; Bӓr, Boettger, Koschke et al., 2007; Boettger et al., 2006; Chang et al., 2009; Kim et al., 2004; Lee et al., 2011). Thus, a pattern of reduced complexity in heart rate fluctuations in schizophrenia suggests that these individuals experience difficulty in adapting their heart rate in response to environmental stimuli (Bӓr, Boettger, Koschke et al., 2007; Chang et al., 2009). Although previous studies identifying elevated levels of resting skin conductance response or elevated cortisol levels suggest that heightened sympathetic activation may represent a concomitant of schizophrenia (Zahn et al., 1979, 1997; Walker et al., 2010, 2013), the majority of these methods are limited in scope in that they did not also incorporate a corresponding measure of parasympathetic activation. Berntson et al. (2008) note that contemporary understanding of autonomic nervous system (ANS) balance indicates that it is driven by both sympathetic and parasympathetic activity and that the overall resulting balance may result from combinations of both ANS branches, such as reciprocal sympathetic control, reciprocal parasympathetic control, co-inhibition, and co-activation. Thus, relative sympathetic and parasympathetic contributions to overall autonomic balance vary individually and do not always operate in complete reciprocal control of one another (Berntson et al., 2008). Through the use of pupillometry, previous studies have been able to examine parasympathetic function in the context of schizophrenia. Specifically, Spohn & Patterson (1979) identified “sluggish” parasympathetic function among schizophrenia patients. Further, Rubin (1974) discussed findings in which schizophrenia patients experienced difficulty exerting appropriate reciprocal parasympathetic control following stress cessation and throughout the restitution period. As cholinergic activity has been previously identified as being associated with the PNS (Rubin, 1974), research into this neurotransmitter system has also elucidated information suggesting parasympathetic dysfunction in schizophrenia. Singh and Kay (1985) noted reductions in cholinergic activity among schizophrenia patients, while Tandon and Greden (1989) hypothesized that the cholinergic system may serve as a protective mechanism against positive symptom expression associated with dopaminergic hyperactivity in individuals susceptible to schizophrenia development. Moreover, it was suggested that such an increase in cholinergic activity may be indicative of a better prognosis and recovery from a psychotic episode (Tandon and Greden, 1989; Tandon et al., 1991), while other evidence has also shown that psychotic symptoms become exacerbated when anticholinergic drugs are used to address side effects in schizophrenia patients treated with first-generation antipsychotics (Raedler et al., 2007). Given the mounting evidence that individuals with schizophrenia may be at an elevated risk of stress sensitivity, a review of relevant literature is needed to afford researchers and clinicians insight into the specific mechanisms through which patients react to environmental stressors.

The notions that schizophrenia patients exhibit difficulty regulating autonomic homeostasis (Rubin, 1974; Venables, 1964), or that either hypoactivity or hyperactivity of the ANS may be associated with the disease, are not new concepts (Rubin, 1974). However, HRV has emerged as a somewhat novel method for examining autonomic balance (Berntson et al., 2008). Recent research employing HRV spectral analyses have extended the findings of previous research by further examining the components and characteristics of ANS dysfunction and stress sensitivity in the context of schizophrenia. Specifically, this psychophysiological measure adds another dimension to the findings of previous research in that information derived from HRV can provide separate metrics of sympathetic and parasympathetic activity. Berntson et al. (2008) note that in such analyses, high frequency (HF) HRV represents a marker of parasympathetic activity, while low frequency (LF) HRV is a composition of both parasympathetic and sympathetic activity. Thus, the LF/HF ratio is commonly utilized as an estimate of sympathovagal balance in research employing HRV analyses (Berntson et al., 2008). One such study in individuals with schizophreniaspectrum disorders revealed a bimodal split, whereby more than half of the patients exhibited vagal tone deficits as compared to the remaining patients, which was related to receiving a diagnosis of schizophrenia rather than schizoaffective disorder, as well as to a later age of schizophrenia onset (Malaspina et al., 1997). Later studies again examined ANS dysfunction in the context of psychosis and schizophrenia through HRV data analyses, and findings specifically demonstrated that reduced parasympathetic activity, also referred to as diminished vagal tone or decreased parasympathetic modulation, was observed among schizophrenia patients (Akar et al., 2015; Bӓr et al., 2005; Bӓr, Boettger, Berger et al., 2007; Bӓr, Boettger et al., 2008; Bӓr, Wernich et al., 2008; Berger et al., 2010; Boettger et al., 2006; Castro et al., 2008; Fujibayashi et al., 2009; Ieda et al., 2014; Iwamoto et al., 2012; Khandoker et al., 2010; Mathewson et al., 2012; Moon et al., 2013; Mujica-Parodi et al., 2005; Toichi et al., 1999; Valkonen-Korhonen et al., 2003). An overview of HRV and vagal tone findings within schizophrenia samples is presented in Table 1. 2. Nature of the sympathovagal imbalance in schizophrenia As diminished vagal tone has been clearly implicated in the overwhelming majority of research that has examined HRV data in the context of schizophrenia, the next natural question focuses upon the potential role that sympathetic activity may play in the overall ANS imbalance. Results from several studies that collected HRV data from schizophrenia patients suggest that the ANS imbalance in question is more likely a result of diminished parasympathetic rather than elevated sympathetic activity (Bӓr, Boettger, Berger et al., 2007). Findings from Bӓr, Boettger et al. (2008), Bӓr, Koschke et al. (2007), and Ieda et al. (2014) expand upon previous research by providing evidence that poor parasympathetic modulation is accompanied by relative sympathetic nervous system (SNS) dominance. In another study, Bӓr, Wernich et al. (2008) failed to identify any HRV indicators of sympathetic modulation in patients that significantly differed from that of control subjects. The interpretation made by Bӓr, Wernich et al. (2008) was that the observed SNS dominance in schizophrenia results from a relatively normal level of SNS activity that becomes dominant due to a lack of a normal level of inhibition from the parasympathetic nervous system (PNS). Thus, a potential factor contributing to the observed diminished complexity of cardiac modulation in schizophrenia is decreased vagal modulation; thereby, resulting in increased sympathetic cardiac influence (Bӓr, Boettger, Koschke et al., 2007). Castro et al. (2008) provided supportive evidence for this theory.

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Table 1 HRV and vagal tone findings among individuals with schizophrenia and first-degree relatives, as compared to healthy controls. Study

SCZ vs. HC

SCZ, n ¼ 19 HC, n ¼ 20 B€ ar et al. (2005) SCZ, n ¼ 30 HC, n ¼ 30 B€ ar, Boettger, Berger SCZ, n ¼ 21 et al. (2007) HC, n ¼ 21 B€ ar, Boettger, Koschke SCZ, n ¼ 20 et al. (2007) HC, n ¼ 20 ar, Koschke SCZ, n ¼ 25 B€ et al. (2007) HC, n ¼ 25 €r et al. (2008) Ba SCZ, n ¼ 28 HC, n ¼ 28 Akar et al. (2015)

B€ ar et al. (2008)

SCZ, n ¼ 40 HC, n ¼ 58 Birkhofer et al. (2013) SCZ, n ¼ 20 SCZ, n ¼ 40 HC, n ¼ 40 Boettger et al. (2006) SCZ, n ¼ 20 HC, n ¼ 20 SCZ, n ¼ 25 Castro et al. (2008) b HC, n ¼ 25 Chang et al. (2009) SCZ, n ¼ 30 HC, n ¼ 30 Chang et al. (2010) SCZ, n ¼ 16 HC, n ¼ 16 Chung et al. (2013) SCZ, n ¼ 94 HC, n ¼ 51 SCZ, n ¼ 71 Fujibayashi et al. (2009) HC, n ¼ 71 Henry et al. (2010) SCZ, n ¼ 14 HC, n ¼ 23 Ieda et al. (2014) SCZ, n ¼ 25 HC, n ¼ 25 Iwamoto et al. (2012) SCZ, n ¼ 211 HC, n ¼ 44 Kim et al. (2004) SCZ, n ¼ 50 HC, n ¼ 50 SCZLG, n ¼ 32 Khandoker c SCZHG, n ¼ 32 et al. (2010) HC, n ¼ 118 Lee et al. (2011) SCZ, n ¼ 308 HC, n ¼ 719 Mathewson SCZ, n ¼ 40 et al. (2012) HC, n ¼ 28

Moon et al. (2013) Mujica-Parodi et al. (2005) Peupelmann et al. (2009) Rechlin et al. (1994) Toichi et al. (1999) Valkonen-Korhonen et al. (2003)

Study

B€ ar et al. (2009)

SCZ, n ¼ 35 HC, n ¼ 27 SCZ, n ¼ 19 HC, n ¼ 24 SCZ, n ¼ 25 HC, n ¼ 25 SCZ, n ¼ 20 HC, n ¼ 20 SCZ, n ¼ 53 HC, n ¼ 53 SCZ, n ¼ 17 HC, n ¼ 21

SCZ vs. HC vs. FDR

Measure(s) of symptom severity

Antipsychotic medication LF

Not specified

e

Not specified

SCZ ¼ HC

SCZ < HC SCZ > HC

SCZ < HC

Acute, n ¼ 30

SAPS SANS SAPS SANS SAPS SANS SAPS SANS SAPS SANS PANSS BPRS

Unmedicated

SCZ ¼ HC

SCZ < HC e

SCZ < HC

Unmedicated

e

e

SCZ ¼ HC

SCZ < HC

Unmedicated

e

e

e

SCZ < HC

Unmedicated

e

e

e

SCZ < HC

Unmedicated

SCZ > HC SCZ < HC e

SCZ < HC

Unmedicated

SCZ ¼ HC

SCZ < HC SCZ > HC

SCZ < HC

Unmedicated, n ¼ 20 Medicated, n ¼ 50

e

e

e

SCZ ¼ HC

Acute, n ¼ 13 FEP, n ¼ 8 Acute, n ¼ 20 Acute, n ¼ 25 FEP, n ¼ 9

Not specified Not specified

HF

LF/HF ratio

Vagal tone findinga

Stage of illness

Unmedicated

SCZ ¼ HC

SCZ ¼ HC

e

SCZ < HC

Not specified

BPRS CGI ESI SAPS SANS PANSS

Unmedicated

e

e

e

e

Not specified

PANSS

Unmedicated

SCZ ¼ HC

SCZ < HC SCZ > HC

SCZ < HC

Acute, n ¼ 16

PANSS CGI-S PANSS GAF GAF

Medicated

SCZ ¼ HC

SCZ < HC SCZ > HC

SCZ < HC

Medicated

SCZ < HC SCZ < HC SCZ ¼ HC

SCZ < HC

Unmedicated

SCZ < HC SCZ < HC e

SCZ < HC

Medicated

SCZ ¼ HC

SCZ ¼ HC

SCZ ¼ HC

SCZ ¼ HC

SCZ < HC e

SCZ < HC SCZ < HC SCZ ¼ HC

SCZ < HC

SCZ < HC SCZ < HC e

SCZ < HC

Acute, n ¼ 20

Chronic, n ¼ 94 Not specified Not specified Not specified

BPRS YMRS BPRS

Not specified

GAF

Medicated, n ¼ 23 Unmedicated, n ¼ 2 Medicated

Not specified

PANSS

Medicated

SCZ ¼ HC

SCZ < HC

LG

e

e

Medicated

SCZ > HC SCZ < HC SCZHG ¼ HC SCZLG ¼ SCZHG SCZ > HC SCZ > HC SCZ ¼ HC e

WCST Paranoid, n ¼ 26 PANSS Schizoaffective Disorder, n ¼ 5 Residual Type, n ¼ 7 Disorganized Type, n ¼ 1 Undifferentiated Type, n ¼ 1 Not specified e

Medicated, n ¼ 40

e

e

Medicated

SCZ ¼ HC

SCZ < HC SCZ ¼ HC

SCZ < HC

Not specified

PANSS

Medicated, n ¼ 10

SCZ < HC SCZ < HC SCZ ¼ HC

SCZ < HC

Paranoid, n ¼ 25

SAPS SANS PANSS e

Unmedicated

e

e

SCZ ¼ HC

SCZ < HC

Unmedicated

SCZ ¼ HC

SCZ ¼ HC

e

SCZ ¼ HC

PANSS

Medicated

e

e

e

SCZ < HC

FEP, n ¼ 17

SCID PANSS WCST

Unmedicated

SCZ ¼ HC

SCZ < HC e

SCZ < HC

Stage of illness

Measure(s) Antipsychotic medication LF of symptom severity

HF

Vagal tone findinga

Paranoid, n ¼ 36

SCID SCID II

Not specified

GAF

Not Specified

Not specified

e

Paranoid, n ¼ 20 FEP, n ¼ 10 Chronic, n ¼ 53

Unmedicated, n ¼ 16 Medicated, n ¼ 27

e

e

SCZ < HC

LF/HF ratio

e (continued on next page)

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Table 1 (continued ) Study

SCZ vs. HC

B€ ar et al. (2012)

Berger et al. (2010)

Castro et al. (2009)

b

J auregui et al. (2011)

d

SCZ, n ¼ 36 HC, n ¼ 36 FDR, n ¼ 36 SCZ, n ¼ 23 HC, n ¼ 30 FDR, n ¼ 20 SCZ, n ¼ 19 HC, n ¼ 19 FDR, n ¼ 19 HC, n ¼ 22 FDR, n ¼ 22 SCZ, n ¼ 19 HC, n ¼ 19 FDR, n ¼ 19

Stage of illness

Measure(s) of symptom severity

Antipsychotic medication LF

FEP, n ¼ 8 PANSS Not specified, n ¼ 15 SANS SAPS FEP, n ¼ 8 PANSS

Unmedicated

e

e

Unmedicated

Not specified

PANSS

Unmedicated

Unmedicated

SCZ < HC FDR < HC SCZ ¼ FDR SCZ ¼ HC FDR ¼ HC SCZ ¼ FDR e

HF

LF/HF ratio

SCZ > HC FDR ¼ HC SCZ > FDR SCZ < HC e FDR < HC SCZ ¼ FDR SCZ ¼ HC e FDR ¼ HC SCZ ¼ FDR e e

SCZ < HC SCZ < HC e FDR ¼ HC FDR < HC

Vagal tone findinga

SCZ < HC FDR ¼ HC SCZ < FDR e

SCZ < HC FDR < HC SCZ ¼ FDR e SCZ < HC FDR < HC

Abbreviations:SCZ, Schizophrenia patients; HC, Healthy controls; FDR, First-degree relatives; LF, Low frequency; HF, High frequency; FEP, First-episode psychosis; BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; CGI-S, Clinical Global Impressions e Severity of Illness Scale; EPI, Eppendorf Schizophrenia Inventory; PANSS, Positive and negative syndrome scale; SAPS, scale for the assessment of positive symptoms; SANS, scale for the assessment of negative symptoms; SCID, Structural Clinical Interview for DSM-IV Axis-I Diagnosis; SCID-II, Structured Clinical Interview for DSM-IV Axis-II Personality Disorders; YMRS, Young Mania Rating Scale. a Vagal tone finding: Description of parasympathetic activity which may include parasympathetic markers other than HF (e.g., cross-ApEn, ApEn, RMSSD, SampEn, ToneEntropy) or the LF/HF ratio. b Castro et al. (2008, 2009): LF and HF contributions were measured across three conditions, (1) baseline, (2) mental arithmetic stress task, and (3) post-task HRV. Resting ANS functioning in SCZ and FDR was comparable to that of HC; however, a pattern of protracted stress response was identified among SCZ and FDR that was significantly different than that of HC. Results from FDR was similar (although less severe) than that previously found among SCZ. c Khandoker et al. (2010): SCZLG and SCZHG distinguish between low-GAF and high-GAF scoring participants. d  Jauregui et al. (2011): Descriptions of LF and HF contributions were indicative of changes measured between baseline and a social cognition task.

Namely, schizophrenia patients and nonpsychiatric controls were given an arithmetic stress task while HRV data was recorded. While both groups exhibited similar responses during the stress task, individuals with schizophrenia demonstrated deficits in baseline uregui et al. (2011), and were unable HRV, a finding replicated by Ja to recover their resting pattern of HRV following task cessation. More specifically, patients (relative to controls) exhibited prolonged ANS activity levels distinguished by decreased PNS and elevated SNS activity across the task recovery period (Castro et al., 2008). These results are consistent with research that assessed the skin conductance response (SCR) and skin conductance level (SCL) among schizophrenia samples. While Zahn et al. (1997) found that childhood-onset schizophrenia patients exhibited elevated SCRs during rest as compared to control participants; the additional finding that patients produced more erratic habituation responses is consistent with results from Castro et al. (2008). Specifically, the control participants showed a rapid decrease in SCLs during the rest period, but the patients did not show this expected SCL decrease (Zahn et al., 1997). Another study asked individuals with schizophrenia and nonpsychiatric controls to view positively-, negatively, and neutrally-valenced images while being evaluated with several different physiological measurements (Hempel et al., 2005). As the groups did not differ on measures of SCL and blood pressure, the authors theorized that deficits in PNS activity were likely responsible for the observed changes in HR relative to the images presented. Thus, the findings of Castro et al. (2008) in conjunction with other research examining diminished vagal tone among schizophrenia patients suggests that patients likely exhibit an initially “normal” sympathetic stress response, but thereafter experience difficulty recovering from the stress inducing event which subsequently leads to the maintenance of a sympathovagal imbalance characterized by an overall elevated state of sympathetic arousal and decreased parasympathetic activity. Additional HRV research assessing response to auditory stimulation produced similar results; whereby, unlike controls, individuals with schizophrenia failed to exhibit the normal expected decrease in LF HRV in the rest period following auditory stimulation (Akar et al., 2015). Interestingly, this pattern of reduced vagal tone may not be specific to

schizophrenia, as depressed HRV and vagal tone have also been found among individuals with bipolar disorder (Moon et al., 2013). Although Moon et al. (2013) failed to identify the precise pattern of sympathovagal imbalance previously found among schizophrenia samples, another study did in fact identify a pattern of sympathovagal imbalance among bipolar disorder patients that was characteristic of sympathetic dominance resulting from diminished parasympathetic activity (Henry et al., 2010). In comparison to data simultaneously collected from a schizophrenia sample, the authors of the latter study theorized that the mechanism underlying ANS disruption was the same for both schizophrenia and bipolar disorder patients. The question has been posed as to whether observed parasympathetic tone deficits in schizophrenia patients are accompanied by sympathetic hyperactivity (Bӓr et al., 2005). In finding that the LF HRV remained unaltered among their patient group, Bӓr et al. (2005) failed to identify any evidence of accompanying sympathetic hyperactivity. Similarly, Toichi et al. (1999) found an inverse relationship between parasympathetic tone and psychotic state severity, whereby parasympathetic tone decreased as psychotic state severity increased, while no change was observed in SNS activity over the course of the 8-week study period. These results were again later replicated by Moon et al. (2013), as schizophrenia patients exhibited reduced PNS activity relative to nonpsychiatric controls, while no difference was observed for LF HRV. Although HRV analyses were not employed, Hempel et al. (2007) found that, unlike controls, heart rate (HR) deceleration was not observed when individuals with schizophrenia oriented to newly presented images with emotionally laden content. However, patient HR responses demonstrated a positive relationship with subjective assessments of both image valence and image arousal level. This finding, coupled with the fact that patients did not differ from controls in skin conductance or systolic blood pressure responses (both known to be predominately influenced by the SNS), suggested that observed differences in HR response between groups might have resulted from PNS modulation alone. Bӓr et al. (2009) shed additional light on the dynamics of the hypothesized sympathovagal imbalance in schizophrenia while

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attempting to explore the potential heritability of autonomic dysfunction by examining HRV data across patients, their firstdegree relatives, and nonpsychiatric matched controls. During this study, simultaneous measurements of HRV, blood pressure variability, baroreflex sensitivity, and QT variability were collected from all participants. Neither patients nor their first-degree relatives were found to exhibit blood pressure variability significantly different from that of controls. The authors ultimately suggested the non-significance of blood pressure variability was indicative of a genetic cardiovascular phenotype specific to the PNS versus the SNS, as well as that diminished heart rate complexity and HRV were likely the primary pathophysiological abnormalities of interest. Finally, a study conducted by Ieda et al. (2014) identified diminished parasympathetic activity within a schizophrenia sample, but failed to identify any differences in SNS activity between individuals with schizophrenia and non-psychotic controls. However, a unique aspect of the study was the measurement of salivary alpha-amylase (sAA) as an additional marker of ANS performance, and the patient group was identified as having a significantly elevated sAA levels as compared to controls. Ieda et al. (2014) concluded that the observed relative elevation in SNS activity resulted from parasympathetic activity suppression, and the subsequent sympathovagal imbalance ultimately contributed to elevated sAA levels identified in the patient group. Thus, these findings appear to support those of Castro et al. (2008), and suggest that the diminished capacity of schizophrenia patients to recover from stress inducing events ultimately leads to dominant state of sympathetic arousal despite the fact that these patients exhibit an initially “normal” sympathetic stress response. Further, findings from Ieda et al. (2014) demonstrate how vagal tone deficits may contribute to observations of HPA-axis hyperactivity in research employing cortisol-sampling procedures across schizophrenia patients. 2.1. Contradictory findings Only findings from a relatively few number of studies have been at odds with the aforementioned conclusions. In a critical examination of research findings most contradictory with the aforementioned conclusions, the work of Lee et al. (2011) is most notable. While this study did identify poorer cardiac autonomic control among schizophrenia patients that is consistent with the findings of previous research, the LF and HF markers of sympathetic and parasympathetic activity were not consistent with the previously described sympathovagal imbalance in schizophrenia. Specifically, schizophrenia patients examined by Lee et al. (2011) demonstrated significantly elevated values of both LF and HF HRV. Although the authors reported that they did not attempt to control for the effect of antipsychotic medication as being a major study limitation, the large sample size of 308 schizophrenia patients nevertheless remains a distinct advantage in its comparison with other similar HRV studies. In addition, research conducted by Birkhofer et al. (2013) failed to replicate previous findings of diminished vagal tone among patients with schizophrenia. Further, Rechlin et al. (1994) found that unmedicated paranoid schizophrenia patients exhibited “normal” HRV; however, spectral analyses displaying particularly elevated sympathetic activity were noted as being unusual. Similarly, Henry et al. (2010) identified a non-significant pattern of depressed HRV among individuals with schizophrenia. However, low sample size and the heterogeneity of schizophrenia subtypes included in the study were cited as possible limitations. Thus, Henry et al. (2010) indicated that their findings were supportive of previous research identifying diminished HRV and parasympathetic activity among uregui et al. (2011) reported schizophrenia samples. Finally, Ja

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somewhat mixed findings among HRV data collected from patients. Namely, social cognition tasks were found to decrease both parasympathetic and sympathetic activity among patients. Using social cognitive tasks as the experimental stressor may have placed the study at odds with other research that employed more generic stress inducing stimuli. HRV data also could have been obscured by the fact that all patients were taking medication at the time of the study. Furthermore, the testing session design represented another deviation from previous research in that it did not incorporate a baseline or recovery phase during HRV data collection. Still, uregui et al. (2011) concluded that the results provide additional Ja evidence of ANS dysfunction within schizophrenia. 3. Vagal tone deficits among first-degree relatives of schizophrenia patients While HRV data analyses in schizophrenia samples have shed light on disease pathophysiology, several questions linger. In particular, initial findings do not discriminate as to whether depressed vagal tone is truly representative of the underlying risk for schizophrenia or whether stress and anxiety produced by the experience of psychotic symptoms ultimately cause ANS disruption. To address this question, several studies have evaluated HRV from unaffected first-degree relatives of schizophrenia patients. Some research has identified diminished HRV among individuals with schizophrenia and first-degree relatives in comparison to nonpsychiatric controls (Bӓr et al., 2012), while other research has specifically identified decreased vagal modulation in both sample populations relative to nonpsychiatric controls (Berger et al., 2010; uregui et al., 2011). Berger et al. (2010) also specified that no form Ja of psychopathology was present among first-degree relatives evaluated in their study. Findings from other studies have gone a step further and identified an attenuation effect between schizophrenia samples and first-degree relatives, whereby, relatives show a similar, but less pronounced, deficit in parasympathetic activity as €r et al., 2009; Castro et al., 2009). Further, compared to patients (Ba Castro et al. (2009) identified a pattern of protracted stress response among first-degree relatives that was similar but less severe than that previously found among schizophrenia samples. Likewise, comparisons between offspring and siblings of individuals with schizophrenia have shown vagal tone deficits to be more pronounced in offspring (Bӓr et al., 2009). Also noteworthy was the finding that resting ANS functioning in first-degree relatives was comparable to that of controls (Castro et al., 2009), while patients had exhibited abnormalities in resting ANS functioning relative to nonpsychiatric controls (Castro et al., 2008). Overall, these findings in first-degree relatives support the theory that diminished vagal tone may actually be characteristic of those susceptible to developing schizophrenia rather than just the mere result of chronic stress. An overview of HRV and vagal tone findings among first-degree relatives of schizophrenia patients is provided in Table 1. 4. Relationships between HRV and schizophrenia symptom severity Additionally, the question has been posed as to whether the relationship between ANS dysfunction and psychotic symptom severity may be state- or dose-dependent. Some research has suggested that increased disease duration is associated with depressed parasympathetic activity (Bӓr et al., 2005). However, not all studies have replicated these findings (Iwamoto et al., 2012; Kim et al., 2004). In one early study evaluating autonomic and psychophysiological variables related to clinical improvement in schizophrenia, patients were assessed on several measures of HR

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and SCR at admission and again at discharge following a threemonth intensive treatment period. Patients deemed “improved” displayed only moderate elevations in ANS arousal at admission, which subsequently dropped to normal or below levels of ANS arousal by the time of discharge (Zahn et al., 1979). Patients deemed “not improved” exhibited elevated ANS arousal at both admission and discharge. One study found a relationship between several HRV parameters and scores on the Positive and Negative Syndrome Scale in a sample of individuals suffering from either schizophrenia or other psychotic disorders (PANSS; Valkonen-Korhonen et al., 2003). Additional research identified an inverse relationship between PANSS scores and parasympathetic activity, whereby schizophrenia patients with higher PANSS scores displayed lower levels of parasympathetic activity (Okada et al., 2003; Toichi et al., 1999). Okada et al. (2003) and Toichi et al. (1999) further specified that SNS activity showed no change in response to fluctuations in psychotic symptom severity, findings which corroborate evidence that SNS activity in schizophrenia is not actually hyperactive. Significant negative correlations have also been found between sample entropy (an HRV complexity measure) and PANSS ratings (Kim et al., 2004). In addition, Chung et al. (2013) and Mathewson et al. (2012) utilized the PANSS and identified parasympathetic activity level as being inversely related to the presence of negative symptoms. Further, Mathewson et al. (2012) also found higher parasympathetic activity to be correlated with relatively better Wisconsin Card Sorting Test (WCST) performance (a measure of central executive functioning) among patients. Findings from MujicaParodi et al. (2005) appear to be the only significant variant from the consensus of the aforementioned evidence. Specifically, these authors only found respective correlations between the PANSS “suspiciousness and feelings of persecution” item and (1) lower parasympathetic activity and (2) lower nocturnal HRV. Several other measures have also been used to examine the possible relationship between HRV and schizophrenia symptom severity. Reduced vagal modulation and reduced vagal information flow have both been correlated with total scores on the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS; Boettger et al., 2006). Elevated negative symptomology, as measured by the SANS, has also been correlated with deficits in heart rate complexity among un-medicated paranoid schizophrenia patients (Peupelmann et al., 2009). Reductions in parasympathetic and overall ANS activity have also been found among patients with low Global Assessment of Functioning (GAF) scale scores as compared to patients with highGAF scores, thereby suggesting an association exists between ANS depression and disease severity in schizophrenia (Fujibayashi et al., 2009). While, Iwamoto et al. (2012) failed to replicate these findings, Khandoker et al. (2010) produced findings similar to those of Fujibayashi et al. (2009). Specifically, Khandoker et al. (2010) found statistically significant vagal tone deficits in low-GAF participants as compared to healthy participants. The authors also noted that vagal tone deficits among high-GAF participants fell midway between that observed among the low-GAF and healthy participants; however, this finding did not meet statistical significance. Finally, Henry et al. (2010) examined Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS) scores in conjunction with HRV data collected from schizophrenia and manic bipolar disorder samples, as well as nonpsychiatric controls. A negative correlation was found between HFn (a parasympathetic activity marker) and total YMRS score in schizophrenia, while total YMRS scores in the manic bipolar group were positively correlated with elevated sympathetic dominance. Unusual thought content BPRS subscale scores also correlated with a sympathovagal imbalance characterized by dominant sympathetic and depressed parasympathetic

activity in manic bipolar patients; however, no correlations with the BPRS were identified among schizophrenia patients. Similarly, Malaspina et al. (1997) failed to identify any correlation between HRV parameters in schizophrenia and BPRS ratings. Henry et al. (2010) ultimately concluded that an association does exist between sympathovagal imbalance and symptom severity, as well as that HRV dysfunction may be state-dependent in the context of the phase of the psychiatric disease for both schizophrenia and bipolar mania. While correlational analyses that examine the relationship between diminished vagal tone and the positive, negative, and cognitive symptoms of schizophrenia appear to offer very heterogeneous findings, findings do present a general consensus in one area. That is, disease severity and measures of HRV and parasympathetic activity level typically appear inversely related. Again, these findings are significant in that they support the theory that a connection exists between autonomic regulatory capacity and psychotic symptom severity in schizophrenia. In sum, these results suggest that decreased complexity as assessed by HRV analysis is associated with increased psychotic symptom severity; however, any relationship between HRV and specific psychotic symptoms remains unclear. Information derived from HRV data on the treatment of schizophrenia via antipsychotic medication may provide additional supportive evidence regarding this issue. 5. Antipsychotic medication and HRV Several studies have demonstrated that antipsychotic medications can exacerbate ANS dysfunction in schizophrenia patients (Birkhofer et al., 2013; Huang et al., 2013; Rechlin et al., 1994; Iwamoto et al., 2012). Still, Bӓr et al. (2005) failed to find any significant change in autonomic functioning after antipsychotics were administered to patients, while Henry et al. (2010) found that psychotropic medication (i.e., risperidone, valproate, or mood stabilizers) did not significantly affect HRV in bipolar or schizophrenia patients. Although the effects of antipsychotic medication are complex and often vary across individuals, an examination of their effects upon HRV and psychotic symptom severity may provide information relevant to further understanding any possible relationship between HRV and schizophrenia disease state. Several studies have assessed the relationship between various antipsychotic medications and subsequent alterations in psychotic symptom severity and parasympathetic activity. Specifically, some research has found HRV deficits in medicated schizophrenia patients, as compared to unmedicated patients, to be exacerbated by antipsychotic medication (Mujica-Parodi et al., 2005). However, in this study, both groups still showed statistically significant HRV deficits compared to that of controls, and vagal tone deficits among patients were deemed to be independent of antipsychotic side effects. Research has also identified that significant negative correlations exist between various HRV measures and psychotic symptom severity indicators and that these correlations are independent of the effects clozapine dosage, the antiparkinsonian drug biperiden, or the state-of-change in neuroleptic-induced parkinsonism among patients (Kim et al., 2004; Okada et al., 2003). Further, Mathewson et al. (2012) found that clozapine-treated patients displayed both poorer performance on the WCST and lower levels of parasympathetic activity relative to schizophrenia patients treated with other antipsychotic medications. Similarly, Wang et al. (2008) examined schizophrenia patients who were switched from typical antipsychotic medication to either amisulpride or olanzapine. Parasympathetic activity improvements were observed in patients who were transitioned to amisulpride versus olanzapine. In another study, the sympathovagal balance in unmedicated schizophrenia patients moved toward a state of parasympathetic

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dominance following a six-week treatment trial of risperidone. Additionally, risperidone was found to have a large effect upon psychotic symptom severity, suggesting the presence of an inverse relationship between parasympathetic activity and schizophrenia symptomology (Chang et al., 2010). Interestingly, other research has similarly demonstrated that antipsychotic medication can have a normalizing effect on HPA-axis hyperactivity in patients suffering from psychosis, as evidenced by reduced cortisol secretion (Mondelli et al., 2010). Overall, the aforementioned evidence seems to suggest that when antipsychotic medication effectively treats symptoms of schizophrenia, improvements can sometimes also be simultaneously observed in the sympathovagal imbalance characteristic of schizophrenia. Nonetheless, it is clear that several antipsychotics have also been found to be associated with the depression of HRV parameters and may potentially put patients at a higher risk of cardiac mortality. Thus, the exact interplay of antipsychotic medication on the sympathovagal imbalance in schizophrenia is likely complex, varies among individuals, and is in need of further study.

6. Discussion In conclusion, there has been a high degree of replicability (with few notable exceptions) among the empirical findings of the vast majority of research conducted on ANS dysfunction in schizophrenia. Findings from more than two-dozen empirically-based studies have been largely confirmatory. While the results of the previous research utilizing HRV analyses of patients with schizophrenia and their first-degree relatives is compelling in terms of a vagal tone deficit representing an underlying physiological characteristic of the disorder, the research is correlational in design and cannot address causal mechanisms. Nonetheless, the utilization of HRV data analyses in examining both stress sensitivity and psychotic symptom severity in schizophrenia within the context of the stress-vulnerability hypothesis has elucidated several things. First, the diminished vagal tone commonly identified among schizophrenia patients has also been found among their first-degree relatives; however, vagal tone deficits in first-degree relatives are often attenuated in comparison to patient groups. Although the SNS may initially appear to be hyperactive in patients with schizophrenia, in actuality the observed deficits in parasympathetic activity seem to subsequently produce a sympathovagal imbalance characterized by sympathetic dominance. Thus, schizophrenia patients would seem to exhibit normal SNS responses, but thereafter experience difficulty recovering from environmental stressors due to vagal tone deficits. Research conducted with first-degree relatives of patients with schizophrenia offers some support for the notion that observed vagal tone deficits may represent one possible heritable vulnerability characteristic for schizophrenia and not a mere result of an affective reaction to psychotic symptomology. Observed dosedependent effects between symptom severity and diminished vagal tone among schizophrenia patients would again suggest the possibility that diminished vagal tone represents at least one mechanism of action in the overall maintenance of schizophrenia. Lastly, results from studies employing HRV analyses appear complementary, not contradictory, to research conducted on HPA-axis hyperactivity among schizophrenia patients. In particular, HRV data extend previous findings by demonstrating that what initially appears to be sympathetic hyperactivity within the HPA-axis hyperactivity literature may in fact be sympathetic dominance resulting from vagal tone deficits present in schizophrenia patients.

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6.1. Methodological considerations and limitations Despite the encouraging findings among the research utilizing HRV analyses among schizophrenia patients, potential moderators of diminished vagal tone in schizophrenia should always be examined, including substance abuse, specific symptom profiles, and psychosocial stressors. Additionally, approximately fifty percent of individuals with schizophrenia also carry a comorbid diagnosis of substance abuse (Regier et al., 1990) and chronic cannabis use has been linked to abnormal development of neural regions related to stress sensitivity (Dean and Murray, 2005). One of the most common substances used by individuals with schizophrenia is alcohol, which has demonstrated effects on HRV (Ingjadsson et al., 2003), and is often controlled for in HRV studies. For example, Ieda et al. (2014) specifically screened out any drug or alcohol abuse among participants, Lee et al. (2011) asked participants to refrain from consuming alcohol for 12 h prior to data collection, and Bӓr et al. (2012) controlled for both illegal and legal substances via monitoring serum drug levels. In addition, many HRV research designs have also attempted to match members of the patient and control groups based on smoking habits (Bӓr, Wernich et al., 2008; Bӓr et al., 2012; Berger et al., 2010), requested participants refrain from smoking ranging between 30 min to 6 h before the evaluation (Bӓr et al., 2005; Castro et al., 2008, 2009; uregui et al., 2011; Lee Chang et al., 2009, 2010; Henry et al., 2010; Ja et al., 2011; Moon et al., 2013), or both (Bӓr, Boettger, Berger et al., 2007; Bӓr, Boettger, Koschke et al., 2007; Bӓr, Koschke et al., 2007; Bӓr et al., 2009). Further, several studies have failed to find that smoking had any statistically significant effect on vagal tone in comparisons between patient and control groups (Birkhofer et al., 2013; Henry et al., 2010; Malaspina et al., 1997). Nonetheless, the direction of the relationship between substance abuse and HRV abnormalities is unclear. It is possible that low vagal tone may impair inhibitory physiological responses (Thayer and Lane, 2000) and contribute to substance abuse rather than result from it. Future research should examine substance abuse in regards to HRV and the addiction vulnerability hypothesis (Chambers et al., 2001). Additional methodological limitations with respect to HRV are also notable. Although the two most commonly employed metrics across studies include HF and LF (Berntson et al., 2008), it is possible to use HRV analyses to derive several other distinct measures of sympathetic and parasympathetic functioning. As different markers of parasympathetic activity may be employed across various HRV studies, interpretation and integration of results can become increasingly difficult. This is especially true of HRV studies in which control and patient groups are revealed to have nonsignificant differences in HF, but significant differences in other HRV indices of parasympathetic activity (e.g., ApEn, cross-ApEn, QT variability index, RMSSD, SampEn, Tone-Entropy). In our present examination of the literature, we identified several instances of this disparity between HF and alternative markers of parasympathetic activity (Bӓr, Boettger, Berger et al., 2007; Boettger et al., 2006). Further, Berntson et al. (2008) noted that the LF/HF ratio has been challenged on conceptual grounds due to the fact that the LF component is not a pure marker of sympathetic activity. Thus, the LF/HF ratio likely does not produce a clean ratio of sympathetic/ parasympathetic activity. Nonetheless, interpretation of HRV frequency components across studies is further complicated by the fact that the LF/HF ratio (Bӓr et al., 2005, 2012; Bӓr, Boettger et al., 2008; Berger et al., 2010; Boettger et al., 2006; Fujibayashi et al., uregui et al., 2011; Kim et al., 2004; 2009; Ieda et al., 2014; Ja Rechlin et al., 1994; Valkonen-Korhonen et al., 2003), both of the individual LF or HF bandwidths (Bӓr et al., 2009; Bӓr, Boettger, Berger et al., 2007; Peupelmann et al., 2009), or all three of these metrics (Bӓr, Boettger, Koschke et al., 2007; Bӓr, Koschke et al.,

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2007; Birkhofer et al., 2013; Mathewson et al., 2012; Toichi et al., 1999) are sometimes omitted from publications of study findings. Additionally, time domain measures of HRV may even produce limitations for interpreting findings across studies. For instance, Berntson et al. (2005) noted that while the root mean square successive difference (RMSSD) remains commonly utilized in clinical cardiology, it still nonetheless carries limitations in that it may not represent a pure index of vagal control and may be influenced by a number of variables (e.g., age, physical health, respiration rate) outside of cardiac vagal control. Interpretation of HRV findings can be even further complicated when one considers that a number of time domain measures exist (e.g., SDNN, SDANN) which could be employed across HRV research. Finally, HRV abnormalities are observed across several psychiatric disorders (Moon et al., 2013); thereby representing possibly either an underling risk factor for general vulnerability to psychiatric illness or a common physiological consequence of psychiatric illness. While this limits the utility of HRV in discriminating between psychiatric illness, HRV (especially HF HRV) may be useful in discriminating between healthy controls and individuals with a psychiatric disorder (Moon et al., 2013). Furthermore, HRV measures continue to demonstrate utility in monitoring and assessing the progression of disease state within individual patients over time (Voss, 2007). To this end, HRV may be an ideal candidate for a transdiagnostic approach to examine the relationship between environmental stress, HRV abnormalities, and illness onset. 6.2. Future directions The utilization of HRV analyses in the context of evaluating stress sensitivity in schizophrenia is useful in several ways. Many researchers agree that examining the role of stress in disease onset and maintenance of schizophrenia is important. Nonetheless, the mechanism through which stress may contribute to schizophrenia development remains rather elusive (Gispen-de Wied, 2000). In the previously described sympathovagal imbalance, the sympathetic response to stress inducing stimuli remains protracted due to the fact that the reciprocal parasympathetic response is insufficient in strength to quickly return sympathetic activation to baseline. Due to the deleterious effects of prolonged exposure to sympathetic activation, the observed sympathovagal imbalance thereby produces a pattern of stress sensitivity in persons at high-risk for developing schizophrenia. Researchers evaluating HPA-axis hyperactivity in the context of schizophrenia have theorized that such impairment may contribute to disease onset by catalyzing gene expression associated with normal brain maturation; thereby, suggesting that stress exposure may contribute to the gene expression involved in triggering schizophrenia onset (Aiello et al., 2012). Should the tenets of the diathesis-stress/vulnerability-stress model hold true, then the aforementioned information provides data on how a sympathovagal imbalance characterized by sympathetic dominance could place high-risk individuals at an increased likelihood of developing first-episode psychosis (FEP) following chronic stress exposure. Nevertheless, any possible gene systems involved in this process remain elusive. Moreover, the etiology of schizophrenia is complex and multiple contributing factors are likely involved in producing disease onset. Further research will be necessary before any connection can be established between chronic stress exposure and specific gene systems specific to schizophrenia. Additionally, the relationships between trauma and environmental stress exposure should be examined as they correlate with HRV measurements and diminished vagal tone among both patients and their first-degree relatives. One would likely expect to see significantly elevated levels of stress and trauma exposure

among patient groups prior to disease onset, as compared to firstdegree relatives. In keeping with this recommendation, uniformity in reporting both the individual LF and HF HRV bandwidth components and the LF/HF ratio in all research employing HRV analyses among schizophrenia patients will only improve the interpretability of results across studies. While inclusion of additional metrics that may eventually prove to be useful markers of sympathetic or parasympathetic activity is encouraged, researchers evaluating results of individual experiments will be more readily able to critique the sympathovagal imbalance in schizophrenia when LF, HF, and the LF/HF ratio are all presented. Further, additional efforts should be made to improve our contemporary comprehension of the sympathovagal imbalance in schizophrenia as it may relate to documented HPA-axis hyperactivity in schizophrenia. While present research suggests that sympathetic dominance occurs as a result of vagal tone deficits, Ieda et al. (2014) is the only known study to actually incorporate sAA as an independent marker of SNS activity along with simultaneously collected HRV data. Finally, future research should seek to better clarify the relationships between symptom severity and disease duration with ANS abnormalities and diminished parasympathetic activity in schizophrenia. Such an understanding could have vast potential for screening individuals who may be at an especially high-risk of progressing toward FEP. Role of the funding source This work was unfunded. Contributors JMM and BJT developed the conceptual idea of this review paper. JMM participated in and supervised the literature search, conducted the comprehensive literature review, and composed the first draft of this review paper. Both BJT and JSB critiqued paper drafts. JSB contributed to the majority of the editorial and revision process, with some assistance also provided by BJT. All authors approved the final version of the manuscript. Conflicts of interest There is no conflict of interest. Acknowledgment The authors are grateful to and would like to thank undergraduate research assistants Mr. Brennan Baker, Mr. Stanley Desire, and Mr. Nicholas Joseph for their contribution in conducting comprehensive literature searches, as well as reviewing the final product of this review article. The authors would also like to especially thank Ms. Cierra Godwin. In addition to assisting with literature searches, reviews, and critiquing, Ms. Godwin also contributed to the completion of Table 1. References Aiello, G., Horowitz, M., Hepgul, N., Pariante, C.M., Mondelli, V., 2012. Stress abnormalities in individuals at risk for psychosis: a review of studies in subjects with familial risk or with “at risk” mental state. Psychoneuroendocrinology 37, 1600e1613. lu, F., Bilgiç, V., 2015. Analysis of heart rate variability Akar, S.A., Kara, S., Latifog during auditory stimulation periods in patients with schizophrenia. J. Clin. Monit. Comput. 29, 153e162. €r, K.J., Berger, S., Metzner, M., Boettger, M.K., Schulz, S., Ramachandraiah, C.T., Ba et al., 2009. Autonomic dysfunction in unaffected first-degree relatives of patients suffering from schizophrenia. Schizophr. Bull. 36, 1050e1058. €r, K.J., Boettger, M.K., Berger, S., Baier, V., Sauer, H., Yeragani, V.K., et al., 2007a. Ba

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