Psychiatry and Clinical Neurosciences 2014; 68: 674–682

doi:10.1111/pcn.12178

Regular Article

Heart rate variability in unmedicated patients with bipolar disorder in the manic phase Hsin-An Chang, MD,1 Chuan-Chia Chang, MD,1 Nian-Sheng Tzeng, MD,1,2 Terry B. J. Kuo, MD, PhD,3 Ru-Band Lu, MD4 and San-Yuan Huang, MD, PhD1* 1

Department of Psychiatry, Tri-Service General Hospital, 2Student Counseling Center, National Defense Medical Center, Institute of Brain Science, National Yang-Ming University, Taipei, and 4Institute of Behavioral Medicine and Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3

Aims: Decreased heart rate variability (HRV) has been proposed in bipolar disorder. To date, there has been no adequate study that has investigated resting HRV in unmedicated patients with bipolar disorder in the manic state. Methods: To examine whether bipolar mania is associated with decreased HRV, 61 unmedicated patients with bipolar mania and 183 healthy volunteers aged 20–65 years were recruited for this case–control analysis. The Young Mania Rating Scale (YMRS), Clinical Global Impression-Severity, Hamilton Depression Rating Scale (HAM-D), and Hamilton Anxiety Rating Scale (HAM-A) were used for the clinical ratings. Cardiac autonomic function was evaluated by measuring HRV parameters and the frequency-domain indices of HRV were obtained. Results: Patients with bipolar mania exhibited significantly lower mean RR interval, variance, low-

UTONOMIC NERVOUS SYSTEM (ANS) dysregulation is associated with a variety of psychiatric disorders, including major depression,1,2 schizophrenia,3 and post-traumatic stress disorder.4 However, the precise mechanism of ANS dysregulation in psychiatric disorders still remains unclear, complicated by the large number of cortical, sub-cortical, and brainstem structures that coor-

A

*Correspondence: San-Yuan Huang, MD, PhD, Department of Psychiatry, Tri-Service General Hospital, No. 325, Cheng-Kung Road, Sec. 2, Nei-Hu District, Taipei, 114, Taiwan. Email: [email protected] Received 25 September 2013; revised 29 January 2014; accepted 18 February 2014.

674

frequency (LF)-HRV, and high-frequency (HF)-HRV but higher LF/HF compared to controls. Decreased HRV (variance) was associated with the YMRS total scores. Both the YMRS total scores and the Clinical Global Impression-Severity scores were positively correlated with the LH/HF ratio and inversely correlated with the HF-HRV. There was no significant correlation between the HAM-D/HAM-A scores and any HRV parameter.

Conclusions: Bipolar mania is associated with cardiac autonomic dysregulation, highlighting the importance of assessing HRV in manic patients. Further studies examining the influence of anti-manic psychotropic drugs on cardiac autonomic regulation in bipolar mania are needed. Key words: bipolar disorder, cardiac autonomic function, heart rate variability, mania, vagal control.

dinate autonomic function. Of note, recent reports suggest that ANS dysregulation is associated with increased impulsivity5 and behavioral disinhibition.6 Impulsivity is a frequent component of the course and presentation of bipolar disorder (BD) and has been proposed to represent a core feature of the illness.7 There is increasing evidence suggesting ANS involvement in BD.8,9 Therefore, ANS regulation in BD is considered a promising candidate for psychophysiological differentiation from healthy subjects. In studying the ANS, various techniques have been developed to detect the function of the sympathetic and parasympathetic systems. Frequency-domain analysis of heart rate variability (HRV), with its

© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2014; 68: 674–682

Bipolar mania and heart rate variability 675

standard procedure and interpretation first reported in 1996, is a sophisticated and non-invasive tool for detecting ANS regulation of the heart.10 Aside from being non-invasive, its important advantage is that it utilizes spontaneous fluctuations in heart rate (HR) to estimate tonic ANS functions. In the last 2 decades, short-term frequency-domain analysis of HRV has been developed as a useful tool to probe the peripheral autonomic output in the cardiovascular territory.11 Previous research has examined indices of sympathetic activity as evidenced by electrodermal activity in patients with BD. For example, Zahn et al.9 and Iacono et al.12 reported higher sympathetic activity in BD patients compared to controls. Moreover, Lake et al. demonstrated sympathetic hyperactivity as indexed by higher levels of plasma norepinephrine and heart rate in patients with BD compared to healthy controls.13 As for the effect of BD on HRV, linear and non-linear analyses of HRV have been performed on euthymic BD patients, with mixed results. Cohen et al. reported a decrease in the LF/HF ratio and an increase in HF power compared to healthy controls,14 whereas Todder et al. reported no difference in the non-linear analysis of resting HRV between the euthymic BD patients and controls.15 There is scant data regarding the influence of manic episodes on the ANS. Only a single study reported a significant reduction in HRV, parasympathetic activity, and heart rate complexity in manic BD patients compared to controls.16 However, the sample size of that study was small (23 manic BD patients vs 23 controls) and the study enrolled manic BD patients taking mood stabilizing medication and/or other psychotropic drugs. Thus, it is difficult to discern the extent to which the effect is inherent to the bipolar mania or if it is a consequence of treatment. Indeed, there are many potentially confounding variables that can affect autonomic tone in studies on patients with BD, including medication, physical health, habitual physical activity, smoking, and psychiatric co-morbidities.11,17 In particular, some mood stabilizers have the ability to alter cardiac function. For instance, lithium and carbamazepine have been associated with sinus node arrhythmias, while sodium valproate is relatively free of any untoward cardiac effects.18 Mood stabilizers and/or other psychotropic drugs must be taken into account in any study on the effect of bipolar mania on HRV. However, previous published work lacks evidence

regarding resting HRV in physically healthy, unmedicated BD patients in the manic state. This study aimed to compare unmedicated, bipolar mania patients with age- and sex-matched controls on frequency-domain indices of resting HRV. Based on the previous HRV findings on BD, we speculate that bipolar mania is associated with decreased HRV and parasympathetic activity, but increased sympathetic modulation.

METHODS Participants This study was approved by the Institutional Review Board for the Protection of Human Subjects of the Tri-Service General Hospital, a medical teaching hospital of the National Defense Medical Center in Taipei, Taiwan. All participants provided written informed consent. The initial study entry criterion was age of 20–65 years. After detailed questionnaire screening, clinical examination and chart review, subjects with pregnancy, smoking, diabetes, cancer, neuropathy, hypertension, cardiac arrhythmia, or other cardiovascular diseases that affect HRV, or those engaging in regular physical training exceeding 10 h per week, were excluded. Subjects who used psychotropic medication or any medication (e.g., anti-psychotics, anti-cholinergics, antidepressants, oral contraceptives, anti-convulsants, anxiolytics, cerebral metabolic activators, or cerebral vasodilators) that have been reported to affect ANS functioning for at least 2 weeks prior to the beginning of the study evaluation were also excluded. Of the 784 eligible inpatients identified for study participation, 93 (11.86%) were enrolled. Based on the same methodology as previously reported,2,19,20 each patient was evaluated using the Chinese version of the Modified Schedule of Affective Disorder and Schizophrenia-Lifetime (SADSL)21 to obtain the DSM-IV criteria for a primary diagnosis of bipolar I disorder, current episode manic. A previous study has reported diagnostic data with satisfactory inter-rater reliability.22 Here, individuals with a history of substance dependence, organic brain disease, or any concomitant major psychiatric disorders were also excluded. The Young Mania Rating Scale (YMRS), Clinical Global Impression-Severity (CGI-S), 17-item version of the Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale

© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

676 H-A. Chang et al.

Psychiatry and Clinical Neurosciences 2014; 68: 674–682

(HAM-A) were administered by an attending psychiatrist. Patients with BD had a minimum score of 16 on the YMRS. Only drug-naïve or drug-free patients for at least 1 month were included. The BD patients were tested within an average of 2.95 ± 1.43 h of admission to the psychiatric ward. Thirty-two BD patients (mean YMRS score, 45.38 ± 5.33) were excluded from the statistical analysis as being too anxious, excited, or physically active to finish the HRV measurements. Sixty-one (7.78%, 14 drug-naïve and 47 drug-free) BD patients were included in the final statistical analysis. The control group included 183 sex-, age- and educational-attainment-matched healthy volunteers recruited from the community. The modified Chinese version of SADSL21 was used to exclude individuals with psychiatric conditions. The control subjects had no lifetime history of mental disorder.

tral analysis was performed using a non-parametric method of fast Fourier transformation (FFT). The direct current component was deleted and a Hamming window was used to attenuate the leakage effect.24 The power spectrum was then quantified into standard frequency-domain measurements defined previously,10,24,25 which consisted of variance (variance of RR-interval values), low frequency (LF, 0.04–0.15 Hz), high frequency (HF, 0.15–0.40 Hz), and the ratio of LF to HF (LF/HF). All of the measurements were logarithmically transformed to correct skewed distribution.24,25 Vagal control of HRV was represented by HF, whereas both vagal and sympathetic control of HRV were jointly represented by LF. The LF/HF ratio could mirror sympathovagal balance or sympathetic modulations, with a larger LF/HF ratio indicating a greater predominance of sympathetic activity over cardiac vagal control.10 For BD patients, two strategies were used to promote the completion rate: (i) the HRV measurement was set as the first priority of the admission routine examinations; and (ii) the whole procedure of HRV measurement was done by these patients’ attending psychiatrist (H.A.C.), who was responsible for reducing patients’ excitement during HRV exam without using any medication.

Measurements of habitual physical activity The participants’ self-reported weekly habitual physical activity was registered. It was calculated by the formula: average frequency of physical exercise × time spent on a typical exercise day (h). The average frequency of physical exercise was in a form with five-point scales and was described by the frequency of exercising with hard breathing and sweating (‘never’, ‘seldom’, ‘once a week’, ‘twice a week’ and ‘more than twice a week’).23

Measurements of heart rate variability Detailed procedures for analysis of HRV were as reported previously.24,25 Briefly, after sitting quietly for 20 min, a lead I electrocardiogram (ECG) was taken for 5 min while the subject lay quietly in a supine position. The values of HRV indices are greatly influenced by breathing frequency.26 We ensured that subjects were breathing with normal respiratory rate of 12–15 breaths/min by recording the respiratory movements to avoid respiratory interference during the HRV measurement.27 An HRV analyzer (SSIC, Enjoy Research Inc., Taipei, Taiwan) acquired, stored and processed the ECG signals. Under a sampling rate of 512 Hz, the signals were recorded using an 8-bit analog-todigital converter. Stationary RR interval values were re-sampled and interpolated at a rate of 7.11 Hz to produce continuity in a time domain. Power spec-

Statistical analyses SPSS 13.0 (SPSS, Taipei, Taiwan) was used for all analyses. Discrete variables in the patients and controls were compared by the χ2-test, while continuous variables were compared using an independent-samples t-test. The associations among HRV measurements and age, body mass index (BMI), and habitual physical activity were analyzed with product–moment correlations, whereas point-bi-serial correlations were used to assess correlations of HRV measurements with sex. Results of these correlations were identical to those arising from comparisons using the t-tests. Scores of YMRS, CGI-S, HAM-D, and HAM-A were correlated with HRV measurements using Pearson’s test. Linear regression analyses were used to primarily assess associations of scores of clinical ratings with HRV measures. To control for confounding effect, multiple regression analysis was used on the HRV indices, with HRV-associated factors as covariates. All results are two-tailed and statistical significance was set at P < 0.05.

© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2014; 68: 674–682

Bipolar mania and heart rate variability 677

Table 1. Characteristics of the study cohorts Clinical and demographic data

Manic BD patients

Healthy controls

Omnibus P-value

Number of participants Duration of disease, mean ± SD, years Age, mean ± SD, years Education, mean ± SD, years Female sex (%) BMI, mean ± SD Weekly regular exercise, h SBP, mean ± SD, mmHg DBP, mean ± SD, mmHg YMRS scores, mean ± SD CGI-S scores, mean ± SD HAM-D scores, mean ± SD HAM-A scores, mean ± SD

61 8.15 ± 7.07 39.28 ± 12.60 14.20 ± 2.71 26 (42.62) 25.24 ± 5.35 1.56 ± 2.59 119.87 ± 9.35 74.23 ± 9.97 28.48 ± 4.63 3.38 ± 0.58 4.85 ± 2.50 5.33 ± 2.64

183 – 40.75 ± 11.89 14.42 ± 2.59 78 (42.62) 24.14 ± 3.22 0.95 ± 1.78 122.47 ± 14.64 76.13 ± 10.83 – – – –

– – 0.41 0.56 1.0 0.13 0.09 0.11 0.23 – – – –

BD, bipolar disorder; BMI, body mass index (weight in kg divided by height in m2); CGI-S, Clinical Global Impression-Severity; DBP, diastolic blood pressure; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; SBP, systolic blood pressure; SD, standard deviation; YMRS, Young Mania Rating Scale.

RESULTS

Association between clinical ratings and resting HRV indices

Demographics and clinical characteristics The BD patients and controls were similar with respect to demographic data and other remaining characteristics (Table 1).

HRV parameters The mean RR intervals in patients with BD were significantly shorter than those of the controls (Fig. 1). Spectral HRV analysis showed that the BD patients exhibited significantly lower variance, LF, and HF, but a higher LF/HF compared to the controls.

Factors associated with resting HRV Associations between resting HRV measures and potential confounding variables are summarized in Table 2. Older participants had reduced variance and LF, but increased LF/HF. Participants with higher BMI had lower variance. Those who were habitually more physically active had significantly slower heart rates (longer RR interval), lower LF/HF ratio, and greater HF. The correlation analysis of individual HRV indices showed that variance was positively correlated with mean RR intervals, LF, and HF.

Correlation analyses showed that YMRS total scores positively correlated with the LH/HF ratio and inversely correlated with the variance and HF (Table 3). The CGI-S scores were positively correlated with the LH/HF ratio and inversely correlated with HF. Adjustments for age, BMI, and physical activity did not significantly alter the previous associations (Table 4). There was no significant correlation between the HAM-D/HAM-A scores and HRV parameters.

DISCUSSION To date, this is the first study that examined resting HRV in physically healthy, unmedicated BD patients in the manic state. This study had three main findings. First, BD patients in the manic state have significantly lower HRV than healthy controls. The results corroborate findings of an earlier study.16 The findings are reliable because this study has four important strengths. One, the study excluded subjects with psychiatric and physical co-morbidities that may confound the association between bipolar mania and cardiac autonomic functions. Two, BD is frequently comorbid with anxiety disorders28 and HRV measures

© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

678 H-A. Chang et al.

Psychiatry and Clinical Neurosciences 2014; 68: 674–682

***

(a)

***

(b)

750.00

*

(c) 5.00

6.00

4.00 4.00

LF

Var

Mean

500.00

2.00

2.00

250.00

3.00

1.00 0.00

BD

(d)

0.00

NC

BD

NC

NC

*

(e)

***

0.80

5.00 4.00

0.60 Ratio

HF

BD

3.00

0.40

2.00 0.20

1.00

BD

NC

0.00

BD

NC

Figure 1. Mean RR interval and spectral heart rate variability (HRV) indices in patients with bipolar disorder (BD) mania compared to healthy age- and sex-matched normal controls (NC). (a) Mean RR interval, (b) total variance, (c) low frequency (LF), (d) high frequency (HF) and (e) ratio of LF to HF were all significantly different between patients and controls. *P < 0.05, or significant between-groups differences. Var, total variance [ln(ms2)].

are profoundly influenced by anxiety.29 Both BD patients and controls have been interviewed using the SADSL.21 This type of interview rules out psychiatric comorbidity and psychiatric disorders. Thus, a false-positive finding due to the inclusion of anxiety disorders or substance use disorders is unlikely. In addition, there is no significant correlation between participant anxiety, as assessed by the HAM-A, and any HRV measure, suggesting that group differences in HRV measurements are not simply mediated by anxiety responses. Three, all of the subjects are unrelated Han Chinese drawn from a population pool in Taiwan that is known to be genetically homogeneous.20 All of the biological grandparents of the recruited subjects are of Han Chinese ancestry, which lessened the possibility that ethnic stratification bias may produce a false-positive result. This possibility

has been raised by the study by Martin et al., which showed ethnic stratification among study samples could lead to resetting population HRV patterns,30 which might in turn produce false-positive or -negative results by chance rather than reveal a direct relation. Four, none of the study subjects are smokers or have a history of smoking. Smoking clearly depresses HRV in current and past smokers. Moreover, HRV remains lower compared to that of nonsmokers.31 Thus, smoking must be taken into account in any study that evaluates the effect of BD on HRV because a substantial proportion of BD patients smoke or have a history of smoking.32 The second main finding of this study was that the BD patients are expected to be associated with lower parasympathetic activity, higher sympathetic activity, and subsequent displacement of the sympathovagal

© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2014; 68: 674–682

Bipolar mania and heart rate variability 679

Table 2. Factors associated with resting HRV indices among patients with bipolar disorder

Sex (women/men) Age‡ BMI‡ Physical activity‡ RR interval Var LF HF LF/HF



RR interval

Var

LF

HF

LF/HF

−0.12 0.13 0.09 0.32* − 0.56*** 0.46*** 0.63*** −0.43**

−0.10 −0.31* −0.27* 0.22 0.56*** − 0.92*** 0.91*** −0.18

−0.15 −0.39** −0.25 0.15 0.46*** 0.92*** − 0.85*** 0.07

−0.05 −0.21 −0.22 0.30* 0.63*** 0.91*** 0.85*** − −0.46***

−0.14 0.26* −0.01 −0.32* −0.43** −0.18 0.07 −0.46*** −

*P < 0.05; **P < 0.01; ***P < 0.001. † Point-bi-serial correlations; first category in parentheses is the reference group. ‡ Product–moment correlations. BMI, body mass index (weight in kg divided by height in m2); HF, high frequency power [ln(ms2)]; HRV, heart rate variability; LF, low frequency power [ln(ms2)]; LF/HF, ratio of LF to HF [ln(ratio)]; Var, total variance [ln(ms2)].

balance in favor of sympathetic modulation. However, there are lower LF levels in BD patients than in controls, which is an unexpected finding. This may be due to several reasons. For one, the traditional interpretations of HRV measures used in this study are that HF power estimates vagal tone, while LF power reflects both vagal and sympathetic influences. It has also been reported that when LF power is assessed in the supine position, administration of atropine (a potent inhibitor of parasympathetic muscarinic receptors) eliminates most of the LF region of the power spectrum.33 This does not occur when LF power is assessed in the sitting position, suggesting that the resting LF power in the present study may primarily reflect vagal influences.34 Consistent with

this is evidence that there is a 0.85 correlation between LF-HRV and HF-HRV (Table 2). The third main finding was that correlation analysis shows a strongly positive association between variance and HF-HRV (r = 0.91; P < 0.001), suggesting that an overall reduction in HRV in BD patients is at least partly derived from the suppression of parasympathetic input as indicated by low HF-HRV. The following two findings further complement the results regarding lower HF-HRV in bipolar mania. Patients with more severe manic symptoms tend to have lower vagal tone (HF-HRV) and dysfunction in the balance between cardiac sympathetic and parasympathetic tone (LF/HF ratio) than those with less severe manic symptoms. While definite mechanisms

Table 3. Correlation between HRV indices and scores of YMRS, CGI-S, HAM-D and HAM-A

Heart rate variability measures RR interval, mean ± SD, ms Var, mean ± SD LF, mean ± SD HF, mean ± SD LF/HF, mean ± SD

YMRS

CGI-S

HAM-D

HAM-A

−0.24 −0.32* −0.22 −0.4** −0.38**

−0.06 −0.22 −0.15 −0.27* −0.26*

−0.09 −0.21 −0.14 −0.18 −0.1

−0.08 −0.08 −0.10 −0.11 −0.03

*P < 0.05; **P < 0.01; ***P < 0.001. CGI-S, Clinical Global Impression-Severity; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; HF, high frequency power [ln(ms2)]; HRV, heart rate variability; LF, low frequency power [ln(ms2)]; LF/HF, ratio of LF to HF [ln(ratio)]; Var, total variance [ln(ms2)]; YMRS, Young Mania Rating Scale.

© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

680 H-A. Chang et al.

Psychiatry and Clinical Neurosciences 2014; 68: 674–682

Table 4. Multiple regression analysis of HRV parameters by YMRS/CGI-S scores after adjusting for age, BMI, and weekly regular exercise Unstandardized β coefficients (95% confidence interval) Unadjusted YMRS scores RR interval, mean ± SD, ms Var, mean ± SD LF, mean ± SD HF, mean ± SD LF/HF, mean ± SD CGI-S scores RR interval, mean ± SD, ms Var, mean ± SD LF, mean ± SD HF, mean ± SD LF/HF, mean ± SD

P

Model 1

P

Model 2

P

Model 3

P

−8.01 (−16.49–0.47) −0.09 (−0.15–0.02) −0.08 (−0.17–0.01) −0.16 (−0.25–0.06) 0.08 (0.03–0.13)

0.06 0.012 0.087 0.002 0.003

−8.17 (−16.65–0.31) −0.08 (−0.15–0.02) −0.07 (−0.16–0.01) −0.15 (−0.25–0.06) 0.08 (0.03–0.13)

0.06 0.011 0.084 0.002 0.001

−8.04 (−16.69–0.61) −0.09 (−0.16–0.03) −0.08 (−0.17–0.01) −0.17 (−0.26–0.08) 0.08 (0.04–0.13)

0.07 0.004 0.05 0.001 0.001

−7.56 (−15.86–0.73) −0.09 (−0.15–0.03) −0.08 (−0.16–0.01) −0.16 (−0.25–0.08) 0.08 (0.03–0.13)

0.07 0.004 0.05

Heart rate variability in unmedicated patients with bipolar disorder in the manic phase.

Decreased heart rate variability (HRV) has been proposed in bipolar disorder. To date, there has been no adequate study that has investigated resting ...
139KB Sizes 3 Downloads 3 Views