Physical Fitness and Heart Rate Recovery Are Decreased in Major Depressive Disorder

Physical Fitness and Heart Rate Recovery Are Decreased in Major Depressive Disorder SILKE BOETTGER, MD, FRANZISKA WETZIG, CHRISTIAN PUTA, LARS DONATH, HANS-JOSEF HOLGER H. W. GABRIEL, MD, AND KARL-JÜRGEN BÄR, MD MÜLLER, Objective: To investigate whether physical fitness is decreased in patients with major depressive disorder (MDD) in comparison to matched healthy controls because low physical fitness has been shown to be associated with metabolic syndrome or autonomic dysfunction. Cardiovascular morbidity and mortality are known to be increased in patients with MDD. Furthermore, the effect of a single exhaustive exercise task on heart rate recovery (HRR) and mood was examined. Methods: Peak oxygen consumption (VO2peak), maximum workload (Ppeak), and individual anaerobic threshold (IAT) were assessed in 22 patients suffering from MDD and 22 controls in a stepwise exhaustion protocol, using spirometry and lactate diagnostics. HRR was detected within the first minute after recovery. The Self-Assessment Manikin (SAM) was used to assess mood before and after exercise. Results: VO2peak, Ppeak, and IAT were decreased significantly in patients, indicating reduced physical fitness in MDD as compared with control subjects. A single exercise exhaustion significantly improved mood in patients, but not in controls. Mood improvement in patients correlated with maximum lactate levels. Significantly reduced HRR values in patients further point to an elevated cardiovascular risk profile and autonomic dysfunction. Conclusions: Our results indicate reduced physical fitness in patients with MDD. Thus, special training programs should be developed to improve their cardiovascular risk profile. In addition, the intriguing finding of a correlation between lactate levels and mood changes should be followed up in future studies to unravel putative mechanisms. Key words: physical fitness, peak oxygen consumption, individual anaerobic threshold, heart rate recovery, major depressive disorder, autonomic nervous system. BDI ⫽ Beck Depression Inventory; BMI ⫽ body mass index; CO2 ⫽ carbon dioxide; DSM-IV ⫽ Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; ECG ⫽ electrocardiogram; HAMD-21 ⫽ Hamilton Depression Rating Scale; HRR ⫽ heart rate recovery; IAT ⫽ individual anaerobic threshold; IPAQ ⫽ international physical activity questionnaire; MDD ⫽ major depressive disorder; MET ⫽ metabolic equivalent; Ppeak ⫽ maximal work load; RQ ⫽ respiratory quotient; rpm ⫽ revolutions per minute; SAM ⫽ Self-Assessment Manikin; SCID ⫽ Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders; VO2 ⫽ oxygen consumption; VO2peak ⫽ peak oxygen consumption; W ⫽ Watt. INTRODUCTION growing number of studies have reported a positive effect of physical training on mood and quality of life in patients suffering from depressive disorders (1– 4). However, the biological basis of this phenomenon remains elusive to date. As one putative mechanism, changes in neurotrophic factor concentrations (e.g., brain-derived neurotrophic factor) that are capable of influencing neurotransmitters such as norepinephrine, serotonin, dopamine, or ␤-endorphin after exercise have been discussed (5,6). In addition, psychological effects such as increasing perceived self-efficacy have been postulated (1). Although the influence of physical activity on mood is well established, few studies have examined the impact of the disease-associated physiological changes on physical fitness. A From the Department of Psychiatry and Psychotherapy (S.B., F.W., K.-J.B.), University Hospital, Jena, Germany; and the Department of Sports Medicine (C.P., L.D., H.-J.M., H.H.W.G.), Friedrich-Schiller-University Jena, Jena, Germany. Address correspondence and reprint requests to Karl-Jürgen Bär, Department of Psychiatry and Psychotherapy, University Hospital Jena, Philosophenweg 3, 07743 Jena, Germany. E-mail: Karl-Juergen.Baer@ med.uni-jena.de Received for publication August 16, 2008; revision received January 6, 2009. We received no funding for this study and there are no potential of actual conflict of interests to declare. DOI: 10.1097/PSY.0b013e3181a55303 Psychosomatic Medicine 71:519 –523 (2009) 0033-3174/09/7105-0519 Copyright © 2009 by the American Psychosomatic Society For instance, Martinsen and colleagues found peak oxygen consumption (VO2peak) to be reduced in major depression when compared with normative data (7). It has further been shown that low physical activity is associated with depressive symptoms in the general population and with the risk for the development of a depressive disorder (8 –11). In addition, depressed patients are less active than nonpsychiatric controls, especially in terms of social contacts and leisure activities (12,13). Furthermore, obesity and a metabolic syndrome are more frequently seen in these patients (14,15). However, to the best of our knowledge, there are no data comparing physical fitness of depressed patients with control subjects matched for physical activity to investigate the disease-specific impact on fitness. Thus, we hypothesized that physical fitness parameters are decreased in depressed patients as compared with controls due to the influence of the disease on physiological regulation and not due to physical inactivity. Parameters such as VO2peak during exercise have been developed in sports medicine to assess objectively the degree of physical fitness. The validity of these measures can be increased by relating them to a metabolic parameter like the individual anaerobic threshold (IAT), which characterizes the threshold between aerobic and anaerobic metabolism during exercise. Furthermore, heart rate recovery (HRR), defined as the decrease in heart rate from peak exercise to 1 minute after cessation of exercise (16), is influenced by physical fitness as well as parasympathetic activity (17,18). Furthermore, this measure has been attributed a predictive value for cardiac mortality (16,19). The main aim of this study was to assess objectively physical fitness levels by means of VO2peak and IAT in patients with a major depressive disorder (MDD) and to compare these with values obtained from healthy control subjects matched for body mass index (BMI) and physical activity. In addition, HRR was determined to study autonomic reactivity after exercise in patients and controls. The obtained parameters were furthermore 519 S. BOETTGER et al. correlated to exercise-induced mood changes to gain more insights in the antidepressive effects of physical activity. Twenty-six patients with MDD assessed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) (SCID) criteria (20) were included into the study. Patients were treated either at the specialized unit for affective disorders or in the outpatient department of the University Hospital in Jena, Germany. The severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale (HAMD-21) (21), rated by a psychiatrist as well as by the self-rating Beck Depression Inventory (BDI) (22). A minimum of 18 points in the HAMD-21 scale and 15 points in the BDI was required to include patients into the study (Table 1). Data of 22 patients (n ⫽ 15 females and 7 males) were analyzed, since four patients did not reach objective exhaustion levels due to hypertension (n ⫽ 3) and subjectively perceived discomfort (n ⫽ 1). Side effects such as hypertention (blood pressure ⬎200 mm Hg within low exercise levels) appeared unexpectedly during the exercise test, which thus had to be discontinued. Four participants in the control group were excluded for the same reasons. Objective exhaustion levels were determined by the subjective exhaustion Borg Scale (23), maximum lactate levels, maximum heart rate (HRmax), and by the respiratory quotient (RQ) of carbon dioxide (CO2) production and oxygen consumption (Table 2). Furthermore, a rate of perceived exhaustion of ⬎15 had to be reached, indicating intense effort. In addition, subjects had to achieve maximal lactate levels of at least 5 mmol/l and RQs of ⬎1.0. An individual HRmax of approximately 208 minus (0.7 ⫻ age) (24) had to be reached. Both groups had comparable exhaustion levels according to the statistical comparison (Table 2). Control subjects were matched for sex, age, BMI, and total physical activity per week using the short version of the international physical activity questionnaire (IPAQ-total) in metabolic equivalent (MET) minutes per week. The IPAQ-total included intensive, moderate, and walking physical activities. Furthermore, the sitting time per week (IPAQ-sitting) was measured (25). Results of patients and controls are displayed in Table 2. In addition, body fat in % (using the anthropometric caliper method) (26) and the hip-to-waist-ratio (27) were measured as additional cardiovascular risk factors (Table 2). For inclusion, clinical investigations including physical examination and 12-lead electrocardiogram (ECG) at rest and during exercise had to be completely normal. Control subjects did not receive any medication. Most depressed patients received antidepressant treatment (Table 1). In patients, disease duration, duration of the current depressive episode, work incapacity, and number of Depression-Related Data Parameters Time since disease manifestation (weeks) Number of depressive episodes Duration of current depressive episode (weeks) Current period of work incapacity (weeks) BDI HAMD-21 Total number of patients with antidepressant medication Norepinephrine and SSRIs Selective SSRIs Patients (n ⫽ 22) Mean ⫾ SD Controls (n ⫽ 22) Mean ⫾ SD 68.5 ⫾ 80.3 NA 2.3 ⫾ 1.2 20.1 ⫾ 16.2 NA NA 14.9 ⫾ 17.1 NA 29.9 ⫾ 11.8 26.3 ⫾ 8.6 19/22 2.9 ⫾ 2.1 1.4 ⫾ 0.9 NA 16 3 NA NA SD ⫽ standard deviation; BDI ⫽ Beck’s Depression Inventory (22); HAMD21 ⫽ Hamilton Depression Rating Scale (21); NA ⫽ not applicable; SSRIs ⫽ selective serotonin reuptake inhibitors. 520 Characteristics of Participants and Exercise Data Parameters METHODS Subjects TABLE 1. TABLE 2. Age (years) BMI (kg/m2) Body fat (%) Hip-to-waist-ratio IPAQ-total (MET minutes per week) IPAQ-moderate-intensive (MET minutes per week) IPAQ-sitting (hours per week) Heart rate pre exercise at rest (beats/min) Exercise exhaustion data at maximal work load Heart rate maximum (beats/min) Lactate maximum (mmol/l) Borg Scale maximum RQ at exhaustion Patients (n ⫽ 22) Mean ⫾ SD Controls (n ⫽ 22) Mean ⫾ SD 36.9 ⫾ 13.1 24.4 ⫾ 4.4 18.2 ⫾ 4.9 0.79 ⫾ 0.1 1810 ⫾ 1095 37.0 ⫾ 12.3 23.3 ⫾ 4.0 16.5 ⫾ 4.3 0.80 ⫾ 0.1 1824 ⫾ 956 422 ⫾ 626 430 ⫾ 601 51.1 ⫾ 21.6 85.3 ⫾ 14.5 52.2 ⫾ 15.6 84.7 ⫾ 14.4 176.2 ⫾ 17.1 182.2 ⫾ 12.6 8.6 ⫾ 2.7 17.3 ⫾ 1.4 1.11 ⫾ 0.07 9.2 ⫾ 2.2 18.1 ⫾ 1.3 1.10 ⫾ 0.06 Student’s t test was applied to compare data. There were no statistically significant differences between groups on any listed measure. SD ⫽ standard deviation; BMI ⫽ body mass index; IPAQ ⫽ International physical activity questionnaire; IPAQ-total score ⫽ total physical activity within the last week; IPAQ-sitting score ⫽ sitting time per week in hours (25); IPAQ-moderate-intensive ⫽ moderate and intensive activities only; MET ⫽ metabolic equivalent to a consumption of 3.5 ml of oxygen per kilogram body weight per minute; RQ ⫽ respiratory quotient. depressive episodes were documented (Table 1). All procedures in this study were approved by the Ethics Committee of the University Hospital, Jena. Data were collected from March 2007 to January 2008. Study Design The fitness parameters IAT according to Stegmann et al. (28), VO2peak and maximal workload (Ppeak), were assessed during a spiroergometry and ECG controlled exercise test. In addition, the Borg Scale (starting from 6 ⫽ extremely easy to 20 ⫽ extremely exhausting) (23) was used to assess the level of exhaustion at the end of each interval. Mood of participants was rated before the exercise task and 11 as well as 45 minutes after the exercise task by applying the Self-Assessment Manikin (SAM) rating scale (29). Maximal Exercise Test for Physical Fitness Assessment All participants performed a standardized incremental maximal exercise test on a bicycle ergometer (Ergometrics 900, Ergoline, Bitz, Germany) starting from 25 W. Workload was stepwise increased every 3 minutes by 25 W (at approximately 70 –90 revolutions per minute (rpm)) until exhaustion occurred. After reaching exhaustion, all subjects cycled with a low workload (15 W, approximately 30 rpm) for the next 3 minutes and remained sitting for another 12 minutes. Subjects were wearing a face mask, which was connected to a spirometric system (MetaLyzer II, Cortex, Leipzig, Germany) to assess spiroergometry parameters (VO2, CO2 production, RQ). The highest oxygen uptake at the end of the test was regarded as VO2peak (in ml VO2 per minute per kg body weight). Ppeak (in W per kg body weight) was corrected for time, when participants were not able to cycle at the end of the last 3-minute interval. Capillary blood samples of 20 ␮l were obtained from the ear lobe at rest, at the end of each exercise level, and at the end of the 1st, 3rd, 5th, 10th, and 15th minute of the recovering period. Lactate concentrations in mmol/l were measured by the EBIO basic system analyzer, using an enzymaticamperometric measuring system (Eppendorf, Hamburg, Germany). Psychosomatic Medicine 71:519 –523 (2009) REDUCED PHYSICAL FITNESS IN MAJOR DEPRESSION Lactate concentrations of each exercise level were used to determine the IAT (28). The IAT (in W per kg body weight) characterizes the shift from aerobic to anaerobic metabolism, thus reflecting an objective parameter for physical fitness. HRR Assessment HRR was defined as the decrease in heart rate from peak exercise to 1 minute after the cessation of exercise (16). These changes were assessed using ECG recordings. Mood Assessment Affective changes before and after the graduated maximal exercise test were monitored applying the SAM, an affective rating system described by Lang (29) and used for the assessment of mood changes (30). In this system, ratings are divided into nine subitems indicated by graphical representations of facial expressions ranging from a severe frown (most sad ⫽ minus 4) to a broad smile (most positive ⫽ plus 4). Thus, plus 4 represents the extreme of pleasantness and minus 4 the extreme of unpleasantness. Statistical Analyses The parameters VO2peak, Ppeak, IAT, and HRR were tested for normal distribution, using the Kolmogorov-Smirnov test. Then, a multivariate analysis of variance (MANOVA) with the between-subject factor GROUP (patients versus controls) was performed for VO2peak, Ppeak, IAT and HRR, followed by univariate ANOVAs for each parameter. Mood changes over time were analyzed by repeated-measures ANOVA with the between-subject factor GROUP (patients versus controls) and the within-subject factor TIME (before versus after exercise), followed by post hoc t tests for descriptive analysis. VO2peak, Ppeak, IAT, and IPAQ-total were correlated with HRR and depression scales (HAMD-21, BDI, disease manifestation, duration of current episode and work incapacity, number of depressive episodes). In addition, mood changes were correlated with maximal lactate levels after exercise. For correlative analyses, parametric Pearsoncorrelation tests were applied. Significance was assumed for ␣ ⬍ .05. RESULTS Physical Fitness and HRR Assessment All tested parameters showed normal distribution according to the Kolmogorov-Smirnov test. The performed MANOVA revealed a significant effect for the between-subject factor GROUP (F(4,39) ⫽ 4.805, p ⬍ .003). Follow-up univariate ANOVAs showed significant differences for IAT (p ⬍ .001), VO2peak (p ⬍ .01), Ppeak (p ⬍ .003), and HRR (p ⬍ .032), indicating lower fitness levels in patients (Figure 1). Correlations Between Physical Fitness and Patient Characteristics The duration of disease-dependent unemployment (work incapacity) correlated significantly with VO2peak (r ⫽ ⫺.63, p ⬍ .01), Ppeak (r ⫽ ⫺.64, p ⬍ .007), and IAT (r ⫽ ⫺.62, p ⬍ .011) in patients. No correlation was detected between the severity of depression (HAMD-21, BDI) and fitness parameters. Influence of Exercise on Mood Repeated-measures ANOVA showed a significant GROUP ⫻ TIME interaction (F(2,13) ⫽ 9.499, p ⬍ .003). Post hoc t tests revealed that mood improved significantly in the patient group after exercise (p ⬍ .002) (Figure 2A), whereas no change was observed in the control subjects (p ⬍ .387). Psychosomatic Medicine 71:519 –523 (2009) Figure 1. Individual anaerobic threshold (A), maximal oxygen consumption (B), maximal workload (C), and heart rate recovery (D) in controls and patients. Boxes indicate data between the 25th and 75th percentile with the supine bar reflecting the median (f ⫽ mean; E ⫽ 1st and 99th percentile; - ⫽ minimum and maximum of data; *p ⬍ .05, **p ⱕ .01). IAT ⫽ individual anaerobic threshold; VO2peak ⫽ peak oxygen consumption; Ppeak ⫽ maximal work load; HRR ⫽ heart rate recovery. Correlations Between Metabolic Parameters During Exercise and Mood Maximum lactate levels correlated significantly with mood change for both patients and controls (patients p ⬍ .044, controls p ⬍ .006) (Figure 2B). Intriguingly, the slopes of these correlations were inverse in both groups. DISCUSSION Here, we present evidence for reduced physical fitness levels in patients suffering from MDD when compared with controls as assessed using objective spirometric and metabolic parameters. Overall, our results are in line with earlier reports showing reduced VO2peak levels in patients with MDD. However, although these data were compared with normative data only (7), we included a thoroughly matched control group for the first time. To exclude possible confounding factors, the 521 S. BOETTGER et al. Figure 2. A: Mood quality as assessed using the Self-Assessment Manikin (SAM) (29) rating system, ranging from minus 4 (most sad) to plus 4 (most positive) over time (before, 11 and 45 minutes after exercise) in patients (black boxes) and control subjects (circles). Data are presented as mean ⫾ standard deviation. **p ⬍ .01. Mood change presented as gray color boxes. B: Inverse correlations between maximal lactate levels and mood changes for patients and controls. matching procedure included age, gender, BMI, and weekly physical activity. Our data suggest that pathophysiological changes that occur during the course of depression influence physical fitness levels in patients. However, there was a negative correlation between work incapacity and fitness parameters. This, however, can be interpreted in two ways. On the one hand, incapacity to work implies changes in daily life that might consecutively lead to lower physical fitness. On the other hand, an increase in disease-related sick leave might indicate more severe depression. Low physical activity and fitness are known to affect autonomic function (31) and might thus add to the increased cardiovascular risk, which is known to be associated with depression (32). To investigate these clinically important interrelations, HRR which has been identified as an indicator for autonomic modulation (17,18) and more importantly for cardiovascular risk (16,19) has been assessed. We could find reduced HRR in our primarily depressed study population that did not correlate with disease severity. This is well in line with previous studies, in which other parameters of autonomic dysfunction, namely, heart rate variability, has been shown to be overall present in patients suffering from MDD, but no clear-cut correlation to disease severity could be shown (33). In contrast, a correlation for HRR has been shown with scores of BDI in coronary artery disease patients in a recent study (34). In addition, reduced values of HRR further support the evidence of autonomic dysregulation in depressed patients (35,36). However, the effect of antidepressive medication on autonomic function limits our result. Prospective studies need to assess the predictive value of HRR in depressed patients and the possible influence of medication. In addition, HRR might be a helpful aim parameter for intervention studies to assess the effect of fitness training on the autonomic function in depressed patients. Furthermore, we analyzed the effect of the exercise task on mood of patients and controls, measuring mood with SAM 522 (29) before and after the exercise. These effects were inverse between patients and controls. Although mood did not improve in healthy subjects, patients showed a significantly elevated mood after exercise as described previously (37). Interestingly, the improvement of mood in depressed patients was further associated with higher lactate levels. This observation has not been demonstrated before and is of special interest. The relationship of higher maximal lactate levels with decreased mood in control subjects are in line with former studies (38 – 40). This constellation is surprising and further investigations are warranted. Lactate could have direct metabolic effects in patients. Possible effects could also be related to differential effect of ␤-endorphins in patients and controls (41) or due to the influence of exercise on the hypothalamicpituitary-adrenocortical (HPA) axis in patients (42). In addition, one could assume a ceiling effect of mood in control subjects as they did not indicate decreased mood before the test. As a possible confounder, one could speculate about slightly different exhaustion levels between patients and controls. On the other hand, both groups achieved anaerobic metabolism ⬎5 mmol/l lactate at the end of the exercise test. The lactate-mood interaction was described before for lactate levels approximately ⬎4 mmol/l (38) and might therefore not depend on the level of exhaustion. Thus, the relationship between metabolic responses to exercise and changes of mood in depressed patients should be investigated further in future studies. 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