Loss of efferent vagal activity in acute schizophrenia

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Abstract

An increased heart rate has been reported in schizophrenia. It is unclear whether this is due to disease-related autonomic nervous system changes or a side effect of antipsychotic medication. Altered cardiac autonomic function might to some extent account for the elevated cardiovascular mortality rate of schizophrenic patients.

We assessed heart rate variability (HRV) in 30 acute unmedicated schizophrenic patients and matched controls. Patients were re-investigated 2–4 days after initiation of treatment to assess effects of medication.

Our study demonstrates that non-medicated schizophrenic patients were significantly different in heart rate (increase) and parasympathetic parameters (loss of efferent vagal activity) at rest and during deep respiration. No significant effect was found after initiation of neuroleptic therapy. We found a correlation between duration of disease and parasympathetic parameters as well as very low frequency power (VLF) and delusion (SAPS subscale).

These data suggest that schizophrenia is accompanied by a loss of vagal efferent activity, probably due to disturbed cortical–subcortical circuits modulating the autonomic nervous system in acute psychosis. The definite mechanisms by which vagal activity might be suppressed in schizophrenia are unknown.

Parasympathetic hypoactivity might increase the risk for sudden cardiac death and arrhythmias in this disease. Future studies are warranted to investigate the interaction between cardiac autonomic function and schizophrenia and to identify patients on risk.

Introduction

Patients with schizophrenia have a mortality rate two to three times higher than that of the general population (Brown et al., 2000). This elevated mortality has been attributed to both suicide and natural causes, including cardiovascular disease (Brown et al., 2000; Mortensen and Juel, 1990). The higher cardiovascular mortality rate could reflect the unhealthy lifestyle among patients with schizophrenia, e.g., the high prevalence of smoking or obesity (Haupt and Newcomer, 2001; Procyshyn et al., 2004). In addition, the influence of the disease itself and antipsychotic treatment on cardiac autonomic function is under debate (Hennessy et al., 2002). Of particular interest is the extent of corrected QT time (QTc) interval prolongation due to some antipsychotics (Su et al., 2003) which is a predictor of life-threatening cardiac arrhythmias (Vieweg, 2002). The development of serious ventricular arrhythmias is also facilitated due to a depressed parasympathetic tone (Kannankeril and Goldberger, 2002).

The influence of altered brain activity in schizophrenia on cardiac autonomic function is still unclear (Toichi et al., 1999). It has been postulated, that cortical–subcortical circuits modulating the autonomic nervous system are disturbed in acute psychosis (Valkonen-Korhonen et al., 2003). Most studies have reported an increased heart rate in schizophrenic patients (Rechlin et al., 1994; Zahn et al., 1981; Zahn et al., 1997), whereas others found no difference (Nielsen et al., 1988) or even a lower resting heart rate (Dykman et al., 1968). Only a few studies investigated heart rate variability (HRV) in relation to disease or medication (Agelink et al., 1998; Agelink et al., 2001; Malaspina et al., 1997; Rechlin et al., 1994; Zahn et al., 1997) but measures of HRV differed among investigations and their definite physiological meaning remains unclear. HRV is a particularly sensitive method used to study autonomic dysfunction (Low and Pfeifer, 1997). It shows the extent of average heart rate fluctuations and reflects the interplay and balance between sympathetic and parasympathetic input displayed on the cardiac pacemaker. Peripheral control of HRV functions mainly via the parasympathetic cholinergic vagus nerve (Low and Pfeifer, 1997). The hypothalamus, the limbic system and the brain stem are the dominant regulators of the central generation and control of heart rate. A high degree of HRV is observed in subjects with normally functioning hearts, whereas significantly decreased levels of HRV can be observed in patients with low parasympathetic tone. Conventional HRV analysis has been incorporated into clinical standards in both the time and frequency domains (Ziegler et al., 1992).

Time domain measures are parameters calculated via descriptive statistics of the R–R interval distribution within a given ECG recording. Commonly used time domain measures are the mean R–R interval or the RMSSD (root mean square of successive differences) representing interval differences of successive heart beats. These parameters can be calculated at rest or in autonomic tests. The most reliable test for parasympathetic function is the “deep breathing test”, whereas the “heart rate response to standing” is not entirely mediated via the vagal nerve (Low and Pfeifer, 1997).

Frequency domain parameters are calculated by power spectrum analysis (PSA) techniques, which transform time series data into specific frequency components. These frequencies might correspond to specific autonomic physiological processes (Kamath and Fallen, 1993). Respiratory frequency is the most conspicuous of the periodic components of HRV. This high frequency (HF) is considered to range from about 0.15 to 0.4 Hz (Berntson et al., 1997) and is assumed to provide an index of vagal activity. Furthermore, it has been suggested that R–R interval oscillations at low frequencies, about 0.05–0.15 Hz, may reflect mainly sympathetic outflow, although some researchers consider them to be of both sympathetic and vagal origin (Berntson et al., 1997). Very low frequencies and ultra low frequencies have been reported for circadian rhythm, change in activity, thermoregulatory cycles and fluctuations in plasma renin activity (Berntson et al., 1997). The definite origins and mechanisms of very low frequencies, however, remain unclear (Lombardi, 2002).

Based on spectral analyses, Rechlin et al. (1994) reported no significant differences in HRV between schizophrenic patients and control subjects. In contrast, Toichi et al. (1999) demonstrated that the psychotic state can affect the ANS (autonomic nervous system), presumably mediated through the parasympathetic nervous system. In particular, it was shown that the parasympathetic index was significantly decreased when the psychotic state was more pronounced (Okada et al., 2003; Toichi et al., 1999). However, those studies were performed on chronic patients receiving neuroleptic treatment similarly to other reports of diminished cardiac vagal tone (Malaspina et al., 1997). Only one study described reduced parasympathetic tone in acutely psychotic, drug-naive, first-episode patients (Valkonen-Korhonen et al., 2003). However, this study included patients suffering from schizophrenia as well as from psychotic depression.

We therefore assessed HRV in 30 acute schizophrenic patients not receiving antipsychotic treatment for at least 8 weeks and compared parameters to age and sex-matched controls. Patients were reinvestigated 2–4 days after initiation of treatment to analyze the effect of medication. To investigate possible interactions we correlated epidemiological data and psychopathological scales to autonomic parameters.

Section snippets

Participants

Standardized heart rate assessment (HRA) was performed in 30 patients suffering from paranoid schizophrenia and 30 matched (age, sex and education) controls (Table 1). Control persons were recruited from hospital staff. Patients and controls had to be free of any relevant medical or psychiatric disease. Any interfering medication was an exclusion criteria. Participants were asked to refrain from smoking (17 control subjects were smokers), heavy eating or exercising two hours before the

Baseline measures (time point A)

MANOVA for time category A revealed significant overall differences between acutely ill patients and controls for the factor GROUP (Wilks’ Λ = 0.55; F(11, 48) = 3.575; p = 0.001; Fig. 1, Fig. 2(a) and (b)).

Five minutes resting study of HRV

Follow-up univariate ANOVAs showed significantly increased heart rate in schizophrenic patients (F(1, 58) = 20.848; p = 0.0001; Fig. 1(a)). RMSSD (F(1,58) = 9.813; p = 0.003; Fig. 1(b)) and high frequency power, HF (F(1, 58) = 7.298; p = 0.009; Fig. 1(c)) were significantly decreased, reflecting decreased

Cardiac autonomic function in acute schizophrenia

The aim of our study was to examine heart rate variability in acute non-medicated schizophrenic patients to further evaluate the influence of the disease on cardiac autonomic function (CAF). Previous studies have shown alterations in autonomic function in patients with schizophrenia using electrophysiological methods, such as electrodermal measures (Dawson et al., 1994; Hazlett et al., 1997) and heart rate analyses (Agelink et al., 2001; Malaspina et al., 1997; Valkonen-Korhonen et al., 2003;

Acknowledgment

We are grateful to Dr. R. Vollandt (IMSID, Institute for Medical Statistics, University of Jena, Germany) for his advice on statistics.

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