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Aims: Schizophrenia patients have a mortality rate two to three-fold higher than that of the general population. Despite the disorder's widespread recognition, how and to what extent autonomic nervous system (ANS) activity contributes to schizophrenia remains inconclusive. The aim of the present study, therefore, was to determine the extent of ANS activity depression with respect to healthy, well-matched control subjects and the severity of psychiatric disorders as determined using the Global Assessment of Functioning (GAF) scale among schizophrenia patients with special reference to antipsychotic dose.
Methods: This study included 71 schizophrenia patients and 72 healthy controls. ANS activity was assessed by means of heart rate variability power spectral analysis.
Results: ANS-related spectral parameters were three–four-fold lower in the patients compared to the control group (P < 0.01). Furthermore, when the patients without cardiovascular complications were classified according to GAF score, overall ANS (P = 0.033) and parasympathetic nervous system (PNS) activity (P = 0.025) were significantly reduced in the low-GAF as compared to the high-GAF group. Partial correlation analyses demonstrated that ANS activity was significantly correlated with GAF score while statistically eliminating the effects of age, gender, body mass index, antipsychotic dose, and lipid profiles of the patient population.
Conclusion: The significantly lower ANS activity in the low-GAF group suggests that such autonomic functional depression could be associated with the severity of schizophrenia. The present data further imply that schizophrenia patients with more depressed overall ANS and PNS activity might encounter increasing risks for cardiovascular events such as sudden death.
SCHIZOPHRENIA, A CHRONIC psychiatric disorder, creates numerous challenges, not only in terms of its clinical management, but also in the psychosocial consequences for the patient. The clinical picture, depending on the phase of illness, includes a wide range of positive and negative symptoms and/or a broad range of cognitive symptoms. Epidemiological studies have shown that schizophrenia affects approximately 1% of the population, with point prevalence ranging from 0.6 to 8.3 cases per 1000 population.1,2
Previously, Ruschena et al. reported that patients with schizophrenia are threefold more likely to experience sudden unexpected death than individuals from the general population.3 Increased mortality in patients with schizophrenia, compared to the general population, has been consistently reported worldwide.4 Furthermore, individuals with schizophrenia have more major coronary heart disease events, such as acute myocardial infarction.5,6 The underlying bio-psychological mechanisms, however, which are complex and multidimensional and might affect diverse neurophysiologic systems, remain unknown.
Although all body systems contribute, the relative stability of the human internal environment depends largely on the functioning of the autonomic nervous system (ANS) that innervates organs and glands throughout the body. Therefore, even a slight disorder of the ANS could induce broadly ranged neuropsychophysiological disorders and ultimately, far-reaching adverse effects on health.
The electrocardiogram (ECG) R-R interval or inter-beat interval is determined by the net effect of sympathetic and parasympathetic input. Because it is accessible and non-invasive, the spectral analysis of heart rate variability (HRV) has gained popularity as a functional indicator of the ANS.7–9 In addition, HRV power spectral analysis lightens the burden imposed on subjects during an experiment, unlike invasive measurements, such as plasma catecholamine concentration and muscle sympathetic nervous activity. In short, it offers a practical and valuable approach to evaluation of the sympatho-vagal activity in various clinical science fields, including psychiatry research.7–12
Accordingly, the present study was proposed to evaluate resting ANS activity by means of HRV power spectral analysis of patients with schizophrenia and healthy well-matched controls and to investigate whether reduced sympatho-vagal activity contributes to unfavorable pathological alteration in patients with schizophrenia. We also examined a possible association between psychiatric severity and sympatho-vagal activities to investigate the nature of ANS alteration as a possible clinical feature of schizophrenia.
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Schizophrenia, a severe mental disorder, requires lifelong treatment, and therefore information on its pathophysiological features and psychotropic effects together with cardiovascular health, is of clinical importance. Although schizophrenia has a multicausal origin, and its pathogenesis is not yet clearly understood, it is conceivable that altered function of the ANS – a vital player in modulating the relative stability of a human's internal environment – is associated with the severity and frequency of the symptom cluster appearing with schizophrenia.
In the present study we used a computer-assisted 5-min measurement of resting HRV to evaluate ANS activity in schizophrenia patients. Measurement of HRV integrates pre-synaptic and post-synaptic end-organ response and provides a comprehensive quantitative and qualitative evaluation of autonomic function under various physiological conditions and clinical settings.19,21,22 Although quantification and interpretation of HRV remain an intricate issue,7,23 the efficacy and applicability of the technique as demonstrated in a pharmacological blockade experiment with atropine, a parasympathetic muscarinic antagonist and propranolol, a β-adrenoceptor antagonist,15,24 have supported the classical studies18,19 and confirmed that (i) HF power is associated solely with PNS activity and LF power is jointly mediated by PNS and SNS activity; and (ii) R-R interval variability and TP – the integrated values of all the components of power spectra – could reflect overall ANS activity.
We are aware of the fact that LF and HF powers in schizophrenia are reduced as reported in previous studies.12,25 In the present study we therefore attempted to determine the extent of ANS activity depression with respect to (i) healthy, well-matched control subjects and (ii) the severity of psychiatric disorders as determined by the GAF scale among schizophrenia patients with special reference to daily dosage of antipsychotic drugs.
We found three–fourfold lower ANS activities in the patient group than in the control group, implying that the previously reported threefold-higher mortality rate, including sudden cardiac death, might be, at least in part, associated with severely depressed PNS activity in schizophrenia patients.3 Further evidence would be provided by the significantly higher resting heart rate often seen in diabetics, with some degree of autonomic neuropathy, which in turn causes cardiac parasympathetic withdrawal leading to elevated heart rate.9,21,22,26
In addition, we have re-examined the effect of antipsychotic dosages27–29 and other lipid and cardiovascular complications15,21,26 that may have a large impact upon ANS activity as well as, indirectly, the GAF scores. After eliminating patients with these complications, we then compared the net relationship between ANS activity and low- and high-GAF groups. Intriguingly, we found that the low-GAF group showed significantly lower TP (overall ANS activity) and HF power (PNS activity), despite the fact that the low-GAF group was significantly younger (nearly 10 years difference), with non-significant differences in CPZeq as well as BMI, waist circumference, blood glucose, and lipid profiles.
Among the entire patient population, partial correlation analysis demonstrated that TP and HF power had significant correlation with the GAF score, while statistically eliminating the effects of age, gender, BMI, CPZeq, and biochemical profiles. We think that these findings, derived from comparisons between normal and patient groups as well as low- and high-GAF patients, do provide some new insight into the pathophysiological nature of schizophrenia, that is, depression of PNS activity may play an important role in the development of schizophrenia and possible etiology of sudden cardiac death.3–5,21,26
Previous studies suggest that a dysfunction of both SNS and PNS contribute to psychosomatic disorders as well as to cardiovascular and metabolic malfunction.9,11,15,21,22,26,30 As to psychiatric diseases, a recent clinical study by Bar et al. showed that patients displaying stronger psychotic symptoms as according to total scores of the Brief Psychiatric Rating Scale, exhibit more severe cardiac autonomic disturbances as indicated by a reduced HF power compared with controls.25 According to Jindal et al., autonomic deficits have been shown to be more pronounced during acute psychotic episodes in patients with first-episode schizophrenia, implying that autonomic dysfunction in schizophrenia may also be a ‘disease effect’.31 Toichi et al., using HRV measurements, showed that psychotic states affect the ANS, suggesting a relationship between cerebral cognitive and peripheral ANS activities, and that this is presumably mediated through PNS activity.32
The present study supports these previous findings and suggests that schizophrenia patients possessed markedly depressed ANS activity, which was further associated with the degree of psychiatric severity on schizophrenia. Taken together, physiological functions in both branches of the ANS might deteriorate more as the schizophrenia becomes more severe. Further research is needed to assess patient condition using other scores of psychiatric symptoms, such as the Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale and to examine an association between ANS activity and these scores. As to the pharmacological effects, previous research has found significant negative correlation between the daily dosage of anticholinergic drugs converted into biperiden milligram equivalents and HRV.30 Wang et al., in contrast, recently examined an association of ANS activity and atypical antipsychotic drugs and demonstrated that amisulpride has more vagotonic effect as compared with olanzapine when subjects are switched from typical antipsychotic agents.33 Although we investigated the effect of CPZeq as an index of daily dose of antipsychotic drugs on ANS activity in schizophrenia patients, it would also be of clinical importance to further scrutinize how and to what extent pharmacological treatments – dosage, types, and combination of medications and duration of drug administration – influence schizophrenia symptomatology as well as sympatho-vagal function together with cardiovascular safety.