Marcus W. Agelink

Standardized tests of heart rate variability: normal ranges obtained from 309 healthy humans, and effects of age, gender, and heart rate

The authors undertook this study to determine the effects of age, gender, and heart rate (HR) on the results of cardiac autonomic function tests for measuring heart rate variability (HRV) in a large sample of healthy subjects (n=309). Conventional tests (deep breathing, maximum/minimum 30∶15 ratio), and a standardized 5-minute resting study, including spectral analysis of HR, were used. The main findings included (1) the indices of all tests, except for the ratio of the low- (LF) to high-frequency (HF) spectral power (LF/HF ratio) and HR itself, are inversely related to age in both sexes; (2) the 5-minute spectral bands (except for the LF/HF ratio), the variation coefficient, expiratory-inspiratory ratio during deep breathing, and the maximum/minimum 30∶15 ratio are independent of HR; (3) women up to the age of 55 years have a higher resting HR compared with men; (4) young and middleaged women show a significantly lower LF power and LF/HF ratio compared with age-matched men, whereas no significant gender differences are observed in the absolute HF power. The authors computed age- and gender-dependent normal values for each of the HRV indices studied here and discuss the clinical consequences arising from gender differences in HRV.

Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment.

A high sympathetic and/or a low cardiovagal activity in patients with major depression (MD) may contribute to the higher cardiac morbidity and mortality of MD patients. Standardized tests of heart rate variability (HRV) allow a quantitative estimation of autonomic nervous system function. However, previous studies on the relationship between HRV and MD have revealed conflicting results. Our study compared time and frequency domain HRV indices (5-min resting study, deep breathing test, Valsalva test) between 32 patients with MD (DSM-III-R) and 64 non-depressed controls. The severity of depressive symptoms was assessed by the Hamilton Depression Scale (HAM-D); patients were divided into subgroups with moderate (M-HAM-D<25) or severe depressive symptoms (S-HAM-D>or=25). After controlling for age, gender and smoking, S-HAM-D patients showed a higher heart rate and a significantly lower modulation of cardiovagal activity compared to controls. Although some of the HRV indices of the M-HAM-D group did not differ significantly from controls, they were in the expected direction. There was a significantly negative correlation between the HAM-D scores and the vagal HRV indices, suggesting a direct association between the severity of depressive symptoms and the modulation of cardiovagal activity. Clinical consequences arising from these findings and possible implications for treatment are discussed.

Volume deficits of subcortical nuclei in mood disorders A postmortem study.

AbstractStructural changes in subcortical nuclei may underlie clinical symptoms of mood disorders. The goal was to determine whether macrostructural changes exist in brain areas assumed to be involved in regulation of mood and whether such changes differ between major depressive disorder and bipolar disorder. A case–control design was used to compare volumes of all major subcortical nuclei. Brains of patients with major depressive disorder (n = 9) or bipolar disorder (n = 11) or of individuals without a neuropsychiatric disorder (n = 22) were included. Exclusion criteria were a history of substance abuse or histological signs of neurodegenerative disorders.Volumes of the striato–pallidal nuclei, of the hypothalamus, thalamus, amygdala, hippocampus and basal limbic forebrain were determined in the right and left hemisphere by planimetry of 20 μm whole brain serial paraffin sections. Comparisons between patients with bipolar disorder, major depressive disorder and controls showed a significant (Λ = 0.35, F20,56 = 1.93, P = 0.028) overall difference in volumes of all investigated regions with strong effect sizes ( ƒ > 0.40) contributed by the hypothalamus, external pallidum, putamen and thalamus. As compared to controls, a strong effect size (ƒ > 0.40) was found in the bipolar group for smaller volumes of the hypothalamus, external pallidum, putamen and thalamus,whereas in patients with major depressive disorder a strong effect size was only found for a smaller volume of the external pallidum. In conclusion our data suggest that pathways presumably involved in mood regulation have structural pathology in affective disorders with more pronounced abnormalities in bipolar disorder.

Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam, and lorazepam.

ObjectivesTo evaluate the effects of intravenously applied diazepam, lorazepam, and midazolam on autonomic neurocardiac regulation assessed by standardized measurements of heart rate variability. DesignProspective, randomized clinical study. SettingUniversity teaching hospital. PatientsForty-five patients, who underwent a gastroscopy, were randomly assigned to intravenous premedication with midazolam (5 mg), diazepam (10 mg), or lorazepam (4 mg). Six subjects refused an injection and served as nonpremedicated controls. InterventionsSerial recordings of the 5-min resting heart rate variability were obtained before and 15 and 30 mins after premedication. Seven benzodiazepine-treated patients received intravenous flumazenil (0.5 mg). Measurements and Main ResultsThe average doses applied were 0.07 mg/kg for midazolam, 0.13 mg/kg for diazepam, and 0.06 mg/kg for lorazepam. Fifteen minutes after intravenous benzodiazepines were administered, we found an increase in resting heart rate and a reduction of vagal tone compared with baseline in all three benzodiazepine-treated subgroups. Multivariate analysis (covariate age) of the changes in heart rate variability indices over the experimental course revealed a significant reduction in absolute high-frequency power with midazolam or diazepam compared with nonpremedicated subjects. Moreover, midazolam-treated subjects showed a significantly larger reduction in relative high-frequency power not only compared with nontreated subjects, but also compared with lorazepam- or diazepam-treated subjects. Vagal tone remained reduced compared with baseline even 30 mins after benzodiazepine application, however, the resting heart rate decreased toward baseline levels. After flumazenil administration, there was a linear correlation between an increase in high-frequency power and a corresponding decrease in resting heart rate. ConclusionsBenzodiazepines can influence autonomic neurocardiac regulation in man, probably through their interaction with the &ggr;-aminobutyric acidA-receptor chloride ion channel complex. The pattern of findings suggests that intravenous midazolam, diazepam, and lorazepam influence human autonomic neurocardiac regulation in a biphasic way. First, they cause a reduction of central vagal tone, and second, they may decrease the cardiac pacemaker directly. Flumazenil completely abolished the autonomic neurocardiac regulation effects of benzodiazepines.

The interaction between pupil function and cardiovascular regulation in patients with acute schizophrenia

OBJECTIVE Cardiac autonomic dysregulation has been reported in patients with schizophrenia. However, there are no definite data examining whether other branches of the autonomic nervous system are compromised as well and how they interrelate with cardiac function. In this study, we tested the hypothesis that the autonomic dysregulation at the heart is reflected in the regulation of the pupillary light reflex. METHODS We assessed heart rate variability and baroreflex sensitivity parameters as well as pupillographic measures in 28 unmedicated patients with schizophrenia and compared these measures to those of 28 controls. In addition, cardiovascular and pupillographic parameters were correlated in both groups. RESULTS The obtained cardiovascular parameters indicated decreased parasympathetic modulation. Patients showed a significantly increased resting pupil diameter as well as reduced relative amplitude, suggesting a dominance of sympathetic control and a lack of parasympathetic modulation at the pupil. Intriguingly, the parasympathetic latency of the pupil constriction was similar in both groups and correlated with several cardiovascular parameters. These correlations were in the opposite direction in patients compared to controls. Furthermore, shorter latencies of the pupil constriction were associated with symptom severity in patients. CONCLUSIONS Overall, we found evidence for an autonomic dysregulation at the pupil and heart in patients with schizophrenia. Future studies are warranted to describe this complex interaction at different levels of the autonomic system. SIGNIFICANCE The interrelationship of both the systems indicates that the autonomic dysfunction affects the regulation in different branches of the autonomic network as well as their interaction in schizophrenia.

Alcoholism, peripheral neuropathy (PNP) and cardiovascular autonomic neuropathy (CAN)

In contrast to diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN) in long-term alcoholics has been studied rarely. Using both standardized bedside tests and computer-assisted analysis of heart rate variability (HRV), we prospectively compared autonomic neurocardial function between 35 strictly selected, detoxified alcoholics (DSM-III-R), and 80 well matched healthy controls. Evidence for a potential CAN was found in 25.7% of all the alcoholics studied and in 41% of those with clinically manifest PNP (n=22). Overall, our results demonstrated a significant association between the presence of a CAN and peripheral neuropathy (PNP) amongst chronic alcoholics (chi-square test P<0.05); there was no evidence of a CAN in any of the alcoholics without a clinically manifest PNP. The CAN was characterized by a dissociated appearance of parasympathetic and sympathetic disorders. Our findings provide reason to suspect that the total lifetime dose of alcohol and the duration of alcohol dependence are the most important factors contributing to the pathogenesis of both PNP and sympathetic dysfunction. As is the case with diabetics, computer-assisted measurements of HRV including spectral analysis appear to be far superior to conventional bedside tests for detecting evidence of cardiovagal dysfunction in long-term alcoholics.

Differences in activation of the dorsal raphe nucleus depending on performance of suicide

The serotonergic system has been implicated in the pathogenesis of mood disorders as well as in suicidal behavior. It is unknown, however, whether raphe neurons, which are mostly serotonergic, show altered activity in patients with mood disorders who complete suicide as compared to those without suicidal behavior. In order to measure cellular markers of serotonergic activity in the dorsal raphe nucleus in brains of 12 people with mood disorders and of 12 controls (C), stereological measurements were carried out of nucleolar organizer regions (AgNORs) and of serotonergic neuron numbers. Six patients died from suicide (S) and the other six patients died from natural causes (NS). Results were assessed using ANOVA and post hoc Tukey-HSD tests looking for effects of diagnostic group (S, NS, C). Results show that in the rostral subnuclei of the dorsal raphe there was a significant effect of diagnostic group on the ratios of the nucleolar organizer regions to nuclear area (NOR ratio) and a nearly significant effect on numbers of serotonergic neurons. Post hoc tests revealed larger values for those dependent variables in S compared to NS. Dose equivalents of antidepressants correlated positively with NOR ratios and numbers of serotonergic neurons in the rostral part of the dorsal raphe. In conclusion, the present data suggest that there are functional differences in the dorsal raphe of patients with mood disorders depending on suicidal behavior. Antidepressants appear to contribute to cellular activation in the rostral part of the dorsal raphe.

Repetitive transcranial magnetic stimulation (rTMS) improves facial affect recognition in schizophrenia.

OBJECTIVE Facial affect recognition, a basic building block of social cognition, is often impaired in schizophrenia. Poor facial affect recognition is closely related to poor functional outcome; however, neither social cognitive impairments nor functional outcome are sufficiently improved by antipsychotic drug treatment alone. Adjunctive repetitive transcranial magnetic stimulation (rTMS) has been shown to enhance cognitive functioning in both healthy individuals and in people with neuropsychiatric disorders and to ameliorate clinical symptoms in psychiatric disorders, but its effects on social cognitive impairments in schizophrenia have not yet been studied. Therefore, we evaluated the effects of sham-controlled rTMS on facial affect recognition in patients with chronic schizophrenia. METHOD Inpatients (N = 36) on stable antipsychotic treatment were randomly assigned to double-blind high-frequency (10 Hz) rTMS or sham stimulation for a total of ten sessions over two weeks. In the verum group, each session consisted of 10 000 stimuli (20 trains of 5 s) applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. Facial affect recognition was assessed before (T0) and after (T1) the ten sessions. RESULTS Facial affect recognition improved significantly more after rTMS (accuracy change: mean = 8.9%, SD = 6.0%) than after sham stimulation (mean = 1.6%, SD = 3.5; Cohens d = 1.45). There was no correlation with clinical improvement. CONCLUSION Our results indicate that prefrontal 10 Hz rTMS stimulation may help to ameliorate impaired facial affect recognition in schizophrenia.

Cardiovagal modulation upon postural change is altered in Huntington’s disease

Background:  Cardiac autonomic nervous system (ANS) dysfunction in Huntington’s disease (HD) might affect both the sympathetic and parasympathetic branch of the ANS.

Cardiovascular Adverse Reactions During Antidepressant Treatment: A Drug Surveillance Report of German-Speaking Countries Between 1993 and 2010

Background: Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations. Methods: Of 169 278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed. Results: Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%), TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure. Conclusions: Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings.