Pseudohypoalgesia on the skin: a novel view on the paradox of pain perception in depression.

Previous studies reported increased heat pain thresholds and decreased ischemic pain thresholds in patients experiencing depression. The increased sensitivity to ischemic muscle pain was assumed to represent a model for the investigation of physical symptoms in the disease. Here, we explored how the serotonin and noradrenaline reuptake inhibitor duloxetine influences experimental pain thresholds and tolerances in depressed patients during treatment. Twenty-two patients experiencing unipolar depression were included. Pain assessments were conducted unmedicated at baseline, after 1 week, and after 6 weeks of duloxetine treatment. We observed the expected clinical response of patients indicated by a significant reduction in the Montgomery Depression Rating Scale after 6 weeks. At baseline, we found increased heat pain thresholds in patients in comparison to controls while patients simultaneously rated augmented pain perception on the visual analog scale. In contrast, patients were significantly more perceptive to ischemic muscle pain at baseline. During treatment, the examined pain thresholds showed differential changes: Increased heat pain thresholds of patients normalized during treatment, whereas no significant change was observed for ischemic pain thresholds. Thus, our results might change the view on the paradox of pain perception in major depression because increased heat pain thresholds are associated with augmented pain perception in the disease.

Ventilatory inefficiency in major depressive disorder: a potential adjunct for cardiac risk stratification in depressive disorders?

BACKGROUND: Cardiopulmonary exercise testing (CPET) provides insights into ventilatory, cardiac and metabolic dysfunction in heart and lung diseases and might play a role in cardiac risk stratification in major depressive disorder (MDD). OBJECTIVE: The VE/VCO(2)-slope indicates ventilatory efficiency and has been applied to stratify the cardiac risk in heart failure (HF). Therefore, the current study was conducted to evaluate and classify ventilatory efficiency and its relationship to physical fitness and disease severity in MDD. METHODS: Exhaustive incremental exercise testing was completed by 15 female MDD patients and pair matched controls. The ventilatory threshold (VT) and the VE/VCO(2)-slope were assessed. Statistical analyses were conducted by means of MANOVAs and follow-up univariate ANOVAs. RESULTS: In patients with MDD, significant different relative work rates and oxygen uptakes at the VT in comparison to healthy controls were observed. Furthermore, we found an increased VE/VCO(2)-slope in depressed patients. We additionally report an inverse relationship between the VE/VCO(2)-slope and peak power output as well as peak oxygen uptake solely in patients. We did not observe any association of assessed parameters with disease severity. CONCLUSION: CPET measures indicate ventilatory inefficiency in patients with MDD. The elevated VE/VCO(2)-slope indicates that patients with MDD need to ventilate significantly more to a given amount of developing CO(2). Further investigations are needed to verify the application of the ventilatory classification system to stratify cardiovascular risk in depressive disorder.

Inflammatory changes upon a single maximal exercise test in depressed patients and healthy controls.

Patients with major depressive disorder (MDD) have repeatedly been described to exhibit both a humoral as well as a cellular pro-inflammatory state. Acute exercise, representing physical stress, can further aggravate such an immune dysbalance. In the light of recommended exercise programmes for depressed patients, we aimed to investigate the inflammatory response to exercise in patients with MDD. Blood cells counts and concentrations of the pro-inflammatory cytokines IL-1ss and IL-6 as well as the anti-inflammatory cytokine IL-10 were obtained before and after a single maximum exercise test in 15 patients suffering from MDD and 15 controls applying a stepwise exhaustion protocol. Patients showed increased white cell counts before and after exercise. While starting from different baseline levels, however, the relative increase in both humoral and cellular inflammatory parameters did not differ between groups. The results from this study suggest that physical training programmes for MDD patients do not bear a dramatically increased risk for acute pro-inflammatory exacerbations. Thus, continuous training programmes that have been shown to reduce the pro-inflammatory state in these patients can be recommended.

Dissociation of performance parameters at the IAT requires specific exercise recommendations for depressed patients.

Aerobic exercise training is considered an adequate complementary treatment strategy for major depressive disorder (MDD). However, there is a need for comparative methodological investigations to determine the appropriate exercise intensity for these patients. The study compared submaximal exercise intensity determination with those derived from maximal parameters such as percentages of heart rate reserve (HRR), maximal heart rate (HR(max)) and peak oxygen uptake (VO(2peak)) of patients and controls. An exhaustive incremental bicycle exercise test was completed by 15 female MDD patients and matched controls. The individual anaerobic lactate threshold (IAT) as a gold standard to determine individual aerobic exercise intensity was assessed according to Stegmann and coworkers. Exercise intensities at 70 and 85% of HR(max), 70 and 85% of HRR and 50 to 80% of VO(2peak) were compared to the IAT. Patients suffering from MDD switched earlier to anaerobic metabolism than matched healthy controls. But interestingly, the level of self-rated perceived exertion, concentration of lactate, respiratory exchange ratio and heart rate at the IAT level revealed no significant difference between both groups. Due to a growing number of clinical aerobic exercise treatments in depressive disorders exercise intensities >70% of (a) HR(max), (b) HRR, (c) VO(2peak) should be amended by the IAT and Borg scale measurements to avoid over challenging as well as increased anaerobic metabolism.

Heart rate variability, QT variability, and electrodermal activity during exercise.

PURPOSE: Various measures of autonomic function have been developed, and their applicability and significance during exercise are controversial. METHODS: Physiological data were therefore obtained from 23 sport students before, during, and after exercise. Measures of R-R interval variability, QT variability index (QTvi), and electrodermal activity (EDA) were calculated. We applied an incremental protocol applying 70%, 85%, 100%, and 110% of the individual anaerobic threshold for standardized comparison. RESULTS: Although HR increased stepwise, parasympathetic parameters such as the root mean square of successive differences were not different during exercise and do not mirror autonomic function satisfactorily. Similar results were observed with the approximate entropy of R-R intervals (ApEnRR). In contrast, the increase in sympathetic activity was well reflected in the EDA, QTvi, and ApEn of the QT interval (ApEnQT)/ApEnRR ratio. CONCLUSION: We suggest that linear and nonlinear parameters of R-R variability do not adequately reflect vagal modulation. Sympathetic function can be assessed by EDA, QTvi, or ApEnQT/ApEnRR ratio.

Physical fitness and heart rate recovery are decreased in major depressive disorder.

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 (VO(2)peak), maximum workload (P peak), 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: VO(2)peak, P peak, 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.

Nonlinear broad band dynamics are less complex in major depression.

OBJECTIVES: Cardiac mortality is known to be increased in depressive patients. However, the underlying mechanisms remain elusive to date. Decreased heart rate variability (HRV) has been discussed as contributing to increased cardiac mortality, but studies examining patients suffering from major depressive disorder (MDD) have revealed inconsistent results. This study aimed to investigate long-term and broad band parameters of heart rate regulation in MDD, which have been shown to be more sensitive for the assessment of autonomic dysfunction. METHODS: A total of 18 non-medicated patients suffering from MDD and 18 matched control subjects without cardiac disease were recruited and 24-h ambulatory electrocardiograms were recorded. Data were recorded during three distinct time intervals linear and nonlinear parameters as well as autonomic information flow (AIF) were calculated. RESULTS: The power law slope was significantly reduced in the patient group for all intervals investigated and correlated with symptom severity, whereas standard deviation of the 5-min NN intervals (SDANN) and area under the AIF curve (INT(NN)) showed significant differences between groups in the morning hours only. Analysis of standard HRV parameters in the time and frequency domain revealed no significant differences between groups. CONCLUSIONS: The evidence for decreased complexity of cardiac regulation in depressed patients presented here might be useful as an indicator of the increased cardiac mortality known in depression, especially since these parameters are capable of predicting cardiac mortality in other diseases. The importance of these parameters for patients at risk should be evaluated in future prospective studies.

Relationship between cardiovagal modulation and psychotic state in patients with paranoid schizophrenia.

Disturbed autonomic nervous system (ANS) function in schizophrenia might contribute to increased cardiovascular mortality. We obtained heart rate variability indices from 40 unmedicated schizophrenic patients and 58 matched controls. Mainly we found that patients displaying stronger psychotic symptoms as assessed by the Brief Psychiatric Rating Scale exhibit more severe cardiac ANS disturbances compared with controls.

Increased prefrontal activation during pain perception in major depression.

BACKGROUND: To further elucidate the close interrelation of pain and depression, we investigated cerebral responses to parametrically varied thermal pain intensities in female patients suffering from major depressive disorder (MDD) (n = 13) and matched control subjects (n = 13) by means of functional magnetic resonance imaging (fMRI). METHODS: After the assessment of the individual thermal pain threshold, an fMRI-compatible thermode was used to deliver thermal painful stimuli to the right arm. All stimuli were initiated for 10 sec from a baseline resting temperature (32 degrees C) in three different conditions (37 degrees C, 42 degrees C, 45 degrees C). Statistical Parametric Mapping 2 (SPM2) software was used for image processing and statistical analyses. RESULTS: Patients displayed significantly increased thermal pain thresholds. A comparable increase in blood oxygenation level-dependent (BOLD) signal was observed in key structures of the pain matrix in patients and control subjects. Patients displayed hyperactivation in comparison with control subjects for the painful 45 degrees C condition in the left ventrolateral thalamus, in the right ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC), as well as a stronger parametric BOLD signal increase in the right VLPFC, DLPFC, and in the contralateral insula. Symptom severity correlated positively with the BOLD signal in the left ventrolateral nucleus of the thalamus. CONCLUSIONS: We present evidence that cortical structures of the pain matrix are similarly activated in depressed patients and healthy subjects. We report increased prefrontal and lateral thalamic activation during the presentation of painful stimuli, which might explain reduced thermal pain perception on the skin in depressed patients.

Increased QT interval variability index in acute alcohol withdrawal.

OBJECTIVE: Acute alcohol withdrawal is associated with increased cardiovascular mortality, most likely due to cardiac arrhythmias. As the QT interval reflects the most critical phase for the generation of reentry and thus for arrhythmia, we examined QT variability in patients suffering from acute alcohol withdrawal. METHODS: High resolution electrocardiographic recordings were performed in 18 male unmedicated patients suffering from acute alcohol withdrawal, 18 matched controls and 15 abstained alcoholics. From these, parameters of beat-to-beat heart rate and QT variability such as approximate entropy and QT variability index (QTvi) were calculated. Measures were correlated with the severity of withdrawal symptoms and with serum electrolyte concentrations. RESULTS: Heart rate and QTvi were significantly increased in acute alcohol withdrawal. Abstained alcoholics did not significantly differ from controls. While QTvi correlated with the severity of alcohol withdrawal symptoms, the mean QT interval duration showed an inverse relationship with serum potassium concentrations. CONCLUSION: Our data indicate increased QT variability and thus increased repolarization lability in acute alcohol withdrawal. This might add to the elevated risk for serious cardiac arrhythmias. In part, these changes might be related to increased cardiac sympathetic activity or low potassium, thus suggesting the latter as possible targets for adjuvant pharmacological therapy during withdrawal.

Altered diurnal autonomic variation and reduced vagal information flow in acute schizophrenia.

OBJECTIVE: This study aimed to further investigate autonomic function in schizophrenic patients using long-term electrocardiographic (ECG) recordings. METHODS: Twenty unmedicated patients suffering from an acute episode of paranoid schizophrenia and 20 matched control subjects were recruited and 24-h ambulatory electrocardiograms were recorded. In order to investigate complexity of heart rate fluctuations related to different physiological time scales, linear heart rate variability (HRV) as well as autonomic information flow (AIF) parameters were calculated from day and night time intervals. RESULTS: While heart rates were increased, root mean successive square difference (RMSSD), a measure for vagal function as well as standard deviation of 5-min mean NN-intervals (SDANN), reflecting parasympathetic and sympathetic tone, were decreased in schizophrenia. Furthermore, a decrease of vagal information flow was apparent during night time (decreased mean high frequency peak decay (PD(mHF))). In addition, increased INT(NN) (area under the AIF curve) as well as decreased beat decay (BD(NN)) and mean very low frequency PD (PD(mVLF)) indicated reduced complexity in patients during day and night time. CONCLUSIONS: HRV and AIF parameters indicate altered diurnal autonomic variation in schizophrenia. SIGNIFICANCE: Reduced vagal modulation and loss of complexity might both contribute to the increased risk for sudden cardiac death in schizophrenia.

Changes of pain perception, autonomic function, and endocrine parameters during treatment of anorectic adolescents.

OBJECTIVES: The underlying mechanisms of reduced pain perception in anorexia nervosa (AN) are unknown. To gain more insight into the pathology, the authors investigated pain perception, autonomic function, and endocrine parameters before and during successful treatment of adolescent AN patients. METHOD: Heat pain perception was assessed in 15 female adolescent AN patients and matched controls. Results were correlated with autonomic and endocrine parameters (free triiodothyronine, free cortisol). Autonomic function was studied using heart rate variability and pupillary light reflex assessment. To investigate the influence of therapy on these parameters, data were obtained at three different time points. RESULTS: Heat pain thresholds were significantly increased in the acute state and decreased after weight had been regained for 6 months. Similarly, an increased parasympathetic tone was present in the acute state only. The relative amplitude of the pupillary light reflex showed a positive correlation to pain thresholds over time and predicted disease progression. In addition, the authors found a negative correlation between increased pain thresholds and low free cortisol. CONCLUSION: Increased pain thresholds are associated with increased parasympathetic tone and a hypothyroid state in AN. This may either indicate common central mechanisms or suggest a causative interaction.

Reduced baroreflex sensitivity in acute alcohol withdrawal syndrome and in abstained alcoholics.

Acute alcohol withdrawal is often associated with increased sympathetic activity, and a decreased baroreflex sensitivity (BRS) can be assumed. Parameters of heart rate variability (HRV), blood pressure variability (BPV), BRS as well as cardiac index (CI), left ventricular work index (LVWI) and total peripheral resistance (TPR) were investigated in 20 patients undergoing acute alcohol withdrawal and matched controls. Measures were obtained during the peak of withdrawal symptomatology prior to treatment as well as 2 and 24h under continuous clomethiazole treatment. Alcohol withdrawal scores were obtained and correlated with autonomic measures. In addition, parameters were assessed in 15 subjects who abstained from alcohol after long-term intake. We found a severe down-regulation of BRS during acute alcohol withdrawal and to a milder extent in abstained alcoholics. Furthermore, HRV and BPV did not unequivocally reveal signs of elevated sympathetic activity. Non-linear parameters of HRV and parameters of BRS correlated with the severity of AWS. The distinct decrease of BRS in AWS and in long-term abstained subjects described here is of importance since similar alterations have been identified as independent prognostic factors for cardiac mortality in other diseases.

Decreased sensitivity to experimental pain in adjustment disorder.

An altered perception of pain has been described for several psychiatric disorders. To date the influence of adjustment disorders (AD) on pain perception has not been described. Here, we investigated perception of experimentally induced pain in 15 patients suffering from AD (subtype with depressive symptoms) and controls matched for age and sex. Thresholds and tolerances were assessed for thermal and electrical pain on both sides of the body. We found an overall increase of pain thresholds and tolerances in AD patients as compared to controls, predominately on the right side of the body. Analogue findings have been reported for pain perception in major depressive disorder (MDD). Of the data obtained, only thermal pain threshold on the right arm correlated with the severity of depressive symptoms. Although the underlying pathology is elusive it is likely that the mechanisms for reduced pain sensitivity are comparable in MDD and AD.

Pain perception in major depression depends on pain modality.

One frequently described feature of depression is an increased vulnerability to pain complaints, and chronic pain is frequently accompanied by symptoms of depression. In contrast to this, a decreased sensitivity to experimental pain has been described in major depression. The physiological basis of this phenomenon is yet elusive. We investigated 30 patients suffering from a major depressive disorder and matched controls. Pain testing (threshold and tolerance) was performed on both sides of the body and included assessment of thermal, electrical and ischemic pain. While confirming hypoalgesia to heat and electrical pain in comparison to controls, we found hyperalgesia to ischemic muscle pain. Furthermore, thermal pain tolerance and electrical pain tolerance were significantly increased on the right hand side confirming previous results of a lateralized perception of pain in depression. Our main finding suggests that painful stimuli are processed differentially depending on the localization of pain induction in depression. This knowledge may enable us to understand and ultimately treat pain complaints more appropriately in depressed patients.