Timo Siepmann

The effects of venlafaxine on autonomic functions in healthy volunteers

Antidepressants that block norepinephrine uptake may cause unwanted effects on autonomic functions such as reduction of heart rate variability. This randomized, double-blind, placebo-controlled study examined the effects of venlafaxine on heart rate variability, vasoconstrictory responses (VRs) of cutaneous blood vessels, and pupillary light reflex in humans. Twelve healthy male subjects aged 23 to 32 years (mean ± SD, 26 ± 3 years) orally received 37.5 mg of venlafaxine BID for 7 days and subsequently 75 mg BID for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized double-blind crossover conditions. Heart rate variability was diminished, and the dilation phase of VR was prolonged during multiple dosing with venlafaxine (P < 0.05). A significant increase in resting pupil diameter, a decrease in amplitude, an increase in latency, and a shortening of the 33% recovery time of the pupillary light reflex were noted with the drug, whereas no changes were observed under placebo condition. Sustained VR and shortening of the recovery time of the pupillary light reflex are consistent with sympathetic potentiation resulting from noradrenaline reuptake blockade in cutaneous blood vessels and iris. The decrease in amplitude and increase in latency of the pupillary light reflex could be indicative of centrally mediated parasympathetic inhibition.

Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence

Several clinical studies have indicated that selective serotonin reuptake inhibitors (SSRIs) administered in patients after acute ischemic stroke can improve clinical recovery independently of depression. Due to small sample sizes and heterogeneous study designs interpretability was limited in these studies. The mechanisms of action whereby SSRI might improve recovery from acute ischemic stroke are not fully elucidated.

Exploring the risk-factor association between depression and incident stroke: a systematic review and meta-analysis

There is growing evidence that depression increases the risk of incident stroke. However, few studies have considered possible residual confounding effects by preexistent cerebrovascular and cardiac diseases. Therefore, we synthesized data from cohort studies to explore whether depressed individuals free of cerebrovascular and cardiac diseases are at higher risk of incident stroke. We searched the electronic databases PubMed and Medline for eligible cohort studies that examined the prospective association between depression and first-ever stroke. A random-effects model was used for quantitative data synthesis. Sensitivity analyses comprised cohort studies that considered a lag period with exclusion of incident strokes in the first years of follow-up to minimize residual confounding by preexistent silent strokes and excluded cardiac disease at baseline. Overall, we identified 28 cohort studies with 681,139 participants and 13,436 (1.97%) incident stroke cases. The pooled risk estimate revealed an increased risk of incident stroke for depression (relative risk 1.40, 95% confidence interval [CI] 1.27–1.53; P<0.0001). When we excluded incident strokes that occurred in the first years of follow-up, the prospective association between depression and incident stroke remained significant (relative risk 1.64, 95% CI 1.27–2.11; P<0.0001). This positive association also remained after we considered only studies with individuals with cardiac disease at baseline excluded (relative risk 1.43, 95% CI 1.19–1.72; P<0.0001). The prospective association of depression and increased risk of first-ever stroke demonstrated in this meta-analysis appears to be driven neither by preexistence of clinically apparent cerebrovascular and cardiovascular diseases nor by silent stroke.

Laser Doppler imaging in the detection of peripheral neuropathy

Small fiber neuropathy is common in a number of systemic diseases and is often challenging to diagnose. Laser Doppler imaging (LDI) is a test of small fiber neurovascular function that can quantify the integrity of the vasomotor C-fiber mediated axon-reflex, but no standardized method of analysis exists. We developed a novel LDI analysis technique and tested it in a human model of small fiber neuropathy. Eighteen healthy subjects (age 24 ± 3 years) underwent LDI testing to assess the axon-mediated flare area in response to 10% acetylcholine iontophoresis. LDI measurements were taken before and longitudinally after a 48-hour application of 0.1% capsaicin (to cause a transient small fiber neuropathy) on the skin of the thigh; placebo cream was placed on the contralateral thigh as a control. We compared our new LDI image analysis technique to two previously published methods. The new LDI analysis technique was the only method to show a consistent difference in axon-reflex area between capsaicin treated and placebo treated skin on all testing days (p<0.05) with maximum attenuation of the flare area immediately post-application (438 ± 298 mm(2) vs. 824 ± 375 mm(2), p<0.05). In conclusion, this study demonstrates that our novel flare area method for LDI analysis can detect neurovascular dysfunction in a model of small fiber neuropathy, is an improvement over existing methods, and may supplement clinical assessment of small fiber neuropathy.

Long-term cerebral white and gray matter changes after preeclampsia

Objective: To determine whether changes in cerebral structure are present after preeclampsia that may explain increased cerebrovascular risk in these women. Methods: We conducted a case control study in women between 5 and 15 years after either a preeclamptic or normotensive pregnancy. Brain MRI was performed. Analysis of white matter structure was undertaken using voxel-based segmentation of fluid-attenuation inversion recovery sequences to assess white matter lesion volume and diffusion tensor imaging to measure microstructural integrity. Voxel-based analysis of gray matter volumes was performed with adjustment for skull size. Results: Thirty-four previously preeclamptic women (aged 42.8 ± 5.1 years) and 49 controls were included. Previously preeclamptic women had reduced cortical gray matter volume (523.2 ± 30.1 vs 544.4 ± 44.7 mL, p < 0.05) and, although both groups displayed white matter lesions, changes were more extensive in previously preeclamptic women. They displayed increased temporal lobe white matter disease (lesion volume: 23.2 ± 24.9 vs 10.9 ± 15.0 μL, p < 0.05) and altered microstructural integrity (radial diffusivity: 538 ± 19 vs 526 ± 18 × 10−6 mm2/s, p < 0.01), which also extended to occipital and parietal lobes. The degree of temporal lobe white matter change in previously preeclamptic women was independent of their current cardiovascular risk profile (p < 0.05) and increased with time from index pregnancy (p < 0.05). Conclusion: A history of preeclampsia is associated with temporal lobe white matter changes and reduced cortical volume in young women, which is out of proportion to their classic cardiovascular risk profile. The severity of changes is proportional to time since pregnancy, which would be consistent with continued accumulation of damage after pregnancy.

Autonomic Dysregulation in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. These autonomic disturbances reduce the quality of life of affected patients and constitute a clinical challenge to the physician due to variability of clinical presentation and inconsistent data on diagnosis and treatment. Early diagnosis and initiation of individualized interdisciplinary and multimodal strategies is beneficial in the management of autonomic dysfunction in MS. This review summarizes the current literature on the most prevalent aspects of autonomic dysfunction in MS and provides reference to underlying pathophysiological mechanisms as well as means of diagnosis and treatment.

Pharmacokinetic/pharmacodynamic modelling of venlafaxine: pupillary light reflex as a test system for noradrenergic effects.

AbstractBackground and objective: Venlafaxine and its major active metabolite O-desmethylvenlafaxine selectively inhibit serotonin and norepinephrine reuptake from the synaptic gap. The inhibition of norepinephrine uptake is assumed to enhance antidepressant efficacy when venlafaxine is given at higher therapeutic doses. Thus investigation of the concentration-response relationship of noradrenergic effects is of clinical interest. We used pupillography as a test system for the pharmacodynamic response to venlafaxine, since it had been shown to be useful for assessment of noradrenergic effects on the autonomous nervous system. The aim of the study was to develop a pharmacokinetic/pharmacodynamic model by means of nonlinear mixed-effects modelling in order to describe the time course of the noradrenergic response to venlafaxine. Subjects and methods: Twelve healthy male subjects received venlafaxine 37.5 mg or placebo orally twice daily for 7 days and subsequently 75 mg or placebo twice daily for another 7 days. After a 14-day washout phase, the two groups were crossed over. After the last dose of venlafaxine or placebo on day 14, blood samples were drawn to determine venlafaxine and O-desmethylvenlafaxine concentrations and the amplitude and recovery time of the pupillary light reflex were measured. A pharmacokinetic/pharmacodynamic model was developed to describe the data using nonlinear mixed-effects modelling. Results: The pharmacokinetic part of the model could be simultaneously fitted to both venlafaxine and O-desmethylvenlafaxine data, yielding precise parameter estimates that were similar to published data. The model detected high variability of the intrinsic clearance of venlafaxine (94.8%), most likely due to cytochrome P450 2D6 polymorphism. Rapid development of tolerance of the pupillary light reflex parameters was seen and could be successfully accounted for in the pharmacodynamic part of the model. The half-life of development and regression of tolerance was estimated to be 30 minutes for the amplitude and 40 minutes for the recovery time. Conclusion: The time course of the effect and the concentration-response relationship were successfully described by a pharmacokinetic/pharmacodynamic model that takes into account the rapid development of tolerance of pupillary light reflex parameters. This provides a basis for further investigations of the applicability of pupillography as a surrogate measurement of the effectivity of antidepressant drugs with norepinephrine reuptake-inhibiting properties.

The Effects of Pretreatment versus De Novo Treatment with Selective Serotonin Reuptake Inhibitors on Short-term Outcome after Acute Ischemic Stroke

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) administered in patients following acute ischemic stroke have shown to improve clinical recovery independently of changes in depression. Animal studies have demonstrated that sustained SSRI treatment is superior to short-term SSRI in evoking neurogenesis but how this benefit translates into humans remains to be answered. We hypothesized that in acute ischemic stroke patients, SSRI treatment started before the event leads to improved short-term outcomes compared to de novo SSRI treatment poststroke. METHODS We performed an exploratory analysis in consecutive acute ischemic stroke patients and compared patients already receiving fluoxetine, citalopram, or escitalopram with those who started treatment de novo. RESULTS Of 2653 screened patients, 239 were included (age, 69 ± 14 years; 42% men, baseline median National Institutes of Health Stroke Scale score, 7 [IQR, 10]). Of these patients, 51 started treatment with SSRI before stroke and 188 were prescribed newly SSRIs during hospitalization. In the adjusted multivariate logistic regression models, SSRI pretreatment was associated with favorable functional outcome at discharge defined as a modified Rankin Scale score of 2 or less (odds ratio [OR], 4.00; 95% confidence interval [CI], 1.68-9.57; P < .005), improved early clinical recovery (OR, 2.35; 95% CI, 1.15-4.81; P = .02), and a trend toward prediction of superior motor recovery (OR, 1.82; 95% CI, .90-3.68; P < .01). CONCLUSIONS Our data suggest that SSRI pretreatment may improve clinical outcomes in the early stages of acute ischemic stroke supporting the hypothesis that prolonged SSRI treatment started prestroke is superior to poststroke SSRI.

Neuropsychiatric symptoms in untreated parkinson’s disease

Neuropsychiatric and cognitive symptoms are common in Parkinson’s disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment.

Heart rate variability biofeedback in patients with alcohol dependence: a randomized controlled study

Background and objective In patients with alcohol dependence, ethyl-toxic damage of vasomotor and cardiac autonomic nerve fibers leads to autonomic imbalance with neurovascular and cardiac dysfunction, the latter resulting in reduced heart rate variability (HRV). Autonomic imbalance is linked to increased craving and cardiovascular mortality. In this study, we sought to assess the effects of HRV biofeedback training on HRV, vasomotor function, craving, and anxiety. Methods We conducted a randomized controlled study in 48 patients (14 females, ages 25–59 years) undergoing inpatient rehabilitation treatment. In the treatment group, patients (n=24) attended six sessions of HRV biofeedback over 2 weeks in addition to standard rehabilitative care, whereas, in the control group, subjects received standard care only. Psychometric testing for craving (Obsessive Compulsive Drinking Scale), anxiety (Symptom Checklist-90-Revised), HRV assessment using coefficient of variation of R-R intervals (CVNN) analysis, and vasomotor function assessment using laser Doppler flowmetry were performed at baseline, immediately after completion of treatment or control period, and 3 and 6 weeks afterward (follow-ups 1 and 2). Results Psychometric testing showed decreased craving in the biofeedback group immediately postintervention (OCDS scores: 8.6±7.9 post-biofeedback versus 13.7±11.0 baseline [mean ± standard deviation], P<0.05), whereas craving was unchanged at this time point in the control group. Anxiety was reduced at follow-ups 1 and 2 post-biofeedback, but was unchanged in the control group (P<0.05). Following biofeedback, CVNN tended to be increased (10.3%±2.8% post-biofeedback, 10.1%±3.5% follow-up 1, 10.1%±2.9% follow-up 2 versus 9.7%±3.6% baseline; P=not significant). There was no such trend in the control group. Vasomotor function assessed using the mean duration to 50% vasoconstriction of cutaneous vessels after deep inspiration was improved following biofeedback immediately postintervention and was unchanged in the control group (P<0.05). Conclusion Our data indicate that HRV biofeedback might be useful to decrease anxiety, increase HRV, and improve vasomotor function in patients with alcohol dependence when complementing standard rehabilitative inpatient care.