Martin Siepmann

Pharmacokinetics and Pharmacodynamics of Scopolamine after Subcutaneous Administration

The effects of subcutaneously administered scopolamine on quantitative electroencephalogram (qEEG) and cognitive performance were evaluated and correlated with pharmacokinetic parameters in a randomized, double‐blind placebo‐controlled crossover study of 10 healthy male volunteers. Changes in qEEG and cognition were determined for 8 hours after drug administration. Scopolamine produced dose‐ and time‐dependent impairments of attention and memory and a time‐dependent increase in delta power (1.25‐4.50 Hz) and a decrease in fast alpha power (9.75‐12.50 Hz) on qEEG compared with placebo. Maximum serum concentrations of scopolamine occurred 10 to 30 minutes after drug administration. Mean peak serum concentrations (free base) were 3.27, 8.99, and 18.81 ng/mL after administration of 0.4, 0.6 mg, and 0.8 mg scopolamine, respectively. Elimination half‐life was approximately 220 minutes. The findings indicate temporary changes in qEEG and psychometric tests, and support the possible use of such a testing model for impaired cognitive functions such as age‐related memory disturbances.

Effects of Caffeine on Topographic Quantitative EEG

Despite the widespread use of caffeine as a central nervous stimulant, the central pharmacodynamic properties of the drug have not yet been conclusively evaluated in humans. The present study was undertaken to assess the acute effects of caffeine on measures of topographical quantitative electroencephalogram (EEG) in normal subjects. Ten healthy male volunteers (mean age ± SD 25 ± 4 years) received placebo and 200 mg of caffeine as powder with oral water solution (caffeine amount = 2 cups of coffee) under randomized, double-blind crossover conditions on two different occasions. Before administration and 30 min afterwards, a 17-channel quantitative EEG was recorded during relaxation with eyes open and closed (15 min each). Caffeine caused a significant reduction of total EEG power at fronto-parieto-occipital and central electrode positions of both hemispheres when the subjects kept their eyes open. Absolute power of the slow and fast alpha and slow beta activities was diminished in various regions of the brain (p < 0.05). The effect was more pronounced with the subjects keeping their eyes open than with eyes closed. It can be concluded that quantitative EEG is a sensitive method to assess the effects of psychostimulants on the human brain. Therefore, in pharmaco-EEG studies, environmental factors such as caffeine have to be excluded.

Acute effects of caffeine on heart rate variability in habitual caffeine consumers.

During the last years, heart rate variability (HRV) has become a promising risk factor for cardiovascular events. However, the effect of caffeine on HRV in habitual caffeine consumers has barely been investigated. Therefore, we treated 30 male habitual caffeine users in a randomized double‐blinded crossover study design with either placebo, 100 or 200 mg caffeine orally and determined parameters of HRV under resting conditions and metronomic breathing. As result, we could not detect significant differences in HRV parameters up to 90 min after drug ingestion. We conclude that modest amounts of caffeine do not reveal negative nor positive effects on HRV within the first 90 min after drug ingestion in young and healthy habitual caffeine consumers. However, further research is necessary to determine the effects of caffeine on HRV in habitual caffeine users, healthy as well as suffering from diabetes, hypertension and postmyocardial infarction.

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.

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 bupropion on cognitive functions in healthy subjects

Bupropion is an antidepressant of the aminoketone class (amfebutamone), which is structurally unrelated to the tricyclic antidepressants and is considered to be devoid of any sedative effects. In healthy volunteers, single doses of bupropion do not influence cognitive functions or quantitative EEG (qEEG; Peck et al. 1979; Hamilton et al. 1983). In a non-blind study of depressed patients comparing bupropion with drug-free controls, perceptual changes and reduced ability to ignore distractions were noted with bupropion (Becker and Dufresne 1982). Difficulties in concentration were previously reported in nicotine dependants who received cessation treatment with bupropion (Jorenby et al. 1999; Swan et al. 2003). The aim of the present study was to compare the effects of subchronic administration of bupropion with those of placebo on various cognitive functions. The design of the study and the methods used to assess cognitive functions as well as qEEG were described in detail elsewhere (Siepmann et al. 2004, 2005). Briefly, a randomized, double-blind, placebo-controlled study was conducted in 12 healthy male volunteers aged 26±3 years (mean±standard deviation). Subjects orally received 50 mg bupropion t.i.d. for 7 days and, subsequently, 100 mg t.i.d. for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized crossover conditions. A liquid chromatographic–tandem mass spectrometric (LC-MS-MS) method with a rapid, simple sample preparation was developed to detect bupropion in serum. Bupropion serum concentrations were noted highest at hours 3 and 5 following last dosing with the drug (71.8± 30.0 and 42.0±16.9 ng/ml respectively; mean±standard deviation). As outlined in Table 1, bupropion significantly reduced absolute alpha 2 and theta power density in the qEEG, with the subjects keeping their eyes closed 3 h after the last dose was given. Absolute power density in the alpha 1 and theta frequency bands was found attenuated under eyes-open conditions 5 h following last dosing with the drug. Bupropion did not influence power density of other frequency ranges such as the beta 1, beta 2 and delta bands nor did it have an effect on choice reaction, memory, psychomotor performance, flicker fusion frequency and subjective mood (data not shown). QEEG provides one of the most sensitive pharmacodynamic measures of central drug action, and qEEG power reduction is predictive for a psychostimulant effect as previously described with amphetamine, metamphetamine, methylphenidate and caffeine (Herrmann et al. 1979; Siepmann and Kirch 2002). In the present study, reductions of absolute alpha and theta power density were observed when serum concentrations of bupropion were measured highest. In conclusion, bupropion does not improve nor deteriorate cognitive functions when given to healthy humans subchronically at daily doses of 300 mg, but qEEG changes hint at a subtle psychostimulant drug effect.

Disposition, Elimination and Haemodynamic Effects of Verapamil and Trandolapril in Patients with Fatty Liver Disease

SummaryTwenty hypertensive patients were treated orally with a fixed combination of verapamil 180mg and trandolapril 1mg in a sustained-release formulation for 7 days. 10 patients had normal liver function (antipyrine clearance 38.9 ± 5.1 ml/min; mean ± SD), while 10 patients had fatty liver disease (antipyrine clearance 23.1 ± 5.1 ml/min). For the verapamil component no significant differences were observed when comparing patients with and without fatty liver disease with regard to peak plasma concentration (Cmax), area under the plasma concentration-time curve from 0 to 24 hours (AUC24h) and elimination half-life, whereas for trandolaprilat, the active metabolite of trandolapril, Cmax and AUC24h values were elevated in patients with fatty liver disease (p < 0.05). No significant differences were seen between the two groups of patients with regard to the effects of the verapamil/trandolapril combination on heart rate, PQ-time in the ECG and blood pressure. Adverse events were reported by 2 patients. One patient with impaired liver function dropped out because of an increasing frequency of angina pectoris. Another patient with normal liver function complained about tiredness. The patient developed a first degree AV-block and had bradycardia during treatment with the combination of verapamil and trandolapril. First degree AV-blocks were found in 3 other patients during drug treatment. Two of them had fatty liver disease, and one had normal liver function.In conclusion, no clinically relevant differences in the pharmacokinetic and pharmacodynamic parameters were observed between patients with and without fatty liver disease following oral administration with a fixed combination of verapamil and trandolapril in a sustained-release formulation. Thus, there seems to be no need to adjust the dose in patients with mild to moderate impairment of liver function.

Online Self-Help as an Add-On to Inpatient Psychotherapy: Efficacy of a New Blended Treatment Approach

Background: Depression is one of the most frequent and costly mental disorders. While there is increasing evidence for the efficacy of online self-help to improve depression or prevent relapse, there is little evidence in blended care settings, especially combined with inpatient face-to-face psychotherapy. Therefore, we evaluated whether an evidence-based online self-help program improves the efficacy of inpatient psychotherapy. Methods: A total of 229 depressed patients were randomly allocated either to an online self-help program (intervention group [IG]; Deprexis) or an active control group (CG; weekly online information on depression) in addition to inpatient psychodynamic psychotherapy. Both groups had access to their respective experimental intervention for 12 weeks, regardless of inpatient treatment duration. Reduction of depressive symptoms, as measured with the Beck Depression Inventory-II, was the primary outcome at the end of the intervention (T2). Results: Depressive symptoms were statistically significantly lower in the IG compared to the active CG at T2 with a moderate between-group effect size of d = 0.44. The same applied to anxiety (d = 0.33), quality of life (d = 0.34), and self-esteem (d = 0.38) at discharge from inpatient treatment (T1). No statistically significant differences were found regarding dysfunctional attitudes (d = 0.14) and work ability (d = 0.08) at T1. Conclusions: This is the first evidence for blended treatment combining online self-help with inpatient psychotherapy. The study opens new and promising avenues for increasing the efficacy of inpatient psychotherapy. Future studies should determine how integration of online self-help into the therapeutic process can be developed further.

Evaluation of a video-based Internet intervention as preparation for inpatient psychosomatic rehabilitation: study protocol for a randomized controlled trial

BackgroundPatients’ treatment expectations are a key factor in psychotherapy. Several studies have linked higher expectations to better treatment success. Therefore, we want to evaluate the impact of a targeted video-based intervention on patients’ expectations and the treatment success of inpatient rehabilitation.Methods/designAll patients who will be referred to inpatient psychosomatic rehabilitation in three clinics will receive a study flyer with information about how to log in to the study platform together with the usual clinic information leaflet. Patients will receive the study information and informed consent upon login and will be randomized into the intervention or the control group. The intervention group (n = 394) will get access to our virtual online clinic, containing several videos about inpatient rehabilitation, until their admission to inpatient rehabilitation. The control group (n = 394) will receive no special treatment preparation. Questionnaires will be given at study inclusion (T0), two weeks before admission to (T1), and at the end of (T2) inpatient rehabilitation. The primary outcome is the outcome expectancy measured with the Credibility Expectancy Questionnaire at T1. Secondary outcomes include treatment motivation, mental health, work ability, depression, anxiety, and satisfaction with and usage of the Internet platform.DiscussionWe expect the intervention group to benefit from the additional preparation concerning their outcome expectancy. If successful, this approach could be used in the future to enhance the efficacy of inpatient rehabilitation.Trial registrationClinicalTrials.gov: NCT02532881. Registered on 25 August 2015.

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.