Stefan Unterecker

Reduced response-inhibition in obsessive–compulsive disorder measured with topographic evoked potential mapping

Recent neuroimaging studies have suggested that a hyperactivity of the frontal-striate neuronal circuits, including the orbitofrontal cortex and the basal ganglia, mediates the symptomatology of obsessive-compulsive disorder (OCD). However, there is also some evidence that the superior frontal cortex is less activated in OCD, and this local hypoactivity has been shown to be negatively associated with the symptomatology. As the superior frontal cortex is believed to be involved in inhibitory control, this study investigated the brain electrical activity during response inhibition in OCD. Twelve patients with OCD and 12 healthy controls performed a cued Go-NoGo task (continuous performance test), while event-related potentials were registered with 21 electrodes. Patients reacted significantly faster than controls, but did not differ from controls regarding the error rate. As a main result, we found a reduced frontal activity during the NoGo condition in OCD, which was condensed in a reduced anteriorisation of the brain electrical field. We suggest that this inhibitory deficit in OCD has a major contribution to the pathophysiology of OCD, which is underscored by the fact that the anteriorisation during the NoGo condition (NGA) was negatively correlated with the symptomatology as measured by the Yale-Brown Obsessive-Compulsive Scale.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

Authors C. Hiemke1, 2, N. Bergemann3, H. W. Clement4, A. Conca5, J. Deckert6, K. Domschke7, G. Eckermann8, K. Egberts9, M. Gerlach9, C. Greiner10, G. Gründer11, E. Haen12, U. Havemann-Reinecke13, G. Hefner14, R. Helmer15, G. Janssen16, E. Jaquenoud17, G. Laux18, T. Messer19, R. Mössner20, M. J. Müller21, M. Paulzen11, B. Pfuhlmann22, P. Riederer6, A. Saria23, B. Schoppek24, G. Schoretsanitis25, M. Schwarz26, M. Silva Gracia12, B. Stegmann12, W. Steimer27, J. C. Stingl10, M. Uhr28, S. Ulrich29, S. Unterecker6, R. Waschgler30, G. Zernig23, 31, G. Zurek32, P. Baumann33

Correlation of QTc interval prolongation and serum level of citalopram after intoxication--a case report.

Citalopram (CIT) is a widely used antidepressant which acts by a selective serotonin reuptake inhibition. It is considered to be safer than tricyclic antidepressants at therapeutic levels, but also with respect to intoxications. We report the case of a 46-year-old woman, who ingested in suicidal intention 1400 mg CIT. During the following inpatient treatment repeatedly ECGs and determinations of the serum level of CIT were performed. Initially the patients serum level of CIT was 1231 ng/mL and QTc interval was 541.60 ms. It took 12 days until the serum level of CIT fell below the upper threshold of the recommended therapeutic range (130 ng/mL). The QTc interval on the sixth day after the intoxication for the first time was below 500 ms. The QTc interval correlated significantly with the serum level of CIT after intoxication (r=0.943; p<0.005). Although CIT is estimated as a safe antidepressant regarding serious adverse effects, toxic doses can lead to potentially hazardous ECG changes which according to our findings correlate strongly with the serum level of the drug.

Therapeutic drug monitoring of tricyclic antidepressants in everyday clinical practice

Data about therapeutic drug monitoring (TDM) of psychotropic medications are often obtained from samples of highly selected individuals, who may not be representative for the average psychiatric patient. These data therefore may have limitations with regard to their transferability to everyday clinical practice. Therefore studies under naturalistic conditions are important to clarify the full clinical relevance of TDM. We retrospectively evaluated all TDM-analyses of the tricyclic antidepressants (TCA) amitriptyline and clomipramine during a 12-month period in an unselected sample of patients in a standard clinical setting. We especially examined the relationship between serum levels on one hand and clinical response and adverse effects on the other hand. In patients with amitriptyline, responders showed a significantly higher serum level than non-responders, whereas in patients with clomipramine a serum level within the recommended therapeutic range was associated with clinical response. We also found significantly higher serum concentrations in patients with adverse effects compared to patients without adverse effects in the clomipramine group. No such relationship could be shown in patients treated with amitriptyline. Our results suggest that therapeutic ranges in naturalistic settings in some ways differ from those obtained in controlled clinical settings and that TDM studies in everyday clinical practice are necessary and beneficial.

The Effect of Age, Sex, Smoking and Co-Medication on Serum Levels of Venlafaxine and O-Desmethylvenlafaxine under Naturalistic Conditions

INTRODUCTION Venlafaxine (VEN) is a modern antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. In this study we examined the influence of age, sex, smoking, and co-medication on serum levels of VEN and its metabolite O-desmethylvenlafaxine (ODVEN) in patients treated with VEN under naturalistic conditions. METHODS We retrospectively evaluated 478 TDM analyses of VEN requested in the Pychiatric University Hospitals of Mainz, Regensburg, and Würzburg. The determination of serum levels was performed by virtually identical chromatographic methods in the TDM laboratories of the participating hospitals. RESULTS Serum levels varied widely on each dose level. Women had about 30% higher dose-corrected serum levels of VEN and ODVEN than men (p<0.01), and patients older than 60 years showed about 46% higher levels of both compounds than younger ones (p<0.01). In smokers, mean serum levels of ODVEN were 21% lower than in non-smokers. Combining these variables a considerable increase of the differences between the subgroups was found indicating an additive effect. ANOVA over the 8 different groups was significant for ODVEN (p<0.01) and sum (p<0.01), but not for VEN (n.s.). Co-medication with other psychotropic drugs was associated with a decreasing ODVEN/VEN ratio indicating a reduced metabolism in patients receiving polypharmacy. DISCUSSION These findings show that TDM is useful to identify factors affecting the pharmacokinetic properties of VEN. It is concluded that sex, age and smoking should be considered for optimal dosing of patients with VEN.

No influence of body weight on serum levels of antidepressants.

Background: Body weight may affect pharmacokinetic parameters in various ways and may therefore have a significant impact on the serum concentration of a drug at a given dose. Although patients with major depressive disorder frequently show an elevated body mass index, studies investigating the relation between body weight and serum concentration of antidepressants are lacking. This study should help to clarify the influence of body weight on the serum levels of the antidepressants amitriptyline (AMI), clomipramine (CLO), doxepine (DOX), escitalopram (ESC), and venlafaxine (VEN) in a naturalistic clinical setting. Methods: Therapeutic drug monitoring analyses obtained in the psychiatric university hospital of Wuerzburg from patients treated with AMI (n = 171), CLO (n = 94), DOX (n = 133), ESC (n = 19), and VEN (n = 24) were retrospectively assessed. The influence of body weight on dose-corrected serum concentrations was evaluated by Spearman-Rho correlations and by comparing dose-corrected serum levels in patients with low and high body weight (first versus fourth quartile). The serum concentrations were determined by high-performance liquid chromatography methods in the therapeutic drug monitoring laboratory of the psychiatric university hospital of Wuerzburg. Results: Dose-corrected serum concentrations did not significantly correlate with body weight in patients treated with AMI, CLO, DOX, ESC, or VEN. There was no significant difference in the dose-corrected serum concentrations of AMI, CLO, and DOX between patients of the first and fourth quartiles of body weight. The latter evaluation was not performed for ESC and VEN because of too small samples. Conclusions: Against the intuitive presumption of a weight dependency of dose-corrected serum concentrations, the findings suggest that there is no relevant influence of body weight on the dose-corrected serum level of several widely used antidepressants even if extreme subgroups of patients with low and high body weights are considered.

Classification of advanced stages of Parkinson’s disease: translation into stratified treatments

Advanced stages of Parkinson’s disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain milestones of motor disability apparently fall short in addressing the increasingly recognized complexity of motor and non-motor symptoms and do not allow to account for the clinical heterogeneity that require more personalized approaches. Therefore, deep phenotyping approaches are required to characterize the broad-scaled, continuous and multidimensional spectrum of disease-related motor and non-motor symptoms and their progression under real-life conditions. This will also facilitate the reasoning for clinical care and therapeutic decisions, as neurologists currently have to refer to clinical trials that provide guidance on a group level; however, this does not always account for the individual needs of patients. Here, we provide an overview on different classifications for advPD that translate into critical phenotypic patterns requiring the differential therapeutic adjustments. New concepts refer to precision medicine approaches also in PD and first studies on genetic stratification for therapeutic outcomes provide a potential for more objective treatment recommendations. We define novel treatment targets that align with this concept and make use of emerging device-based assessments of real-life information on PD symptoms. As these approaches require empowerment of patients and integration into treatment decisions, we present communication strategies and decision support based on new technologies to adjust treatment of advPD according to patient demands and safety.

Increase of Heart Rate and QTc by Amitriptyline, But Not by Venlafaxine, Is Correlated to Serum Concentration.

Abstract Electrocardiographic pathologies are a common problem during antidepressant treatment. The authors investigated the association of serum concentrations of antidepressants and heart rate, QT, and QTc. Polymorphisms of NOS1AP (nitric oxide synthase 1 adaptor protein) rs10494366 and rs12143842 as potential influence factors also were considered. In the amitriptyline sample (n = 59), significant Spearman &rgr; correlations were found between serum concentration and QTc (r = 0.333, P = 0.010), as well as heart rate (r = 0.407, P = 0.001). Patients with a serum concentration greater than the therapeutic range (>200 ng/mL) exhibit significantly higher heart rates (87.0 ± 13.3 vs 80.0 ± 13.9, U test P = 0.011) and higher QTc values (443.8 ± 28.8 vs 427.9 ± 20.6, U test P = 0.022). Excluding the 26 patients with a serum concentration greater than the therapeutic range, patients with rs12143842 risk alleles exhibit higher heart rates and as a trend lower QT intervals with no difference in QTc. In the venlafaxine sample (n = 81), no significant association between serum concentration and heart rate, QT, or QTc was revealed. In summary, the risk for relevant electrocardiographic alterations induced by tricyclic antidepressants, such as amitriptyline, is dependent on serum concentrations. NOS1AP polymorphisms may be a genetic vulnerability factor.

The comparison of brand-name and generic formulations of venlafaxine: a therapeutic drug monitoring analysis.

Objective: Venlafaxine (VEN) is a widely used antidepressant drug, which is available in both brand-name and generic formulations. Bioequivalence studies indicate some pharmacokinetic variability. However, naturalistic therapeutic drug monitoring studies of different generic formulations are lacking. Methods: In 2010, inpatients of the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, were treated with either slow-release brand-name VEN (Trevilor) or slow-release generic VEN (Venlafaxin Hexal) depending on the respective inpatient ward. Routine therapeutic drug monitoring analyses of both groups were compared after matching samples regarding dose of VEN, gender, age, smoking habits, and evaluation of co-medication. Results: Both groups did not differ in mean values of VEN, O-desmethyl-VEN (ODV), VEN + ODV serum concentrations, and ODV/VEN ratio. No difference in dose-corrected serum concentrations between generic and brand-name VEN was revealed for males, females, smokers, or nonsmokers. In both groups, Spearman Rho correlation between VEN dose and VEN + ODV serum concentration was moderate but significant (P < 0.001; generic: r = 0.554; brand name: r = 0.668). Within the generic subgroup, females had a significantly higher dose-corrected serum concentration of VEN (U test, P < 0.05), whereas within brand name, no gender influence was detected. Spearman Rho correlation of age and dose-corrected ODV (P < 0.05) and VEN + ODV (P < 0.05) was significant only in the generic group. In the brand-name sample, smokers had significantly lower dose-corrected serum concentrations of ODV (U test, P < 0.01) and VEN + ODV (P < 0.01). In the generic group, smoking habit was without any influence. Discussion: No differences in serum concentrations in dependence of either VEN formulations suggest a safe and efficient treatment of patients using the evaluated generic VEN. However, differences within one formulation regarding gender, age, and smoking status suggest variability of serum concentrations and thus could endanger safety and efficacy of drug use.

Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine: analysis of therapeutic drug monitoring data under naturalistic conditions.

Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P<0.003). We also found a significant correlation between valproic acid serum level and dose-corrected doxepin+N-doxepin serum level (Spearman’s &rgr; r=0.602, P<0.014). The mean dose-corrected serum level of venlafaxine+O-desmethylvenlafaxine in 41 patients who received valproic acid comedication did not differ significantly from that of the matched controls (P<0.089), but there was a significant difference between both groups in the dose-corrected serum level of O-desmethylvenlafaxine (1.403±0.665 vs. 1.102±0.444, P<0.017). As a consequence, if a combination of valproic acid with doxepin or venlafaxine is administered, cautious dosing is advisable and TDM should be performed.