Dirk Lang

Effects of low-dose aspirin on uterine and fetal blood flow during pregnancy: results of a randomized, placebo-controlled, double-blind trial

Objective  This study was conducted to evaluate uteroplacental and fetal hemodynamics in fetuses exposed to low‐dose aspirin (100 mg/d).

Hepatotoxicity associated with agomelatine and other antidepressants: Disproportionality analysis using pooled pharmacovigilance data from the Uppsala Monitoring Centre

Since its marketing approval, the attention to the hepatic side‐effect profile of the antidepressant agomelatine (AGM) has gradually increased. Several cases of severe hepatotoxic adverse drug reactions (ADR) have been reported and the European Medicines Agency has released a safety warning regarding AGM‐associated hepatotoxicity. However, there are insufficient data for an adequate safety assessment of AGM‐related hepatotoxicity. Therefore, we performed a quantitative signal detection analysis using pharmacovigilance data from the Uppsala Monitoring Centre from the WHO that records ADR data from worldwide sources; we calculated reporting odds ratios (ROR) as measures for disproportionality within a case/non‐case approach for AGM and several other antidepressants. AGM was statistically associated with an increased risk of hepatotoxicity (ROR 6.4 [95%CI 5.7–7.2]) as well as both positive controls: amineptine (ROR 38.4 [95%CI 33.8–43.6]) and nefazodone (ROR 3.2 [95%CI 3.0–3.5]). Following amineptine, AGM was associated with the second highest ROR, followed by tianeptine (ROR 4.4 [95%CI 3.6–5.3]), mianserin (ROR 3.6 [95%CI 3.3–3.9]), and nefazodone. These results support the hypothesis that AGM is associated with relevant hepatotoxicity. However, the used data and applied method do not allow a quantitative evaluation of hepatotoxicity or assessment of substance‐specific differences regarding the extent of hepatotoxicity.

Linking Annual Prescription Volume of Antidepressants to Corresponding Web Search Query Data: A Possible Proxy for Medical Prescription Behavior?

AbstractPersons using the Internet to retrieve medical information generate large amounts of health-related data, which are increasingly used in modern health sciences. We analyzed the relation between annual prescription volumes (APVs) of several antidepressants with marketing approval in Germany and corresponding web search query data generated in Google to test whether web search query volume may be a proxy for medical prescription practice. We obtained APVs of several antidepressants related to corresponding prescriptions at the expense of the statutory health insurance in Germany from 2004 to 2013. Web search query data generated in Germany and related to defined search terms (active substance or brand name) were obtained with Google Trends. We calculated correlations (Person’s r) between the APVs of each substance and the respective annual “search share” values; coefficients of determination (R2) were computed to determine the amount of variability shared by the 2 variables. Significant and strong correlations between substance-specific APVs and corresponding annual query volumes were found for each substance during the observational interval: agomelatine (r = 0.968, R2 = 0.932, P = 0.01), bupropion (r = 0.962, R2 = 0.925, P = 0.01), citalopram (r = 0.970, R2 = 0.941, P = 0.01), escitalopram (r = 0.824, R2 = 0.682, P = 0.01), fluoxetine (r = 0.885, R2 = 0.783, P = 0.01), paroxetine (r = 0.801, R2 = 0.641, P = 0.01), and sertraline (r = 0.880, R2 = 0.689, P = 0.01). Although the used data did not allow to perform an analysis with a higher temporal resolution (quarters, months), our results suggest that web search query volume may be a proxy for corresponding prescription behavior. However, further studies analyzing other pharmacologic agents and prescription data that facilitate an increased temporal resolution are needed to confirm this hypothesis.

Drug‐Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms

Drug‐induced liver injury is a major problem of pharmacotherapy and is also frequent with antidepressive psychopharmacotherapy. However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepress ants. We performed a quantitative signal detection analysis using data from the Uppsala Monitoring Centre from the WHO that records adverse drug reaction (ADR) data from worldwide sources; we retrieved substance‐ and country‐specific (Australia, France, Germany, Italy, Spain, the United Kingdom, and the United States) ADR data and calculated reporting odds ratios as measures for disproportionality within a case/noncase approach. To allow for identification of agents that cause severe forms of hepatotoxic ADRs, we used 2 terms of the MedDRA (“drug‐related hepatic disorders‐comprehensive search” [DRHD‐CS] and “… ‐severe events only” [DRHD‐SEO]). Distribution of signals was heterogeneous throughout the different data sets, and consistent findings were present for only a few substances: agomelatine (AGM) and tianeptine as well as both positive control agents (amineptine, nefazodone) generated signals related to DRHD‐CS and DRHD‐SEO in all analyzed data sets. Tri‐ and tetracyclic antidepressants (here amitriptyline, clomipramine, mianserin, mirtazapine, trimipramine) were associated with hepatotoxicity in several data sets. Using 2 MedDRA terms did not allow for detection of agents that cause severe hepatotoxic ADR. Our results support the findings of previous, primarily literature‐based, systematic analyses of hepatotoxicity related to antidepressive psychopharmacotherapy. No new safety information could be generated. Application of 2 MedDRA terms did not increase the substance‐specific safety information.

Psychiatric emergencies in the emergency room of the Ulm University Hospital in 2000 and 2010

Objective: Despite of the importance of psychiatric emergencies (PE) requiring treatment at an emergency room (ER) little is known about their frequency and current trends in terms of quantity and quality. Methods: A retrospective analysis of all PE treated at the ER of the University Hospital Ulm (Germany) in 2000 and 2010. Results: 6 % (2000) or 5 % (2010) of the ER cases were PE. Despite an increase from 369 to 430 cases (+ 16,5 %) their share decreased because of an even stronger increase of other emergencies (+ 33 %). The most frequent PE in 2000 was alcohol intoxication (37,7 %), while it was intoxication with prescribed and/or illicit drugs in 2010 (47,9 %). Patients with alcohol intoxications were significantly younger in 2010 as compared with 2000. Suicide attempts were seen in every fourth PE. They were significantly more frequent in 2010. PEs were generally more frequent in the evening and over the night. Conclusion: This study provides first insight into current trends in PE treated at the ER in Germany. Our data provide an empirical starting point for optimizing clinical care, although the study is limited by its retrospective and mono-centric design.

Psychiatrische Notfälle im Notarzt- und Rettungsdienst in Ulm in den Jahren 2000 und 2010 und Konsequenzen für die Praxis

Background Psychiatric emergencies (PE) in preclinical emergency medical services are about 5 - 10 % of all emergencies and represent often a source of difficulties in handling for the non-psychiatric professional helpers that deal with them. Studies informing about quantitative and qualitative changes of PEs in preclinical emergency medicine in Germany are scarce. Methods Therefore, we conducted a retrospective cross-sectional study of PE in a preclinical emergency medical service based on the protocols of the emergency ambulance of the Section for Emergency Medicine at the University Hospital Ulm comparing the years 2000 and 2010. Results We observed a significant increase of PEs from 8.8 % in the year 2000 (n = 285, from a total of n = 3227) to 10.3 % in 2010 (n = 454, from a total of n = 4425). In both years intoxications were the most common PE [2000: n = 116 (44.4 %); 2010: n = 171 (37.7 %)], followed by suicide-related behavior [2000: n = 59 (22.6 %); 2010: n = 78 (17.2 %)] and acute anxiety disorders [2000: n = 37 (13 %); 2010: n = 105 (23.1 %)]. The mentioned three conditions accounted for about 80 % of all PE. Most frequently PE occurred at the weekend and with the highest density in the evening and at night (18 - 24 h) in both years. Patients with PE were predominantly men, but the rate of women causing PE increased between 2000 and 2010. Discussion/Conclusion This study provides preliminary data on current trends in PEs in preclinical emergency medicine in Germany and has implications for improving the medical care provided.

Drug safety and adverse drug reaction reporting behavior related to outpatient opioid replacement therapy: Results from a survey among physicians

To study drug safety and the reporting behavior of adverse drug reactions (ADR) related to agents used for opioid replacement therapy (ORT) we conducted a cross-sectional questionnaire-based telephone survey among physicians who provide outpatient ORT in Germany (n=176; response rate=55.7%). Most respondents (n=97/55.1%) reported that they observe ADR related to buprenorphine, (dihydro)codeine, and (levo)methdone rarely (n=38/21.6%), very rarely (n=39/22.2%) or never (n=20/11.4%). Methadone was reported to be most frequently associated with the occurrence of ADR (n=82/46.6%), followed by levomethadone (n=33/18.8%), buprenorphine (n=6/3.4%), and dihydrocodeine (n=3/1.7%). Frequently observed ADR related to these agents were gastrointestinal, nervous system/psychiatric disorders, and hyperhidrosis. Methadone and levomethadone (not buprenorphine) were frequently associated with fatigue, weight gain, and sexual dysfunction. Hundred twenty nine participants (73.3%) stated that they never report ADR related to ORT; n=19 (10.8%) did so when referring to ADR related to their complete medical practice (X2=141.070; df=1; p<0.001). Similar patterns of ADR related to outpatient ORT as those reported in the product information or in pain therapy were found. Motivation to report ADR related to ORT may be reduced compared to ADR related to the general medical practice.