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Levonorgestrel (LNG)-intrauterine devices (IUDs) are an effective method of contraception; however, there is growing evidence regarding potential psychiatric side effects such as depressive symptoms, anxiety, and suicidal thoughts. Therefore, we conducted this systematic review to summarise the psychiatric effects of using LNG-IUDs.We searched six databases (MEDLINE, Web of Science, Scopus, Science Direct, Cochrane Library, and PsycInfo), and we included all study designs. The included studies were extracted, quality assessed, and qualitatively summarised.Out of the screened studies, only 22 were finally included. While ten studies showed increased depressive symptoms, two studies showed reduced symptoms. Moreover, one study showed increased anxiety, another one reported an increased risk of suicide, four studies concluded no association with depressive symptoms, and four other studies showed uncertainty about a potential association but mentioned other psychiatric symptoms.Despite unreliable data, many studies report psychiatric symptoms associated with LNG-IUDs, predominantly depression. Gynaecologists, general practitioners, and psychiatrists should therefore be aware of these potential risks, especially depressive symptoms and suicidality. Counselling patients about these risks should be mandatory. Further studies should investigate the absolute risk of mental disorders associated with LNG-IUDs and other hormonal contraceptives.KEY MESSAGESMany researchers are reporting adverse psychiatric events associated with levonorgestrel intrauterine devices (LNG-IUDs).Despite their effectiveness, a proper psychiatric assessment should be done before inserting LNG-IUDs.Proper counselling regarding the depressive symptoms and suicidality should be done by the treating obstetrician.Further studies should investigate the absolute risk of mental disorders associated with LNG-IUDs and other hormonal contraceptives.

Purpose In aut-idem or generic substitution, discrepancies between summaries of product characteristics (SmPCs) referring to the same active substance (AS) may cause difficulties regarding informed consent and medical liability. The qualitative and quantitative characteristics of such discrepancies are insufficiently studied, impeding harmonization of same-substance SmPCs and compromising safe drug treatment. Methods SmPCs of the one hundred most frequently prescribed ASs in Germany were analyzed for discrepancies in the presentation of indications (Inds) and contraindications (CInds). Inclusion and exclusion criteria of drugs/SmPCs were chosen according to the standards of the aut-idem substitution in Germany. Results According to the study protocol, we identified 1486 drugs, of which 1426 SmPCs could be obtained. 41% respectively 65% of the ASs had same-substance SmPCs that differed from the respective reference SmPC in the number of listed Inds respectively CInds. The number of listed Inds/CInds varied considerably between same-substance SmPCs with maximum ranges in Inds of 7 in amoxicillin, and in CInds of 11 in lisinopril. Many ASs had large proportions (> 50%) of associated same-substance SmPCs that differed from the respective reference SmPC. A considerable proportion of ASs had same-substance SmPCs with formal and content-related differences other than the discrepancy in the number of Inds/CInds. Conclusion This evaluation of same-substance SmPCs shows a clear lack of harmonization of same-substance SmPCs. Considering that generic substitution has become the rule and that physicians usually do not know which drug the patient receives in the pharmacy, these discrepancies raise several questions, that require a separate legal evaluation., publishedVersion

PURPOSE/BACKGROUND The alleged primary mechanism underlying bleeding events associated with antidepressants is inhibition of serotonin uptake in platelets resulting in reduced platelet aggregability and activity, and prolonged bleeding time. There is some evidence that a substance's degree of serotonin reuptake inhibition in terms of its binding affinity to the serotonin transporter (SERT) affects the magnitude of bleeding risk increase. METHODS/PROCEDURE To test this hypothesis, we performed data mining in the worldwide largest pharmacovigilance database (VigiBase) and conducted pharmacodynamically informed quantitative signal detection. Reporting odds ratios related to the standardized Medical Dictionary of Regulatory Activities query term "haemorrhages" and 24 antidepressants were calculated, and SERT binding affinities (pKi) were obtained and correlated (Pearson correlation). FINDINGS/RESULTS A strong and statistically significant correlation between substance-related reporting odds ratios and SERT binding affinities was found (r = 0.63; 95% confidence interval, 0.30-0.82; P = 0.00097). IMPLICATIONS/CONCLUSIONS Our findings strengthen the hypothesis that inhibition of serotonin uptake contributes to the antidepressant-related bleeding risk and suggest an association between the degree of the SERT binding affinity and the bleeding risk. This supports the preferential use of antidepressants with low or no SERT binding affinity in depressed patients at risk of bleeding.

Background To date, disproportionality analysis has been unable to demonstrate the increased bleeding risk associated with antidepressant drugs, especially selective serotonin reuptake inhibitors. Objective We hypothesised that a potential signal for an increased bleeding risk may be mitigated by the effects of agents other than antidepressant drugs that are strongly associated with haemorrhages, especially antithrombotics. In addition, we investigated if the use of more specific search terms of the Medical Dictionary for Regulatory Activities facilitates the detection of signals. Methods Pharmacovigilance data from the Uppsala Monitoring Centre were used to calculate substance-specific reporting odds ratios (RORs) for all types of bleeding and gastrointestinal bleeding. Reporting odds ratios were calculated with and without antithrombotic comedication. Results Regarding any type of bleeding, no signals were found in association with antidepressant drugs. Concerning upper gastrointestinal bleeding, signals were found related to citalopram (ROR: 1.56 [95% confidence interval 1.11–2.20]) and escitalopram (ROR: 1.52 [95% confidence interval 1.03–2.25]). After removal of reports related to antithrombotics, these signals could no longer be detected, but a new signal related to St. John’s Wort associated with haemorrhages was found (ROR: 1.50 [95% confidence interval 1.21–1.86]). Conclusions Antithrombotics seem unlikely to have a major impact on the detection of the bleeding risk of antidepressant drugs. The different categorisation of adverse drug reactions regarding the strength of a causal relationship between a drug and an event in the database may be relevant for this negative finding. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-021-00260-9.

Drug-associated liver injury is one of the most common causes for acute liver failure and market withdrawal of approved drugs. In addition, the potential for hepatotoxicity related to specific substances has to be considered in psychopharmacotherapy. However, systematic evaluations of hepatotoxicity related to antipsychotics are limited.We conducted an exploratory case/non-case study and evaluated pharmacovigilance data from VigiBase related to 30 antipsychotics marketed in the European Union. Reporting odds ratios were calculated for antipsychotics associated with the Standardized Medical Dictionary of Regulatory Activities queries "Drug-related hepatic disorders-comprehensive search" (DRHD-CS) and "Drug-related hepatic disorders-severe events only" (DRHD-SEO).We found several signals for drug-associated liver injury including signals for severe events: 17 of 30 antipsychotics were associated with DRHD-CS and 10 of 30 antipsychotics with DRHD-SEO. Amisulpride, fluphenazine, levomepromazine, loxapine, olanzapine, perazine, perphenazine, pipamperone, sulpiride, and thioridazine were associated with both, DRHD-CS and DRHD-SEO. No association with fatal outcomes was detected.Several common antipsychotics are associated with hepatotoxicity, partly also with severe hepatotoxicity. Our data do not allow to account for patient-related risk factors for drug-associated liver injury. This should be addressed in further studies.

There has recently been a renewal of interest in psychedelic research on the use of psilocybin in psychiatric treatment and, in particular, for the treatment of major depressive disorder (MDD). Several state-of-the-art studies have provided new insight into the mechanisms of action of psilocybin and its therapeutic potential. Nevertheless, many questions remain unanswered. With this review, we provide an overview of the current state of research on the potential mechanisms of psilocybin, its antidepressant potential, and the associated risks and adverse effects, to provide an update on a controversial topic discussed in psychopharmacology. A database search was conducted in Medline including articles on psilocybin over the period of the last 20 years. Despite the promising progress in understanding the mechanisms of psilocybin, the exact antidepressive mechanism and the role of the psychedelic experience remain elusive. The studies included in this review found high treatment effect sizes for psilocybin as an antidepressant. However, the results must be regarded as preliminary due to several limitations. Although the current studies observed no severe adverse events, several questions regarding safety and utility remain and must be subject of future research.

Background: Interventions for improving reporting and management of adverse drug reactions (ADRs) need regular evaluations of attitude and knowledge of health care professionals regarding pharmacov...

Gegenstand und Ziel: Blutungsereignisse unter Therapie mit Antidepressiva, die die Serotoninwiederaufnahme hemmen (SRI), sind in den Fokus der klinischen und wissenschaftlichen Aufmerksamkeit geruckt. In der vorliegenden Ubersichtsarbeit wird ein Uberblick uber den Kenntnisstand zu SRI-assoziierten Blutungen, insbesondere in Hinblick auf moglichen Pathomechanismen und verschiedene Blutungslokalisationen gegeben. Material und Methoden: Es wurde eine narrative Ubersichtsarbeit erstellt. Die Literaturrecherche wurde in der bibliografischen Datenbank MEDLINE durchgefuhrt. Ergebnisse: Zahlreiche Studien deuten darauf hin, dass SRI, insbesondere SSRI, das Risiko fur obere gastrointestinale Blutungen erhohen konnen; eine Komedikation mit NSAID oder Thrombozytenaggregationshemmern erhoht dieses Risiko deutlich. Die Datenlage zu anderen Blutungslokalisationen ist fur sichere Bewertungen gegenwartig unzureichend. Es gibt Hinweise auf einen positiven Zusammenhang zwischen der Affinitat eines SRI zum Serotonintransporter (5-HTT) und dem assoziierten Blutungsrisiko. Schlussfolgerungen und klinische Relevanz: Ein erhohtes Risiko fur Blutungen (insbesondere obere gastrointestinale Blutungen) durch SRI sowie eine Erhohung dieses Risikos durch NSAID und/oder Thrombozytenaggregationshemmer sollte bei der Verordnung von SRI, insbesondere von SRI mit hoher Affinitat zum 5-HTT (z. B. SSRI), beachtet werden. Objective: Hemorrhages associated with the use of antidepressants that inhibit serotonin reuptake (SRI) have become a focus of attention in clinical practice and science. This review article provides an overview of the currently available data regarding bleeding events associated with SRI with a focus on pathophysiology and different sites of bleeding. Material and methods: A narrative review article was created. Literature search was performed in the bibliographic database of MEDLINE. Results: Numerous studies have demonstrated an increased risk for upper gastrointestinal bleeding related to SRI, particularly, SSRI; comedication with NSAID or anti-platelet agents increases this risk remarkably. The currently available data does not allow reliable evaluation regarding other sites of bleeding. There is indication for an association between the affinity of an SRI to the serotonin transporter (5-HTT) and the associated risk of bleeding. Conclusion: An increased bleeding risk of bleeding (particularly upper gastrointestinal bleedings) associated with the use of SRI and an additionally increased risk under comedication with NSAID and/or antiplatelet agents should be taken into account, especially regarding SRI with high affinity to the 5-HTT (e. g., SSRI).

Zusammenfassung Gegenstand und Ziel Psychopharmakotherapie hat bei der Behandlung zahlreicher psychischer Störungen einen großen Stellenwert. Unerwünschte Arzneimittelwirkungen (UAW) beeinflussen dabei die Compliance und Verträglichkeit. Auch Beeinträchtigungen des Schlafs können als UAW einer Psychopharmakotherapie auftreten. Schlafstörungen sind mit einem erhöhten Risiko für körperliche und psychische Erkrankungen assoziiert und beeinträchtigen Kognition, Impulskontrolle, Emotionsregulation und Stimmung. Ziel der vorliegenden Arbeit ist die systematische Darstellung der Art und des Risikos für Schlafstörungen/Beeinträchtigungen des Schlafs durch häufig verordnete Psychopharmaka. Methodik Auf der Basis des Arzneiverordnungs-Reports 2016 wurden die in Deutschland verordnungsstärksten Psychopharmaka identifiziert. Die Fachinformationen (FI) der zugehörigen Originalpräparate wurden im Hinblick auf Nennung und Häufigkeitsangaben von Schlafstörungen/Beeinträchtigungen des Schlafs gemäß der International Classification of Sleep Disorders 3 (ICSD-3) untersucht. Ergebnisse Es wurden n = 64 FI untersucht. Bei der überwiegenden Zahl wurde mindestens eine Schlafstörung aufgeführt (50/64; 78 %). In den Kategorien Insomnien (52 %), Parasomnien (33 %) und schlafbezogene Bewegungsstörungen (20 %) wurde am häufigsten mindestens eine FI mit entsprechender UAW gefunden; schlafbezogene Atmungsstörungen (6 %) und Hypersomnien zentralnervösen Ursprungs (5 %) waren selten aufgeführt; zirkadiane Schlaf-Wach-Rhythmusstörungen wurden nicht gefunden. In den FI der vier verordnungsstärksten Wirkstoffe (Citalopram > Venlafaxin > Mirtazapin > Sertralin) war Insomnie aufgeführt. Nahezu alle untersuchten Hypnotika (Ausnahme: Chlorahlydrat) waren mit Albträumen assoziiert. Schlussfolgerung(en) Die meisten der in Deutschland häufig verordneten Psychopharmaka können Schlafstörungen/Beeinträchtigungen des Schlafs induzieren. Bei den vier verordnungsstärksten Wirkstoffen handelte es sich um Antidepressiva und in den zugehörigen FI war jeweils Insomnie aufgeführt. Bei der Behandlung mit Psychopharmaka sollte auf das Auftreten von Schlafstörungen als eine mögliche Nebenwirkung geachtet werden.

Zahlreiche Psychopharmaka sowohl aus dem Bereich der Antidepressiva als auch der Antipsychotika sind mit metabolischen unerwunschten Arzneimittelwirkungen (UAW) assoziiert. Der zweite Teil unseres Beitrags befasst sich mit dem Risiko fur Gewichtszunahme und fur andere metabolische UAW im Zusammenhang mit konkreten Wirkstoffen. Zugleich werden die gegenwartig verfugbaren therapeutischen Masnahmen bei psychopharmakaassoziierten metabolischen UAW erlautert.

Im Rahmen von zwei Ubersichtsarbeiten werden die wesentlichen Aspekte der metabolischen Nebenwirkungen von Psychopharmaka erlautert. Teil 1 gibt einen Uberblick uber die epidemiologischen Aspekte und den aktuellen Stand zur Pathophysiologie der psychopharmakaassoziierten metabolischen Nebenwirkungen. In Teil 2 erfolgt eine substanzspezifische Betrachtung und eine Zusammenfassung der zur Verfugung stehenden Interventionsmoglichkeiten fur psychopharmakaassoziierte metabolische Nebenwirkungen.

Background: It is repeatedly reported that pregabalin (PRG) and gabapentin feature a potential for abuse/misuse, predominantly in patients with former or active substance use disorder. The most common route of use is oral, though reports of sublingual, intravenous, rectal, and smoking administration also exist. A narrative review was performed to provide an overview of current knowledge about nasal PRG use. Methods: A narrative review of the currently available literature of nasal PRG use was performed by searching the MEDLINE, EMBASE, and Web of Science databases. The abstracts and articles identified were reviewed and examined for relevance. Secondly, a request regarding reports of cases of nasal PRG administration was performed in the worldwide spontaneous reporting system of adverse drug reactions of the European Medicines Agency (EMA, EudraVigilance database). Results: The literature search resulted in two reported cases of nasal PRG use. In the analysis of the EMA-database, 13 reported cases of nasal PRG use (11 male (two not specified), mean age of users = 34.2 years (four not specified)) were found. In two cases fatalities occurred related to PRG nasal use. Conclusions: Even if only little evidence can be found in current literature, the potential for misuse/abuse of PRG via nasal route might be of particular importance in the near future in PRG users who misuse it. Physicians should be aware of these alternative routes of administration.

ZusammenfassungMetabolische unerwünschte Arzneimittelwirkungen (UAW) unter Psychopharmakotherapie besitzen in Hinblick auf Morbidität, Mortalität und Therapieadhärenz eine erhebliche klinische Relevanz. Die vorliegende Übersichtsarbeit gibt einen Überblick über epidemiologische Aspekte, prädiktive Faktoren, die Pathophysiologie sowie über Monitoring und mögliche therapeutische Ansätze hinsichtlich metabolischer Nebenwirkungen von Psychopharmaka. Zudem wird das Risiko für metabolische UAW von häufig verordneten Substanzen anhand von Informationen aus Fachinformationen dargestellt.Es wurde eine narrative Übersichtsarbeit erstellt. Die Literaturrecherche wurde in der bibliografischen Datenbank MEDLINE durchgeführt.Die Pathomechanismen, die psychopharmakotherapieassoziierten metabolischen UAW zugrunde liegen, sind unvollständig verstanden; genetische Faktoren und die Modulation zahlreicher Neurotransmittersystem (insbesondere das histaminerge und dopaminerge System) scheinen relevant zu sein. Vor allem Antipsychotika, Antidepressiva und Phasenprophylaktika sind mit einem Risiko für metabolische Nebenwirkungen assoziiert, wobei innerhalb der Indikationsgruppen Unterschiede zwischen einzelnen Substanzen hinsichtlich des Risikos für metabolische UAW bestehen. Gegenwärtig gibt es nur bei antipsychotikaassoziierten metabolischen UAW Evidenz für die Wirksamkeit und Verträglichkeit pharmakologischer und/oder nicht pharmakologischer Behandlungsoptionen. Hinsichtlich der therapeutischen Ansätze stehen sowohl nicht pharmakologische Interventionen (Verhaltensänderungen und diätetische Maßnahmen) als auch medikamentöse Ansätze (Metformin zur Behandlung von antipsychotikaassoziierter Gewichtszunahme oder Wechsel zu einem Präparat mit geringerem Risiko für metabolische UAW) zur Verfügung.Metabolische UAW haben erhebliche klinische Relevanz. Bei Verordnung eines Präparates, das mit dem Risiko metabolischer Nebenwirkungen verbunden ist, sollte stets eine ausführliche Aufklärung und adäquates Monitoring erfolgen.

Psychopharmacotherapy is essential in the treatment of many mental disorders. Adverse drug reactions (ADR) have impact on compliance and tolerability. Sleep disorders or impaired sleep may occur as ADRs of psychopharmacotherapy. Sleep disorders are associated with an increased risk for physical and mental illness and may impair cognition, impulse control, emotion regulation and mood. Objective of the following study was the systematic presentation of type and risk of sleep disorders/impairments of sleep of frequently prescribed psychotropic drugs.Psychotropic agents that are most frequently prescribed in Germany were identified by using the Arzneiverordnungs-Report 2016. Summaries of product characteristics (SmPC) of corresponding original products were analyzed regarding presence and frequency of sleep disorders/impairments of sleep according to the International Classification of Sleep Disorders 3 (ICSD-3).N = 64 SmPCs were analyzed. In most of the analyzed SmPCs, at least one sleep disorder (50/64; 78 %) was listed. At least one SmPC with a corresponding ADR was found in the categories insomnia (52 %), parasomnias (33 %), and sleep-related movement disorders (20 %); sleep-related breathing disorders (6 %) and central disorders of hypersomnolence (5 %) were rarely listed; circadian rhythm sleep-wake disorder was not found. The SmPCs of the four most frequently prescribed agents (citalopramvenlafaxinemirtazapinesertraline) listed insomnia as an ADR. Nearly all analysed hypnotics (except chloral hydrate) were associated with nightmares.Most of the psychotropic agents frequently prescribed in Germany may induce sleep disorders/impairments of sleep. The four most frequently prescribed agents were antidepressants and all of the corresponding SmPCs listed insomnia as a possible ADR. Sleep disorders should be taken seriously as possible ADRs of psychopharmacotherapy.Psychopharmakotherapie hat bei der Behandlung zahlreicher psychischer Störungen einen großen Stellenwert. Unerwünschte Arzneimittelwirkungen (UAW) beeinflussen dabei die Compliance und Verträglichkeit. Auch Beeinträchtigungen des Schlafs können als UAW einer Psychopharmakotherapie auftreten. Schlafstörungen sind mit einem erhöhten Risiko für körperliche und psychische Erkrankungen assoziiert und beeinträchtigen Kognition, Impulskontrolle, Emotionsregulation und Stimmung. Ziel der vorliegenden Arbeit ist die systematische Darstellung der Art und des Risikos für Schlafstörungen/Beeinträchtigungen des Schlafs durch häufig verordnete Psychopharmaka.Auf der Basis des Arzneiverordnungs-Reports 2016 wurden die in Deutschland verordnungsstärksten Psychopharmaka identifiziert. Die Fachinformationen (FI) der zugehörigen Originalpräparate wurden im Hinblick auf Nennung und Häufigkeitsangaben von Schlafstörungen/Beeinträchtigungen des Schlafs gemäß der International Classification of Sleep Disorders 3 (ICSD-3) untersucht.Es wurden n = 64 FI untersucht. Bei der überwiegenden Zahl wurde mindestens eine Schlafstörung aufgeführt (50/64; 78 %). In den Kategorien Insomnien (52 %), Parasomnien (33 %) und schlafbezogene Bewegungsstörungen (20 %) wurde am häufigsten mindestens eine FI mit entsprechender UAW gefunden; schlafbezogene Atmungsstörungen (6 %) und Hypersomnien zentralnervösen Ursprungs (5 %) waren selten aufgeführt; zirkadiane Schlaf-Wach-Rhythmusstörungen wurden nicht gefunden. In den FI der vier verordnungsstärksten Wirkstoffe (CitalopramVenlafaxinMirtazapinSertralin) war Insomnie aufgeführt. Nahezu alle untersuchten Hypnotika (Ausnahme: Chlorahlydrat) waren mit Albträumen assoziiert.Die meisten der in Deutschland häufig verordneten Psychopharmaka können Schlafstörungen/Beeinträchtigungen des Schlafs induzieren. Bei den vier verordnungsstärksten Wirkstoffen handelte es sich um Antidepressiva und in den zugehörigen FI war jeweils Insomnie aufgeführt. Bei der Behandlung mit Psychopharmaka sollte auf das Auftreten von Schlafstörungen als eine mögliche Nebenwirkung geachtet werden.

Inhibition of serotonin uptake in platelets seems to be the crucial mechanism underlying SSRI-associated haemorrhages. This effect is also present in antidepressants featuring non-selective serotonin reuptake inhibition (non-SSRI). Impact of selectivity of serotonin reuptake and/or affinity to the serotonin reuptake transporter on the bleeding risk have not yet been studied sufficiently. We retrieved country- and SSRI-/non-SSRI-specific data from the Uppsala Monitoring Centre and used a case/non-case approach to calculate substance-specific reporting odds ratios (ROR) to evaluate the statistical association of treatment with SSRI/non-SSRI and haemorrhages. Country-specific analysis revealed no clear trends towards an increased risk of bleeding related to particular agents of group SSRI/non-SSRI (sporadically ROR1 for citalopram, duloxetine, escitalopram, fluvoxamine, paroxetine, sertraline, St. John's wort). There was a clear trend in the total dataset towards a "reduced protective effect" (suggested by ROR1) on the development of haemorrhages with agents featuring comparatively high affinity to the 5-HTT and/or selective serotonin reuptake inhibition (as with escitalopram, citalopram, duloxetine or venlafaxine) in comparison to agents with lower affinity or non-selective serotonin reuptake inhibition (as with mirtazapine or doxepin). Comparison of group-specific aggregated data (SSRI vs. non-SSRI) revealed significant differences regarding the "protective effect" on the development of haemorrhages between groups SSRI vs. non-SSRI in favour of non-SSRI in nearly all countries as well as in the total dataset. Our findings provide preliminary evidence that agents with increased affinity to the 5-HTT and/or selective serotonin reuptake inhibition may be associated with an increased risk of bleeding.

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.

Pharmacological neuroenhancement (PNE) is a form of abuse and has not yet been addressed by methods of pharmacovigilance. In the present study, we tested if quantitative signal detection may be sensitive in regards to PNE. We evaluated the risk of drug abuse and dependence (DAAD) related to substances that are known to be used for PNE and divided this group into agents with (methylphenidate) and without a known abuse potential outside the field of PNE (atomoxetine, modafinil, acetylcholine esterase inhibitors, and memantine). Reporting odds ratios (RORs) were calculated using a case/non-case approach based on global and country-specific drug safety data from the Uppsala Monitoring Centre (UMC). Both control substances (diazepam and lorazepam) and methylphenidate were statistically associated with DAAD in all datasets (except methylphenidate in Italy). Modafinil was associated with DAAD in the total dataset (ROR, 2.7 (95% confidence interval (CI), 2.2–3.3)), Germany (ROR, 4.6 (95% CI, 1.8–11.5)), and the USA (ROR, 2.0 (95% CI, 1.6–2.5)). Atomoxetine was associated with DAAD in the total dataset (ROR, 1.3 (95% CI, 1.2–1.5)) and in the UK (ROR, 3.3 (95% CI, 1.8–6.1)). Apart from memantine, which was associated with DAAD in Germany (ROR, 1.8 (95% CI, 1.0–3.2)), no other antidementia drug was associated with DAAD. Quantitative signal detection is suitable to detect agents with a risk for DAAD. Its sensitivity regarding PNE is limited, although atomoxetine and modafinil, which do not have a known abuse potential outside PNE, and no antidementia drugs, whose use in PNE is presumably low, were associated with DAAD in our analysis.

Persons 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 (R) 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, R = 0.932, P = 0.01), bupropion (r = 0.962, R = 0.925, P = 0.01), citalopram (r = 0.970, R = 0.941, P = 0.01), escitalopram (r = 0.824, R = 0.682, P = 0.01), fluoxetine (r = 0.885, R = 0.783, P = 0.01), paroxetine (r = 0.801, R = 0.641, P = 0.01), and sertraline (r = 0.880, R = 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 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.

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.

IntroductionPersons using the Internet generate large amounts of health-related data, which are increasingly used in modern health sciences.Objectives/aimsWe analysed the relation between annual prescription volumes (APV) of several antidepressants with marketing approval in Germany and corresponding web search query data generated in Google to test, if web search query volume may be a proxy for medical prescription practice.MethodsWe obtained APVs of several antidepressants related to corresponding prescriptions at the expense of the statutory health insurance in Germany from 2004–2013. 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 (Pearson'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 two variables.ResultsSignificant and strong correlations between substance-specific APVs and corresponding annual query volume 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).ConclusionsAlthough the used data did not allow to perform an analysis with a higher temporal resolution our results suggest that web search query volume may be a proxy for corresponding prescription behaviour. However, further studies analysing other pharmacologic agents and prescription data that facilitates an increased temporal resolution are needed to confirm this hypothesis.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionDrug-induced liver injury is a major problem of pharmacotherapy and is also frequent with anti-depressive psychopharmacotherapy.Objectives/aimsHowever, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepressants.MethodsWe performed a quantitative signal detection analysis using pharmacovigilance data from the Uppsala monitoring center from the WHO that records adverse drug reaction data from worldwide sources; we calculated reporting odds ratios (ROR) as measures for disproportionality within a case-/non-case approach for several frequently prescribed anti-depressants.ResultsBoth positive controls, amineptine (ROR 38.4 [95% CI: 33.8–43.6]) and nefazodone (ROR 3.2 [95% CI: 3.0–3.5]), were statistically associated with hepatotoxicity. Following amineptine, agomelatine (ROR 6.4 [95% CI: 5.7–7.2]) 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: 3.3–3.4]) and nefazodone.ConclusionsIn line with previous studies our results support the hypothesis that agomelatine and several other anti-depressants may be 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.Disclosure of interestThe authors have not supplied their declaration of competing interest.

There is increasing evidence for an association between treatment with selective serotonin reuptake inhibitors (SSRI) and an increased risk of bleeding events. The most important underlying mechanism appears to be inhibition of serotonin uptake in platelets, an effect that is also present in antidepressants with non-selective serotonin-reuptake inhibition (NSRI). Accordingly, also NSRI may be associated with an increased risk of bleeding. However, there is little data in this regard.Based on data (spontaneous reports of adverse drug reactions) from 2 pharmacovigilance databases (WHO-database/Vigibase™; BfArM/AkdÄ-database in Germany) we used a case/non-case approach and calculated reporting odds ratios (ROR) as measures for disproportionality regarding the association of treatment with an agent of the group SSRI/NSRI and haemorrhages.Whereas both positive control agents (ASS and diclofenac) were statistically associated with haemorrhages in both databases (ASS: BfArM/AkdÄ, ROR 13.62 [95% CI 12.76-14.53]/WHO, ROR 12.96 [95% CI 12.75-13.16]; diclofenac: BfArM/AkdÄ, ROR 3.01 [95% CI 2.71-3.21]/WHO, ROR 2.11 [95% CI 2.05-2.16]), none of the agents of the group SSRI (ROR1) was associated with haemorrhages. In group NSRI, only St. John's wort/hypericum was associated with haemorrhages (WHO-database, ROR 1.31 [95% CI 1.06-1.63]).Signal detectioning in 2 pharmacovigilance databases suggest that serotonin reuptake inhibition is not associated with an increased risk of bleeding. However, underreporting may have accounted for the evaluated absent associations, particularly concerning SSRI. Regarding the detected increased risk of bleeding associated with hypericum, pharmacokinetic drug-drug interactions may be relevant independent of serotonin reuptake inhibition.