Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders

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Abstract

Introduction

The aim of this study was to describe the number and type of drugs used to treat depressive disorders in inpatient psychiatry and to analyse the determinants of potential drug-drug interactions (pDDI) and potentially inappropriate medication (PIM).

Methods

Our study was part of a larger pharmacovigilance project funded by the German Innovation Funds. It included all inpatients with a main diagnosis in the group of depressive episodes (F32, ICD-10) or recurrent depressive disorders (F33) discharged from eight psychiatric hospitals in Germany between 1 October 2017 and 30 September 2018 or between 1 January and 31 December 2019.

Results

The study included 14,418 inpatient cases. The mean number of drugs per day was 3.7 (psychotropic drugs = 1.7; others = 2.0). Thirty-one percent of cases received at least five drugs simultaneously (polypharmacy). Almost one half of all cases received a combination of multiple antidepressant drugs (24.8%, 95% CI 24.1%–25.5%) or a treatment with antidepressant drugs augmented by antipsychotic drugs (21.9%, 95% CI 21.3%–22.6%). The most frequently used antidepressants were selective serotonin reuptake inhibitors, followed by serotonin and norepinephrine reuptake inhibitors and tetracyclic antidepressants. In multivariate analyses, cases with recurrent depressive disorders and cases with severe depression were more likely to receive a combination of multiple antidepressant drugs (Odds ratio recurrent depressive disorder: 1.56, 95% CI 1.41–1.70, severe depression 1.33, 95% CI 1.18–1.48). The risk of any pDDI and PIM in elderly patients increased substantially with each additional drug (Odds Ratio: pDDI 1.32, 95% CI: 1.27–1.38, PIM 1.18, 95% CI: 1.14–1.22) and severity of disease (Odds Ratio per point on CGI-Scale: pDDI 1.29, 95% CI: 1.11–1.46, PIM 1.27, 95% CI: 1.11–1.44), respectively.

Conclusion

This study identified potential sources and determinants of safety risks in pharmacotherapy of depressive disorders and provided additional data which were previously unavailable. Most inpatients with depressive disorders receive multiple psychotropic and non-psychotropic drugs and pDDI and PIM are relatively frequent. Patients with a high number of different drugs must be intensively monitored in the management of their individual drug-related risk-benefit profiles.

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Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Spencer L James, Degu Abate, Kalkidan Hassen Abate … (2020)

Summary Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1–4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0–8·4) while the total sum of global YLDs increased from 562 million (421–723) to 853 million (642–1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6–9·2) for males and 6·5% (5·4–7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782–3252] per 100 000 in males vs s1400 [1279–1524] per 100 000 in females), transport injuries (3322 [3082–3583] vs 2336 [2154–2535]), and self-harm and interpersonal violence (3265 [2943–3630] vs 5643 [5057–6302]). Interpretation Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury. Funding Bill & Melinda Gates Foundation.

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What is polypharmacy? A systematic review of definitions

Nashwa Masnoon, Sepehr Shakib, Lisa Kalisch-Ellett … (2017)

Background Multimorbidity and the associated use of multiple medicines (polypharmacy), is common in the older population. Despite this, there is no consensus definition for polypharmacy. A systematic review was conducted to identify and summarise polypharmacy definitions in existing literature. Methods The reporting of this systematic review conforms to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist. MEDLINE (Ovid), EMBASE and Cochrane were systematically searched, as well as grey literature, to identify articles which defined the term polypharmacy (without any limits on the types of definitions) and were in English, published between 1st January 2000 and 30th May 2016. Definitions were categorised as i. numerical only (using the number of medications to define polypharmacy), ii. numerical with an associated duration of therapy or healthcare setting (such as during hospital stay) or iii. Descriptive (using a brief description to define polypharmacy). Results A total of 1156 articles were identified and 110 articles met the inclusion criteria. Articles not only defined polypharmacy but associated terms such as minor and major polypharmacy. As a result, a total of 138 definitions of polypharmacy and associated terms were obtained. There were 111 numerical only definitions (80.4% of all definitions), 15 numerical definitions which incorporated a duration of therapy or healthcare setting (10.9%) and 12 descriptive definitions (8.7%). The most commonly reported definition of polypharmacy was the numerical definition of five or more medications daily (n = 51, 46.4% of articles), with definitions ranging from two or more to 11 or more medicines. Only 6.4% of articles classified the distinction between appropriate and inappropriate polypharmacy, using descriptive definitions to make this distinction. Conclusions Polypharmacy definitions were variable. Numerical definitions of polypharmacy did not account for specific comorbidities present and make it difficult to assess safety and appropriateness of therapy in the clinical setting.

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Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

Andrea Cipriani, Toshi Furukawa, Georgia Salanti … (2018)

Summary Background Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

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Author and article information

Contributors

Jan Wolff:

ORCID: https://orcid.org/0000-0003-2750-0606

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Pamela Reißner:

ORCID: https://orcid.org/0000-0001-8171-0861

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: Writing – review & editing

Gudrun Hefner: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – review & editing

Claus Normann: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing

Klaus Kaier: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: ValidationRole: Writing – review & editing

Harald Binder: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ValidationRole: Writing – review & editing

Christoph Hiemke: Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing

Sermin Toto: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing

Katharina Domschke: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing

Michael Marschollek: Role: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing

Ansgar Klimke: Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: Writing – review & editing

Angela Lupattelli: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS One

Journal ID (publisher-id): plos

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 22 July 2021

Publication date Collection: 2021

Volume: 16

Issue: 7

Electronic Location Identifier: e0255192

Affiliations

[1 ] Peter L. Reichertz Institute for Medical Informatics of TU Braunschweig and Hannover Medical School, Hannover, Germany

[2 ] Faculty of Medicine, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany

[3 ] Evangelical Foundation Neuerkerode, Braunschweig, Germany

[4 ] Vitos Hochtaunus, Friedrichsdorf, Germany

[5 ] Vitos Clinic for Forensic Psychiatry, Eltville, Germany

[6 ] Faculty of Medicine, Institute of Medical Biometry and Statistics, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany

[7 ] Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany

[8 ] Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany

[9 ] Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

University of Oslo, NORWAY

Author notes

Competing Interests: Independent of the present study, KD received fees from Janssen Pharmaceuticals, Inc. for her consultancy work on the Neuroscience Steering Committee. CN received lecture and consultancy fees from Janssen-Cilag and Neuraxpharm as well as fees for conducting clinical studies from Janssen-Cilag. ST has received lecture fees from Janssen-Cilag, Otsuka / Lundbeck and Servier and is a member of the Advisory Board of Otsuka and Janssen-Cilag. CH has received lecture fees from Otsuka. The commercial funding sources were unrelated to the present study and did not alter our adherence to PLOS ONE policies on sharing data and materials.

* E-mail: janwolff123@ 123456gmail.com , wolff.jan@ 123456mh-hannover.de

Author information

Jan Wolff https://orcid.org/0000-0003-2750-0606

Pamela Reißner https://orcid.org/0000-0001-8171-0861

Article

Publisher ID: PONE-D-21-11326

DOI: 10.1371/journal.pone.0255192

PMC ID: 8297778

PubMed ID: 34293068

SO-VID: f09afdfe-40b8-4bb1-82b7-43e7e0c5eacc

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 April 2021

Date accepted : 11 July 2021

Page count

Figures: 4, Tables: 2, Pages: 16

Funding

Funded by: Innovations Funds of the German Federal Joint Committee

Award ID: 01VSF16009

Award Recipient : Ansgar Klimke

Financial support for this study was provided by a grant from the Innovations Funds of the German Federal Joint Committee (grant number: 01VSF16009, www.g-ba.de/english/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability Our study required potentially identifying and sensitive human research participant data, such as psychiatric diagnoses, medication data and many others. We cannot share these data because legal restrictions in Germany and the European Union (“General Data Protection Regulation” and “Processing of special categories of personal data”) prohibit sharing these sensitive data. Further information can be obtained from the ethics committee of the State Medical Association of Hesse, info@ 123456laekh.de , Hanauer Landstraße 152, 60314 Frankfurt, Germany, under the file number FF116 / 2017.”

Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders

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Most cited references 79

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

What is polypharmacy? A systematic review of definitions

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

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