Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000054.xml
CC BY-NC-ND 4.0 · Pharmacopsychiatry 2024; 57(04): 191-203
DOI: 10.1055/a-2292-1438
DOI: 10.1055/a-2292-1438
Original Paper
Risk Phenotypes, Comorbidities, Pharmacotherapy, and Electroconvulsive Therapy (ECT) in a Cohort with Difficult-to-Treat Depression in Comparison to an Unmedicated Control Group
Funding This project was supported by the PRACTIS-Clinician Scientist Program of Hannover Medical School, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, ME3696/3–1) – Project-ID 413617135 and in-house funding from Hannover Medical School. The funding agencies had no role in the design of the study, data collection, analyses, or interpretation, writing of the manuscript, or in the decision to publish the results. Deutsche Forschungsgemeinschaft — http://dx.doi.org/10.13039/501100001659; ME3696/3–1 – Project-ID 413617135
Abstract
Background Approximately 15–25% of depressed patients suffer from difficult-to-treat depression (DTD). Patients with DTD require a thorough examination to avoid the oversight of treatable (psychiatric/somatic) comorbidities or (pseudo-)resistance to antidepressant drugs (ADs). Polymorphisms of the cytochrome P450 (CYP) enzymes 2D6 and 2C19, which play a major role in the metabolism of ADs, may contribute to resistance to ADs. Patients with DTD might benefit from electroconvulsive therapy (ECT).
Methods We enrolled 109 patients with DTD and 29 untreated depressed controls (UDC). We assessed risk phenotypes, comorbidities, and treatment, including ECT. We also performed pharmacokinetic analyses of CYP2D6 and CYP2C19.
Results DTD patients significantly more often suffered from comorbid psychiatric diseases, especially ICD-10: F40-F48 (DTD:40.4%, UDC:17.2%, OR 11.87, p=0.011) than UDC patients. DTD patients receiving ECT were more likely to achieve remission (37.7% vs. 11.8%, OR=3.96, p=0.023). Treatment with ADs did not differ between remitters and non-remitters. No significant differences were observed in the distribution of CYP2D6 and CYP2C19 variants between both groups.
Conclusion Patients with DTD appear to experience comorbid neurotic stress and somatoform disorders (ICD-10: F40 – F48) more frequently. Therefore, a comprehensive differential diagnosis is crucial when patients do not respond sufficiently to antidepressant medication. Genotyping CYP2D6 and CYP2C19 should be considered.
Keywords
difficult-to-treat-depression - phenotyping - CYP enzymes - psychiatric comorbidities - pharmacogenetics - ECTPublication History
Received: 09 August 2023
Received: 07 March 2024
Accepted: 11 March 2024
Article published online:
02 May 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. 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. Lancet 2018; 392: 1789-1858
- 2 Sobocki P, Jönsson B, Angst J. et al. Cost of depression in Europe. J Ment Health Policy Econ 2006; 9: 87-98
- 3 Malhi GS, Mann JJ. Depression. Lancet 2018; 392: 2299-2312
- 4 Rush AJ, Trivedi MH, Wisniewski SR. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905-1917
- 5 McAllister-Williams RH, Arango C, Blier P. et al. The identification, assessment and management of difficult-to-treat depression: An international consensus statement. J Affect Disord 2020; 267: 264-282
- 6 Rush AJ, Sackeim HA, Conway CR. et al. Clinical research challenges posed by difficult-to-treat depression. Psychol Med 2022; 52: 419-432
- 7 Demyttenaere K, Van Duppen Z. The impact of (the concept of) treatment-resistant depression: An opinion review. Int J Neuropsychopharmacol 2019; 22: 85-92
- 8 Szegedi A, Jansen WT, Willigenburg van. et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: A meta-analysis including 6562 patients. J Clin Psychiatry 2009; 70: 344-353
- 9 Otte C. Incomplete remission in depression: Role of psychiatric and somatic comorbidity. Dialogues Clin Neurosci 2008; 10: 453-460
- 10 Fava M, Rush AJ, Alpert JE. et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: A STAR*D report. Am J Psychiatry 2008; 165: 342-351
- 11 Trivedi MH, Rush AJ, Wisniewski SR. et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 2006; 163: 28-40
- 12 McHugh RK, Weiss RD. Alcohol use disorder and depressive disorders. Alcohol Res 2019; 40 arcr.v40.1.01
- 13 Hawton K, Casañas I, Comabella C, Haw C. et al. Risk factors for suicide in individuals with depression: A systematic review. J Affect Disord 2013; 147: 17-28
- 14 Espinoza RT, Kellner CH. Electroconvulsive therapy. N Engl J Med 2022; 386: 667-672
- 15 Bundesärztekammer (BÄK), Kassenärztliche Bundesvereinigung (KBV), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Nationale VersorgungsLeitlinie Unipolare Depression –Langfassung, Version 3.1. 2022
- 16 National Institute for Health and Care Excellence. Depression in adults: Treatment and management: NICE guideline short version 2018.
- 17 APA Guideline for the treatment of depression 2019.
- 18 Mutz J, Vipulananthan V, Carter B. et al. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: Systematic review and network meta-analysis. BMJ 2019; 364: l1079
- 19 Bewernick B, Schlaepfer TE. Update on neuromodulation for treatment-resistant depression. F1000Res 2015; 4F1000 Faculty Rev -1389
- 20 Moeller SB, Gbyl K, Hjorthøj C. et al. Treatment of difficult-to-treat depression – clinical guideline for selected interventions. Nord J Psychiatry 2022; 76: 177-188
- 21 Strandberg P, Nordenskjöld A, Bodén R. et al. Electroconvulsive therapy versus repetitive transcranial magnetic stimulation in patients with a depressive episode: A register-based study. J ECT 2023; Epub ahead of print
- 22 Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013; 138: 103-141
- 23 Relling MV, Klein TE. CPIC: Clinical pharmacogenetics implementation consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther 2011; 89: 464-467
- 24 Scherf-Clavel M, Frantz A, Eckert A. et al. Effect of CYP2D6 pharmacogenetic phenotype and phenoconversion on serum concentrations of antidepressants and antipsychotics: A retrospective cohort study. Int J Clin Pharm 2023; 45: 1107-1117
- 25 Dubovsky SL. The usefulness of genotyping cytochrome P450 enzymes in the treatment of depression. Expert Opin Drug Metab Toxicol 2015; 11: 369-379
- 26 Scherf-Clavel M, Weber H, Wurst C. et al. Effects of pharmacokinetic gene variation on therapeutic drug levels and antidepressant treatment response. Pharmacopsychiatry 2022; 55: 246-254
- 27 Greden JF, Parikh SV, Rothschild AJ. et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res 2019; 111: 59-67
- 28 Sim SC, Nordin L, Andersson TM. et al. Association between CYP2C19 polymorphism and depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1160-1166
- 29 Kennedy SH, Lam RW, McIntyre RS. et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological treatments. Can J Psychiatry 2016; 61: 540-560
- 30 Müller DJ, Brandl EJ, Degenhardt F. et al. Pharmacogenetics in psychiatry: State of the art. Nervenarzt 2018; 89: 290-299
- 31 Brown LC, Stanton JD, Bharthi K. et al. Pharmacogenomic testing and depressive symptom remission: A systematic review and meta-analysis of prospective, controlled clinical trials. Clin Pharmacol Ther 2022; 112: 1303-1317
- 32 Purcell S, Neale B, Todd-Brown K. et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559-575
- 33 Cicali EJ, Elchynski AL, Cook KJ. et al. How to integrate CYP2D6 phenoconversion into clinical pharmacogenetics: A tutorial. Clin Pharmacol Ther 2021; 110: 677-687
- 34 CPIC—Clinical Pharmacogenetics Implementation Consortium. 2023 https://cpicpgx.org/
- 35 The Flockhart Cytochrome P450 Drug-Drug Interaction Table: Updated 2021. 2023; https://drug-interactions.medicine.iu.edu/
- 36 Baumann P, Eap CB, Gastpar M. The effect of perazine on the CYP2D6 and CYP2C19 phenotypes as measured by the dextromethorphan and mephenytoin tests in psychiatric patients. Basic Clin Pharmacol Toxicol 2020; 126: 444-447
- 37 Hefner G, Unterecker S, Shams MEE. et al. Melperone but not bisoprolol or metoprolol is a clinically relevant inhibitor of CYP2D6: Evidence from a therapeutic drug monitoring survey. J Neural Transm (Vienna) 2015; 122: 1609-1617
- 38 RCoreTeam, R: A language and environment for statistical computing. In R Core Team R Foundation for Statistical Computing, Vienna, Austria. 2014 https://www.R-project.org/
- 39 Kautzky A, Dold M, Bartova L. et al. Clinical factors predicting treatment resistant depression: Affirmative results from the European multicenter study. Acta Psychiatr Scand 2019; 139: 78-88
- 40 Huang S, Chen H, Wang J. et al. Investigation of early and lifetime clinical features and comorbidities for the risk of developing treatment-resistant depression in a 13-year nationwide cohort study. BMC Psychiatry 2020; 20: 541-z
- 41 Hampf C, Scherf-Clavel M, Weiß C. et al. Effects of anxious depression on antidepressant treatment response. Int J Mol Sci 2023; 24: 17128
- 42 Tiller JWG. Depression and anxiety. Med J Aust 2013; 199: 28
- 43 Demyttenaere K, Heirman E. The blurred line between anxiety and depression: Hesitations on comorbidity, thresholds and hierarchy. Int Rev Psychiatry 2020; 32: 455-465
- 44 Brady KT, Killeen TK, Brewerton T. et al. Comorbidity of psychiatric disorders and posttraumatic stress disorder. J Clin Psychiatry 2000; 61: 22-32
- 45 Flory JD, Yehuda R. Comorbidity between post-traumatic stress disorder and major depressive disorder: Alternative explanations and treatment considerations. Dialogues Clin Neurosci 2015; 17: 141-150
- 46 Hoppen TH, Priebe S, Vetter I. et al. Global burden of post-traumatic stress disorder and major depression in countries affected by war between 1989 and 2019: A systematic review and meta-analysis. BMJ Glob Health 2021; 6: e006303
- 47 Hoppen TH, Morina N. The prevalence of PTSD and major depression in the global population of adult war survivors: A meta-analytically informed estimate in absolute numbers. Eur J Psychotraumatol 2019; 10: 1578637
- 48 Newton-Howes G, Tyrer P, Johnson T. Personality disorder and the outcome of depression: Meta-analysis of published studies. Br J Psychiatry 2006; 188: 13-20
- 49 Ceresa A, Esposito CM, Buoli M. How does borderline personality disorder affect management and treatment response of patients with major depressive disorder? A comprehensive review. J Affect Disord 2021; 281: 581-589
- 50 Lee JH, Kung S, Rasmussen KG. et al. Effectiveness of electroconvulsive therapy in patients with major depressive disorder and comorbid borderline personality disorder. J ECT 2019; 35: 44-47
- 51 Beatson JA, Rao S. Depression and borderline personality disorder. Med J Aust 2013; 199: 24
- 52 Husain MM, Rush AJ, Fink M. et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): A Consortium for Research in ECT (CORE) report. J Clin Psychiatry 2004; 65: 485-491
- 53 Dierckx B, Heijnen WT, Broek vanden. et al. Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: A meta-analysis. Bipolar Disord 2012; 14: 146-150
- 54 Ogawa Y, Takeshima N, Hayasaka Y. et al. Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database Syst Rev 2019; 6: CD001026
- 55 Furukawa T, Streiner DL, Young LT. Antidepressant plus benzodiazepine for major depression. Cochrane Database Syst Rev 2000; 4: CD001026
- 56 Read JR, Sharpe L, Modini M. et al. Multimorbidity and depression: A systematic review and meta-analysis. J Affect Disord 2017; 221: 36-46
- 57 Nemeroff CB. The state of our understanding of the pathophysiology and optimal treatment of depression: Glass half full or half empty?. Am J Psychiatry 2020; 177: 671-685
- 58 Zimmerman M, Mattia JI, Posternak MA. Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice?. Am J Psychiatry 2002; 159: 469-473
- 59 Weinshilboum R. Inheritance and drug response. N Engl J Med 2003; 348: 529-537
- 60 Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76: 391-396
- 61 Arnone D, Omar O, Arora T. et al. Effectiveness of pharmacogenomic tests including CYP2D6 and CYP2C19 genomic variants for guiding the treatment of depressive disorders: Systematic review and meta-analysis of randomised controlled trials. Neurosci Biobehav Rev 2023; 144: 104965
- 62 Wagner E, McMahon L, Falkai P. et al. Impact of smoking behavior on clozapine blood levels – a systematic review and meta-analysis. Acta Psychiatr Scand 2020; 142: 456-466
- 63 Anderson GD, Chan L. Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products. Clin Pharmacokinet 2016; 55: 1353-1368
- 64 Lundstrøm NH, Holgersen NK, Haastrup MB. The effect of smoking on the plasma concentration of tricyclic antidepressants: A systematic review. Acta Neuropsychiatr 2022; 34: 1-9
- 65 Gazzaz M, Kinzig M, Schaeffeler E. et al. Drinking ethanol has few acute effects on CYP2C9, CYP2C19, NAT2, and P-glycoprotein activities but somewhat inhibits CYP1A2, CYP2D6, and intestinal CYP3A: So what?. Clin Pharmacol Ther 2018; 104: 1249-1259
- 66 Vincent-Viry M, Fournier B, Galteau MM. Short communication. The effects of drinking and smoking on the CYP2D6 metabolic capacity. Drug Metab Dispos 2000; 28: 617-619
- 67 Ampong DN. Depression and pharmacogenetics. Arch Psychiatr Nurs 2018; 32: 71-74
- 68 Benkert O, Hippius H. Kompendium der psychiatrischen pharmakotherapie. 13 Auflage Edition. Berlin, Germany: Springer; 2021