{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T08:39:15Z","timestamp":1782031155931,"version":"3.54.5"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T00:00:00Z","timestamp":1667952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001455","name":"American Foundation for Suicide Prevention","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001455","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Using other central nervous system (CNS) medications in combination with selective serotonin reuptake inhibitor (SSRI) treatment is common. Despite this, there is limited evidence on the impact on suicidal behavior of combining specific medications. We aim to provide evidence on signals for suicidal behavior risk when initiating CNS drugs during and outside of SSRI treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Using a linkage of Swedish national registers, we identified a national cohort of SSRI users aged 6\u201359 years residing in Sweden 2006\u20132013. We used a two-stage Bayesian Poisson model to estimate the incidence rate ratio (IRR) of suicidal behavior in periods up to 90 days before and after a CNS drug initiation during SSRI treatment, while accounting for multiple testing. For comparison, and to assess whether there were interactions between SSRIs and other CNS drugs, we also estimated the IRR of initiating the CNS drug without SSRI treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 53 common CNS drugs initiated during SSRI treatment, dispensed to 262,721 individuals. We found 20 CNS drugs with statistically significant IRRs. Of these, two showed a greater risk of suicidal behavior after versus before initiating the CNS drug (alprazolam, IRR = 1.39; flunitrazepam, IRR = 1.83). We found several novel signals of drugs that were statistically significantly associated with a reduction in the suicidal behavior risk. We did not find evidence of harmful interactions between SSRIs and the selected CNS drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Several of the detected signals for reduced risk correspond to drugs where there is previous evidence of benefit for antidepressant augmentation (e.g., olanzapine, quetiapine, lithium, buspirone, and mirtazapine). Novel signals of reduced suicidal behavior risk, including for lamotrigine, valproic acid, risperidone, and melatonin, warrant further investigation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2022.1012650","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T13:54:32Z","timestamp":1668002072000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Use of central nervous system drugs in combination with selective serotonin reuptake inhibitor treatment: A Bayesian screening study for risk of suicidal behavior"],"prefix":"10.3389","volume":"13","author":[{"given":"Tyra","family":"Lagerberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvid","family":"Sj\u00f6lander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Gibbons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick D.","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"D\u2019Onofrio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Hellner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Lichtenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seena","family":"Fazel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1007\/s00228-014-1676-z","article-title":"Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications.","volume":"70","author":"Abbing-Karahagopian","year":"2014","journal-title":"Eur J Clin Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"S47","DOI":"10.1186\/1744-859X-7-S1-S47","article-title":"Polypharmacy in psychiatric inpatients: data from AMSP, a European pharmacovigilance system.","volume":"7","author":"Konstantinidis","year":"2008","journal-title":"Ann Gen Psychiatry."},{"key":"B3","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1001\/archgenpsychiatry.2009.175","article-title":"National trends in psychotropic medication polypharmacy in office-based psychiatry.","volume":"67","author":"Mojtabai","year":"2010","journal-title":"Arch Gen Psychiatry."},{"key":"B4","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1177\/070674371305800708","article-title":"Trends in psychotropic use in Saskatchewan from 1983 to 2007.","volume":"58","author":"Meng","year":"2013","journal-title":"Can J Psychiatry."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1007\/s00787-018-01269-2","article-title":"Antidepressant prescription patterns and CNS polypharmacy with antidepressants among children, adolescents, and young adults: a population-based study in Sweden.","volume":"28","author":"Lagerberg","year":"2019","journal-title":"Eur Child Adolesc Psychiatry."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1016\/j.jaac.2010.07.007","article-title":"National trends in child and adolescent psychotropic polypharmacy in office-based practice, 1996-2007.","volume":"49","author":"Comer","year":"2010","journal-title":"J Am Acad Child Adolesc Psychiatry."},{"key":"B7","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/mp.2015.53","article-title":"Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression.","volume":"21","author":"Hieronymus","year":"2016","journal-title":"Mol Psychiatry."},{"key":"B8","first-page":"8","article-title":"Limitations in efficacy of antidepressant monotherapy.","volume":"68","author":"Rush","year":"2007","journal-title":"J Clin Psychiatry."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.7573\/dic.2020-2-2","article-title":"Antidepressant efficacy and side effect burden: an updated guide for clinicians.","volume":"9","author":"Kutzer","year":"2020","journal-title":"Drugs Context."},{"key":"B10","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1023\/B:PHAR.0000026800.13888.b0","article-title":"Reasons for polypharmacy among psychiatric patients.","volume":"26","author":"Viola","year":"2004","journal-title":"Pharm World Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.jad.2019.01.044","article-title":"Prevalence, treatment patterns, and stay characteristics associated with hospitalizations for major depressive disorder.","volume":"249","author":"Citrome","year":"2019","journal-title":"J Affect Disord."},{"key":"B12","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1046\/j.1365-2710.1999.00200.x","article-title":"Clinically significant pharmacokinetic drug interactions with psychoactive drugs: antidepressants and antipsychotics and the cytochrome P450 system.","volume":"24","author":"Tanaka","year":"1999","journal-title":"J Clin Pharm Ther."},{"key":"B13","doi-asserted-by":"publisher","first-page":"465","DOI":"10.7861\/clinmedicine.16-5-465","article-title":"The epidemiology of polypharmacy.","volume":"16","author":"Payne","year":"2016","journal-title":"Clin Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1016\/S0140-6736(17)32802-7","article-title":"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.","volume":"391","author":"Cipriani","year":"2018","journal-title":"Lancet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1162\/99608f92.6fdaa9de","article-title":"Medications and suicide: high dimensional empirical bayes screening (iDEAS).","volume":"1","author":"Gibbons","year":"2019","journal-title":"Harvard Data Sci Rev."},{"key":"B16","doi-asserted-by":"publisher","first-page":"110531","DOI":"10.1016\/j.biopha.2020.110531","article-title":"Screening to identify signals of opioid drug interactions leading to unintentional traumatic injury.","volume":"130","author":"Leonard","year":"2020","journal-title":"Biomed Pharmacother."},{"key":"B17","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1007\/s10654-009-9350-y","article-title":"The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research.","volume":"24","author":"Ludvigsson","year":"2009","journal-title":"Eur J Epidemiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1002\/pds.1294","article-title":"The new Swedish prescribed drug register\u2014opportunities for pharmacoepidemiological research and experience from the first six months.","volume":"16","author":"Wettermark","year":"2007","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B19","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1186\/1471-2458-11-450","article-title":"External review and validation of the Swedish national inpatient register.","volume":"11","author":"Ludvigsson","year":"2011","journal-title":"BMC Public Health."},{"key":"B20","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1007\/s10654-017-0316-1","article-title":"The Swedish cause of death register.","volume":"32","author":"Brooke","year":"2017","journal-title":"Eur J Epidemiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/s10654-016-0117-y","article-title":"Registers of the Swedish total population and their use in medical research.","volume":"31","author":"Ludvigsson","year":"2016","journal-title":"Eur J Epidemiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"491","DOI":"10.2147\/CLEP.S90589","article-title":"Ethical aspects of registry-based research in the Nordic countries.","volume":"7","author":"Ludvigsson","year":"2015","journal-title":"Clin Epidemiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1016\/S0140-6736(14)60379-2","article-title":"Antipsychotics, mood stabilisers, and risk of violent crime.","volume":"384","author":"Fazel","year":"2014","journal-title":"Lancet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e809","DOI":"10.4088\/JCP.13m08899","article-title":"Suicide, hospital-presenting suicide attempts, and criminality in bipolar disorder: examination of risk for multiple adverse outcomes.","volume":"75","author":"Webb","year":"2014","journal-title":"J Clin Psychiatry."},{"key":"B25","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1097\/00001648-200011000-00012","article-title":"Multilevel modeling in epidemiology with GLIMMIX.","volume":"11","author":"Witte","year":"2000","journal-title":"Epidemiology."},{"key":"B26","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s10654-019-00517-2","article-title":"Frequentist versus bayesian approaches to multiple testing.","volume":"34","author":"Sj\u00f6lander","year":"2019","journal-title":"Eur J Epidemiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.bjpt.2018.12.006","article-title":"Understanding and interpreting confidence and credible intervals around effect estimates.","volume":"23","author":"Hespanhol","year":"2019","journal-title":"Braz J Phys Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1001\/archgenpsychiatry.2011.2048","article-title":"Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine.","volume":"69","author":"Gibbons","year":"2012","journal-title":"Arch Gen Psychiatry."},{"key":"B29","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1001\/jama.2017.8036","article-title":"Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial.","volume":"318","author":"Mohamed","year":"2017","journal-title":"JAMA."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1176\/ajp.2006.163.9.1519","article-title":"A comparison of lithium and T 3 augmentation following two failed medication treatments for depression: a STAR* D report.","volume":"163","author":"Nierenberg","year":"2006","journal-title":"Am J Psychiatry."},{"key":"B31","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1177\/070674371506000104","article-title":"The STAR* D trial: it is time to reexamine the clinical beliefs that guide the treatment of major depression.","volume":"60","author":"Pigott","year":"2015","journal-title":"Can J Psychiatry."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1056\/NEJMoa052964","article-title":"Medication augmentation after the failure of SSRIs for depression.","volume":"354","author":"Trivedi","year":"2006","journal-title":"N Engl J Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/S0006-3223(01)01262-8","article-title":"A double-blind, placebo-controlled study of antidepressant augementation with mirtazapine.","volume":"51","author":"Carpenter","year":"2002","journal-title":"Biol Psychiatry."},{"key":"B34","doi-asserted-by":"publisher","first-page":"k4218","DOI":"10.1136\/bmj.k4218","article-title":"Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR).","volume":"363","author":"Kessler","year":"2018","journal-title":"BMJ."},{"key":"B35","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1176\/appi.ajp.2018.17101112","article-title":"Medications for alcohol and opioid use disorders and risk of suicidal behavior, accidental overdoses, and crime.","volume":"175","author":"Molero","year":"2018","journal-title":"Am J Psychiatry."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1798","DOI":"10.1001\/jama.2016.15380","article-title":"Association between prescription of major psychotropic medications and violent reoffending after prison release.","volume":"316","author":"Chang","year":"2016","journal-title":"JAMA."},{"key":"B37","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1111\/ajad.12185","article-title":"Addiction and suicide: a review.","volume":"24","author":"Yuodelis-Flores","year":"2015","journal-title":"Am J Addict."},{"key":"B38","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1146\/annurev-statistics-030718-105108","article-title":"Self-controlled case series methodology.","volume":"6","author":"Whitaker","year":"2019","journal-title":"Annu Rev Stat Appl."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.4088\/PCC.16r02037","article-title":"Prescribed benzodiazepines and suicide risk: a review of the literature.","volume":"19","author":"Dodds","year":"2017","journal-title":"Prim Care Companion CNS Disord."}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2022.1012650\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T13:54:37Z","timestamp":1668002077000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2022.1012650\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,9]]},"references-count":39,"alternative-id":["10.3389\/fpsyt.2022.1012650"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2022.1012650","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,9]]},"article-number":"1012650"}}