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Risk of Seizures Associated with Antidepressant Use in Patients With Drug Saf (2016) 39:307–321 DOI 10.1007/s40264-015-0363-z ORIGINAL RESEARCH ARTICLE Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case– Control Analysis Using the Clinical Practice Research Datalink 1 2,3 4 2 Marlene Bloechliger • Alessandro Ceschi • Stephan Ru¨egg • Hugo Kupferschmidt • 5 6 1,6,7 Stephan Kraehenbuehl • Susan S. Jick • Christoph R. Meier • Michael Bodmer1,8 Published online: 9 December 2015 Ó Springer International Publishing Switzerland 2015 Abstract Methods We conducted a retrospective follow-up study Introduction Antidepressant use has been associated with with a nested case–control analysis between 1998 and 2012, an increased risk of seizures. Evidence on the association using data from the UK-based Clinical Practice Research between antidepressant use at therapeutic doses and sei- Datalink (CPRD). We estimated crude incidence rates with zures mainly comes from clinical trials that were not 95 % confidence intervals (CIs) of seizures in depressed designed to investigate this potential relationship. patients who used selective serotonin reuptake inhibitors Objective The objective of this study was to assess the (SSRIs), serotonin–norepinephrine reuptake inhibitors risk of first-time seizures in association with exposure to (SNRIs), tricyclic antidepressants (TCAs), ‘other antidepres- antidepressants in patients with depressive disorders. sants’, no antidepressants, or who had used antidepressants in the past. To adjust for potential confounding, we estimated odds ratios of antidepressant drug use among cases with sei- zures and matched controls in a nested case–control analysis. Electronic supplementary material The online version of this article (doi:10.1007/s40264-015-0363-z) contains supplementary material, which is available to authorized users. & Christoph R. Meier 2 National Poisons Centre, Tox Info Suisse, Associated [email protected] Institute of the University of Zurich, Zurich, Switzerland Marlene Bloechliger 3 Division of Clinical Pharmacology and Toxicology, [email protected] Department of Internal Medicine, Ente Ospedaliero Cantonale Lugano, Lugano, Switzerland Alessandro Ceschi [email protected] 4 Division of Clinical Neurophysiology, Department of Neurology, University Hospital Basel, Basel, Switzerland Stephan Ru¨egg [email protected] 5 Division of Clinical Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Basel, Hugo Kupferschmidt Basel, Switzerland [email protected] 6 Boston Collaborative Drug Surveillance Program, Boston Stephan Kraehenbuehl University School of Public Health, Lexington, MA, USA [email protected] 7 Hospital Pharmacy, University Hospital Basel, Spitalstrasse Susan S. Jick 26, 4031 Basel, Switzerland [email protected] 8 Medical Department, Zuger Kantonsspital, Zug, Switzerland Michael Bodmer [email protected] 1 Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, Basel Pharmacoepidemiology Unit, University of Basel, Basel, Switzerland 308 M. Bloechliger et al. Results Of 151,005 depressed patients, 619 had an inci- norepinephrine reuptake inhibitors (SNRIs), or ‘other dent seizure during follow-up. Incidence rates per 10,000 antidepressants’ (such as trazodone, reboxetine, bupropion, person-years were 12.44 (95 % CI 10.67–14.21) in SSRI or mirtazapine) are preferred to older tricyclic antidepres- users, 15.44 (95 % CI 8.99–21.89) in SNRI users, 8.33 sants (TCAs) or tetracyclic antidepressants as first-line (95 % CI 4.68–11.98) in TCA users, 9.33 (95 % CI antidepressants [4]. 6.19–12.46) in non-users of antidepressants, and 5.05 Most antidepressants induce seizures in overdose [5–7], (95 % CI 4.49–5.62) in past users of antidepressants. In the but the seizure risk at therapeutic dose ranges remains case–control analysis, relative risk estimates for seizures unclear. A meta-analysis of clinical trials reported higher were increased in current users of SSRIs (adjusted odds seizure incidence in patients assigned to placebo than to ratio 1.98, 95 % CI 1.48–2.66) and SNRIs (adjusted odds most second-generation antidepressants, a finding the ratio 1.99, 95 % CI 1.20–3.29), but not TCAs (adjusted authors explained by untreated depression being a major odds ratio 0.99, 95 % CI 0.63–1.53), compared with non- risk factor for seizures [8]. Therapeutic use of TCAs has users. been associated with an increased risk of seizures, a risk Conclusion Current use of SSRIs or SNRIs was associ- reported to be higher than the risk for therapeutic use of ated with a twofold increased risk of first-time seizures SSRIs [6, 9–12]. Conversely, a recent British observational compared with non-use, while current use of TCAs (mostly study found that use of SSRIs, venlafaxine, or mirtazapine low dose) was not associated with seizures. Treatment was associated with an increased risk of seizures compared initiation in SSRI and SNRI users was associated with a with use of TCAs in depressed patients aged 65 years or higher risk of seizures than longer-term treatment. older [13]. Evidence to date mainly comes from trials that were limited to few patients and focused on efficacy and short- term safety [6, 8, 10, 11, 14]. Most of these trials lacked Key Points data on seizure incidence in the placebo groups [8], and were therefore not suited to study the association between Patients with depression who currently used antidepressant use and seizures. Additionally, most trials antidepressants had a slightly higher incidence rate were limited to sample sizes not adequate to study rare of seizures than non-users or past users of adverse events such as seizures. To analyze seizure risk in antidepressants. a large ‘real-life setting’ we estimated absolute and relative Current use of selective serotonin reuptake inhibitors risk estimates of seizures in 151,005 adult patients with and serotonin–norepinephrine reuptake inhibitors depression who used various types of antidepressants and was associated with a twofold increased risk of were followed over a period of up to 14 years. seizures compared with non-use. Current use of tricyclic antidepressants at low doses was not associated with seizures compared with non- 2 Methods use. 2.1 Study Design and Data Source Treatment initiation rather than longer-term treatment and increasing dose in some but not all We conducted a retrospective population-based follow-up substances were associated with an increased risk of study with a nested case–control analysis, using data from seizures. the UK-based Clinical Practice Research Datalink (CPRD). The CPRD encompasses some 10,000,000 patient records provided by some 600 participating general practitioner (GP) practices [15]. Specialist or hospital care is provided 1 Introduction at the request of the GP or, if directly assessed, full dis- closure from secondary care is reported back to the GP Depression is among the top three leading causes of disease [16]. Patients are representative of the UK with regard to burden in terms of disability-adjusted life-years in high- age, sex, and geographic distribution. GPs provide data on income countries [1]. In the UK, about 25 % of adults patient characteristics, medical diagnoses (recorded as experience an episode of major depression at least once in ‘Read codes’), and drug prescriptions in a standardized and their lifetime [2]. Patients with moderate to severe anonymous form. The records of diagnoses and drug pre- depression should receive treatment including pharma- scriptions have been validated and proven to be of high cotherapy [3]. Second-generation antidepressants such as quality [17, 18]. Data from the CPRD have been used to selective serotonin reuptake inhibitors (SSRIs), serotonin– conduct observational studies on depression or Antidepressants and the Risk of Seizures 309 Fig. 1 Flowchart of study Individuals aged 18-89 with first-time depression during population the study period (n=443,081) <3 years of recorded history on the database prior to the start date (n=225,631) ≥3 years of recorded history on the database prior to the start date (n=217,450) Seizures/epilepsy, or antiepileptic prescriptions, prior to the start date (n=7,718) No seizures/epilepsy or antiepileptic prescriptions prior to the start date (n=209,732) Major risk factors for seizures prior to the start date, or no antidepressants prescribed at any time after start date (n=58,727) Patients who met all inclusion criteria for follow-up (n=151,005) No seizure during follow-up (n=150,386) Potential controls for nested case-control analysis First-time seizure during follow-up (n=619) Cases for nested case-control analysis antidepressant use [19–23] and on seizures [23–26]. This alcoholism, drug abuse, head trauma, intracerebral bleed- study was approved by the Independent Scientific Advisory ing, brain tumor, brain abscess, sinus vein thrombosis, Committee for Medicines and Healthcare products Regu- meningitis, encephalitis, HIV, or cancer prior to the start latory Agency research. date (see Fig. 1). Because depression is an important co- morbidity of patients with dementia or a history of 2.2 Study Population ischemic stroke, we included patients with these disorders even though they are strong risk factors for seizures [24, Between 1998 and 2010, we identified all patients aged 27], and aimed to investigate potential effect modification 18–89 years with an incident depression diagnosis fol- by these disorders on our results. Patients had to
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