Antidepressant use has been associated with an increased risk of seizures. Evidence on the association between antidepressant use at therapeutic doses and seizures mainly comes from clinical trials that were not designed to investigate this potential relationship.; The objective of this study was to assess the risk of first-time seizures in association with exposure to antidepressants in patients with depressive disorders.; We conducted a retrospective follow-up study with a nested case-control analysis between 1998 and 2012, using data from the UK-based Clinical Practice Research Datalink (CPRD). We estimated crude incidence rates with 95 % confidence intervals (CIs) of seizures in depressed patients who used selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), 'other antidepressants', 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 seizures and matched controls in a nested case-control analysis.; Of 151,005 depressed patients, 619 had an incident seizure during follow-up. Incidence rates per 10,000 person-years were 12.44 (95 % CI 10.67-14.21) in SSRI users, 15.44 (95 % CI 8.99-21.89) in SNRI users, 8.33 (95 % CI 4.68-11.98) in TCA users, 9.33 (95 % CI 6.19-12.46) in non-users of antidepressants, and 5.05 (95 % CI 4.49-5.62) in past users of antidepressants. In the case-control analysis, relative risk estimates for seizures were increased in current users of SSRIs (adjusted odds ratio 1.98, 95 % CI 1.48-2.66) and SNRIs (adjusted odds ratio 1.99, 95 % CI 1.20-3.29), but not TCAs (adjusted odds ratio 0.99, 95 % CI 0.63-1.53), compared with non-users.; Current use of SSRIs or SNRIs was associated with a twofold increased risk of first-time seizures compared with non-use, while current use of TCAs (mostly low dose) was not associated with seizures. Treatment initiation in SSRI and SNRI users was associated with a higher risk of seizures than longer-term treatment.