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Long-term Antidepressant Drug Use Linked With Risk of Epilepsy


Individuals exposed to antidepressant drugs for longer than 365 days had an increased risk of epilepsy, particularly those given escitalopram, venlafaxine, and mirtazapine, according to a recent study conducted in Taiwan.

Long-term exposure to antidepressant drugs (ADs) may increase risk of epilepsy, according to study findings published recently in Epilepsy & Behavior.

Use of ADs have been steadily increasing in recent years, with findings from the National Health and Nutrition Examination Survey (2015-2018) indicating that 13.2% of US adults aged 18 years or older reported use in the past 30 days.

Although these drugs have proven generally well tolerated with side effects generally mild and occuring within a week of treatment, studies have demonstrated considerable adverse events, such as metabolic syndrome, sexual dysfunction, and a possible increased risk of epilepsy.

For instance, researchers noted that findings of a nested case-control study of 151,005 patients with depression using selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors were 2 times more likely to develop first-time seizures compared with non-use, while current use of low-dose tricyclic antidepressants was not associated with seizures.

However, ADs are a poor proxy for depression treatment in real-world situations, they said, with only 55.2% of AD prescriptions indicated for depression, whereas other ADs are used for anxiety disorders, insomnia, pain, and panic disorders, which are also risk factors for epilepsy.

“It remains unclear whether ADs elevate the risk of epilepsy,” said the study authors.

A case-control study using Taiwan’s National Health Insurance Research Database between 1998 and 2013 was conducted to examine the association between exposure to ADs and the risk of epilepsy among community-dwelling adults exposed to ADs, including fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, duloxetine, milnacipran, bupropion, and mirtazapine.

ADs use patterns were separated into 4 subgroups based on the cumulative defined daily dose (cDDD): cDDD 30 days, cDDD 31-120 days, cDDD 121-365 days, and cDDD greater than 365 days.

Individuals with no history of epilepsy and convulsions at the time of enrollment and subsequently developed epilepsy, as determined by board-certified neurologists based on their clinical judgment and electroencephalogram during the follow-up period, were enrolled as the case cohort.

Additional analyses were performed to assess if individual antidepressants expressed variable risk of epilepsy, if the risk of epilepsy was AD dose-dependent, and after adjusting for confounding variables cited as the indications for antidepressant use, including depressive disorders, anxiety disorders, and other physical diseases (cardiovascular disease [CVD], central nervous system [CNS] infections, and traumatic brain injury [TBI]).

A total of 863 patients with epilepsy and 3452 controls were enrolled in the analysis. The mean (SD) ages at enrollment were 48.12 (18.56) and 48.12 (18.55) years in patients with epilepsy and controls, respectively. The mean follow-up duration was 3.53 years for both groups.

Between the 2 cohorts, patients with epilepsy showed higher frequency physical comorbidities (CVD, 33.5% vs 12.8%; TBI, 25.4% vs 8.6%; CNS infection, 4.2% vs 0.8%; all P < .001), higher mean [SD] Charlson Comorbidity Index (CCI) score (1.46 [1.69] vs 1.28 [1.76]; P = .008) than the controls.

“Furthermore, patients with epilepsy had a higher percentage use of ADs during the follow-up period and lower socioeconomic status, as measured by the income-related insured amount, than the controls. Age at enrollment, sex, indications for ADs use, level of urbanization, and follow-up duration did not differ between the 2 groups,” added researchers.

After adjusting for comorbidities and indications of AD use, AD exposure of cDDD greater than 365 days was associated with a 37% increase in risk of epilepsy compared with those reporting cDDD use less than 90 days (OR, 1.37; 95% CI, 1.12-1.68). No significant increase in risk of epilepsy was observed for individuals reporting AD exposure of cDDD 90-365 days vs less than 90 days (OR, 1.07; 95% CI, 0.87-1.30). Other identified risk factors for the development of epilepsy included CVD, TBI, and CNS infection.

Findings for the subgroup analysis of individual ADs showed that exposure to escitalopram was significantly associated with the highest risk of epilepsy (OR, 1.93; 95% CI, 1.12-3.31), followed by venlafaxine (OR, 1.62; 95% CI, 1.13-2.31), mirtazapine (OR, 1.56; 95% CI, 1.00-2.43), paroxetine (OR, 1.44; 95% CI, 1.08-1.94), and fluoxetine (OR, 1.25; 95% CI, 1.01-1.56). Sertraline, fluvoxamine, citalopram, duloxetine, milnacipran, and bupropion did not show any proconvulsant effects.

Researchers noted that study findings were limited by the lack of inclusion for the combination of other psychotropic agents, such as benzodiazepams, mood stabilizers, and antipsychotics, as well as the absence of data on adherence to ADs from the claims data.

“Our findings on the risk of epilepsy associated with single individual ADs were based on an observational nested case-control study; residual confounding may have influenced our results,” they concluded.

“Therefore, caution should be exercised when interpreting these results. Despite this, the present study provides additional evidence that could help in shared decision-making between physicians and patients indicated for ADs.”


Chu CS, Lee FL, Bai YM, et al. Antidepressant drugs use and epilepsy risk: A nationwide nested case-control study. Epilepsy Behav. Published online February 4, 2023. doi:10.1016/j.yebeh.2023.109102

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