We have conducted a large study of primary care patients aged 20–64 years with depression and with no previous diagnosis of epilepsy/seizures. We have assessed and quantified the absolute risk of epilepsy associated for different classes and individual types of antidepressant. Our analyses have found that all classes of antidepressant were associated with a statistically significant increase in epilepsy/seizures when compared with periods of no treatment. These associations remained for all dose levels for TCAs and for all doses (other than low doses) of SSRIs and other types of antidepressant. There was also an increased risk of epilepsy/seizures in patients prescribed combined antidepressant treatment, but there were relatively few cases in this group, so the result should be treated with caution.

Of the 11 individual drugs we examined, all except sertraline, escitalopram and mirtazapine were significantly associated with the risk of epilepsy/seizures. Individual drugs with the highest risks were trazodone, lofepramine and venlafaxine. When compared against citalopram, the most commonly prescribed antidepressant, only trazodone had a significantly increased risk of epilepsy/seizures. Regarding duration of treatment, there were no clear patterns of risk although for all drug classes the risk of epilepsy/seizures remained significantly increased more than 12 weeks after starting treatment.

The statistically significant increases in risk of epilepsy/seizures described above, for all drug classes and for most dose categories and individual drugs remained largely unchanged when we omitted patients not receiving any antidepressant treatment during follow-up. When we excluded those taking anticonvulsants at baseline the hazard ratios tended to increase. This result confirms the expectation that anticonvulsants increase the fit threshold, and therefore may reduce the risk of epilepsy/seizures associated with antidepressant use. In effect, by including patients on anticonvulsants at baseline in the cohort, the hazard ratios for antidepressant use are attenuated.

Although all the drug classes and most individual drugs were associated with an increased risk of epilepsy/seizures, the NNH over the first year are quite high and mainly in the thousands, with absolute risks mostly less than 2 in 1000. Only combined prescriptions and the drugs trazodone and venlafaxine have NNH values below one thousand for the first year of treatment. Therefore in the main, for courses of antidepressant treatment that are less than one year, the absolute risk is present but low.

It is only under long term treatment, as in our example of five years that the NNH drop into the several hundred. Here, the absolute risks range from 7 per 1000 (SSRIs) to 10 per 1000 (combined) for the drug classes. For individual antidepressants, the drugs with the highest absolute risks over 5 years are: venlafaxine (10 per 1000), lofepramine (11 per 1000) and trazodone (19 per 1000). Therefore our results show that those patients receiving treatment courses in line with guidelines (around 180 days) will have a low absolute risk of epilepsy/seizures. However patients on longer courses will accumulate a moderate absolute risk, which can vary and be quite high depending on the specific drug.

Comparison with other studies

Whilst the association between epilepsy/seizures and depression [8, 16, 17] and that between antidepressant use and epilepsy/seizures [18] has been previously documented, some of this evidence is conflicting. For example some studies claim the effects of antidepressants are anticonvulsant rather than pro-convulsant [19] and other studies claim that most if not all antidepressants lower the seizure threshold [3].

There are studies concerned only with a population already predisposed to the outcome [20–24], however their results may not be directly comparable to ours as we omitted patients with a history of epilepsy/seizures. One of these studies [20] concluded that patients could be safely treated with antidepressants from the TCA or SSRI groups without any significant increase in seizure frequency. However the study only looked at the first 12 months of treatment, only included two of the antidepressants that we did (amitriptyline and paroxetine) and was much smaller than our study (n = 421).

Another large study utilising drug safety data [24] concluded that SSRIs and the antidepressants mirtazapine, venlafaxine and duloxetine might be more appropriate for treating depression than TCAs, in patients with an enhanced seizure risk. They based their analysis on counting the number of grand mal seizures in patients undergoing antidepressant treatment in psychiatric inpatient settings. A limitation of this analysis is that seizures were probably underreported.

A further issue is whether the antidepressants are given in low doses, normal therapeutic doses, or taken in overdose. For example, there is evidence that citalopram has the ability to induce seizures if taken in overdose [25] and that it is more toxic and more likely to provoke seizures in overdose than escitalopram [26]. However a review by Nemeroff [27] concluded that doses of between 20–60 mg of citalopram do not increase risk of seizure.

A study utilising Food and Drug Administration (FDA) Summary Basis of Approval (SBA) Reports in the United States [28] concluded that many second-generation antidepressants, several of which are included in our study (including citalopram and venlafaxine), have anticonvulsant properties. They based their conclusions on comparing seizure incidence between treatment and placebo arms of clinical trials, with numbers of participants less than 5000 in most instances, and with short follow-up periods (the mean duration of the treatment arms was only 116 days, with the mean duration of the placebo arms only 78 days). They also found an incidence of seizures in the placebo groups approximately 19 times that seen in the general population.

These results may seem to contradict our own, but many of the placebo arms of the studies included in the Alper [28] paper did not report the number of seizures, a limitation which they acknowledge. In addition, although many of the antidepressants they looked at are also included in our study, they did not treat each antidepressant individually, but rather they combined them together and compared the overall seizure rate with the placebo arms. Also, seizures are only recorded in SBA reports if the FDA staff physician deems the event was unlikely to have been provoked by an external factor, such as alcohol withdrawal, and could be safely attributed to the drug in question. Our study included all events, without an attempt to distinguish between the possible causes. Generally clinical trials are designed to answer questions regarding benefits of treatments rather than safety and full reporting of adverse effects is often unavailable [29].

In an analysis [30] of the WHO adverse drug reactions (ADR) database, the authors concluded that antidepressant treatment, lowers the seizure threshold and provokes seizures. They looked at 9 of the 11 most commonly prescribed antidepressant medications that we did. There were some differences in their results compared to ours though, since they showed trazodone to have one of the lowest ratios of suspected seizures. There were many limitations to their study however, including the fact that the total number of patients treated with a particular drug was unknown making direct comparisons with our results inappropriate.

In our previous study in people aged 65 years and over [4, 9] we found that SSRIs and other antidepressants were associated with an increased risk of epilepsy/seizures. This situation has been repeated in the present study, with adjusted hazard ratios very similar to the earlier study. Also, citalopram, paroxetine, and venlafaxine were found to be significantly associated with an increased risk of epilepsy/seizures in both studies.

The significant association with sertraline in the earlier study is no longer present whereas there is now a significant association with fluoxetine. But the main difference is that in the present study we have found a significant association with TCAs when before there was none.

The previous study reported an adjusted hazard ratio of 1.02 for TCAs for older people but for the present study it was 2.32. In the previous study, none of the four TCAs were significantly associated with epilepsy/seizure risk, however in the present study they are all associated with a statistically significant increased risk with the highest hazard ratio being for trazodone.

Why TCAs should be significantly associated with an increased risk of epilepsy/seizures in the younger sample but not the older sample is unclear, particularly since the proportion of TCA prescriptions in the present study is far less than the earlier study: 31.6 % vs. 13.3 %. Although there were fewer low dose TCA prescriptions in the new study compared to the older study (60 % vs. 70 % were for ≤ 0.5 DDD), this is not enough to explain the difference between the two results.

Strengths and limitations

We know of no other study utilising a sample as large, and followed-up for as many years as our cohort. We were able to analyse a range of antidepressant medications, including individual drugs and accounted for many confounding factors. We also calculated absolute risks that enable comparisons to be made between different drugs that can be explained to patients.

We have used a very large sample representative of primary care populations where most treatment decisions are made, so our results are likely to be generalizable to people aged 20 to 64 years with a diagnosis of depression in primary care.

Our study included all eligible patients within the study time period, and did not exclude people with any comorbid disease or taking any medications other than those explicitly stated in the exclusion criteria (patients with diagnoses of schizophrenia, bipolar disorder or other types of psychosis, and those prescribed lithium or anti-manic drugs). This limited the potential for selection bias which can affect observational studies. Recall bias was avoided as data on prescriptions and confounding factors were recorded prospectively on the computer system.

We had access to detailed information on antidepressant prescriptions, including class of antidepressant, drug name, dosage and duration, so were able to investigate associations with these factors.

To reduce the effects of bias we adjusted for many confounding factors, however we were unable to control for certain factors such as family history of seizures, seizure history without diagnosis, neurological abnormalities, or other factors known to affect seizure threshold such as antibiotic use [31–34] so there may be some residual confounding. Although we adjusted for depression severity, this was based on a logical but crude classification of diagnostic Read codes that has not been formally validated, since depression severity scores are not routinely recorded in general practice.

We excluded patients with a history of epilepsy/seizures at baseline thereby reducing the possibility of a drug being prescribed on the basis of whether it was known to affect the seizure threshold (channelling bias).

The generally similar patterns of risk for the different drug classes and individual drugs might indicate that depression itself rather than its treatment could be the cause of the increased rates of epilepsy/seizures. We restricted our cohort to patients who had a diagnosis of depression to reduce this potential indication bias however we compared rates during periods of treatment, with untreated periods when the depression may have resolved. Several studies have reported that depression is associated with increased rates of epilepsy/seizures including a bidirectional relationship [8, 16, 17], although it is difficult to fully separate the effects of depression from those of antidepressant treatment.

We do not know whether patients took their medication at the exact prescribed dose or whether they completed the course of medication. As a result, this may mean some periods of antidepressant treatment have been misclassified.

Our outcome was a diagnosis of epilepsy/seizures as recorded in the general practitioners record. The nature of the database and the study design meant that this could not be formally adjudicated as might be the case in a clinical trial. However since epilepsy is considered a major diagnosis with consequences which can affect a person’s employment or ability to drive, we think it is unlikely that it would be entered in the record without there being sufficient evidence to support the diagnosis. Also epilepsy has been a condition included in the GP Quality and Outcomes framework over recent years and this is likely to have resulted in increased diligence regarding the accuracy of the diagnosis recorded on the computer system. Another limitation of our study is that we were not able to distinguish between seizures that were epileptic and non-epileptic in nature, such as psychogenic non-epileptic seizures. There is no reason to believe however that different antidepressants would have a differential effect on inducing non-epileptic seizures.

Implications of our findings

Whilst we acknowledge our results need further confirmation via future studies, there are possible implications of our findings for the treatment of depression.

We have found that treatment with all antidepressants is associated with an increased risk of epilepsy/seizures, with some types of antidepressant being associated with a much higher risk than others. This suggests there is a need to inform patients and their doctors about the increased risks of continued antidepressant therapy that accumulate over long periods of treatment. Consideration of each patient’s individual circumstances must be taken into account, allowing discussion between the clinician and the patient, enabling a shared decision to be reached on future treatments.

Due to the increased absolute risks of epilepsy/seizures that occur under long term use, there is a need for an individual clinical risk-benefit assessment for any patient facing antidepressant treatment over a period of five or more years, bearing in mind the absence of evidence supporting longer term treatment with antidepressants. This may be of particular importance to people with mild and infrequently recurring depression, or those with additional risk factors for seizures such as evidence of cerebrovascular disease.

In instances of mild depression in particular there may be a case for stopping treatment, or a reduced daily dosage, or switching to a different antidepressant that carries a lower risk or seeking alternative treatments, such as cognitive behavioural therapy, rather than continuing with long-term antidepressant treatment which would carry a further increased risk of epilepsy/seizures.

In instances where the choice of antidepressant and dose has already been driven by factors such as how well the patient tolerates the drug or the severity of the depression, our findings can still inform the continued treatment of the patient as the accumulating risk that occurs over time that we have demonstrated can be communicated to the patient by the clinician. An informed decision can then be reached regarding continued antidepressant treatment or alternative options from that point forwards.