Are Antidepressants Dangerous in Epilepsy?

Case

A 24-year-old woman with a history of treatment resistant temporal lobe epilepsy is seen at clinic. She has become significantly depressed. She believes this is partly due to worsening seizure control but also due to strains within her marriage. Her GP has told her that it would not be safe to prescribe an antidepressant. Is his GP right? If not, which class of antidepressant drugs would be best to offer her?

Depression in people with epilepsy is under-number of reasons for this, but one of the most important is the widespread, mistaken belief that antidepressants are unsafe in epilepsy because they lower seizure threshold. In fact, the risks of not treating depression in epilepsy, and the costs in terms of quality of life, far outweigh the slim possibility that antidepressants might worsen a patient’s seizures. Yet the British National Formulary (BNF) lists seizures as an adverse effect with most antidepressants and recommends ‘caution’ in prescribing to people with epilepsy. Where has this idea come from? What evidence is there that, in fact, we should treat depression in patients with epilepsy pretty much ‘as usual’? Before considering these questions, and to put them in context, a brief review of depression in epilepsy is useful.

Depression in Epilepsy

Symptoms of depression in people with epilepsy are classified according to whether they occur as brief, self-limiting episodes before, during or after individual seizures, or whether they occur as relatively prolonged episodes of low mood that have no, or a variable, temporal relationship with seizures. It is these latter, ‘inter-ictal’, depressive episodes that concern us here: episodes of low mood with associated cognitive and somatic symptoms that would in general be recognised as ‘significant depression’.

People with epilepsy whose seizures are in complete remission are probably at no greater risk of depression than the general population. But those who continue to have seizures despite treatment undoubtedly suffer high rates of depression and this risk is related to measures of seizure frequency and severity [1,2]. Among people with the most intractable forms of epilepsy, depression is undoubtedly very common. For example, in patients with temporal lobe epilepsy undergoing pre-surgical evaluation, around one third will have a history of major depression [3].

There are a number of possible causal links between epilepsy and depression[4,5,6] (Table 1). In most cases, the aetiology is likely to be multifactorial. Some potential causes and mechanisms are specific to epilepsy (rather than to chronic disability per se) and clinically of great importance as they may prompt specific treatment strategies. It is particularly important to remember that depression is a fairly common adverseeffect of many anti-epileptic drugs. Phenobarbitone, vigabatrin, levetiracetam and topirimate are especially notable in this respect, but nearly every AED has been implicated. Even antiepileptic drugs with established efficacy as mood stabilisers in bipolar affective disorder will occasionally trigger depression. In some cases the mood disorder appears after seizures are brought under control and may represent part of the spectrum of ‘alternating’ psychiatric presentations associated with ‘forced normalisation’ [7]. This phenomenon can be conceived of as the consequence of removing a biological antagonistic effect of seizures on low mood. Depression is an important complication of temporal lobe surgery for epilepsy, occurring in around one third of patients, especially those with a prior history of depression. Forced normalisation may play a role in this setting too, but depression may occur whether the patient becomes seizure-free after surgery or not. Findings concerning other clinical risk factors for depression in epilepsy have been inconsistent and some risk factors may simply be surrogate markers for severe epilepsy. Temporal lobe epilepsy, for example, is often cited as being especially closely linked with depression, yet a large study that examined a mixed group of patients with both focal and generalised epilepsy syndromes, all of whom had intractable seizures, found similar rates of depression across epilepsy subgroups [8]. Psychosocial factors are undoubtedly important. Poorly controlled epilepsy may have a profound impact on social functioning and there is often a compelling relationship between such factors and the onset of depression in individual cases. In this regard depression in epilepsy has much in common with depression in other medical settings. Whether epilepsy is associated with higher rates of depression compared with other disabling illnesses remains uncertain.

No discussion of the causal links between epilepsy and depression would be complete without mention of the recent findings suggesting that a history of depression may actually be a risk factor for epilepsy. This interesting finding has led to speculation that depression and epilepsy may share a common underlying biochemical substrate [9]. However, there is evidence that alcohol misuse may contribute to this association[10] and other potential mediating factors (eg: structural brain pathology, learning disability) have not been investigated.

Why is depression in epilepsy under-recognised?

Several studies have shown that depression in people with epilepsy is often not recognised by clinicians[11,12]. There are a number of possible explanations for this. As in other liaison psychiatric settings, depressive symptoms are all too readily interpreted as an understandable reaction to disability. Professionals, even those with specialist experience, can sometimes ‘expect’ people with a severe illness to be distressed and may consequently fail even to ask about symptoms of depression. A fear of not knowing what to do if a patient does report depression may also contribute. Another explanation for missed diagnoses is that depression in epilepsy may actually present in ‘atypical’ ways. This intriguing possibility was first documented by Mendez [13] who estimated that 50% of clinically significant depression in people with epilepsy would fail to meet standard diagnostic criteria. There is now fairly good evidence to support this notion and the term ‘Interictal Dysphoric Disorder’ (IDD) has been coined to describe these atypical presentations. These are essentially chronic states of dysthymia with marked irritability whose course is interrupted by brief periods of normality. It is this fluctuation that means such symptoms fail to meet standard diagnostic criteria for chronic dysthymia. There is some evidence that ‘IDD’ responds to antidepressant treatment but further research is needed to answer key questions in this area. If depression in epilepsy often falls below standard diagnostic criteria, is this because it is not, in fact, clinical depression, simply how people react to their illness and disability? Or is it truly a clinical depression, which responds to conventional treatments, but is unique to epilepsy? Comparisons of depressive symptomatology between people with epilepsy and with other disabling illnesses are required, as are well-conducted treatment trials [14].

Why should we treat depression in epilepsy?

The reasons for treating depression in epilepsy are the same as in any other situation: to improve quality of life and to reduce the risk of deliberate self-harm and suicide. As in other medical illnesses, comorbid depression in epilepsy is linked to poor quality of life and greater disability and there is a firmly established association between epilepsy and suicide. Compared with the general population, patients with epilepsy have a 3-4 fold risk of completed suicide [15]. Not surprisingly, a history of psychiatric disorder is a major risk factor. For someone with intractable epilepsy, depression represents a potentially dangerous double burden.

Antidepressants, seizures and epilepsy

Evidence suggesting an association between antidepressants and seizures arises from a number of sources, each of them flawed as a means of predicting the safety or otherwise of antidepressants taken at therapeutic doses by people with epilepsy [16,17]. Most of the data concerns the incidence of seizures in people without epilepsy. Thus, provoked seizures are a well recognised complication following overdose with antidepressants and meta-analyses of pre-clinical trials document seizures as a rare but important adverse event with many drugs. Committee for the Safety of Medicines reports are another source of information but subject to reporting bias. In particular, this data cannot be used to compare the relative safety of different drugs: more reports will inevitably be received for the most commonly prescribed drugs that have been in clinical use the longest. The situation in someone with epilepsy is clearly very different. Most importantly, patients with epilepsy will usually be taking anti-epileptic drugs which are likely to have a protective effect with regards any proconvulsant action of antidepressants. What is needed is information about the safety of antidepressants in people with epilepsy.

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Here the data , though limited, is in fact very reassuring. Although the numbers of subjects in individual studies is relatively small, the message that antidepressants are well-tolerated in people with epilepsy is clear (Table 2). The largest study to date involved 97 patients with epilepsy prescribed sertraline[12]. Five patients had a possible, transient worsening of seizures and only one patient was thought to suffer a clear deterioration in seizure control. Two studies have even found an anti-epileptic effect of anti- depressants in epilepsy [23,25].

Treating depression in epilepsy

The point at which symptoms of depression are considered significant and should prompt treatment is ultimately a matter of clinical judgement. The decision to treat will be based on an assessment of severity (including the presence of associated somatic and cognitive symptoms) and evidence of impaired general function. Whenever depression is identified in a patient with epilepsy, the risk of suicide must always be assessed. It is vital that any relationship between the onset of depression and anti-epileptic drug (AED) treatment is identified. When a specific AED is implicated, the drug will usually have to be withdrawn. Sometimes a dose reduction is sufficient but persisting with the AED and adding an antidepressant is rarely, if ever, satisfactory.

Most people quite sensibly don’t like the idea of taking a second drug to combat side-effects from another. Switching to an AED with mood stabilising (carbamazepine, valproate, lamotrigine) or anxiolytic (pregabalin) efficacy seems intuitively sensible. However, AEDs cannot be switched quickly and although this may be worth considering as a longer term strategy, evidence for this is lacking. Optimised seizure control is, of course, the aim for every patient with epilepsy.

For a patient with epilepsy and depression this becomes especially important. If a patient is not under a specialist epilepsy service, referral should be considered. In addition to specialist medical review, such clinics also provide access to support from Epilepsy Nurse Specialists, specialist counselling and service-user groups. As for patients without epilepsy, psychological therapy should be discussed and offered to patients where practical. A therapist with specialist experience of epilepsy may be particularly helpful.

The pharmacological treatment of depression in epilepsy has been the subject of a number of recent reviews [26,27], including a Consensus Statement from the Epilepsy Foundation [28]. The choice of antidepressant will be guided by three main considerations: 1) propensity to cause a deterioration in seizure control; 2) drug interactions; 3) side-effect profile. As we have already seen, it is very unlikely that an antidepressant will exacerbate a patients seizures, but given the variety of antidepressants available today it seems sensible to avoid those that are, probably, associated with a higher risk. For this reason, amoxapine, buproprion, clomipramine and maprotiline are not recommended. Pharmacokinetic interactions are especially likely with hepatic-enzyme inducing AEDs (carbamazepine, phenytoin, phenobarbital) and with enzyme inhibiting drugs (valproate). Most interactions are not clinically significant, a notable exception being the inhibition of phenytoin’s metabolism (and consequent rise in serum levels) by fluoxetine. It is good practice to check before prescribing for any patient on polytherapy (i.e. consult the BNF) but such interactions are unlikely at therapeutic doses of citalopram, escitalopram and sertraline (SSRIs), duloxetine and venlafaxine (SNRIs) and mirtazepine (NaSSA). Otherwise the side-effect profile will dictate choice of antidepressant as it does in general psychiatric settings and an associated psychotropic effect, for example night-time sedation with mirtazepine, may be of great benefit for some patients. It is important to discuss the issue of seizure exacerbation with the patient preemptively as the information sheet that comes with their antidepressant is likely to be alarming on this subject and might otherwise lead to non- compliance. Specifically, patients should be reassured that this risk is a theoretical one and that, because they are taking AEDs, they are very unlikely to suffer any worsening of their epilepsy.

A ‘start low, go slow’ approach to the starting dose and rate of dose increments is sensible. If there is a definite increase in seizure frequency or severity a better-tolerated substitute is usually easily found. So, by way of conclusion, how should we manage the patient described in the clinical vignette at the beginning of this article? A patient with intractable epilepsy presenting with depression should ring alarm bells. We should assess the severity of her depression and carefully consider her risk of self harm. The patient is probably right in her thoughts about aetiology. We should consider factors related to her epilepsy and its treatment, as well as her social circumstances. She has intractable TLE and should be under a specialist epilepsy service.

Her current presentation should prompt a review of her epilepsy treatment. The GP was wrong to suggest that antidepressants are unsafe for this patient and it will be important to discuss this point in detail with her. Which antidepressant to choose? An SSRI with minimal potential for interactions (eg: citalopram of sertraline) would be a good place to start. Psychological approaches to treatment should be considered as they would for any patient with depression. Finally, this is a patient we should follow-up carefully; to monitor her response to treatment and to ensure effective liaison with her epilepsy service.

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