Antidepressant Drugs: Indications and Guidelines for Usein Epilepsy

Bettina Schmitz

Department of Neurology, Charité, Humboldt-University, Berlin, Germany

Epilepsy patients who are diagnosed with clinical de-pression are often not treated with antidepressant drugs.There are a number of arguments for avoiding antide-pressants in a person with active epilepsy; but there alsoare irrational worries. On the patient’s side, there is oftenthe fundamental problem that a diagnosis of depressioncannot be accepted because psychiatric disorders areseen as even more stigmatizing than epilepsy. However,for the physician, who most often has little or no psy-chiatric training, there is often an inappropriate fear ofusing antidepressants because of proconvulsive proper-ties and of kinetic and dynamic interactions with antiep-ileptic drugs (AEDs).

Before prescribing antidepressants in a patient withepilepsy, it is necessary to consider etiologic factors,both psychological and biologic, which may be respon-sible for the development of a depressive reaction in thepatient. The analysis of the AED regimen in terms ofboth positive and negative psychotropic effects of theprescribed drugs is particularly important.

POSITIVE PSYCHOTROPIC EFFECTS OFANTIEPILEPTIC DRUGS

Mood-stabilizing properties of AED are used in psy-chiatry particularly in the treatment of and prophylaxisfor affective disorders. Carbamazepine (CBZ) is used asan alternative to lithium in the long-term treatment ofbipolar depression. Valproate (VPA) is particularly ef-fective in the management of acute mania, but is alsoused as prophylaxis. Increasingly, AEDs of the new gen-eration are being tested for a broad range of psychiatricindications. Controlled studies have confirmed that la-motrigine (LTG) is useful in the treatment of bipolardisorders (1). Gabapentin (GBP) has proved effective inspecific anxiety disorders (2). Oxcarbazepine (OCBZ) islikely to have comparable mood-stabilizing propertieswith CBZ. There is limited experience with tiagabine(TGB) with mixed results, but based on positive obser-

vations, topiramate (TPM) is currently being tested in-tensively in affective disorders. There are, however, nocontrolled data as yet (3,4).

Unfortunately there is a lack of systematic studies in-vestigating the positive psychotropic effects of AEDs inepilepsy patients. Positive experiences with AEDs inpsychiatry are not necessarily applicable to epileptology.Psychiatric disorders in epilepsy are different in theirphenomenology and likely to have specific etiologies.Psychiatric treatment studies with AEDs focus on bipolardisorders, which are extremely rare in patients with epi-lepsy.

NEGATIVE PSYCHOTROPIC EFFECTSOF ANTIEPILEPTICS

Our knowledge of the negative psychiatric effects ofconventional AEDs is largely empiric, based on anec-dotal reports or small case series in the literature (Table1). The exceptions are the barbiturates: several studieshave shown that there is an increased risk of pharmaco-genic depression in both adults and children treated withbarbiturates (5–7).

With respect to the so-called new AEDs, there is aconsiderable amount of data on negative psychotropiceffects in epilepsy patients. However, the quality of thisis limited because the source is drug trials that are de-signed to test antiseizure efficacy; and psychiatric sideeffects are not systematically documented. Further, thesedata do not allow the comparison of psychiatric risk pro-files of new AEDs. Study designs are not homogeneous,and in particular, inclusion criteria vary between studies,and often patients with a psychiatric history are ex-cluded, resulting in an underestimation of psychiatriccomplications. Finally, these data are not fully transpar-ent to the interested epileptologist, at least not as soon aswe would wish. Thus, there are many open questionswith respect to psychiatric side effects of new AEDs(Table 2).

Vigabatrin (VGB) was the first AED of the new gen-eration to be licensed. There are two meta-analyses ofplacebo-controlled trials, which show that psychiatriccomplications occurred significantly more frequently in

Address correspondence and reprint requests to Dr. B. Schmitz atNeurologische Klinik und Poliklinik, Virchow Klinikum, Humboldt-Universitaet, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail:bettina.schmitz@charite.de

Epilepsia, 43(Suppl. 2):14–18, 2002Blackwell Publishing, Inc.© International League Against Epilepsy

14

the VGB-treated patients than in the placebo groups.Levinson and Devinsky (8) and Ferrie et al. (9) analyzed10 double-blind placebo-controlled studies. Psychiatriccomplications were differentiated by summarizing psy-chiatric complaints and psychopathologic symptoms intosyndromatic diagnoses. Depressive episodes occurred in12.1% of patients treated with VGB. The rate for depres-sion in the placebo group was only 3.5%.

From a detailed analysis of cases reported with seriouspsychiatric adverse events to the manufacturer of VGBin Europe, Thomas et al. (10) concluded that patients inwhom psychotic episodes developed often had completecontrol of seizures with VGB (13 of 28 patients), con-sistent with the concept of alternative psychosis or forcednormalization.

In contrast to this, none of the patients with a depres-sive episode secondary to the introduction of VGB hadbecome seizure free. This suggests that the depressiveeffects of VGB are not related to its antiepileptic prop-erties.

Two other new AEDs are associated with an increasedrate of depressive disorders in controlled trials: TGB andTPM (11,12). Barbiturates, VGB, TGB, and TPM areAEDs that have a �-aminobutyric acid (GABA)ergicmode of action, distinguishing them from AEDs that donot carry an increased risk of depression (LTG, GBP,and levetiracetam). It is possible that the commonmechanism involving the GABA receptor is pathogeni-cally relevant for the induction of depression. It is wellknown that GABA plays a role in the origin of depres-sion, although the exact mechanism is unclear.

No AED can be seen as having no risk of psychiatricproblems. There are several reports that GBP may induceaggressive behavioral disorders, particularly in childrenwith learning disabilities and in mentally retarded adults.The alerting effects of LTG, which are beneficial inmany patients, are not tolerated by all, with some pa-tients developing insomnia, irritability, or even hypoma-nia.

Ketter et al. (13) developed a hypothesis suggestingthat the direction of an effect on the mental state of anAED, being either positive or negative, depends on thepreexisting psychopathologic status. The authors differ-entiated two categories of AEDs; the first comprisingsubstances with a GABAergic mode of action and seda-tive and anxiolytic properties: barbiturates, benzodiaz-

epines (BZDs), VPA, VGB, TGB, and GBP. The secondgroup comprises AEDs that are antiglutamatergic andthat are supposed to have antidepressive and anxiogeniceffects: felbamate (FBM) and LTG. In this classification,TPM holds an intermediate position because of its mul-tiple biochemical mechanisms. According to Ketter’s hy-pothesis, patients who are primarily agitated wouldbenefit from sedating drugs, whereas they become worsewith an activating AED. Conversely, patients who areprimarily sedated would benefit with activating andworsen with sedating drugs. This is, of course, a simpli-fying scheme. However, the consideration of the preex-isting mental status when choosing an AED is a usefulapproach that deserves further study.

ANTIDEPRESSANTS

When using an antidepressant drug in a patient withepilepsy, three potential problems warrant consideration:(a) proconvulsive properties, (b) other pharmacodynamicproblems, and (c) pharmakokinetic interactions withAEDs.

The classic tricyclic antidepressants have anticholin-ergic side effects that are unpleasant and potentially dan-gerous. They also have side effects related to their effectson sodium channels, H1 receptors, 5-HT2 receptors, and�1-receptors (Table 3). These side effects are particularlyhard or impossible to tolerate for epilepsy patients whoare treated with AEDs that have a similar spectrum ofside effects (such as cardiotoxicity, sedation, weightgain, tremor).

Because of the poor tolerability of tricyclic antidepres-sants, new AEDs have been developed since the 1980s.The drugs are classified according to their central modeof action into six groups (Table 4). Best known and mostoften used are antidepressants belonging to the cate-gory of SSRIs, selective serotonin reuptake inhibitors(Table 5).

Proconvulsive risksA potential problem of antidepressants is the provo-

cation of epileptic seizures. Table 6 summarizes databased on spontaneous reports of de novo seizures sec-ondary to antidepressants in England. The risk is rela-tively high for the tricyclic clomipramine, as well as forthe tetracyclic maprotiline. It is important to note that theproconvulsive risk is dose dependent. According to the

TABLE 1. Psychotropic effects of classic antiepileptic drugs

Positive affective effects Negative affective effects Other psychiatric problems

Barbiturates, primidone — Aggression, depression, withdrawal syndromes Sedation, hyperactivity in childrenBenzodiazepines Anxiolytic, sedative Withdrawal syndromes Sedation, dependencyEthosuximide — Insomnia Alternative psychosesPhenytoin — ? Toxic schizophreniform psychosesCarbamazepine Mood stabilizing, impulse control Rarely mania or depression —Valproate Antimanic, mood stabilizing — Acute and chronic encephalopathies

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English data, amitriptyline has a risk for de novo seizuresat only relatively high daily dosages, >200 mg.

The risk of inducing seizures is relatively low for thenew generation of antidepressants. In clinical studieswith paroxetine, the seizure risk was 0.1% (six of 4,126patients). In the active control groups (treated with ami-triptyline, imipramine, clomipramine, mianserin, dox-epin, or maprotiline), the rate of seizures was relativelyincreased (0.3%; five of 1,775) (SmithKline Beechamdatabase).

Studies of the risk of increased seizures secondary toantidepressants in epilepsy are rare. In a study by Kanneret al. (14), 100 patients were given sertraline. Interest-ingly, 28 of these patients had an iatrogenic depressionbecause of AEDs. Only one patient had a significantincrease in seizure frequency during a mean follow-up of10 months.

Pharmacokinetic interactionsSome pharmacokinetic interactions between AEDs

and antidepressive drugs are largely predictable becauseof a shared metabolic pathway involving the cytochromeP-450 enzymes. For further details of pharmacokineticinteractions, see chapter by Spina and Perucca (pages37–44) in this issue.

Antidepressant potencyThe only published controlled study on the efficacy of

antidepressants in epilepsy patients failed to demonstratea significant benefit of antidepressants over placebo. Inthe study by Robertson and Trimble (15), 42 patientswith epilepsy plus clinical depression were treated eitherwith 75 mg amitriptyline, nomifensine, or placebo. Aftera treatment period of 6 weeks, there were no group dif-ferences between the (overall poor) treatment results,perhaps because of the low dosages. In a follow-upstudy, 26 nonresponders were openly treated with higher

daily dosages (150 mg). After a further 6 weeks, 17patients had a remission of depressive symptoms.

The experience of Blumer (16) with antidepressivetreatment in epilepsy was recently summarized posi-tively. He treated ∼200 depressive epilepsy patients overa period of 20 months. Initially he used a tricyclic anti-depressant (imipramine or amitriptyline), without ex-ceeding daily dosages >150 mg to avoid side effects.Twenty-two nonresponders were then treated in combi-nation with an SSRI (10–50 mg paroxetine): 15 patientshad a complete remission of depression, four had a par-tial response, and only three patients were consideredrefractory to this regimen.

SUMMARY

There is a need for systematic treatment studies thatinvestigate the efficacy of antidepressants in epilepsypatients. In particular, the efficacy of the new antidepres-sive agents needs confirmation.

The prophylaxis of depression in the treatment of epi-lepsy involves the identification of vulnerable patients(Table 7). Patients at risk for the development of depres-sion are those who have a familial predisposition foraffective disorders, or have had previous episodes of de-pression. Temporal lobe epilepsy and drug-resistant sei-zures are risk factors, as is a recent history of temporallobe resection.

These patients should ideally be treated with AEDsthat have a favorable psychotropic profile, preferably asmonotherapy. If potentially depressogenic AEDs are

TABLE 3. Disadvantages of tricyclic antidepressants

Mechanism Side effect

Anticholinergic Dry mouth, drug deliriumSodium-channel antagonism CardiotoxicityH1-receptor antagonism Sedation5-HT2–receptor stimulation Weight gain�1-Receptor blockade Orthostatic hypotonia

TABLE 4. New antidepressants

1. SSRIs Selective serotonin reuptake inhibitors (e.g.,fluoxetine, fluvoxamine, paroxetine, citalopram,sertraline)

2. DSAs Dual serotonergic antidepressants(serotonin-reuptake inhibitors plus5-HT2–receptor antagonism (e.g., nefazodone)

3. SNRIs Selective serotonin and noradrenaline reuptakeinhibitors (e.g., venlafaxine)

4. NASSAs Noradrenergic and specific serotonergicantidepressants (e.g., mirtazapine)

5. NARIs Selective noradrenaline reuptake inhibitors (e.g.,reboxetine)

6. RIMAs Reversible specific monoamine oxidase inhibitors(e.g., moclobemide)

TABLE 2. Psychotropic effects of new antiepileptic drugs (affective)

Positive affective effects Negative affective effects Open questions

Vigabatrin — Depression Which patients are at risk for psychiatric side effects?Lamotrigine Antidepressive, mood stabilising Insomnia, Tourette syndrome Which patients benefit and which do not?Felbamate Stimulative? Agitation No controlled dataGabapentin Anxiolytic Aggression No controlled dataTiagabine ?? Depression Is there a relation with nonconvulsive status epilepticus?Topiramate ? Depression Are mood problems independent of cognitive side effects?Oxcarbazepine Mood stabilizing — No data in epilepsy patients?

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used, these should be titrated slowly, and patients shouldbe monitored closely.

However, it is not possible to predict the psychotropiceffects of AEDs in individual patients, because drug ef-fects on mood are modulated by the patient’s biologicand biographic predisposition. If a patient becomes de-pressed, it is always necessary to analyze recent changesto the AED regimen, because this may lead to an obvioustreatment. In some cases, an effective AED may lead toan “alternative” depression via the mechanism of “forcednormalization” (17). Such a depressive reaction does notnecessarily require the discontinuation of the responsibleAED. Depending on therapeutic alternatives, in patientswith difficult-to-treat seizures, the add-on treatment withan antidepressant should be considered.

Antidepressants should be used when a depressive epi-sode is severe and long lasting, in particular when thereare no promising options of modifying the AED treat-ment regimen. It is important that antidepressants, whenindicated, be used properly, meaning that adequate dos-ages are prescribed over a sufficiently long period.

Antidepressants with low proconvulsive risks are rec-ommended. However, the risk of antidepressants provok-

ing seizures is generally overestimated. Further,antidepressants that are effective in the treatment of de-pression also may enhance the control of seizures, be-cause patients sleep better and are likely to be morecompliant with their AEDs.

SSRIs have a relatively low epileptogenic potency.Experimental research using animal models showed thatthere may be a dose-dependent antiepileptic effect ofSSRIs. Other drugs with minor seizure risks are themonoamine oxidase inhibitors, as well as atypical anti-depressants such as viloxazine and trazodone. Because oftheir strong proconvulsive effects, among the classic an-tidepressants, maprotiline and clomipramine should beavoided.

TABLE 5. Costs (Germany), standard dosage, and side effects of new antidepressants (20)

Daily costs(DM)

Standard daily dosage(maximal, mg) Side effects

SSRIsCitalopram 3.00 20 (60) With all SSRIsFluoxetine 3.87 20 (80) Gastrointestinal problemsFluvoxamine 2.98 100–200 (300) InsomniaParoxetine 3.87 20 (50) AgitationSertraline 2.98 50 (200) Sexual dysfunction

DSAsNefazodone 3.81 400 (600) Somnolence, nausea, dizziness, orthostatic hypotonia

SNRIsVenlafaxine 3.34 75 (375) Similar to SSRIs, in addition, hypertonia

NASSAsMirtazapine 3.98 30 (45) Somnolence, dry mouth, weight gain

NARIsReboxetine 4.12 8 (12) Dry mouth, constipation, insomnia, increased sweating

RIMAsMoclobemide 3.36 300 (600) Insomnia, agitation at onset of therapy

TABLE 6. The risk for de novo epileptic seizures with oldand new antiepileptic drugs

Dosage/day No.Seizures

(% treated)

Amitriptyline <200 mg 2,848 0.00Amitriptyline >200 mg 0.06Imipramine 50–600 mg 5,334 0.30Clomipramine ? 4,160 0.50Maprotiline ? 6,100 0.40Viloxazine 150–800 mg 7,635 0.13Fluoxetine 20–60 mg 6,000 0.20Fluvoxamine ? 10,401 0.20Paroxetine ? 4,126 0.10Population 0.08

Committee for the Safety of Medicines (England).

TABLE 7. Clinical recommendations for the treatment ofdepression in epilepsy

Identification of patients at risk for affective problemsFamily history of affective disordersPrevious psychiatric problems and suicide attemptsPeriictal psychiatric disturbancesPsychosocial problems

Treatment of epilepsyAchieve seizure freedom (cave: therapeutic nihilism in

psychiatric epilepsy patients)Avoid polytherapyUse positive psychotropic effects of antiepileptic drugsSlow titration of depressogenic anticonvulsants, particularly in

patients at risk, close monitoring (even when patients becomeseizure free) including the active exploration of symptoms ofdepression (patients often do not spontaneously complain)

When a diagnosis of depression has been madeExplore suicidal tendenciesConsider inpatient treatment

If there is an indication for antidepressantsTreatment should not be postponedChoose drugs with low proconvulsive propertiesChoose drugs with a favorable pharmacokinetic profileStart with low dosages, slow titration (not obligatory with SSRIs)Good information from patients and relatives (improve

compliance)When seizures increase, check serum levels of anticonvulsantsIf depression persists, check serum levels of antidepressantsIn cases of pharmacoresistent depression, consult psychiatrist

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In addition to pharmacodynamic interactions, pharma-cokinetic interactions need consideration. For example,with fluoxetine, but not with paroxetine (18), there is asignificant risk of an increase of serum levels of someAEDs. To avoid intoxication with antidepressants (pro-convulsive effects are dose dependent) and pseudoresis-tance due to underdosage (when enzyme-inducing AEDsare prescribed at the same time), or noncompliance (in-formation brochures for patients often warn of seizures),serum drug levels should be checked (of AEDs and an-tidepressants). Individually, depending on the epilepticsyndrome, EEG monitoring may be helpful as an indi-cator of proconvulsive effects.

Tricyclic antidepressants should always be carefullytitrated in patients with epilepsy. With the SSRIs, this isnot obligatory. However, in patients who have a poly-therapy and who are not free from side effects, antide-pressants of the new generation also should beintroduced slowly. Because of their superior tolerability,SSRIs are generally preferred to the tricyclic drugs. Anexception may be patients with a good response to tri-cyclics in the past. The most important adverse effects ofSSRIs are sexual dysfunction and agitation. Alterna-tively, nefazodone or mirtazapine may be used, whichare sedating and have no sexual side effects.

In cases of mild depression, St. John’s wort extractsmay be used. These herbal drugs are effective and havefew side effects. However, in a recent study, it wasshown that serum levels of some drugs were significantlyinfluenced by St. John’s wort (19). This is important toknow, because patients often take these drugs withoutconsulting their epileptologist (Table 8).

Of utmost importance for the success of an antidepres-sive treatment is the information and education of thepatient and his relatives. The prerequisite of good com-pliance with treatment recommendations is the under-standing of the nature of depression, and why anantidepressant drug is necessary. Antidepressants are ef-fective only when taken regularly over a long period.

Epilepsy patients who do not respond to an antidepres-

sant drug treatment should ideally be seen by a psychia-trist. Pharmacotherapy of a depressive disorder is notregarded as an alternative to professional social supportand psychotherapy. Of course, medical and nonmedicaltreatment strategies should be used complementarily inthe management of depression in a person with epilepsy.

Acknowledgment: Professor Trimble and the members ofThe Commission for the Psychobiology of Epilepsy are verygrateful to the International League Against Epilepsy for theirfinancial support of the commission and for their help with thepublication of this supplement.

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2. Letterman L, Markowitz JS. Gabapentin: a review of publishedexperience in the treatment of bipolar disorder and other psychi-atric conditions. Pharmacotherapy 1999;99:565–72.

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4. Walden J, Normann C, Langosch J, et al. Differential treatment ofbipolar disorders with old and new antiepileptic drugs. Neuropsy-chobiology 1998;38:181–4.

5. Brent DA, Crumrine PK, Varma RR, et al. Phenobarbital: treat-ment and major depressive disorder in children with epilepsy. Pe-diatrics 1987;80:909–17.

6. Brent DA. Overrepresentation of epileptics in a consecutive seriesof suicide attempters seen at a children’s hospital, 1978-1983. J AmAcad Child Psychiatry 1986;25:242–6.

7. Robertson MM, Trimble MR, Townsend HRA. Phenomenology ofdepression in epilepsy. Epilepsia 1987;28:364–72.

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9. Ferrie CD, Robinson RO, Panayiotopoulos CP. Psychotic and se-vere behavioural reactions with vigabatrin: a review. Acta NeurolScand 1996;93:1–8.

10. Thomas L, Trimble M, Schmitz B, et al. Vigabatrin and behaviourdisorders: a retrospective study. Epilepsy Res 1996;25:21–7.

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18. Andersen BB, Mikkelsen M, Vesterager A, et al. No influence ofthe antidepressant paroxetine on carbamazepine, valproate andphenytoin. Epilepsy Res 1991;10:201–4.

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TABLE 8. Side effects of antidepressants in epilepsypatients: examples of problematic and

unproblematic substances

Unproblematic Problematic

Anticholinergiceffects

SSRIsSt. John’s wort extracts

Amitriptyline

Proconvulsive effects SSRIs MaprotilineMAOIs ClomipramineSt. John’s wortAmitriptyline <200 mg/day

Pharmacokineticinteractions

SertralineCitalopramParoxetine

St. John’s wortFluoxetineFluvoxamine

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