Clearly, the aim of any treatment of depressive disorders in PWE is the achievement of complete symptom remission, including symptoms of depression and anxiety. Yet, despite the relatively high prevalence of depressive disorders in PWE, there has been a handful of controlled studies published to date, one with psychotropic drugs and one with cognitive behavior therapy (CBT). Accordingly, the treatment strategies continue to have to rely on data derived from the management of primary depressive and anxiety disorders (Barry et al., 2008; Kerr et al., 2012). Treatment modalities include pharmacotherapy with psychotropic drugs, occasionally AEDs, as well as psychotherapy or a combination of pharmacotherapy and psychotherapy.
Interictal depressive/anxiety episodes have been the typical targets of therapy, whereas remission of seizures has been considered to be the strategy to achieve full remission of periictal depressive episodes, with ictal depression being the obvious example. Yet, in patients with treatment-resistant epilepsy, postictal depressive episodes can be seen in up to 43% of patients, with postictal suicidal ideation identified in 13% (Kanner et al., 2004). Unfortunately, there have been no published data on the treatment of preictal and postictal depressive episodes, although anecdotal reports have suggested that postictal symptoms of depression do not respond to pharmacologic treatment.
The pharmacologic treatment of depressive disorders has been based on the monoaminergic theory of mood disorders, which suggests a disturbance in neurotransmitter secretion including serotonin, norepinephrine, and dopamine (Charney et al., 1998; Stahl, 2000). Accordingly, the various classes of antidepressant drugs target serotonergic and/or noradrenergic and/or dopaminergic neurotransmission, with the aim of increasing their synaptic concentrations. More recent studies conducted in patients with treatment-resistant depression have recognized the important pathogenic role of glutamate in depression, which has led to the successful testing of N-methyl-d-aspartate (NMDA) antagonist drugs (e.g., ketamine) (Zarate et al., 2006). The use of this class of drugs remains experimental, but their availability in the future may have greater significance in the management of depressed PWE, given the significant pathogenic role played by glutamate in the seizure disorder as well.
To date, the available families of antidepressant drugs include (1) tricyclic antidepressants (TCAs), which was the first one to be introduced; (2) selective serotonin reuptake inhibitors (SSRIs); (3) serotonin-norepinephrine reuptake inhibitors (SNRIs); (4) serotonin/antagonist reuptake inhibitors (i.e., trazodone, nefazodone); (5) dopamine and norepinephrine agonists (i.e., bupropion); and (6) α-2 antagonist (mirtazapine). Most of the available published data in PWE include open trials with TCAs and SSRIs. In fact, to date there has been only one double-blind placebo-controlled trial of antidepressant drugs in adults with PWE, published in 1975, which compared the efficacy of amitriptyline and mianserin (Robertson, 1985). A randomized double-blind controlled trial comparing the efficacy of the SSRI sertraline and CBT was presented at the annual meeting of the American Academy of Neurology in 2009 but has not been published yet beyond its abstract from the meeting (Gilliam et al., 2009). Given its importance, it deserves to be reviewed in detail (see below). Because there are no data available on the therapeutic expectation of antidepressant drugs in the treatment of depressive disorders in PWE, we have to extrapolate from that obtained in the management of primary depressive disorders.
Therapeutic expectations of pharmacotherapy
Primary major depressive episodes that are left untreated may last between 6 and 24 months in 90–95% of cases, whereas in the remaining 5–10%, they could last more than 2 years (Paykel et al., 1995 Charney et al., 1998; Stahl, 2000). Response to pharmacotherapy in depressive disorders has been divided into three phases: (1) Response, manifested by an improvement of 50% or more in the severity of the depressive symptomatology; this is typically observed in the first 8 weeks of pharmacotherapy. (2) Remission, reflected in a complete symptom remission. Approximately 50% of patients are expected to reach remission within the first 6 months and about two thirds within 2 years of the start of pharmacotherapy. (3) Recovery, defined as the state when remission has lasted for a period of 6–12 months. Symptom relapse is considered to occur when symptoms recur before a full remission has been achieved or before a state of remission has turned into a recovery. If on the other hand symptom recurrence takes place several months into a recovery, it is referred as a recurrence.
The response to pharmacotherapy in primary MDD is illustrated in the STAR*D study, which included 3,671 patients who were initially treated with the SSRI citalopram (Sackeim et al., 2006). Of note, close to 45% of patients were found to have a comorbid anxiety disorder as well as a medical disorder. Two thirds of patients entered remission, but only 37% after the first trial of citalopram. A change to a second antidepressant drug was necessary to achieve remission in an additional 30.6%. A third and fourth trial were necessary to yield remission in 13.7% and 13.0%, respectively. Yet, among all patients, sustained remission was maintained in only 43%.
The variables predictive of relapse include the following: (1) multiple prior episodes; (2) severe episodes; (3) long-lasting episodes; (4) episodes with psychotic or bipolar features; and (5) incomplete recovery between two consecutive episodes. As stated above, complete symptom remission should always be the goal of therapy, as persistence of residual symptoms is a strong predictor for recurrence of MDE (Paykel et al., 1995). Furthermore, premature discontinuation of antidepressant medication can result in relapse.
Pharmacotherapy in PWE
Before starting patients on an antidepressant drug, clinicians must ensure that the patient does not have a bipolar disorder, as the use of antidepressant drugs in a bipolar disorder can cause manic and hypomanic episodes and (even worse!) facilitate the development of a rapid cycling bipolar disorder, defined as a bipolar disorder with four or more depressive and/or manic episode within a 12-month period (Hirschfield et al., 2002). Rapid-cycling bipolar disease has been found in approximately 15% of patients with bipolar disorders and is relatively resistant to pharmacotherapy. The initial manifestations of a bipolar disorder can often consist of recurrent major depressive episodes, and several years can go by before the first manic or hypomanic episode occurs. Accordingly, before starting antidepressant medication for a depressive episode, clinicians must always inquire about any personal or family history of manic or hypomanic episodes, which is a strong risk factor for the development of this disorder in the patient. Finally, the occurrence of a first major depressive disorder before the age of 18 suggests a 40–50% risk that the patient may have bipolar illness. Given the greater severity and worse course of bipolar illness, this condition should be managed only by psychiatrists.
Following a review of the available literature, two groups of experts reached a consensus that antidepressant drugs of the SSRI family should be considered as first line for the treatment of depression in PWE, given their better safety and tolerability (Barry et al., 2008; Kerr et al., 2011). Yet, there has been only one double-blind study with SSRIs in PWE. It consisted of a comparison of sertraline and CBT in 144 PWE with MDE (Gilliam et al., 2009). At the end of the 16-week trial, 60% of patients in each treatment arm achieved full symptom remission. No recurrences were noted by 52 weeks. Of note, in this trial, the response to treatment with either sertraline or CBT appeared to be better than that published for patients with primary MDD (Sackeim et al., 2006). No further comparisons can be made, however, as Gilliam's study has yet to be published and the presence of comorbid anxiety was not included in the initial presentation.
Open trials with SSRIs have been published, suggesting efficacy in the treatment of the depressive disorder. For example, Kanner et al. (2000) found total symptom remission in 57 (59%) of 96 consecutive PWE treated with sertraline in monotherapy. Twenty-nine of these patients met criteria for MDE, whereas the other 67 had an atypical type of depression.
Hovorka et al. (2000) examined the efficacy of citalopram in 43 PWE with a depressive episode established on the 21-item Hamilton Depression Scale (HAMD 21; with a total score >15). The total score on the HAMD 21 decreased from a mean baseline of 21.5 ± 2.9 (range 17–26) to 14.5 ± 2.9 (range 10–19) (p < 0.001) after 4 weeks of treatment and to 9.9 ± 3.1 (range 4–19) (p < 0.001) after 8 weeks of treatment. Nine patients (20.9%) were considered to be responders after 4 weeks of treatment and 28 (65.1%) after 8 weeks. Specchio et al. (2004) conducted a 4-month multicenter open trial of citalopram at a dose of 20 mg/day to assess its safety in 45 PWE and depression. Response of the depressive symptomatology was a secondary outcome measured with the Montgomery-Asberg and Zung depression rating scales. Six patients withdrew from the study. At the end of the trial, 18% of patients experienced full symptom remission and 67% were considered to have experienced a moderate or marked improvement. Kühn et al. (2003) examined the effect of citalopram, mirtazapine, and reboxetine on the depressive episode of 75 PWE. The Hamilton Rating Scale for Depression was used to quantify the symptom severity at admission and after 4 and 20–30 weeks. By the end of the trial, symptom remission had been achieved in 21.2% of patients on citalopram, 14.8% on mirtazapine, and 20% on reboxetine, whereas 36%, 52%, and 53% had a >50% reduction in symptoms severity on the HDRS, respectively. With respect to TCAs, Blumer reported a positive response to the use of low-dose imipramine alone and/or in combination with low-dose sertraline in the treatment of interictal dysphoric disorder, an atypical form of depression in epilepsy (Blumer & Zielinski, 1988). Unfortunately, these findings need to be replicated in double-blind placebo-controlled trials given the relatively high placebo response to pharmacotherapy in primary depressive disorders.
Choice of antidepressant drug
Among the six families of antidepressant drugs, most of the published data in PWE include open trials with SSRIs, SNRIs, and TCAs and the norepinephrine and dopamine reuptake blocker (e.g., bupropion), which is one of the antidepressant drugs that is not recommended in these patients because of a proconvulsant effect in nonepileptic patients (Horne et al., 1988; Davidson, 1989; Jefferson et al., 2005; Alper et al., 2007). In developed countries, SSRIs and SNRIs have become the first line of pharmacotherapy for primary MDD, DD, and anxiety disorders, whereas in developing countries, drugs of the TCA family continue to be the first line of therapy, mainly because of economic reasons. Of note, no difference in efficacy has been demonstrated among SSRIs, SNRIs, and TCAs, but the two former are favored over TCAs because of their lower toxicity risk (particularly in the case of overdose) and better overall tolerance. Furthermore, the potential for cardiac arrhythmias mediated by a sodium channel blocking effect of high serum concentrations of TCAs needs to be factored in the choice of antidepressant drugs in PWE, given the increased risk of sudden death in PWE.
The SSRI family includes six drugs (fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and escitalopram), which have as primary effect to increase the synaptic concentration of serotonin (Tollefson & Rosenbaum, 1998). As stated above, two separate consensus papers have supported the choice of this family of drugs as a first line of antidepressant pharmacotherapy in PWE (Barry et al., 2008; Kerr et al., 2011).
The SNRI family of antidepressants includes four drugs (venlafaxine and its active metabolite desvenlafaxine, duloxetine, and milnacipran), which act by increasing the synaptic concentration of serotonin and norepinephrine. Yet, the effect on these two neurotransmitters varies among the drugs, as it is observed at low doses of duloxetine, whereas it occurs only at moderately high doses of venlafaxine (>150–200 mg/day) (Kent & Gorman, 1998). There are no published data on the use of desvenlafaxine in PWE and milnacipran, which is also not available in the United States. Table 1 summarizes doses and their use with comorbid anxiety disorder:
If at maximal doses the patient continues to be symptomatic, a switch to another class of antidepressant is suggested (i.e., SNRI if the prior trial was with an SSRI). Failure to obtain full remission of symptoms after two trials at optimal doses should lead to referral to a psychiatrist.
One cautionary note is in order, however: the therapeutic effect of SSRIs and SNRIs may not be identified for 3–6 weeks after the start of the drug. Because SSRIs can at times cause restlessness and mild anxiety at the start of therapy, a short course of a benzodiazepine such as clonazepam (0.5–1 mg/day) should be considered in patients with comorbid anxiety and depression.
Adverse effects of SSRIs and SNRIs have been reported in about 20–30% of patients with primary mood disorders and include anxiety and agitation during the acute phase of treatment, gastrointestinal symptoms (i.e., nausea, abdominal cramping, and diarrhea), and changes in appetite and weight, sexual disturbances, and rarely involuntary movements. Furthermore, SSRIs can compound on a weight gain caused by AEDs such as valproic acid, gabapentin, pregabalin, and carbamazepine.
Among the SNRIs, hypertension is a potential adverse event identified in patients taking venlafaxine, but not duloxetine (Kent & Gorman, 1998). Therefore, blood pressures need to be monitored closely and venlafaxine and duloxetine should be used with great caution among patients with a risk or with existing hypertension. Duloxetine should be used with great care in patients with a history of liver disease and should be avoided in those with glaucoma.
All SSRIs and SNRIs can cause sexual disturbances, although the effect is less frequent with the latter. Accordingly, it is essential for clinicians to investigate the existence of sexual disturbances before starting an SSRI, as these are relatively common among PWE, either, as a direct consequence of the seizure disorder, as an adverse event in response to an AED, or a combination of the two factors. The most frequent common sexual disturbances include decreased libido, anorgasmia, impotence, and disturbances in ejaculation, and in women, dyspareunia. Citalopram and escitalopram and the SNRIs have been reported to have a lower incidence of sexual adverse events.
Several population-based studies have suggested that SSRIs can cause osteopenia and/or osteoporosis, which could worsen the effect of enzyme-inducing AEDs (Liu et al., 1998; Warden et al., 2005; Diem et al., 2007) .
TCAs were the first available agents and include 12 drugs, of which 7 are among the most frequently used (imipramine, desipramine, amitriptyline, doxepin, nortriptyline, protriptyline, and clomipramine) (Stahl, 2000). Their efficacy has been demonstrated in major depressive episodes, dysthymia, and generalized anxiety disorder and imipramine was the first drug with prophylactic efficacy in panic disorder, whereas clomipramine was the first agent with proven efficacy in the treatment of obsessive-compulsive disorders; yet, the relatively high proconvulsant risk of clomipramine precludes its use in PWE (Rosenstein et al., 1993).
Although the TCAs intended pharmacodynamic effects include an increase in synaptic serotonin and/or norepinephrine by blocking their reuptake (see Table 2 below), these agents have effects at muscarinic cholinergic receptors, histamine1 (H1) receptors, and alpha1-adrenergic receptors, which mediate several of their adverse events. For example, anticholinergic effects mediate dry mouth, constipation, urinary hesitation/retention, blurred vision, tachycardia, exacerbation of narrow angle glaucoma, problems with memory, and confusion. Blockade of H1 receptors has been associated with weight gain and sedation. Blockade of the alpha1 adrenoreceptor has been associated with postural hypotension, dizziness, and reflex tachycardia, and can potentiate the effects of antihypertensive drugs. The reuptake blocking of serotonin has been associated with sexual disturbances and gastrointestinal symptoms, as well as myoclonic jerks, and diaphoresis, whereas the reuptake blocking of norepinephrine can cause tremors and tachycardia and can exacerbate the pressor effects of sympathomimetic amines. Likewise, the blocking of sodium channels is associated with an increased risk of cardiac arrhythmias and epileptic seizures in case of overdoses.
Table 2. Summary of the target doses and magnitude of the effect in various receptors of the five most frequently used TCAs
As stated above, the use of TCAs has been relegated to third place in North America and Europe given its significantly greater toxicity risks, particular as it pertains to cardiovascular adverse events that significantly increase the lethality potential of these drugs in the case of overdoses. It is recommended that the patient be started on TCAs at a low dose, which should be titrated slowly (Table 2). Furthermore, serum concentrations of most antidepressants of this class are available, and it is recommended that they be measured once the desired dose is reached to identify those patients that may be “slow metabolizers.” Finally, baseline electrocardiography (ECG) studies and a repeat study, once the target dose of the TCA has been reached, are recommended to identify any electrocardiographic disturbance.
Clinicians must factor in the following variables in the process of choosing a first antidepressant drug among SSRIs, SNRIs, and TCAs:
- Whether the depressive disorder is retarded or agitated. Therefore, the use of an SSRI is suggested in case of a depressive disorder associated with anxiety, whereas an SNRI may be more beneficial in a retarded depressive episode in which the patient reports fatigue and slow thinking. Among TCAs, noradrenergic agents like desipramine may be more appropriate in cases of retarded depressive episodes, whereas amitriptyline should be considered in the case of agitated depressive episodes.
- The presence of comorbid anxiety disorder. The SSRIs and SNRIs with anxiolytic effect are listed on Table 1(see also article by Mula, 2013 in this issue). In the case of TCA, imipramine may be ideal in the treatment of depressive episodes with comorbid panic attacks, whereas for general anxiety disorder (GAD), imipramine, nortriptyline, desipramine, and doxepin in case of GAD.
- The potential adverse event profile of the specific antidepressant drug that could worsen underlying medical comorbidities associated with the seizure disorder or other concurrent medical condition, in particular adverse events caused by concomitant AEDs such as weight gain and sexual disturbances. In addition, SSRIs, SNRIs, and TCAs should not be discontinued abruptly as patients may experience withdrawal symptoms, including sensory disturbances and ataxia. These symptoms are less frequent in SSRIs with the longer half-lives, such as fluoxetine.
- Potential pharmacokinetic interactions with concurrent AEDs. Several drugs of the SSRI family are inhibitors of one or more cytochrome P450 (CYP) isoenzymes (Patsalos et al., 2005; Trimble & Mula, 2005). For example, fluoxetine has been shown to inhibit several CYP isoenzymes including CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 (Patsalos et al., 2005; Trimble & Mula, 2005). The active metabolite of fluoxetine, norfluoxetine, has also been shown to inhibit CYP2D6, with inhibition of CYP3A4, CYP2C9, and CYP2C19 yielding the most significant potential interactions with AEDs. Furthermore, several case reports have suggested that SSRIs such as fluoxetine and sertraline have caused increased phenytoin and carbamazepine serum concentrations (Nelson et al., 2001). The antidepressant fluvoxamine, is an inhibitor of CYP1A2, CYP3A4, and a potent inhibitor of CYP2C9 and CYP2C19. Comedication therefore is likely to cause marked increases in phenytoin concentrations (Mamiya et al., 2001). In settings where higher SSRI doses are used, or perhaps in elderly patients who may have reduced clearance of both phenytoin and the SSRI, the potential for a clinically meaningful interaction may be increased.
The SSRIs with the least potential for causing inhibitory interactions are citalopram and escitalopram, followed by sertraline with mild inhibitory effects, paroxetine, fluoxetine with moderate effects and fluvoxamine with maximal effects. Although definitive studies are lacking, it has also been suggested that venlafaxine and duloxetine are unlikely to cause significant interactions with currently available AEDs.
Conversely, first-generation AEDs such as phenytoin, carbamazepine, and phenobarbital are potent inducers of the CYP enzyme system (Patsalos & Perucca, 2003). Oxcarbazepine and topiramate at high doses are much weaker inducers of CYP3A4. AEDs including gabapentin, pregabalin, lamotrigine, levetiracetam, tiagabine, zonisamide, ezogabine, clobazam, vigabatrin, and perampanel do not appear to interfere with CYP activity or other metabolizing pathways (i.e., glucuronidation). Because most SSRIs, SNRIs, and TCA are substrates for one or more or the CYP isoenzymes (Spina & Perucca, 2002; Trimble & Mula, 2005), comedication with an enzyme-inducing AED would be expected to increase their systemic clearance resulting in lower serum concentrations. This effect has been demonstrated in antidepressants such as sertraline, paroxetine, citalopram, as well as in most TCAs, requiring an adjustment of their dose (by 25–30%) to avert recurrence of psychiatric symptoms.
In contrast to the enzyme-inducing drugs, the AED sodium valproate can inhibit certain CYP (2C9) and UDP-glucuronyltransferase enzymes, and may cause significant increases (50–60%) in serum concentrations of antidepressants such as amitriptyline or nortriptyline (Spina & Perucca, 2002).