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Keywords:

  • Epilepsy;
  • Antiepileptic drugs;
  • Antidepressant drugs;
  • Anxiety disorders;
  • Cognitive behavioral therapy

Summary

  1. Top of page
  2. Summary
  3. Pathogenesis of Anxiety in Epilepsy
  4. Classification of Anxiety Disorders in Epilepsy
  5. Treatment of Specific Anxiety Disorders
  6. Conclusions
  7. Disclosure
  8. References

During recent years growing attention has been paid to psychiatric comorbidities in epilepsy. However, anxiety disorders still remain underrecognized and undertreated. This is largely related to the lack of specific screening instruments and the frequent co-occurrence with mood disorders. Data on treatment are insufficient and clinical practice still relies heavily on individual experience. In this article we review evidence-based treatment strategies for primary major anxiety disorders and adapt them to the specific needs of patients with epilepsy. In panic disorder, a combined approach, namely serotonin-reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) is always indicated during the acute phase. Long-term maintenance treatment may include combined therapy or CBT alone depending on individual cases. For generalized anxiety disorders pregabalin has to be considered first choice for short-term and long-term treatment. In social anxiety disorder and posttraumatic stress disorder SSRIs, in particular sertraline and paroxetine, can be safely used. Obsessive-compulsive disorder represents a serious condition that needs to be approached in a psychiatric setting. CBT should be considered as the first choice in patients with epilepsy. If drug treatment is needed, epileptologists have to be aware that high-dose antidepressants are appropriate and that SSRIs, in particular sertraline, should be considered first choice. In these patients, careful clinical monitoring is indicated, in selected cases, for potential seizure precipitation and side effects due to pharmacodynamics interactions.

Although the importance of the psychiatric comorbidities in epilepsy have been increasingly recognized, most attention has been focused on depression, with relatively less focus on anxiety symptoms (Hamid et al., 2011). However, anxiety seems to have prevalence rates among patients with epilepsy comparable to or even higher than those reported for depression. Moreover, anxiety disorders are chronic conditions with a relapsing remitting time course (Narrow et al., 2002) and a complex psychiatric comorbidity pattern that may develop during the longitudinal phase of the disease (Angst & Vollrath, 1991). Finally, anxiety plays a key role in suicidality among patients with depression (Placidi et al., 2000). It seems, therefore, evident that treatment of anxiety symptoms in epilepsy is of great relevance.

Pathogenesis of Anxiety in Epilepsy

  1. Top of page
  2. Summary
  3. Pathogenesis of Anxiety in Epilepsy
  4. Classification of Anxiety Disorders in Epilepsy
  5. Treatment of Specific Anxiety Disorders
  6. Conclusions
  7. Disclosure
  8. References

Psychological hypotheses

In general terms, anxiety disorders have been the main field of research and application for a number of different psychological schools: from the classic Freudian perspective that hypothesizes intrapsychic conflicts (De Bianchedi et al., 1988) to cognitive psychology that investigates conditioned responses to stressful stimuli (Ledoux, 2000). However, to what extent these theories may be applicable in epilepsy regarding anxiety comorbidity has not been well-studied (Hamid et al., 2011). The unpredictability of seizures and the associated sense of vulnerability, with aberrant thought patterns involving overestimation of risk and associated harm, could theoretically lead epilepsy patients to be at particularly high risk. Nevertheless, there are no studies specifically investigating such psychological issues in epilepsy and, as a consequence, no specific treatment protocols have been developed.

Neurobiological hypotheses

It is of interest that the same regions involved in a significant proportion of patients with focal epilepsy, namely the amygdala and the hippocampus, also play a key role in the neurobiology of anxiety. The amygdala is determinant in the experience of fear; it mediates the autonomic and endocrine responses through the output to the hypothalamus, and avoidance behavior through the output to the periaqueductal gray matter (Stahl, 2003). In addition, the hippocampus mediates the reexperiencing of fear and its affective component. Activation of these circuits is the major hypothesis for anxiety symptoms and the reduction in the excessive output from these neurons represents the main treatment target (Stahl, 2003; Rogawski & Loscher, 2004). Such a mechanism has a number of similarities with the excessive outburst typical of epileptic neurons, explaining the effects of antiepileptic agents (such as benzodiazepines or antiepileptic drugs [AEDs]) in the treatment of anxiety (Mula et al., 2007). In fact, the potentiation of γ-aminobutyric acid (GABA)ergic inhibition and the modulation of calcium channels represent valuable antianxiety mechanisms (Stahl, 2003; Mula et al., 2007).

Classification of Anxiety Disorders in Epilepsy

  1. Top of page
  2. Summary
  3. Pathogenesis of Anxiety in Epilepsy
  4. Classification of Anxiety Disorders in Epilepsy
  5. Treatment of Specific Anxiety Disorders
  6. Conclusions
  7. Disclosure
  8. References

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the standard classification of mental disorders used by mental health professionals in the United States and contains a listing of diagnostic criteria for every psychiatric disorder. The current edition, the DSM, fourth edition, text revision (DSM-IV-TR), identifies a number of conditions under the general category of anxiety disorders, namely generalized anxiety disorder, panic disorder (with or without agoraphobia), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), phobias, social anxiety disorder, and anxiety arising as a direct physiologic consequence of a medical disease process. In May 2013, the new version, DSM-5, will be released. According to the new classification system, some conditions that were previously listed in the “Anxiety disorders” chapter in DSM-IV-TR have been distributed throughout separate chapters on “Obsessive-Compulsive and Related Disorders” and “Trauma- and Stressor-Related Disorders.” Although this discussion is of interest for psychiatrists, it remains still unclear how applicable these categories may be in medical conditions such as epilepsy. The proposed classification for psychiatric disorders in epilepsy discusses anxiety disorders marginally or in the context of mood problems (Krishnamoorthy et al., 2007). Therefore, it seems evident that further studies are urgently needed to examine the specific nature of anxiety symptoms in epilepsy and how they may differ from the nature of anxiety in primary anxiety disorders and from anxiety symptoms encountered in other medical and central nervous system (CNS) disorders.

Treatment of Specific Anxiety Disorders

  1. Top of page
  2. Summary
  3. Pathogenesis of Anxiety in Epilepsy
  4. Classification of Anxiety Disorders in Epilepsy
  5. Treatment of Specific Anxiety Disorders
  6. Conclusions
  7. Disclosure
  8. References

Systematic data on treatment strategies for psychiatric disorders in epilepsy remain limited, with clinical practice relying heavily on individual experience. An expert U.S. panel comprising members from the Epilepsy Foundation's Mood Disorders Initiative (Barry et al., 2008) and an international expert panel comprising members of the Commission on Neuropsychiatric aspects of the International League Against Epilepsy (ILAE) (Kerr et al., 2011) composed consensus statements. However, anxiety disorders were marginally discussed in these documents, limiting even further the possibility of standardized therapeutic approaches in the epilepsy setting.

A major limitation of current literature for treatment of psychiatric disorders in epilepsy is the lack of randomized controlled trials (RCTs). RCTs represent the building blocks on which physicians and therapists rely for sound information about the safety and effectiveness of treatments. In this regard, it is important to point out that it is still unclear whether patients with epilepsy respond equally to psychotropic medications or if they have different remission rates.

The present article is aimed at suggesting a guidance of treatment for anxiety disorders in epilepsy. Evidence-based approaches and internationally adopted guidelines for anxiety disorders outside epilepsy are presented and discussed, taking into account a number of recommendations concerning the underlying neurologic condition.

Panic disorder with/without agoraphobia

Panic disorder is characterized by recurring severe panic attacks and may also include significant behavioral changes lasting at least a month and of ongoing worry about the implications or concern about having other attacks. It has an annual incidence of 1.8% in the United States, and it is estimated that approximately 2.4 million people in the United States have panic disorder (McLean et al., 2011). In epilepsy, panic disorder seems to have prevalence rates ranging between 5% and 10% (Mula et al., 2008; Brandt et al., 2010). Panic is not the same as agoraphobia (fear of public places), although many patients with panic disorder also have agoraphobia. Panic disorder is a potentially disabling disorder, but can be controlled and successfully treated. The most widely used treatments for panic disorder are drug therapies and cognitive behavioral therapy (CBT).

Drug treatments depend largely on antidepressants (Table 1) and benzodiazepines. Several meta-analyses have been published demonstrating that antidepressants have at least equally efficacy as compared to benzodiazepines (Wilkinson et al., 1991; Boyer, 1995; van Balkom et al., 1997; Bakker et al., 2002). On the contrary, benzodiazepines are not superior to antidepressants in reducing depressive symptoms that may accompany panic disorder (van Balkom et al., 1997). A meta-analysis comparing short-term efficacy of selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) showed no difference between the two drug classes in terms of efficacy but indicated that SSRIs are usually better tolerated (Bakker et al., 2002).

Table 1. Classification of antidepressant drugs
Reversible inhibitors of monoamine oxidase A (RIMAs)Moclobemide
Tricyclic antidepressant drugs (TCAs)Amitriptyline, clomipramine, desipramine, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine
Selective serotonin reuptake inhibitors (SSRIs)Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
Selective noradrenergic reuptake inhibitors (NRIs)Reboxetine
Noradrenaline and dopamine reuptake blockers (NDRIs)Bupropion
Dual serotonin and noradrenaline reuptake inhibitors (SNRIs)Duloxetine, venlafaxine
Noradrenergic and specific serotoninergic antidepressants (NaSSAs)Manserine, mirtazapine
Dual serotonin 2 antagonists/serotonin reuptake inhibitors (SARIs)Nefazodone, trazodone

The issue of psychotherapy in panic disorder has been reviewed in a Cochrane meta-analysis (Furukawa et al., 2007) that investigated the available evidence concerning short-term and long-term advantages and disadvantages of combined psychotherapy plus antidepressant treatment in comparison with either therapy alone. In the acute phase treatment, the combined therapy was superior to antidepressants alone (relative risk [RR] 1.24, 95% confidence interval [95% CI] 1.02–1.51) or psychotherapy alone (RR 1.17, 95% CI 1.05–1.31). However, the combined therapy produced more dropouts due to side effects than psychotherapy (number needed to harm around 26). After the acute phase treatment, as long as the drug was continued, the combined therapy appeared to be superior to monotherapy. It is interesting to note that the combined therapy was more effective than pharmacotherapy alone (RR 1.61, 95% CI 1.23–2.11) and was as effective as psychotherapy alone (RR 0.96 95% CI 0.79–1.16) during the continuation phase, suggesting that either combined therapy or psychotherapy alone may be chosen as first-line treatment for panic disorder with or without agoraphobia, depending on patient preference (Table 2).

Table 2. Treatment of anxiety disorders in epilepsy
DisorderAcute treatmentLong-term treatment
Panic attack disorder

First choice: SSRIs (any) + CBT

Second Choice: TCAs (any) + CBT

SSRIs (any) + CBT or CBT alone
Generalized anxiety disorder

First choice: pregabalin

Second choice: paroxetine, venlafaxine, imipramine (CBT controversial)

First choice: pregabalin

Second choice: paroxetine, venlafaxine, imipramine (CBT controversial)

Social anxiety disorderFirst choice: SSRIs (sertraline, escitalopram, paroxetine) (CBT controversial)First choice: SSRIs (sertraline, escitalopram, paroxetine) (CBT controversial)
Posttraumatic stress disorderFirst choice: SSRIs (sertraline, paroxetine) (CBT controversial)First choice: SSRIs (sertraline, paroxetine) (CBT controversial)
Obsessive-compulsive disorder

First choice: CBT

Second choice: CBT + sertraline

Third choice: CBT + clomipramine

First choice: CBT

Second choice: CBT + sertraline

Third choice: CBT + clomipramine

Generalized anxiety disorder

Generalized anxiety disorder (GAD) is a common mental disorder affecting approximately 5% of the general population in the United States (Gorman, 2001). In epilepsy, GAD seems to have prevalence rates ranging between 3% and 12% in selected sample populations (Mula et al., 2008; Brandt et al., 2010). It is an impairing disorder, usually characterized by a chronic course and often associated with extensive psychiatric and medical comorbidity.

The most widely used treatments for GAD are drug therapies and cognitive behavioral treatments. Among different compounds, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs) (see Table 1), benzodiazepines, azapirones (e.g., buspirone), antihistamines (e.g., hydroxyzine), and the anticonvulsant pregabalin have been used. At a clinical level, benzodiazepines have, until very recently, been the most widely used anxiolytic drugs (Gorman, 2003). However, benzodiazepines are affected by a number of limitations such as dependency, long-term tolerance, and cognitive disorders. Moreover, a systematic review of 23 RCTs of benzodiazepines in GAD showed that, based on total withdrawals from clinical studies, benzodiazepines do not prove to be definitely better than placebo in short-term treatment (Martin et al., 2007). For these reasons, research into the treatment of GAD shifted toward safer and more effective compounds (Goodman, 2004). A systematic review of antidepressant drugs confirmed their efficacy in GAD especially for imipramine, venlafaxine, and paroxetine (Schmitt et al., 2005). Among other drug classes, a number of studies have established the role of the anticonvulsant pregabalin in the short-term treatment of GAD (Bandelow et al., 2007b; Mula et al., 2007). Recent data are now supporting the efficacy of this compound also in the long-term treatment (Feltner et al., 2008) and in the amelioration of comorbid depressive symptoms (Stein et al., 2008).

The efficacy of CBT for GAD is still controversial. One meta-analysis indicated that CBT is more effective than pharmacologic treatment (Mitte, 2005), but two thirds of the included studies did not use structured interviews to diagnose GAD, and findings for CBT versus drug therapy varied depending on method of analysis (random vs. fixed effects) (Bagby & Quilty, 2006). A more recent meta-analysis of RCTs of psychopharmacologic and psychological treatments pointed out that the number of published studies is too small to draw final conclusions in GAD (Bandelow et al., 2007a). Further studies are needed to clarify whether a combined approach, psychological and pharmacologic, can be useful for long-term treatment and in which specific subpopulation.

Social anxiety disorder

The growing interest in the development of treatment strategies for social anxiety disorder reflects an increasing awareness on the prevalence and clinical significance of this condition, along with the growing availability of new psychological and pharmacologic treatments. In epilepsy, social anxiety seems to have prevalence rates ranging between 3% and 7% (Mula et al. 2008; Brandt et al. 2010). The most widely used treatments for social anxiety disorder are drug therapies and CBT.

A large review of RCTs of a range of medications, from antidepressants to anticonvulsants, demonstrated short-term superiority of all medication groups over placebo (Stein et al., 2004). However, SSRIs were significantly more effective than both moclobemide and, to a lesser extent, brofaromine. In particular, SSRIs were shown to reduce not only social anxiety disorder symptom clusters, but also comorbid depressive symptoms and associated disability. These data have been confirmed by a subsequent meta-analysis (Fedoroff & Taylor, 2001) that pointed out the need for a careful evaluation of long-term maintenance of treatment gains. Comparative evidence from 15 RCTs on second-generation antidepressants showed that, apart from fluvoxamine that did not reach statistical significance (RR 1.5, 95% CI 0.9–2.4), escitalopram (RR 1.3, 95% CI 1.2–1.5), paroxetine (RR 1.9 95% CI 1.5–2.3), sertraline (RR 1.8 95% CI 1.5–2.2), and venlafaxine (RR 1.7 95% CI 1.5–1.9) all produce significantly more responders than placebo in terms of reduction of symptom severity and functional impairment (Hansen et al., 2008). Aside from documented differences in the incidence of specific adverse events, existing evidence does not suggest differences in efficacy of these drugs.

Although CBT showed to be useful in a number of anxiety disorders (Hofmann & Smits, 2008), results from studies in social anxiety are less clear. Only two studies had a combined treatment arm (Blomhoff et al., 2001; Davidson et al., 2004). Data from these studies showed higher effect sizes for the combination drug plus CBT than for placebo plus CBT. In other words, all direct comparisons between different treatments for social anxiety disorder showed no clear superiority of one treatment over another and do not support the use of combined treatment.

Posttraumatic stress disorder

For posttraumatic stress disorder (PTSD), evidence-based data for treatment are very limited, especially if compared to other anxiety disorders. In epilepsy, PTSD is reported in about 1% of patients (Brandt et al. 2010).

Many authors have focused on antidepressants drugs; however, current evidence is unable to demonstrate superior efficacy or acceptability for any particular medication class, despite suggestions that the SSRIs are more effective and tolerable than older antidepressants (Stein et al., 2006). Nevertheless, the fact that the SSRI trials constitute the bulk of the evidence for the efficacy of medication in treating PTSD suggests that it is reasonable to consider SSRIs as first choice. Among SSRIs, it is unlikely that all compounds are equally effective in treating PTSD. There is some evidence favoring paroxetine and sertraline in reducing the severity of PTSD symptoms while, on the other hand, trials of alprazolam, brofaromine, desipramine, lamotrigine, and olanzapine showed no efficacy in terms of treatment response or symptom reduction (Stein et al., 2009). In general terms, treatment response to medications has been generally described as modest in patients with PTSD, and several open studies have been published regarding augmentation strategies to antidepressant drugs. However, controlled data are still limited. A recent meta-analysis of RCTs involving a total of 192 patients with PTSD treated with atypical antipsychotics suggested some beneficial effects of these compounds (Pae et al., 2008). RCTs of topiramate in PTSD failed to demonstrate a significant effect over placebo as either monotherapy or adjunctive therapy (Lindley et al., 2007; Tucker et al., 2007). However, the high dropout rate in the treatment group prohibits definitive conclusions.

Data on psychotherapy in PTSD are limited. A large meta-analysis of RCT on CBT in anxiety disorders showed the strongest effect size for acute stress disorder, whereas reported RCTs in PTSD patients were still controversial (Hofmann & Smits, 2008). According to other authors, PTSD-specific CBT may be of value in severe patients with psychosis or suicidal ideation (Mueser et al., 2008). However, further studies are needed to support the use of specific psychotherapeutic programs in PTSD and to identify populations of patients that may benefit from such a treatment.

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is an impairing condition that affects 1–2% of individuals, causing considerable impairment in both children and adults (Ruscio et al., 2010). In epilepsy, OCD is reported in about 1–5% of patients (Brandt et al., 2010). There are two evidence-based treatment options for OCD: CBT and pharmacotherapy.

CBT is the first-line treatment for children and adults with mild to moderate OCD (Rosa-Alcazar et al., 2008; Watson & Rees, 2008). If symptom severity persists after CBT or OCD symptoms present as severe, pharmacotherapy is indicated (Stein et al., 2007).

Compared with other conditions—such as mood disorders or other anxiety disorders—for which antidepressants are effective at lower doses, many experts advocate the use of high and quickly escalating doses of antidepressant drugs in the treatment of OCD (Stein et al., 1995). Clomipramine, a tricyclic antidepressant (see Table 1), was the first pharmacologic agent to demonstrate efficacy in reducing obsessive-compulsive symptoms (Group TCCS, 1991). Subsequently, high dose SSRIs demonstrated also robust efficacy (Bloch et al., 2010). Despite its therapeutic benefit, clomipramine is accompanied by potential cardiovascular complications, anticholinergic effects (e.g., dry mouth, headaches, and increased heart rate), sedation, weight gain, and sexual dysfunction, which limit its tolerability (Group TCCS, 1991). However, different meta-analyses suggest that clomipramine may be more efficacious than SSRIs in reducing symptom severity, especially in more severe cases (Stein et al., 1995; Watson & Rees, 2008). In the absence of an adverse reaction, a minimum 12-week SSRI trial is recommended to evaluate the medication's therapeutic benefit before transitioning to another medication (Hollander et al., 2000). At any rate, OCD is a severe and disabling disorder that needs to be managed in a psychiatric setting. Epileptologists have to be aware that high doses of antidepressants are needed, and careful neurological clinical monitoring is appropriate for the potential risk of seizure exacerbation and pharmacodynamic interactions with AEDs.

Conclusions

  1. Top of page
  2. Summary
  3. Pathogenesis of Anxiety in Epilepsy
  4. Classification of Anxiety Disorders in Epilepsy
  5. Treatment of Specific Anxiety Disorders
  6. Conclusions
  7. Disclosure
  8. References

Controlled data on treatment of psychiatric disorders in epilepsy are lacking, and therapeutic approaches still rely on individual experience. Evidenced-based therapeutic strategies in patients with anxiety disorders can be easily adapted to patients with epilepsy considering specific needs. In general terms, SSRIs have to be preferred to TCAs because of the safety profile and the clean pharmacokinetics. In panic disorder, a combined approach, namely SSRIs and CBT, is always indicated for the acute phase. Long-term maintenance treatment can adopt a combined approach or CBT alone depending on characteristics of the individual patient. In generalized anxiety disorder, pregabalin has to be considered first choice for short-term and long-term treatment, with considering of the indication in both conditions (i.e., epilepsy and GAD). In social anxiety disorder and PTSD, SSRIs can be considered first choice, in particular sertraline and paroxetine. OCD is a severe and disabling disorder that needs to be approached in a psychiatric setting. CBT has always to be considered first choice in patients with epilepsy. If CBT alone is not sufficient and drug treatment is needed, SSRIs, in particular sertraline, are preferred. Epileptologists need to be aware that high doses of antidepressant are indicated in OCD and careful clinical monitoring is appropriate for potential seizure precipitation or side effects due to pharmacodynamic interactions with AEDs.

Further studies in patients with epilepsy are urgently needed to develop standardized treatments for anxiety disorders in this special population.

Disclosure

  1. Top of page
  2. Summary
  3. Pathogenesis of Anxiety in Epilepsy
  4. Classification of Anxiety Disorders in Epilepsy
  5. Treatment of Specific Anxiety Disorders
  6. Conclusions
  7. Disclosure
  8. References

This author has received travel grants or consultancy fees from various pharmaceutical companies including Pfizer, UCB Pharma, and Janssen, which are involved in the manufacture of antiepileptic drugs. The contents of this supplement reflect the opinions of the individual authors and do not necessarily represent official policy or position of the ILAE. I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Pathogenesis of Anxiety in Epilepsy
  4. Classification of Anxiety Disorders in Epilepsy
  5. Treatment of Specific Anxiety Disorders
  6. Conclusions
  7. Disclosure
  8. References
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