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Jonathan E. Shaywitz MD, and Michael R. Liebowitz, MD
Primary Psychiatry. 2003;10(10):51-56

Dr. Shaywitz is a research fellow in the Anxiety Disorder Clinic at the New York State Psychiatric Institute and instructor in psychiatry at Columbia University, both in New York City.

Dr. Liebowitz is director of the Anxiety Disorder Clinic at the New York State Psychiatric Institute and professor of clinical psychiatry at Columbia University.
Disclosure: Dr. Liebowitz is a consultant for and on the speaker’s bureau of Pfizer, GlaxoSmithKline, and Wyeth; he receives research support and/or honorarium from Pfizer, GlaxoSmithKline, Novartis, Ortho-McNeil, and Wyeth.
 

Please direct all correspondence to: Michael R. Liebowitz, MD, New York State Psychiatric Institute, Unit 54, 1051 Riverside Dr, New York, NY 10032; Tel: 212-543-5366; Fax: 212-543-6915; E-mail: liebowitz@nyspi.cpmc.columbia.edu.

Focus Points

Anxiety disorders are common, with an estimated prevalence ranging from 2.5% for obsessive-compulsive disorder to 13% for social anxiety disorder.

Multiple neurotransmitters are involved in anxiety disorders, and the fear neuro-network centered in the amygdala is involved in at least some of the anxiety disorders.
Antiepileptics interact with neurotransmitter systems involved in anxiety disorders and several have demonstrated efficacy in their treatment.

Abstract

Anxiety disorders are common, with an estimated lifetime prevalence range of 2.5% for obsessive-compulsive disorder to 13% for social anxiety disorders. Since the recognition of these disorders, clinicians have been searching for safe and effective anxiolytic drugs. Benzodiazepines are markedly effective in many patients with generalized anxiety disorder but are associated with withdrawal symptoms upon discontinuation. The selective serotonin reuptake inhibitors have demonstrated efficacy in the treatment of anxiety disorders but only approximately 50% of patients benefit. Many antiepileptics interact with neuropathways thought to be involved with the pathobiology of anxiety disorders, and the results of clinical trials of these agents suggest that they may have utility in the treatment of some anxiety disorders.

Introduction

Anxiety has been recognized in medicine since the 19th century, but has only recently been officially recognized and classified as a mental disorder.1 Researcher and clinicians have since been searching for safe and effective anxiolytic drugs, beginning with barbiturates in 1903, meprobamate in the 1950s, and benzodiazepines during the later parts of the 20th century.2 The search for effective pharmacotherapy continued with emphasis on finding drugs that were free of addiction or dependence issues. The advent of the use of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) was originally thought to address these concerns, but both classes have slow onset of action and dose-limiting toxicity as well as association with discontinuation syndromes.3 Buspirone seemed to solve the dependence and toxicity problems, but has not lived up to its promise in anxiolytic efficacy.4 Other agents used for the pharmacotherapy of anxiety disorders include benzodiazepines, the selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).5

The understanding of the neurobiology of anxiety has progressed rapidly in recent years from basic knowledge that g-aminobutyric acid (GABA) and serotonin neurotransmitter systems were involved in the expression of anxiety to more fully understanding the complex interaction of multiple neurotransmitters, the fear neuro-network centered in the amygdala, and the genetic predisposition. The amygdala is critical to fear responses and projects to multiple brain systems involved in the physiological and behavioral responses to fear. Its involvement in anxiety is suggested by imaging studies which have shown increased amygdala activation in anxious subjects compared to healthy controls in some anxiety disorders.6

The array of neurotransmitter systems associated with anxiety disorders is illustrated by animal studies, human challenge studies, pharmacologic treatment studies, and imaging investigations.

Despite progress in the understanding of the neurobiology and the pharmacotherapy of anxiety disorders, the response rate to pharmacotherapy remains suboptimal, and the search for novel treatments continues. Antiepileptics (AEDs) are a class of agents with an emerging role in the treatment of anxiety disorders. In addition to their known AED activity, the mechanism of action of several of these drugs suggests that they may be effective in the treatment of anxiety disorders. In the remainder of this review the mechanism of action of the AEDs will be described as will the evidence for their use in the treatment of generalized anxiety disorder (GAD), social anxiety disorder (SAD), and obsessive-compulsive disorder (OCD).


Neurobiology of Anxiety Disorders


The anatomical center for anxiety appears to be the hippocampus and amygdala, which in turn activate the hypothalamic-pituitary-adrenocortical (HPA) axis.7,8 Sensory input is sent through the thalamus to the amygdala, which is known to be critical for the evaluation of stress and fear and involved in some of the anxiety disorders, and to the hippocampus, which is thought to be important in processing emotional memory. When a fearful stimulus is perceived by the amygdala, neural projections to multiple brain systems coordinate the appropriate response, for example, activation of the sympathetic nervous system and the release of stress hormones. Pathological anxiety is different from fear in that the provocative stimulus is not threatening, but the response is just as real as if it were.
 

The coordination of the neural response to stress or fear depends on carefully orchestrated neurotransmission, and perturbations in any part of the modulation or feedback control can lead to a dysfunctional response. Changes in activity of many neurotransmitters have been reported in anxiety, for example, GABA, glutamine, norepinephrine, serotonin, corticotropin-releasing hormone, and cholecystokinin.7,8 Many of the AED agents are known to affect GABA and glutamate, providing a rationale for investigating their role in the treatment of anxiety.

Antiepileptics

Research into AED mechanisms has traditionally focused on the ability to inactivate voltage-gated sodium channels, to suppress T-type calcium channels, or to inhibit GABAA receptor-mediated chloride flux. As summarized in Table 1, most AEDs that have been tested in the treatment of anxiety disorders act via one or more of these mechanisms, although how these agents inhibit seizures is not fully understood. For example, the AED mechanism of valproate is unknown, but it enhances brain GABA activity and possibly inhibits glutamate receptors—actions that may contribute to the drug’s efficacy.9 Topiramate enhances neurotransmitter action at GABAA receptors and inhibits glutamate via α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors. It also inhibits voltage-gated sodium and L-type calcium channels.10 It is the activities that influence brain GABA levels and glutamate activity that may be of interest in the treatment of anxiety disorders. The results of clinical studies in which AEDs have been used to treat anxiety disorders are summarized in Table 211-22 and discussed below.

Generalized Anxiety Disorder

GAD is characterized by a period of excessive anxiety or worry occurring over a period of at least 6 months and is often accompanied by multiple associated symptoms: motor tension, fatigability, poor concentration, autonomic hyperactivity, and hyperarousal.23 In the GAD patient, the degree of anxiety or worry is out of proportion to the likelihood or severity of impact of the feared event and cannot be attributable to any other more focal distress. Thus, GAD is more of an exclusionary disorder defined by what it is not: panic disorder, SAD, OCD, or posttraumatic stress disorder. GAD is common, with an estimated 12-month prevalence of 3.1% and a lifetime prevalence of 5.1%, with women diagnosed 60% more frequently than men.24 GAD is a chronic illness, but, despite its high prevalence, little is understood about the course of the disease. GAD often occurs initially during adolescence and the severity of its symptoms can cycle over the lifetime.

GAD is generally treated with a combination of psychotherapy and pharmacotherapy.25 The medications that are typically used to treat GAD are benzodiazepines, antidepressants, and buspirone. Four benzodiazepine drugs are commonly used to treat GAD: diazepam, lorazepam, clonazepam, and alprazolam.26 They are relatively safe and have fast onset anxiolytic and sedative activity. These compounds exert their effect by enhancing the activity of GABA, resulting in a reduced neuronal firing rate in the locus ceruleus. GABA is the most prevalent and important inhibitory neurotransmitter in the human body. Furthermore, the benzodiazepines, some of the most effective pharmacologic treatments for anxiety disorders, exert their effects via the GABAA receptor.27 Benzodiazepines are reported to be effective in approximately 35% of patients,28,29 and adverse effects associated with their use (sedation, psychomotor impairment) are generally mild. Withdrawal symptoms are sometimes seen upon discontinuation of therapy and are more common with the faster-acting compounds. Because of the potential for dependence, the benzodiazepines are commonly used in combination with antidepressant drugs, and tapered as the effect of the antidepressant medication begins to emerge.
 

Depression is a common comorbidity of GAD and antidepressants are reported to be effective in its treatment. However, the beneficial effect of the SSRIs and SNRIs in treatment of anxiety occurs independently of any antidepressant effect. The SSRIs, like fluvoxamine and clomipramine, act by inhibiting the neuronal reuptake of serotonin and thus potentiate the activity of serotonergic pathways. Based on their favorable adverse-effect profile, SSRIs are a preferred class of antidepressant drugs used in the treatment of GAD.30

Buspirone was developed as an anxiolytic drug, but unlike the benzodiazepines, has no abuse potential and is not habit forming. Because of its prolonged onset of anxiolytic activity (2–3 weeks), it cannot be used on an as needed basis. The results of recent studies suggest that buspirone is of limited efficacy in the treatment of some anxiety disorders; it is often used in combination with SSRIs.31

Antiepileptic Treatment of Generalized Anxiety Disorder

Pregabalin


The results of three studies of the effects of pregabalin in the treatment of GAD have been published. Pregabalin is a lipophilic GABA analogue that was originally developed as an AED.32 It is about 3–10 times more potent than gabapentin in AED activity, and it has recently been shown to be effective against neuropathic pain and GAD. Rickels and colleagues19 studied 455 patients with GAD in a randomized, double-blind trial of three doses of pregabalin compared to alprazolam and placebo. Anxiolytic efficacy was evaluated with the Hamilton Rating Scale for Anxiety (HAM-A). Pregabalin at 300, 450, or 600 mg/day and alprazolam 1.5 mg/day produced significantly greater reductions in HAM-A scores than placebo. The onset of the antianxiety effect of pregabalin was fast, with improvement seen within 1 week of starting treatment. Pregabalin and the SNRI venlafaxine were compared to placebo in a randomized, double-blind study of 426 patients.20 Pregabalin 400 or 600 mg/day or venlafaxine 75 mg/day were significantly superior to placebo in reducing symptoms of GAD as measured by the HAM-A. As was true in the Rickels study, no dose response to pregabalin was seen in the dose range tested.

Pande and colleagues21 have recently reported the results of a comparison of pregabalin 150 or 600 mg/day to lorazepam 6 mg/day or placebo in 276 patients with GAD. Both doses of pregabalin and lorazepam resulted in significantly greater reductions in HAM-A scores compared to placebo over the 4-week study. The most common adverse events for both active treatments were somnolence and dizziness. No withdrawal syndrome was seen when pregabalin was tapered over 1 week at the end of the study. Other adverse effects associated with pregabalin include ataxia and headache, which are mild-to-moderate in severity, and transient.32 The results of these studies suggest that pregabalin is an effective treatment for GAD.

Levetiracetam


A single case report describes the use of levetiracetam added to a regimen of the SSRI citalopram, in a 42-year-old female suffering from GAD.33 Levetiracetam 250 mg/day reduced anxiety within 4 or 5 days, and the beneficial effect improved and persisted for over 6 months.

Tiagabine


Tiagabine, an inhibitor of GABA reuptake, was used to treat 18 patients with GAD in an open-label study (10 mg/day). The patients showed a significant improvement of anxiety symptoms as indicated by decreased HAM-A scores.34 In a similar study, tiagabine was evaluated for use in 10 case patients refractory to conventional antianxiety medications.35 All patients were described as “much” or “very much” improved after
4 weeks of treatment.

Social Anxiety Disorder

SAD, also known as social phobia, is a common anxiety disorder in which subjects are unusually fearful of social interactions and are particularly concerned that their actions might cause embarrassment or humiliation.36 The fear can be overwhelming and interfere with school, work, and other ordinary activities. SAD is a surprisingly common anxiety disorder. Using the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R)37 criteria, the 1-year prevalence was estimated to be about 8% and the lifetime prevalence about 13%.24 The onset of SAD is usually in childhood or young adulthood, and it occurs about twice as frequently in women as in men.38

Typical symptoms of SAD include increased sweating, tremor, blushing, dry mouth, hypertension, and tachycardia.36 The causes of SAD are unknown, but there is strong evidence of a biological component, such as heritability, abnormalities in neurotransmitter receptor density, and efficacy of medications used to treat SAD.36 Other anxiety disorders often comorbid with SAD include depression and alcohol abuse.36,39
 

Treatment of SAD involves both psychotherapy and pharmacotherapy, but the rate of improvement is reported to be slower than with some other psychiatric disorders, such as major depressive disorder (MDD).36 SSRIs have become widely used for SAD,40,41 but only about 50% of SAD patients show improvement with any given SSRI, and high doses are required for extended periods of time.36 Benzodiazepines, MAOIs, SSRIs, and SNRIs have all been reported to be effective in the treatment of SAD.36,39

Antiepileptic Treatment of Social Anxiety Disorder

Topiramate


Topiramate has been tested in the treatment of SAD in a single study. Van Ameringen and colleagues17 evaluated 16 adult outpatients with generalized SAD in an open-label study. The dose of topiramate was titrated from 25 mg/day to 400 mg/day over the first 9 weeks of the 16-week study. Efficacy was measured by changes from baseline in the Liebowitz Social Anxiety Scale (LSAS) score and by the Clinical Global Impression-Improvement Scale (CGI-I). Eleven patients completed the study and seven were considered responders based on CGI-I scores of 1 or 2. In the intent-to-treat analysis, mean CGI-Severity changed from 5.1±0.6 (“markedly ill”) to 3.8±1.4 (“mildly or moderately ill,”
P=.001) after 16 weeks. LSAS score decreased by 29% (P=.013). Four patients withdrew from the study because of adverse events and one withdrew because of lack of efficacy. The most common adverse effects were weight loss, paresthesia, and headache. The authors concluded that results of the study showed the potential for using topiramate as a first-line treatment of SAD.

Pregabalin


In a randomized, double-blind study, 135 patients with generalized SAD were randomized to treatment with pregabalin 150 mg/day or 600 mg/day or placebo.22 The primary efficacy measurement was change in LSAS from baseline to the end of study (11 weeks). Patients treated with the high-dose pregabalin had change in LSAS of 28.6±3.2 compared to that seen in the placebo-treated group of 18.4±3.2 (
P<.024). The change in the low-dose pregabalin group was 21.5±3.4 (P>.05 compared to placebo). Based on the CGI-I scale, 43% (20/47) of the high-dose pregabalin group were responders, compared to 22% (10/46) in the placebo group (P=.03, the low-dose pregabalin responder rate was not reported). The magnitude of the response of those treated with high-dose pregabalin was similar to that reported for effective pharmacotherapy in other large clinical studies. A post-hoc analysis indicated that pregabalin was most effective in those patients without comorbid psychiatric disorders. Somnolence was the most common adverse effect and was reported by 43% of the high-dose group, 10% of the low-dose group, and 9% of the placebo group.

Gabapentin


Gabapentin has been reported to be effective in the treatment of SAD in a randomized, double-blind study of 69 patients.14 Patients were dosed flexibly with gabapentin (900–3,300 mg/day) or placebo for 14 weeks and were evaluated with both clinician- and patient-rated scales. A significant reduction in the symptoms of SAD was seen in those treated with gabapentin compared to those treated with placebo, with a reduction of total score on the LSAS being -27.3 for the gabapentin-treated group and -11.9 for the placebo group. The low responder rates (gabapentin, 32%; placebo, 19%) compared with those seen in positive studies of other drugs remain unexplained.14 Only dry mouth and dizziness occurred significantly more frequently in the gabapentin group than in the placebo group. The authors concluded that gabapentin has a favorable risk-benefit profile for the treatment of SAD.

Valproate


Seventeen patients were enrolled in an open-label study of valproate in the treatment of SAD.18 After 12 weeks of treatment at doses between 500 and 2,500 mg/day, both LSAS and CGI-I scores were significantly improved compared to baseline. The response rate was 41% of the intent-to-treat population and 47% of study completers.

Obsessive-Compulsive Disorder

OCD is characterized by unwanted and persistent thoughts or impulses in the mind of the patient (obsessions). The thoughts are unpleasant and cause a high degree of anxiety. The disorder often involves rituals such as repetitive hand washing or checking things (compulsions). Most adults recognize at some point that their obsessions and compulsions are excessive and unreasonable, but are unable to control them. Historically, OCD was thought to be quite rare, but recent studies have estimated the lifetime prevalence to be approximately 2.5%.42 The severity of the disorder may fluctuate, but OCD is a chronic and potentially debilitating illness. Comorbid conditions (eg, depression, other anxiety disorders, eating disorders) are often seen with OCD and can make the diagnosis difficult.

The neurobiology of OCD is complex. The serotonergic neurotransmitter system was first implicated when it was shown that clomipramine, a serotonergic tricyclic compound, reduced the symptoms of OCD.43 Other tricyclic antidepressants with less potent effects on serotonin reuptake, such as amitriptyline, were without effect.43 Support for the role of serotonin in OCD is shown by the fact that the SSRIs all have documented efficacy in the treatment of OCD. However, only 50% to 60% of OCD patients respond to SSRIs, suggesting that other neurotransmitters are involved. Dopamine has been implicated because of the observation that stereotyped movements in animals similar to compulsive behavior in humans are seen after high doses of dopaminergic drugs.44 Similarly, neurological disorders that have a dopamine dysfunction in the basal ganglia, like Tourette’s syndrome, are commonly comorbid with OCD.44 The combined role for dopamine and serotonin in OCD is not surprising based on the extensive interaction of the two neurotransmitters.45 This complexity continues on the neuroanatomical level where the orbitofrontal-limbic-basal ganglia areas are implicated in OCD. PET studies show an increased metabolic rate in the orbitofrontal gyri and caudate nucleus,46 and magnetic resonance imaging studies have shown reduced volumes of orbitofrontal gyri, amygdala, and basal ganglia in adults,47 and an increased thalamic size in children with OCD.47-49 Following successful treatment with SSRIs or behavioral therapy, structural changes in the caudate, orbitofrontal gyri, and cingulate cortex have been described.50-52
 

Clomipramine, a TCA that is a potent serotonin reuptake inhibitor, is effective in about 40% to 60% of OCD patients.53 Although it appears to be as effective as the SSRIs,54 clomipramine is typically reserved for use in those who fail to respond to SSRIs, because of its side-effect profile. Whereas all SSRIs are demonstrably better than placebo,55 only about 50% of OCD patients respond to them, and adjunct therapy is often added. Commonly added drugs include the atypical antipsychotics or clomipramine.56-58 Despite initial success of pharmacotherapy, there is substantial relapse following drug discontinuation.59,60

Antiepileptic Treatment of Obsessive-Compulsive Disorder

Although OCD and epilepsy have similarities (eg, involuntary forced thinking in epilepsy and obsessional thought in OCD,61 similarities of temporal lobe electroencephalogram [EEG] in epileptic and OCD patients62-64), the early use of AEDs in the treatment of OCD yielded meager results. Pacella and colleagues64 described treating four OCD patients with diphenylhydantoin without response.

Carbamazepine


Carbamazepine was given to four OCD patients with temporal EEG abnormalities, and improvement was seen in only one.11 In an open-label trial of carbamazepine (400–1,600 mg/day) involving nine OCD patients, only one of the eight patients who completed the 8-week study showed a substantial reduction in obsessions and compulsions.12 No change in mean behavioral or mood scores was seen. Khanna13 treated seven OCD patients with abnormal EEG with carbamazepine (600–1,000 mg/day) and followed them for 12 weeks.2 No changes in mean mood or behavior scores was found, but two patients reported a >50% reduction in their clinical symptoms. Other case reports of the use of carbamazepine have been reported with similar disparate results. The fact that some individuals have responded positively to carbamazepine has led several investigators to suggest that a small subset of patients may benefit from this treatment.12,13

Gabapentin


The effects of gabapentin in OCD patients who were partial responders to the SSRI fluoxetine were reported by Corà-Locatelli and colleagues.15 In this 6-week trial, five OCD patients who were currently treated with fluoxetine 30–100 mg/day were given gabapentin, which was started at 900 mg/day (in three doses) and titrated to a maximum of 3,600 mg/day. All patients reported improvement in mood, OCD symptoms, anxiety, and sleep, within 2 weeks of starting treatment. The results of this preliminary study were used as the basis of the design of a double-blind study that is in progress.

Lamotrigine


Lamotrigine was tested in an open-label study in eight OCD patients who had responded inadequately to SSRI therapy.16 Sertraline (
200 mg/day) and clomipramine (225 mg/day) had been given for at least 14 weeks and were continued during the study. Lamotrigine was added to therapy at a dose up to 100 mg/day. After a mean treatment period of 47 days, only one patient reported improvement, and no significant changes from baseline were found for the mean Yale Brown Obsessive-Compulsive Scale, CGI-S, or CGI-I scores. However, these results should be interpreted with caution as drugs used in OCD tend to be in the higher dose range, and a more typical dose for lamotrigine would be 150–400 mg/day.

Conclusion

The pharmacotherapy of anxiety disorders has centered around benzodiazepines, buspirone, and antidepressants of the SSRI and SNRI classes. These agents are effective for many patients, but dependence issues limit the use of benzodiazepines, the prolonged onset of action of buspirone prevents “as needed” use, and SSRIs and SNRIs are not effective in all patients. Many AEDs interact with neuropathways thought to be involved in the pathobiology of anxiety disorders, and the results of clinical studies suggest that some of these agents may have utility in the treatment of anxiety disorders.

Pregabalin, an AED chemically related to gabapentin, has been tested in several large, randomized, double-blind studies and has shown efficacy in the treatment of GAD and SAD compared to placebo. Topiramate and valproate have been reported to improve symptoms of SAD in open-label studies, and gabapentin was effective in a double-blind study of SAD patients. Carbamazepine, gabapentin, and lamotrigine have been tested in small studies for the treatment of OCD with disparate results. AEDs, with their neurobiological specificity, clinical efficacy, and tolerability, represent an exciting new option in the treatment of anxiety disorders. Additional large, randomized studies will be needed to further explore the scope of their efficacy. PP

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