Antiepileptic drugs in the treatment of psychiatric disorders

Epilepsy & Behavior 21 (2011) 1–11

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Epilepsy & Behavior

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Review

Antiepileptic drugs in the treatment of psychiatric disorders☆

Kenneth R. Kaufman ⁎UMDNJ—Robert Wood Johnson Medical School, New Brunswick, NJ, USA

☆ Presented in part at the 9th European Congress onJune 27–July 1, 2010, and the Epilepsy and Depressive DUSA, September 12–13, 2010.⁎ UMDNJ—Robert Wood Johnson Medical School, 12

New Brunswick, NJ 08901, USA.E-mail address: [email protected].

1525-5050/$ – see front matter © 2011 Elsevier Inc. Aldoi:10.1016/j.yebeh.2011.03.011

a b s t r a c t
a r t i c l e i n f o
Article history:Received 11 February 2011Revised 5 March 2011Accepted 8 March 2011Available online 16 April 2011

Keywords:Antiepileptic drugsEpilepsyPsychiatric disordersTreatmentAdverse effectsFDA and European Medicines AgencyindicationsPsychotropic propertiesAffective disordersPsychotic disordersAnxiety disordersImpulse control disordersSubstance abuse

The clinical interface between psychiatry and neurology is epilepsy; the pharmacological expression of thisinterface is antiepileptic drugs (AEDs), as they are used to treat both epilepsy and psychiatric disorders,especially bipolar disorders. The prevalence of psychiatric comorbidity and the risk of suicidal behavior/ideation/suicide are markedly increased in patients with epilepsy (PWE). Though AEDs receive initialindications for the treatment of epilepsy, currently the majority of AEDs are used to treat pain and psychiatricdisorders. Thus in selecting the appropriate AEDs for treatment of PWE, consideration should be given towhich AEDs best treat the epileptic disorder and the psychiatric comorbidity. This review is an overview of 21AEDs in which negative psychotropic properties, approved indications in psychiatry, off-label studied uses inpsychiatry, and principal uses in psychiatry are presented with literature review. A total of 40 psychiatric useshave been identified. Of the 21 AEDs reviewed, only 5 have U.S. Food and Drug Administration and/orEuropean Medicines Agency psychiatric approval for limited uses; the majority of AEDs are used off-label.Many of these off-label uses are based on case reports, open-label studies, and poorly controlled or small-sample-size studies. In some instances, off-label use persists in the face of negative pivotal trials. Furtherplacebo-controlled (augmentation and monotherapy) parallel-arm research with active comparators isrequired in the complex field of AED treatment of psychiatric disorders to minimize the treatment gap notonly for PWE with psychiatric disorders, but also for psychiatric patients who would benefit from properlystudied AEDs while minimizing adverse effects.

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1. Introduction

The clinical interface between psychiatry and neurology isepilepsy; the pharmacological expression of this interface is anti-epileptic drugs (AEDs), as they are used to treat both epilepsy andpsychiatric disorders, especially bipolar disorders [1–4]. Further, AEDsare commonly used in the treatment of pain disorders [3,5]. As such,AEDs are prescribed primarily for the treatment of psychiatric and paindisorders, not for the treatment of epilepsy [6]. The choice of whichAED the neurologist will use in the treatment of epilepsy is mostoften based on the classic benefits (seizure control efficacy), risks(adverse side effects), and alternatives (availability, formulary, costs)equation; however, consideration should be given to psychiatriccomorbidities and which AED might best serve the patient in bothmaximizing seizure control andminimizing psychiatric symptoms [7].

Regrettably, both psychiatrists and neurologists are notwell versedin the AED literature that comes from each other's specialty. There are

specific issues attendant to each specialty. Neurologistsmaynot screenfor psychiatric symptoms/disorders including suicidal ideation and/ormay not be cognizant of which AEDs are most effective for differentpsychiatric diagnoses [8,9]. Psychiatrists may not appreciate thedegree of AED negative psychotropic properties, drug–drug interac-tions, and serious adverse effects reported primarily in the neurologyliterature [4,10,11]. Further, psychiatrists often prescribe AEDs off-label, before pivotal trials—in some instances, novelfindings have beenreported leading to better understanding of the AED [12]; however, insome instances, overutilization has occurred for AEDs that later failedin pivotal trials for psychiatric diagnoses [13,14]. The latter issue isimportant to all clinicians as there have been significant FDA-imposedfines on pharmaceutical companies misrepresenting the psychiatricefficacy of AEDs [14,15]; further, in the case of gabapentin, suchinappropriate pharmaceutical marketing resulted in state Medicaidprograms instituting restrictive prior authorization policies [16].

The magnitude of off-label prescriptions of AEDs is oftenunderappreciated. Two recent epidemiological studies suggest thatAEDs are used off-label in ~70% of patients prescribed AEDs. In aGeorgia Medicaid study, 71.3% of 48,648 patients were prescribedAEDs off-label [17]. AEDs prescribed for psychiatric diagnoses inchildren and adolescents are off-label; yet a recent mid-Atlantic stateMedicaid program analyzing AEDs prescribed in the child andadolescent population revealed that of 4522 patients with availablediagnoses, 3061 (67.8%) had psychiatric diagnoses only, 611 (13.5%)

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Table 1Clinical psychiatric uses studied for antiepileptic drugs.

Major depression Alcohol withdrawal and relapse preventionBipolar disorder, depression Benzodiazepine withdrawalBipolar disorder, mania Cocaine dependenceBipolar, mixed Opiate withdrawalBipolar disorder, rapid cycling Methamphetamine dependenceBipolar disorder, maintenance Sedative–hypnotic withdrawalSchizophrenia Behavioral and psychological symptoms

of dementiaSchizoaffective disorder Borderline personality disorderAtypical psychosis Binge eatingAutism ObesityCatatonia Psychotropic-associated weight gainPanic disorder AggressionGeneralized anxiety disorder Anger–hostilitySocial anxiety AgitationParuresis InsomniaObsessive–compulsive disorder Tardive dyskinesiaPosttraumatic stress disorder Tourette syndromeImpulse control disorders Premenstrual dysphoric disorderTrichotillomania Somatoform disordersIntermittent explosive disorderPathological gambling

2 K.R. Kaufman / Epilepsy & Behavior 21 (2011) 1–11

had both a psychiatric disorder and epilepsy, and only 251 (5.6%) hadepilepsy only [18].

Lifetime prevalence of psychiatric disorders in people withepilepsy (PWE) has been estimated to range as high as 80%, thoughcommonly total lifetime prevalence is estimated at 50–60%, withthe majority of psychiatric diagnoses representing mood or anxietydisorders [7,18–23].

In light of the recent Dunedin prospective birth cohort study thatreported lifetime prevalence of psychiatric disorders in a generalpopulation twice that found with retrospective studies, the lifetimeprevalence of psychiatric disorders in PWE may be significantlyunderestimated [24]. Further, there is a 3- to 5-fold increased riskof suicide in patients with epilepsy compared with the generalpopulation [21,25]. The degree of increased risk is dependent onwhether the PWE has a psychiatric diagnosis: those PWE without apsychiatric diagnosis have a 2-fold increased risk, whereas those PWEwith a psychiatric diagnosis have a greater than 13-fold increased riskof suicide, with the greatest risk being in those PWE having affectivedisorders [25]. In addition, suicidal prevalence must also be taken inthe context of treatment with AEDs. Although there is conflictingliterature, the majority of recent articles support a potential increasedrelative risk for suicidal ideation and behaviors when AEDs are usedto treat epilepsy, psychiatric disorders, and/or other conditions(presumptively pain syndromes); further, the literature suggeststhat this increased risk may be AED selective [26–35].

The variances in literature-reported prevalence of psychiatricdisorders in PWE represent methodological flaws (especially lack ofestablished diagnostic criteria, controls, and standardized psycho-metric instruments) and sample populations: comparative preva-lence rates between underdeveloped (poor-resource) countries anddeveloped (industrialized) countries may be strongly impacted bythe increased treatment gap in underdeveloped countries withconcomitant increased seizure frequency and chronic active epilep-sy; specific cultures in which epilepsy and/or psychiatric disordersare stigmatized may have disproportionate prevalence rates;population-based studies compared with community-based sam-ples, representing general and specialist practices, have a lowerprevalence; tertiary centers or specific populations (refractoryepilepsy, mesial temporal sclerosis, or postsurgical PWE) have ahigher prevalence [7,23,36–43]. Clearly, additional well-designedstudies are required to further elucidate accurate prevalence;nonetheless, the concept of comorbid psychiatric disorders in PWEis now a well-accepted clinical issue that requires both appropriatepharmacological interventions and screening [19].

Two key approaches are required to address the treatment ofpsychiatric disorders in PWE: (1) use of psychotropic agents; (2) use ofappropriate AEDs that can effectively treat both the specific epilepsytype and the psychiatric comorbidity. This article is an overview of theuse of AEDs in the treatment of psychiatric disorders. Each AED withspecific psychotropic properties is individually summarized withreference to labeled (approved by U.S. Food and Drug Administration[FDA] and/or European Medicines Agency [EMEA]) and off-label uses.Summary tables are included (Tables 1–3). The treating neurologistand psychiatric consultant can use this article as a guide to bettertreatment of psychiatric comorbidities in PWE.

2. Barbiturates (phenobarbital and primidone)

Negative psychotropic properties. Depression, hyperactivity, de-creased cognition [10,44]; dependence, withdrawal [45].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Sedative–hypnotic [46].

Sedative–hypnotic withdrawal [47]. Alcohol withdrawal [48,49].Refractory depression: mixed results in small case series [50].Refractory bipolar disorder: small case series without control andonly 31% response rate [51]. Tardive dyskinesia: active-comparator

trial in which both phenobarbital and clonazepam significantlyreduced dyskinetic movement [52].

Principal uses in psychiatry. Sedative–hypnotic withdrawal, barbitu-ratewithdrawal, alternative to benzodiazepines for alcohol withdrawal.

3. Phenytoin

Negative psychotropic properties. Decreased cognition [44]; en-cephalopathy [10]; psychosis, adverse behavioral effects [4].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar disorder, mania:

positive response in small placebo-controlled study of phenytoinas adjunct to haloperidol in acute mania [53]. Bipolar disorder,maintenance: positive prophylactic response with phenytoin whenused as adjunct in placebo-controlled maintenance therapy [54].Posttraumatic stress disorder: small open-label study with positiveresponse [55]. Intermittent explosive disorder/impulsive aggression:in a placebo-controlled study comparing premeditated with impul-sive aggression, phenytoin reduced impulsive but not premeditatedaggression [56]; in a positive placebo-controlled parallel-arm study,phenytoin, valproate, and carbamazepine all significantly reducedimpulsive aggression compared with placebo [57].

Principal uses in psychiatry. None.

4. Ethosuximide

Negative psychotropic properties. Anxiety, depression, confusion,psychosis, behavioral disturbances (associated with “forced normal-ization”) [58].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Adjunctive treatment of bipolar

disorder: open-label adjunctive study in acute manic patients withon/off/on design showed no significant effect on course of maniawhen ethosuximide was added to haloperidol [59].


5. Benzodiazepines

Negative psychotropic properties. Decreased cognition [44], anter-ograde amnesia [60], paradoxical aggression/disinhibition [4,61,62],dependence and withdrawal [63].

Table 2Antiepileptic drugs studied by psychiatric diagnostic group.

Affectivedisorders

Psychoticdisorders

Anxietydisorders

Impulse controldisorders

Eating/weightdisorders

Dementia Substancedisorders

Other

Acetazolamide √ √ √ √Barbiturates (phenobarbital and primidone) √ √ √Benzodiazepines √ √ √ √ √Carbamazepine √ √ √ √ √ √ √EslicarbazepineEthosuximide √Felbamate √Gabapentin √ √ √ √ √ √ √Lacosamide √Lamotrigine √ √ √ √ √ √ √Levetiracetam √ √ √ √ √ √Oxcarbazepine √ √ √ √ √ √Phenytoin √ √ √Pregabalin √ √ √ √ √Retigabine √Rufinamide √Tiagabine √ √ √ √ √Topiramate √ √ √ √ √ √ √ √Valproate (divalproex and other formulations) √ √ √ √ √ √ √Vigabatrin √ √ √Zonisamide √ √ √ √

3K.R. Kaufman / Epilepsy & Behavior 21 (2011) 1–11

Approved indications in psychiatry. Anxiety disorders: generalizedanxiety disorder and panic disorder [60]. Alcohol withdrawal [64].Insomnia [65].

Off-label studied uses in psychiatry. Monotherapy and adjunctivetreatment of acute mania: meta-analysis of heterogeneous trialdesigns with results suggesting that clonazepam but not lorazepamis effective [66]. Catatonia: drug of choice [67]. Adjunctive treatment ofschizophrenia: beneficial in decreasing psychotic agitation withirritability, anxiety, and hostility [61]. Tardive dyskinesia: active-comparator trial in which both phenobarbital and clonazepamsignificantly reduced dyskinetic movements [52]. Sedative–hypnoticwithdrawal: positive case reports [68,69].

Principal uses in psychiatry. Anxiety disorders, alcohol withdrawal,benzodiazepine withdrawal, adjunctive use in bipolar disorders,catatonia, agitation.

6. Acetazolamide

Negative psychotropic properties. Rare cognitive effects (case reportof acetazolamide-induced delirium [70]).

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar disorder: small open-

label adjunctive study with positive response for 7 of 16 (44%)patients showing improvement in depressed or rapid-cycling phase[71]; positive case report for adjunctive treatment of acutemania [72].Atypical psychosis: small case series divided into four subtypes inwhich acetazolamide was most effective in those cases with affectivecomponents [73]. Obesity and psychotropic-associated weight gain:positive case-controlled weight loss for reversal of antipsychotic-induced weight gain [74]. Tardive dyskinesia: positive placebo-controlled, double-blind, crossover study with significantly decreasedAbnormal Involuntary Movement Scale (AIMS) and Simpson–AngusNeurological Rating Scale (parkinsonism) scores [75].


Table 3Approved psychiatric indications for antiepileptic drugs.

Benzodiazepines Anxiety disorders, alcohol withdrawal, insomniaCarbamazepine Bipolar disorder, maniaValproate Bipolar disorder, mania and bipolar disorder, mixedLamotrigine Bipolar disorder, maintenancePregabalin Generalized anxiety disorder

7. Carbamazepine

Negative psychotropic properties. Cognitive adverse effects [76].Approved indications in psychiatry. Bipolar disorder, manic phase

[77].Off-label studied uses in psychiatry. Bipolar disorder, depressed phase,

and bipolar prophylaxis: positive placebo-controlled and active-comparator trials [77]. Posttraumatic stress disorder: positive casereports and small open-label case series [55]. Panic disorder: negativecontrolled study [78]. Alcohol withdrawal: multiple double-blindactive-comparator trials noted significant reduction in alcohol with-drawal symptoms [79]. Benzodiazepine withdrawal: multiple positivecase series [80]; positive small open-label placebo-controlled trial [81];double-blind, placebo-controlled trial noted trend toward positivedecrease in patient-reported withdrawal symptoms [82]. Pathologicalgambling: positive small open-label study [83]. Impulsive aggression:case report of successful response to low-dose carbamazepine inbenzodiazepine-resistant impulsive aggression [84]; in a positiveplacebo-controlled parallel-arm study, phenytoin, valproate, andcarbamazepine all significantly reduced impulsive aggression comparedwith placebo [57]. Catatonia: small case series with positive response inlorazepam transient responders [85]. Borderline personality: decreasedbehavioral dyscontrol in two small placebo-controlled trials [86].Schizophrenia: mixed literature with trend toward benefit fromantipsychotic augmentation for violent/affective features, but lack ofefficacy in placebo-controlled trial for relapse prevention [61,87]);behavioral and psychological symptoms of dementia (positive placebo-controlled trials [88,89].

Principal uses in psychiatry. Bipolar disorder, aggression.

8. Valproate (divalproex and other formulations)

Negative psychotropic properties. Decreased cognition [44,76],encephalopathy [10], decreased IQ secondary to fetal exposure [90].

Approved indications in psychiatry. Bipolar disorder,manic ormixedepisodes [4].

Off-label studied uses in psychiatry. Adjunctive treatment of acutemania: positive placebo-controlled valproate augmentation of anti-psychotics with significant reductions in Young Mania Rating Scaleand antipsychotic dose [91]. Bipolar depression: positive placebo-controlled monotherapy trial with significant reduction in depressivesymptoms [92]. Bipolar maintenance: post hoc analysis of 12-month


maintenance study found significant increase in time to first moodepisode for divalproex open-phase patients randomized to divalproexcompared with patients randomized to placebo and patients random-ized to lithium [93]. Autism spectrum disorders: positive smallplacebo-controlled study with reduced repetitive behaviors [94].Obsessive–compulsive disorder: positive case reports [55]. Panicdisorder: positive small open-label studies [55]. Posttraumatic stressdisorder: both positive and negative open-label studies [55,95]. Socialanxiety: positive small open-label study [55]. Impulsive aggression:in a positive placebo-controlled parallel-arm study, phenytoin, valpro-ate, and carbamazepine all significantly reduced impulsive aggressioncompared with placebo [57]. Pathological gambling: positive smallactive-comparator trial [96]. Borderline personality: positive open-label and placebo-controlled trials with decreased symptoms andincreased social function [86]. Alcohol withdrawal: small open-labelactive-comparator trial [97]; positive placebo-controlled trial withdecreased withdrawal symptoms and use of rescue benzodiazepines[97]; positive small active-comparator trial with more rapid reductionin withdrawal symptoms with valproate than with benzodiazepine[97]. Alcohol relapse prevention [97]. Cocaine dependence: open-labelstudies with decreased cravings/use with increased abstinence relatedto therapeutic blood level N50 μg/mL [97]. Benzodiazepinewithdrawal:positive adjunctive case report [98]; negative placebo-controlled active-comparator trial in which valproate did not decrease withdrawalsymptoms in patients tapered from benzodiazepines [99]. Schizophre-nia: nonsuperiority in multiple placebo-controlled augmentation trialscomparing valproate with placebo added to antipsychotics and non-placebo-controlled randomized augmentation comparator trials [100–102]; positive small open-label study of severely ill schizophrenicpatients inwhich atypical antipsychoticswere augmentedwith valproicacid [103]. Behavioral and psychological symptoms of dementia:positive case reports and open-label studies; however, multiplenegative placebo-controlled trials [88,89]. Tardive dyskinesia: negativeplacebo-controlled trial [104].

Principal uses in psychiatry. Bipolar disorder, aggression.

9. Oxcarbazepine

Negative psychotropic properties. Decreased cognition [44,76].Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar disorder: mixed

literature—efficacy equivalent to that of haloperidol and lithium intwo small randomized active-comparator studies for acute mania[105]; positive response in retrospective, open-label adjunctiveand small on/off/on monotherapy studies [106]; negative placebo-controlled monotherapy trial in children/adolescents [107]; negativeplacebo-controlled maintenance study in lithium-remitted bipolarpatients without significant difference in time to relapse betweenoxcarbazepine and placebo augmentation [108]; randomized, paral-lel-arm, active-comparator adjunctive trial for residual symptoms inlithium-maintenance bipolar patients found oxcarbazepine hadgreater efficacy than carbamazepine in symptom reduction asmeasured by multiple psychometric scales [109]. Impulsive aggres-sion: positive placebo-controlled trial with greater improvement inGlobal Overt Aggression with oxcarbazepine than with placebo [110].Borderline personality: significant improvement in global psychopa-thology and core borderline personality disorder features in a smallopen-label trial [86]. Obsessive–compulsive disorder, panic disorder,posttraumatic stress disorder: positive case reports [55]. Alcoholwithdrawal: positive small active-comparator study with significantlyreduced alcohol withdrawal and craving features [111]; negativeplacebo-controlled trial without difference in rescue medication re-quirements, cravings, or withdrawal features [112]. Alcohol depen-dence: active-comparator trial with increased abstinence on high-dosage oxcarbazepine compared with naltrexone or low-dosageoxcarbazepine [113]. Benzodiazepine withdrawal: open case series

with successful rapid detoxification from benzodiazepines [114].Cocaine abuse/dependence: 12-week observational study with in-creased abstinence and significant reduction in cravings/impulsivity[115]. Schizophrenia: positive open-label antipsychotic augmentationcase series [116]. Autism: positive small case series [117].

Principal uses in psychiatry. Bipolar disorder.

10. Lamotrigine

Negative psychotropic properties. Aggression (intellectually im-paired PWE) [118,119], psychosis [120], delirium [121], decreasedcognition [76,122], agitation [10], hyperactivity [119].

Approved indications in psychiatry. Bipolar disorder, maintenance[4,123].

Off-label studied uses in psychiatry. Bipolar disorder, depression:five negative placebo-controlled trials [123], meta-analysis of whichrevealed a statistically significant positive response, specifically in themore severely ill patients [124]; positive placebo-controlled augmen-tation trial of lithium-treated bipolar depressed patients [125].Bipolar, rapid cycling: multiple negative placebo-controlled studies[126]. Bipolar, mania: negative and failed placebo-controlled trials[126]. Autism:negativeplacebo-controlled trial [127].Majordepression:positive retrospective chart reviews for augmentation in treatment-resistant depression [128]; negative small placebo-controlled augmen-tation trial in treatment-resistant depression [129]. Schizophrenia:mixed literature—positive meta-analysis of placebo-controlled cloza-pine-resistant augmentation trials [130]; negative placebo-controlledtrials in augmenting atypical antipsychotics [131]. Schizoaffectivedisorder: positive open-label augmentation study with comorbidobsessive–compulsive symptoms [132]. Obsessive–compulsive disor-der: positive augmentation case report [133]; posttraumatic stressdisorder: positive placebo-controlled trial [55]. Alcohol withdrawal:positive placebo-controlled, active-comparator trial with significantlyreduced withdrawal symptoms and need for supplemental benzodiaz-epines [134]. Opiate withdrawal: negative attenuation of naloxone-induced opiate withdrawal [135]. Cocaine dependence: positive open-label replication study in bipolar patients noted decreased cocainecraving and use [136]. Borderline personality: positive placebo-controlled trial with significantly decreased anger [86]; positive smallplacebo-controlled trial with significantly reduced affective lability andimpulsivity scores [137]. Anger–hostility: positive adjunctive active-comparator trialwith statistically significant reduction inanger–hostilitycompared with levetiracetam in patients with partial epilepsy [138].Intermittent explosive disorder: positive augmentation case reports inPWE [122]. Behavioral and psychological symptoms of dementia:positive case report [139]; positive small open-label trial [140].

Principal uses in psychiatry. Bipolar disorder.

11. Felbamate

Negative psychotropic properties. Depression, anxiety, irritability[10,141].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Depression: on/off/on controlled

case report with decreased depressive symptoms on felbamate [142].Principal uses in psychiatry. None.

12. Vigabatrin

Negative psychotropic properties. Depression, psychosis, aggression[10].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Panic disorder: open-label study

with reduction of experimentally induced panic and anxiety symptoms[143]; positive small case series with reduction of panic attacks andanxiety over a 6-month trial [143]. Posttraumatic stress disorder:


decreased startle response in small case series [144]. Cocaine addiction/craving: small open-label study with 8 of 20 patients N4 weeks cocaineabstinent without further cocaine cravings [145]. Cocaine dependence:positive placebo-controlled parallel arm trial with 14 of 50 patientstreated with vigabatrin (28%) versus 4 of 53 patients treated withplacebo (7.5%) attaining abstinence for the last 3 weeks of a 9-weekstudy; 12 of 14 patients receiving vigabatrin versus 2 of 4 patientsreceiving placebo maintained abstinence during 4-week follow-up[146]. Methamphetamine addiction: positive small open-label 9-weekstudy [147]. Tardive dyskinesia: positive small placebo-controlled trial[148].


13. Gabapentin

Negative psychotropic properties. Behavioral disturbances, espe-cially aggressive behaviors in children [4], dependence and with-drawal [149,150], delusions [151].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Social anxiety: placebo-

controlled 14-week trial with significant reduction in social anxietysymptoms [152]. Paruresis: on/off/on controlled case report witheffective control of paruresis and increased functional status [153].Panic disorder: placebo-controlled study with significant differencesnoted only with more severely ill patients, suggesting gabapentinmay have a role in treating panic disorder in that subpopulation [55].Obsessive–compulsive disorder: an open-label trial comparing fluox-etine with fluoxetine/gabapentin combination noted earlier onset insymptom reduction with combination treatment; however, endpointYale–Brown Obsessive Compulsive Scale scores were not significantlydifferent [154]. Bipolar disorder: randomized placebo-controlledadjunctive trial showed placebo more effective than gabapentin indecreasing Young Mania Rating Scale scores [155]; in comparison tothe Pande randomized control trial, multiple case reports, small caseseries, and small uncontrolled trials suggested that adjunctivegabapentin may have antimanic features [14]. Alcohol dependence:two positive placebo-controlled trials with decreased relapse oralcohol consumption/craving [156,157]. Alcohol withdrawal: anopen-label trial noted differential response based on severity ofalcohol withdrawal syndrome monitored by CIWA-AR score as orallyloaded gabapentin was beneficial in treating less severe and lesscomplicated alcohol withdrawal syndromes only [158]. Behavioraland psychological symptoms of dementia: positive case report [159];positive small open-label study in patients with serious medicalcomorbidities [160]; positive small open-label study [161]. Tardivedyskinesia: positive open-label 1-year follow-up with adjunctivegabapentin noted continued reduction in tardive dyskinesia asmeasured by the total AIMS score [162]. Aggression: positive casereport [163]. Posttraumatic stress disorder: positive case report [164];positive retrospective chart review of adjunctive therapy withgabapentin [165]. Cocaine dependence: negative placebo-controlledtrial with active comparator with no statistical difference inabstinence between placebo and gabapentin [166]; negative smallplacebo-controlled crossover study in which high-dose gabapentindid not reduce cocaine self-administration in cocaine-dependentpatients [167]. Opiate withdrawal: positive small case series withadjunctive gabapentin [168]; negative placebo-controlled trial withadjunctive gabapentin [169]. Methamphetamine dependence: nega-tive placebo-controlled active-comparator trial [170]. Schizophrenia:positive adjunctive small open-label study [171].

Principal uses in psychiatry. Social anxiety disorder.

14. Topiramate

Negative psychotropic properties. Depression, psychosis, decreasedcognition, confusion, suicidality, “psychomotor slowing” [4,76].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar disorder: although

numerous case reports, case series, and small controlled studies haveshown mood-stabilizing properties [172], four pivotal placebo-controlled randomized trials were all negative for mood-stabilizingefficacy [173]. Schizoaffective disorder: negative placebo-controlledadjunctive trial [174]. Binge eating: positive placebo-controlled trialwith greater decrease in BMI and binge episodes with increased bingeeating remission comparing topiramate with placebo [175]. Obesityand psychotropic-associated weight gain: small open-label, random-ized, active-comparator adjunctive trial in patients with bipolardisorder with psychotropic-associated obesity revealed significantweight loss with topiramate, though only 6 of 28 (21%) patientscompleted the trial [176]; retrospective chart review revealed 24 of 41(58.5%) patients with psychotropic-associated weight gain treatedwith topiramate had weight loss [177]. Alcohol dependence: positiveplacebo-controlled trial with decreased heavy drinking in alcohol-dependent patients [178]; positive open-label randomized active-comparator trial with topiramate causing greater reduction in alcoholcraving and intake compared with naltrexone [179]. Cocainedependence: placebo-controlled trial with increased cocaine absti-nence with topiramate compared with placebo treatment [180].Benzodiazepine withdrawal: two positive case reports [181,182].Posttraumatic stress disorder: positive small open-label adjunctiveand monotherapy trial of topiramate with significant decrease insymptoms [183]; randomized trials did not reach statisticallysignificant improvement compared with placebo [184,185]. Patho-logical gambling: positive small randomized active-comparator studywith remission of gambling behaviors on topiramate [186]. Anger andaggression: decreased in male patients with borderline personalitydisorder [4]. Borderline personality: positive placebo-controlled trialwith significant improvement on multiple scales for female patientswith borderline personality treatedwith topiramate [187]. Obsessive–compulsive disorder: positive retrospective analysis of small open-label case series with topiramate augmentation [55]; positive smallplacebo-controlled augmentation study revealing statistically signif-icant reduction in compulsions but not obsessions as measured withthe Yale–Brown Obsessive Compulsive Scale though 67% (12/18) ofthe patients on topiramate either discontinued the study or requireddose reduction secondary to adverse effects [188]. Social anxiety:positive small open-label case series [55]. Behavioral and psycholog-ical symptoms of dementia: double-blind active-comparator study inwhich both low-dose topiramate and risperidone resulted incomparable, statistically significant, improvements in controllingbehavioral symptoms from baseline [189]; positive retrospectivestudy [190]. Tourette syndrome: retrospective chart review withmoderate improvement in tics [191]; placebo-controlled double-blindstudy with statistically significant reduction in the Yale Global TicSeverity score with topiramate treatment compared with placebo[192]. Trichotillomania: positive small open-label study with signif-icant reduction as measured with the Massachusetts General HospitalHair-Pulling Scale [193].

Principal uses in psychiatry. Weight loss, binge eating.

15. Levetiracetam

Negative psychotropic properties. Irritability, emotional lability[10]; behavioral abnormalities [194,195]; decreased cognition [76].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar disorder, mania:

positive open-label on/off/on trial with haloperidol [196]. Bipolar,depression: negative placebo-controlled adjunctive trial for Bipolar Ior II outpatients in depressed phase [197]. Bipolar disorder, rapidcycling: positivemonotherapy case report with 1-year follow-up [12];positive adjunctive case reports [128]. Bipolar disorder, treatment-resistant: open-label augmentation study with mixed response [198].


Autism: positive small open-label study [199]; negative smallplacebo-controlled trial [200]. Panic disorder: positive small open-label study [201]. Posttraumatic stress disorder: positive retrospectivechart analysis for augmentation of antidepressant partial responders[55]. Social anxiety: positive open-label trial and negative placebo-controlled trial [55]. Anger–hostility: negative adjunctive active-comparator trial in anger compared with lamotrigine in patients withpartial epilepsy [138]. Impulsive aggression: negative placebo-controlled trial [202]. Alcohol dependence: open-label study withsignificantly decreased alcohol consumption [203]. Alcohol with-drawal: negative placebo-controlled trial without difference in rescuemedication requirements or withdrawal symptoms [204]. Behavioraland psychological symptoms of dementia: positive open-labelaugmentation trial [205]. Tardive dyskinesia: positive small open-label study [206]; positive case report with reduction in AIMS totalscore from 27 to 8 [207]; positive placebo-controlled trial withsignificant reduction in AIMS total score on levetiracetam comparedwith placebo [208]. Tourette syndrome: positive case report [209];positive open-label study [210]; negative placebo-controlled cross-over study [211]; negative small, double-blind, active-comparatorstudy [212]. Premenstrual dysphoric disorder: positive small open-label study [213].


16. Zonisamide

Negative psychotropic properties. Cognitive deficits [76]; behavioraldisturbances, psychosis, depression, agitation [4,10].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Adjunctive treatment of bipolar

disorder: open-label adjunctive study of bipolar patients in manic/depressed/euthymic state with significant decrease in manic anddepressive symptoms during both acute and continuation treatment—however, 32% (20/62) of patients discontinued trial secondary toworsening mood symptoms [214]; small open-label adjunctive studyof bipolar depressed patients with significant reduction in theMontgomery Asberg Depression Rating Scale (MADRS) score—however, 50% (10/20) of patients discontinued trial secondary toadverse effects [215]. Anxiety: positive small open-label adjunctivetrial for treatment-refractory anxiety [216]. Binge eating with obesity:randomized placebo-controlled trial with significant zonisamideefficacy in decreasing binge eating episodes, body weight, and BMI—however, 27% (8/30) of patients discontinued secondary to adverseevents [217]. Weight loss in bipolar patients: adjunctive zonisamidein euthymic bipolar patients significantly reduced BMI, but 44% (11/25) of patients discontinued trial secondary to treatment-emergentmood symptoms [218]. Alcohol dependence: open-label study withsignificant reduction in daily drinks compared with baseline [219];small open-label trial with reduced alcohol consumption, alcoholcraving, and γ-glutamyltransferase levels [220]; placebo-controlledtrial with reduction in drinks consumed weekly and heavy drinkingdays on zonisamide, though there was no significant change inabstinence when compared with placebo [221].

Principal uses in psychiatry. Weight loss, binge eating.

17. Tiagabine

Negative psychotropic properties. New-onset seizures in patientswithout epilepsy [222], depression [223], irritability (dose dependentin case report [1]).

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar, mania:mixed literature—

positive augmentation case reports in refractory bipolar and schizoaf-fective disorder [224]; positive open-label augmentation trial forrefractory bipolar disorder [225]; limited efficacy in open-labelaugmentation trial for refractory bipolar disorder with excessive

adverse effects [226]; negative small case series for acute mania inmonotherapy or augmentation treatment [227]. Obsessive–compulsivedisorder: positive augmentation case report [228]. Posttraumaticstress disorder: negative placebo-controlled trial [229]. Generalizedanxiety disorder: positive open-label, active-comparator trial [230];negative placebo-controlled trials for primary outcome measure [231].Panic disorder: negative small placebo-controlled trial [232]. Socialanxiety: positive open-label study [233]. Impulse control disorder inPWE: positive case reports with behavioral control in one caseassociated with seizure control but in another case independent ofseizure control as determined by video/EEG monitoring [1]. Rage andaggression: positive retrospective chart review of tiagabine augmenta-tion [234]. Alcohol dependence: deceased cravings and relapse rate inadjunctive open-label trial with psychotherapy [235]; retrospectivechart review with efficacy equivalent to that of benzodiazepine forwithdrawal [236]. Cocaine dependence: negative placebo-controlledtrial in augmenting cognitive-behavioral therapy [237]; positiveplacebo-controlled trial with active comparator with statisticallysignificant greater abstinence with tiagabine than with either gaba-pentin or placebo [166]. Benzodiazepine dependence: positive casereport [238].

Principal uses in psychiatry. Anxiety disorders.

18. Pregabalin

Negative psychotropic properties. Limited negative cognitive ef-fects: sedation, decreased arousal, and decreased attention [239];statistically significant negative effects on Stroop, Controlled OralWord Association, and Digit Symbol cognitive tests as well as thePortland Neurotoxicity Scale in double-blind, placebo-controlled trialtesting cognitive effects of pregabalin in healthy volunteers [240];dependence and withdrawal [241].

Approved indications in psychiatry. Generalized anxiety disorder:replicated positive randomized placebo-controlled and active-comparator studies [55,242].

Off-label studied uses in psychiatry. Bipolar disorder, mania:positive case report with pregabalin used adjunctively with quetia-pine [243]. Major depression: positive augmentation case report[244]. Social anxiety: placebo-controlled trial with significant efficacynoted at pregabalin 600 mg daily but not 150 mg daily compared withplacebo [245]. Posttraumatic stress disorder: small open-labelaugmentation study with significant positive responses on multiplepsychometric scales suggesting need for adequately powered con-trolled trials [246]. Alcohol withdrawal: open-label study withsignificant reduction in withdrawal features and alcohol craving[247]; positive randomized, single-blind and double-blind active-comparator trials with significant reduction in alcohol withdrawalsymptoms and alcohol craving with efficacy similar to that oflorazepam [248,249]. Benzodiazepine dependence: positive smallopen-label study for discontinuation of long-term benzodiazepine use[250]. Schizophrenia: positive small augmentation open-label caseseries with reduction in positive and negative symptoms ofschizophrenia, antipsychotic total daily dose, and comorbid anxietyfeatures [251]. Somatoform disorder: positive small open-labelaugmentation study with reduction in somatoform features inantidepressant treatment-resistant patients [252].

Principal uses in psychiatry. Generalized anxiety disorder.

19. Lacosamide

Negative psychotropic properties. Cognitive effects: slower reactiontime, decreased attention, fatigue, and somnolence, which may bedose dependent and worse during the titration phase [253–255];psychosis [254].

Approved indications in psychiatry. None.


Off-label studied uses in psychiatry. No human studies reported;positive anxiolytic effect in rodent model [256].

Principal uses in psychiatry: None.

20. Rufinamide

Negative psychotropic properties. Somnolence, fatigue, agression[257,258]; behavioral disturbances, depression [259].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar disorder with comorbid

psychopathology: mixed literature—two positive case reports inwhich refractory bipolar patients were treated with adjunctiverufinamide: in case 1 adjunctive rufinamide resulted in decreaseddepressive, anxiety, and obsessive features with mood stabilization;in case 2 adjunctive rufinamide resulted in decreased depressive,anxiety, binge eating, and alcohol craving features with moodstabilization [260]; two negative case reports in which refractorybipolar patients treated with adjunctive rufinamide led to treatment-emergent suicidal ideation: in case 1 active intrusive suicidal ideation,increased irritability, and increased depression returned to baselinewith discontinuation of rufinamide; in case 2 active suicidal ideation,command auditory hallucinations to harm self, and increasedagitation reverted to baseline noncommand auditory hallucinationsand nonactive suicidal ideation with diminished agitation ondiscontinuation of rufinamide [30].


21. Eslicarbazepine

Negative psychotropic properties. Somnolence, fatigue [261]; min-imal cognitive effects [262].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. None.Principal uses in psychiatry. None.

22. Retigabine

Negative psychotropic properties. Confusion, amnesia, abnormalthinking [263]; somnolence, fatigue [264].

Approved indications in psychiatry. None.Off-label studied uses in psychiatry. Bipolar disorder: negative small

open-label trial in which retigabine was not effective in treatment-resistantmanic patients with only 3 of 10 patients showing a responseand 7 of 10 patients not completing the study [265].


23. Conclusion

This article has summarized the varied uses of AEDs in psychiatry. Ofthe 21 AEDs reviewed, clinical studies have addressed 40 possible uses(Tables 1 and 2). Too often these studies are uncontrolled case reports,open-label case series, and underpowered randomized controlled trials(e.g., in lamotrigine treatment of bipolar depression, five placebo-controlled trials were negative, whereas the meta-analysis of thesetrials was positive [123,124]) with methodological flaws. Thesemethodological limitations include polypharmacy (drug–drug interac-tions without therapeutic drug monitoring), inappropriate inclusion/exclusion criteria with heterogeneous populations studied, lack ofstandardized psychometrics, and cross-over rather than parallel-armdesigned randomized trials [266]. Selective outcome reporting inindustry-sponsored trials is another complicating factor [267].

The limited number of pivotal placebo-controlled parallel-armstudies has resulted in the FDA and/or EMEA having approved only 5of these 21 AEDs for psychiatric indications (Table 3). Regardless of thelimited approved indications and, in some instances, negative pivotaltrials, AEDs continue to be used adjunctively or in monotherapy

treatment for a plethora of psychiatric diagnoses. The lack of commu-nication among psychiatrists and neurologists is a critical problemwhenaddressing the treatment of psychiatric symptoms of PWE and the use ofAEDs to treat psychiatric disorders [268]. This is especially pertinent andraises ethical issues regarding off-label uses of AEDs in psychiatry whenthe neurological literature has reported significant adverse effects (suchas vigabatrin with visual field defects [269]).

Further placebo-controlled (augmentation and monotherapy)parallel-arm research with active comparators is required in thecomplex field of AED treatment of psychiatric disorders to minimizethe treatment gap not only for PWE with psychiatric disorders, butalso for psychiatric patients who would benefit from properly studiedAEDs while minimizing adverse effects [266].

Acknowledgments

This review is an expansion/update of the book chapter entitled“Antiepileptic Drugs in the Treatment of Psychiatric Disorders” inAtlas of Epilepsies [270]. All materials previously published are donewith kind permission from Springer Science+Business Media. Theauthor received no specific grant from any funding agency in thepublic, commercial, or not-for-profit sectors. There are no conflicts ofinterest to declare.

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Antiepileptic drugs in the treatment of psychiatric disorders