Use of Antiepileptics in Traumatic Brain Injury: A Review for Psychiatrists

P1: GKW/SPH P2: GKW/RKP QC: GKW/RKP T1: GKW

Annals of Clinical Psychiatry (ACLI) PP279-347315 September 29, 2001 10:28 Style file version Nov. 07, 2000

Annals of Clinical Psychiatry, Vol. 13, No. 3, September 2001 ( c© 2001)

Use of Antiepileptics in Traumatic Brain Injury: A Reviewfor Psychiatrists

Richard Kennedy, MD,1,4 Derek M. Burnett, MD,2 and Brian D. Greenwald, MD3

In recent years, the number of new antiepileptic agents has been growing, as have the potentialapplications. Traumatic brain injury (TBI) patients often present with behavioral disturbancesthat may be amenable to treatment with antiepileptic drugs. These conditions include bipolardisorder, as well as posttraumatic seizures and agitation. We review treatment of these threeconditions with newer agents, as well as past literature on treatment with older antiepilepticdrugs. We also review the pharmacology of newer antiepileptic drugs and summarize reportsthat indicate possible utility in the TBI population. Although there is a paucity of evidencefor brain injury patients specifically, experience with similar groups suggests that these drugsmay be useful. Further trials are indicated to clarify the role of the new antiepileptic agents,which may offer more tolerable side effect profiles than do current treatments.

KEY WORDS: anticonvulsants; traumatic brain injury; agitation; bipolar disorder; seizures.

INTRODUCTION

The use of antiepileptic drugs (AEDs) in thetreatment of seizures, agitation, and unstable mood isincreasing, as is the number of new agents. Over thelast two decades, AEDs have been shown to demon-strate substantial utility within the neurologic, psychi-atric and TBI populations. The established AEDs arephenobarbital, phenytoin, carbamazepine, and val-proate, while newer AEDs include vigabatrin, lam-otrigine, gabapentin, topiramate, and tiagabene. Thisreview will highlight current applications of the newerAEDs for seizures, agitation, and bipolar disorderassociated with TBI. Although widely used and sus-pected to be helpful, there is limited controlled data.

1Department of Psychiatry, University of Mississippi Medical Cen-ter, Jackson, Mississippi.

2Department of Physical Medicine and Rehabilitation, MedicalCollege of Virginia, Richmond, Virginia.

3Department of Physical Medicine and Rehabilitation, Universityof Medicine and Dentistry of New Jersey, Newark, New Jersey.

4To whom correspondence should be addressed at Department ofPsychiatry, Box 139, 2500 North State Street, Jackson, Mississippi39216.

Seizures

Seizure risk following TBI varies proportionatelywith injury severity, from 2% for mild injuries upto 50% with open severe injuries (1). Posttraumaticseizure risk may also increase in association with age,substance abuse, and antidepressant usage (2). Gen-erally, posttraumatic seizures are classified as general-ized or partial, with the latter further subdivided intosimple (if consciousness is maintained) or complex (ifconsciousness is lost). Temporal division is also usu-ally made into immediate (less than 24 h after injury),early (1–7 days after injury), and late (8 or more daysafter injury). The majority of posttraumatic seizuresare of the partial variety and frequently occur withinthe first two years after injury (2).

Recent guidelines have reviewed evidence forthe prophylaxis and treatment of seizures in the con-text of TBI, with the following recommendations (3).On the basis of randomized controlled trials, AEDsmay be used to prevent early posttraumatic seizuresin the first week after injury. Evidence is inconclu-sive that treatment of early posttraumatic seizures be-yond the first week is useful. Similarly, prophylactictreatment for late posttraumatic seizures beyond the

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164 Kennedy, Burnett, and Greenwald

first week is not recommended for most brain injurypatients.

Agitation

Yudofsky et al. (4) recently described the lackof consistency in definitions of “agitation.” Somephysiatrists define agitation as exceeding certain cut-off scores on standardized rating scales, such as theAgitated Behavior Scale (5), which were developedspecifically for brain injured patients. Although ag-itation is a recognized feature of various psychiatricdisturbances, psychiatrists have not been able to agreeon precise definitions, and these may not be applicablefor patients with TBI (6). Several brain injury expertshave proposed a specific definition for acute posttrau-matic agitation: “A subtype of delirium unique to sur-vivors of a TBI in which the survivor is in a state ofposttraumatic amnesia and there are excesses of be-havior that include some combination of aggression,akathisia, disinhibition, and/or emotional lability (6).”However, this definition is not universally accepted.Because of these difficulties, figures for prevalenceand duration of agitation vary. Wiercisiewski et al.characterized posttraumatic agitation as a short-livedphenomenon lasting between 2 and 4 weeks (7), not-ing an overall prevalence of about 10% in the braininjury population. Silver and Yudofsky (8) noted amuch higher prevalence of agitation—between 11 and96%—though the definitions were often poorly spec-ified. Also, although agitation was a transient occur-rence for many patients, a significant number—up to67%—continued to have agitation on a chronic basis.

Following the acute recovery, an “episodicdyscontrol” syndrome has also been described withTBI patients. This is similar to intermittent explosivedisorder in DSM-IV, with paroxysmal episodes of vi-olence out of proportion to stimulation (9). However,“episodic dyscontrol” is also associated with lesser de-grees of agitation and aggression between episodes,while DSM-IV intermittent explosive disorder specif-ically excludes between-episode violence. Many pa-tients with this diagnosis have historical evidence ofTBI. Whether this diagnosis should be separated fromposttraumatic agitation is unclear, and some cliniciansdo not make a distinction (10).

Bipolar Disorder

Precise figures on the incidence of bipolar dis-order after TBI are lacking, as most reports have

been single cases or small case series (11). With fewcases documented in the literature, bipolar disorderis likely a relatively rare consequence of TBI. In theonly prospective study, six patients of 66 (9%) metcriteria for mania at some point during the year afterinjury (12).

Mania occurring in bipolar disorder due to TBIwould be considered a form of secondary mania, asconceptualized by Krauthammer and Klerman (13).In their original review, they indicate that mania maybe a consequence of a variety of organic disturbances.Initially, TBI was not listed as a possible precipitant,but was included in a follow-up paper (14). In currentterminology, bipolar disorder occurring after TBI isclassified as a mood disorder due to general medicalcondition under DSM-IV (9). Although the require-ment for this condition only stipulates the presenceof expansive, euphoric, or irritable mood, many clini-cians require the presence of other bipolar symptomsfor the diagnosis. Such cases would be indistinguish-able from classic bipolar I disorder. Finally, althoughmost case reports have focused on patients with dis-ease similar to bipolar I illness, the full spectrum ofbipolar disorders have been reported (15–17). Theseinclude bipolar II disorder, schizoaffective disorder,and rapid cycling variants.

No specific risk factors have been identified forthe occurrence of bipolar disorder after TBI. All de-grees of injury, from mild to severe, have been asso-ciated with development of bipolar illness (15). Somereports show an immediate temporal relationship be-tween TBI and bipolar symptoms, while others havereported an asymptomatic interval of up to 12 years.Obviously, in the latter cases, the causal relationshipbetween TBI and bipolar symptoms is much morecontroversial. The role of genetic factors has also notbeen elucidated. In one series of cases, no first degreerelatives had a history of mania, although a significantpercentage did suffer from depression (15). Anotherstudy found a higher prevalence of affective disorderamong families of patients with posttraumatic mania,leading the authors to postulate that genetic factorsinteracted with other variables to contribute to thefinal expression of the disease (18). Finally, the roleof injury location remains unanswered as well. Re-ports of mania due to several general medical condi-tions, mostly stroke, noted a definite preponderanceof right-sided lesions, mostly in the frontotemporalarea and basal ganglia (18–20). Such correlations aredifficult to apply to posttraumatic bipolar disorder,where localization is complicated by the frequentlydiffuse, bilateral nature of the injury (11).



Use of Antiepileptics in Traumatic Brain Injury 165

OLDER AGENTS

The older anticonvulsant agents, carbamazepineand valproate, have well established uses in bipolardisorder. There is much less information about theirusefulness in the TBI population. Although less well-studied, some authors have reported behavioral ef-fects from phenobarbital and phenytoin as well. Wewill briefly review these four agents as a basis for com-parison with the newer AEDs.

Phenobarbital

Phenobarbital and the other barbiturates havehad relatively little use in behavioral disturbances.However, Hayes (21) reported on use of barbitu-rates in 27 patients with affective disorders (bipolardisorder, major depression, or schizoaffective disor-der) who had failed to respond to carbamazepine,valproate, phenytoin, and lithium, with 12 (44%) im-proving. The reports found that long-term, open-labeltreatment with primidone resulted in improvement innine patients, and treatment with mephobarbital im-proved three other patients. Another report detailed26 patients with bipolar disorder refractory to con-ventional treatment who received an open-label trialof primidone (22). In this report, eight of 26 patients(31%) had persistent positive effects, and another five(19%) had temporary improvement. Both of thesestudies are especially notable given the refractory na-ture of the patients treated, and would encourage theuse of barbiturates in other refractory populations.However, more controlled data are required beforeany significant recommendations can be made.

Phenytoin

Phenytoin has also received little attention as apsychotropic agent. Early open-label trials showedimprovement in manic patients treated with pheny-toin (23–25). However, despite these early successes,few further studies have been attempted. Recently,another study (26) reported on 39 patients with bipo-lar disorder and schizoaffective disorder treated withphenytoin for mania. Both groups of patients showedimprovement in mania rating scores, although otherless specific rating scales showed improvement only inthe bipolar group. Barratt et al. described a pilot study(27) and expanded controlled trial (28) of the effectsof phenytoin on aggression in 60 patients. There wasa significant decrease in both frequency and intensityof impulsive aggressive acts, but not premeditated

aggressive acts, in treated patients. This type of impul-sive aggression is often seen in TBI patients; however,this study specifically excluded patients with mentalretardation or neurological disorders, so the resultsmay not be generalizable to TBI. Phenytoin may thusbe seen as an alternative treatment for those unre-sponsive to conventional treatments, but its use awaitsfurther clarification.

Carbamazepine

Carbamazepine has been recognized as a treat-ment for classic bipolar disorder (29, 30) and for bipo-lar disorder after TBI (17). Carbamazepine may alsotreat agitation. A placebo-controlled study of car-bamazepine demonstrated reduced agitation in de-mented patients (31) and reduced aggression in thementally retarded (32). Case reports also demonstratesuccessful treatment of episodic dyscontrol with car-bamazepine (33–35). Case studies have documenteddecreases in agitation and aggression in TBI (36).Another small case series demonstrated reduction inemotional lability in patients with frontal lobe injury(37). Placebo-controlled studies in TBI patients arelacking. Carbamazepine, however, is commonly usedby many physiatrists for agitation in TBI patients (38).

Valproate

Valproate is an established treatment for clas-sic bipolar disorder (39, 40), and would be a first-lineagent for bipolar disorder in TBI patients. Pope et al.reported nine of 10 (90%) cases of bipolar disorderafter TBI that were poorly controlled with lithium butresponded well when valproate was added (16). Val-proate has been used to manage agitation and aggres-sion in demented patients (41), as well as agitationbecause of other organic brain syndromes. In TBI,Wroblewski et al. described five patients with reduc-tion in physical and verbal aggression and destructivebehaviors when other agents failed (42). Controlledtrials are currently lacking.

NEWER AGENTS

For the newer AEDs, little information has ap-peared to date about their usefulness in TBI. Wewill briefly review the pharmacology of these neweragents, then present direct and indirect evidence fortheir use in TBI. Relevant clinical characteristics ofthese agents are summarized in Table 1.




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87).




Gabapentin

Gabapentin was developed as a structural ana-logue to gamma-amino butyric acid (GABA). Its pre-cise mechanism of action has not been established,though modulation of GABA synthesis is a likely can-didate (43). Other possible mechanisms include inhi-bition of voltage-activated sodium channels and alter-ations of amino acid transporters (43). Petroff et al.demonstrated increases in GABA levels using mag-netic resonance spectroscopy in an open-label trialof gabapentin (44). It is approved as an adjunctivemedication for partial seizures (45). Monotherapy tri-als are in progress, but preliminary results suggestgabapentin monotherapy may be comparable to car-bamazepine for new onset partial seizures (46). Thereis also evidence that monotherapy with gabapentinmay be effective in patients with seizures due tostroke and brain tumors (47). Gabapentin is excretedunchanged in the urine, does not affect hepatic en-zymes, and is not protein bound (48). It does notinteract with many antiepileptic agents, which offersdistinct advantages as add-on therapy (48). Commonside effects with gabapentin are somnolence, dizzi-ness, ataxia, nystagmus, headache, tremor, fatigue,and nausea/vomiting. Although some practitionersview gabapentin as less toxic than other agents (49),others have reported high rates of discontinuationthat is not entirely because of lack of efficacy (50).

Although gabapentin is becoming more popu-lar as an adjunctive agent for the treatment of classicbipolar disorder, a double-blind, placebo-controlledstudy of gabapentin as monotherapy for bipolar disor-der showed only modest improvement (51). Anotherdouble-blind, placebo-controlled study of gabapentinaugmentation showed no significant effects (38).Gabapentin in the treatment of posttraumatic bipo-lar disorder may be reasonable, but there are no con-trolled studies. In the demented patient population,open-label reports have indicated decreased agita-tion in a small number of patients (52, 53). There hasalso been a case report of its effectiveness in reduc-ing behavioral dyscontrol in a brain injured patient(54). Therefore, anecdotal evidence exists in supportof the use of gabapentin in posttraumatic agitation;however, there is insufficient data for generalized con-clusions.

Gabapentin may also increase agitation. Two pa-tients with TBI treated with gabapentin demonstratedincreases in agitation (55). Agitation has also beennoted to occur in children with attention deficit disor-der or developmental delay (56). Thus, some patients

experience a calming effect, while other patients mayhave a paradoxical reaction, similar to the benzodi-azepenes. This would not preclude treatment in theTBI population, but would underscore the need forcareful monitoring during treatment and discontinu-ation if behavior worsens.

Lamotrigine

Lamotrigine is approved in the United States forpartial and secondarily generalized seizures, althoughit appears to have a broader spectrum of antiseizureactivity (57). Similar to carbamazepine and pheny-toin, the antiseizure activity of lamotrigine appears tobe mediated by inhibition of sodium currents in a volt-age and use dependent manner (58). Sodium channelblockade results in inhibition of glutamate release anddecreased levels of neuroexcitation.

Martin (59) found no significant cognitive impair-ments in healthy adults when compared to baselineafter initiation of lamotrigine. Reports have showngood tolerability and low discontinuation comparedto other antiepileptic therapies (50). The most com-mon dose-related adverse effects of lamotrigine aredizziness, sedation, headache, diplopia, and ataxia.The most serious adverse effect is rash, which canevolve into the potentially lethal Stevens-Johnsonsyndrome. The overall incidence of rash is 10%. Rashis more common in children and appears to be asso-ciated with fast titration (60). Metabolism of lamot-rigine occurs in the liver and is markedly inhibited byvalproate (60). The combination requires slow, care-ful titration. In contrast, phenytoin, phenobarbital,and carbamazepine induce the oxidative system in theliver, causing an accelerated metabolism of lamotrig-ine (57, 61). For seizure control, the recommendedstarting dose for adults is 25–50 mg/day for 2 weeks,increasing to 50 mg twice daily for 2 weeks. Thereafter,dosage is increased by 100 mg/day each week with agoal of 150–250 mg and maximum dose of 700 mg/d.Studies using lamotrigine for bipolar disorder haveused doses of 50–200 mg/day with increased efficacyat the higher doses (62, 63).

Lamotrigine is rapidly gaining acceptance asa treatment for classic bipolar I disorder, based onseveral studies (62, 63). No studies have specificallyaddressed bipolar disorder after TBI. Moreover,decreases in self-injurious behavior, irritability, andhyperactivity may be seen in some mentally retardedindividuals treated with lamotrigine (46, 64). Ex-trapolating from these reports, lamotrigine may also




treat agitation and aggression in the TBI population.However, in a case series of 19 patients with mentalretardation, lamotrigene caused aggression in nine(47%) during drug treatment (65).

Topiramate

Topiramate, like carbamazepine and phenytoin,has a wide spectrum of antiseizure activity. It also ap-pears to have additive effects when combined withthese drugs. Topiramate is effective for refractory par-tial seizures and also against generalized tonic-clonicseizures (66). Its mechanism of action occurs at leastthree ways: blockade of sodium channels, potentiationof GABA-mediated neuroinhibition, and blockade ofglutamate mediated neuroexcitation (60).

Common side effects include sedation, impairedconcentration, decreased appetite, and weight loss(60). Dose dependent cognitive impairment has beenshown with topiramate (59, 67). Topiramate is pri-marily excreted in the urine unmetabolized, and doseadjustment for patients with renal impairment may benecessary. Adverse side effects appear to be relatedto a rapid titration. Accordingly, slow titration is rec-ommended, with an initial dose of 25–50 mg/day inadults. Weekly increases by the same amount, up to agoal dose of 200–400 mg/day, then follows.

No reports have been made pertaining to efficacyof topiramate for the treatment of behavioral distur-bances in TBI, demented, or mentally retarded pop-ulations; however, recent reports have investigatedthe use of topiramate as a mood stabilizer in classicbipolar disorder. In a retrospective chart review of 44bipolar patients treated with topiramate, 23 patients(52%) were classified as having improvement in bipo-lar symptoms over 16 weeks (68). In another trial, ad-junctive topiramate improved mania in seven of 20patients (35%) (51). Van Kammen et al. used open-label topiramate and demonstrated improvement inbipolar symptoms in five of 11 patients (45%) (69).Kusumakar et al. in another open-label topiramatetrial, showed improvement in mania ratings for nineof 16 patients (56%) (70). Chengappa et al. showedeight of 15 refractory bipolar patients (53%) returnedto euthymia with topiramate augmentation of theircurrent regimen (71). On the basis of these reports,topiramate may be a reasonable treatment for post-traumatic bipolar disorder if a patient cannot toler-ate or does not respond to traditional agents. Its usein other disorders, such as posttraumatic agitation,is still considered to be investigational. Topiramate,

however, has been reported to worsen psychosis infive of 80 patients (6%) in one study (72).

Tiagabine

Tiagabine inhibits the reuptake of GABA. Stud-ies have shown it to be effective as an adjunct in thetreatment of partial seizures (73). More recent studieshave investigated its use in partial complex seizuresand as monotherapy (74, 75). Tiagabine is rapidly me-tabolized by the liver and is accelerated by agents thatinduce the P450 system, such as carbamazepine andphenytoin (76, 77). Common side effects with therapyare dizziness, asthenia, nervousness, tremor, diarrhea,depression, and emotional lability.

There have been a small number of reports sup-porting the use of tiagabine in bipolar disorder (78,79). These have involved small numbers of patients,usually being treated with other agents as well. Ad-ditionally, one study showed no improvement in anopen-label trial of tiagabine when added on to exist-ing therapies (80). Thus, the effects of tiagabine onbipolar disorder still remain uncertain, and its use inposttraumatic bipolar disorder would also be consid-ered investigational. The role of tiagabine as a cause ofpsychiatric symptomatology also awaits further study.

Vigabatrin

Vigabatrin has not yet been released in theUnited States. Its efficacy has been most clearlydemonstrated in controlling partial seizures; in chil-dren it is also used for infantile spasms. Vigabatrin ir-reversibly inhibits the enzyme GABA transaminase.Inhibition of this enzyme increases the amount ofGABA available in the brain for inhibition. Studies ofpatients taking vigabatrin have not shown detrimentaleffects on cognitive performance (81–84).

Common side effects of vigabatrin includedrowsiness, dizziness, ataxia, tremor, depression, andweight gain; hyperactivity in children is also common.Several cases of visual field constriction, bilateral op-tic nerve pallor, and subtle peripheral optic retinopa-thy have been reported; this has slowed FDA approvalof this drug in the United States. In Europe, thesefindings have prompted the recommendation that pa-tients have initial and periodic (3 month) ophthalmo-logic exams while on vigabatrin.

Vigabatrin is renally metabolized and dose ad-justment for patients with renal impairment maybe needed. For seizure control, the recommended




starting dose is 1 g/day in adults, with titration be-tween 2 and 4 g/day.

No reports have been made regarding the effi-cacy of vigabatrin on behavioral disturbance in TBI,demented, or mentally retarded populations. Also,no reports have been made regarding its efficacy inbipolar disorder, so its use in any of these popula-tions would, again, be considered investigational. Ad-verse effects from vigabatrin have been associatedwith a variety of behavioral disturbances in the epilep-tic population, including depression, aggression, andpsychosis (85). Because of this, some investigatorshave viewed previous psychiatric illness as a relativecontraindication to vigabatrin therapy (86). A cau-tious approach is warranted when prescribing vigaba-trin in the TBI population until this issue is furtherclarified.

SUMMARY

AEDs are greatly expanding the pharmacologi-cal armamentarium in treatment of neuropsychiatricdisorders. Neuropsychiatric syndromes are commonin TBI patients and these agents may play an impor-tant role, though efficacy has not been establishedin controlled trials. The older AEDs, such as carba-mazepine and valproate, have case reports and smallstudies to document their usefulness in this group,while anecdotal reports are also beginning to appearin favor of the newer AEDs. Based on experiencewith other populations, the newer AEDs offer advan-tages for the TBI population, including reduced ratesof cognitive impairment and related side effects. Al-though direct data in the TBI population are limited,these agents should be considered in the treatment forseizures, bipolar disorder, and agitation. They offertreatment alternatives in patients who do not respondto, or are intolerant of, more traditional medications.Larger, well-controlled trials will be needed in the fu-ture to establish their place in the overall treatmentregimen.

REFERENCES

1. O’Dell M, Bell K, Sandel M: Brain injury rehabilitation. 2.Medical rehabilitation of brain injury. Arch Phys Med Rehabil1998; 79:S10–15

2. Yablon S: Posttraumatic seizures. Arch Phys Med Rehabil1993; 74:983–1001

3. Brain Injury Special Interest Group of the American Academyof Physical Medicine and Rehabilitation: Practice parameter:Antiepileptic drug prophylaxis of posttraumatic seizures. ArchPhys Med Rehabil 1998; 79:594–597

4. Yudofsky SC, Kopecky HJ, Kunik M, Silver JM, Endicott J:The Overt Agitation Severity Scale for the objective ratingof agitation. J Neuropsychiatry Clin Neurosci 1997; 9:541–549

5. Corrigan JD: Development of a scale for assessment of agita-tion following traumatic brain injury. J Clin Exp Neuropsychol1989; 11:261–277

6. Sandel ME, Mysiw WJ: The agitated brain injured patient.Part 1: Definitions, differential diagnosis, and assessment. ArchPhys Med Rehabil 1996; 77:617–623

7. Wiercisiewski DR, McDeavitt JT: Drugs for management ofacute and chronic behavioral disorders. Phys Med Rehabil ClinN Am 1997; 8:763–780

8. Silver JM, Yudofsky SC: Aggressive disorders. In: SilverJM, Yudofsky SC, Hales RE, eds. Aggressive disorders.Washington, DC: American Psychiatric Press; 1994:314–315

9. American Psychiatric Association: Diagnostic and StatisticalManual of Mental Disorders. Washington, DC: American Psy-chiatric Association; 1994

10. Kavoussi R, Coccaro E: Psychopharmacologic treatment ofhostility and aggressive disorders. Psychiatr Clin N Am AnnuDrug Ther 1998; 5:53–67

11. McAllister T: Neuropsychiatric sequelae of head injuries. Psy-chiatr Clin North Am 1992; 15:395–413

12. Jorge RE, Robinson RG, Starkstein SE, Arndt SV, ForresterAW, Geisler FH: Secondary mania following traumatic braininjury. Am J Psychiatry 1993; 150:916–921

13. Krauthammer C, Klerman GL: Secondary mania: Manic syn-dromes associated with antecedent physical illnesses or drugs.Arch Gen Psychiatry 1978; 35:1333–1339

14. Riess H, Schwartz CE, Klerman GL: Manic syndrome fol-lowing head injury: Another form of secondary mania. J ClinPsychiatry 1987; 48:29–30

15. Shukla S, Cook B, Mukherjee S: Mania following head trauma.Am J Psychiatry 1987; 144:93–96

16. Pope HG, McElroy SL, Satlin A, Hudson JI, Keck PE,Kalish R: Head injury, bipolar disorder, and response to val-proate. Compr Psychiatry 1988; 29:34–38

17. Stewart JT, Hemsath RH: Bipolar illness following traumaticbrain injury: Treatment with lithium and carbamazepine. J ClinPsychiatry 1988; 49:74–75

18. Robinson R, Boston J, Starkstein S: Comparison of mania anddepression after brain injury: Causal factors. Am J Psychiatry1988; 145:172–178

19. Starkstein SE, Boston JD, Robinson RG: Mechanisms of ma-nia after brain injury: 12 case reports and a review of the liter-ature. J Nerv Ment Dis 1988; 176:87–100

20. Starkstein SE, Mayberg HS, Berthier ML, Federoff P, PriceTR, Dannals RF, Wagner HN, Leiguarda R, Robinson RG:Mania after brain injury: Neuroradiological and metabolicfindings. Ann Neurol 1990; 27:652–659

21. Hayes SG: Barbiturate anticonvulsants in refractory affectivedisorders. Ann Clin Psychiatry 1993; 5:35–44

22. Schaffer LC, Schaffer CB, Caretto J: The use of primidone inthe treatment of refractory bipolar disorder. Ann Clin Psychi-atry 1999; 11:61–66

23. Kalinowsky LB, Putnam TJ: Attempts at treatment ofschizophrenia and other nonepileptic psychoses with Dilantin.Arch Neurol Psychiatry 1943; 49:414–420

24. Kubanek JL, Rowell RC: The use of Dilantin in the treatmentof psychotic patients unresponsive to other treatments. DisNerv Syst 1946; 7:47–50

25. Freyhan FA: Effectiveness of diphenylhydantoin in manage-ment of nonepileptic psychomotor excitement states. ArchNeurol Psychiatry 1945; 53:370–374

26. Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH:Phenytoin as an antimanic anticonvulsant: A controlled study.Am J Psychiatry 2000; 157:463–465




27. Barratt ES, Kent TA, Bryant SG, Felthous AR: A controlledtrial of phenytoin in impulsive aggression. J Clin Psychophar-macol 1991; 11:388–389

28. Barratt ES, Stanford MS, Felthous AR, Kent TA: The effectsof phenytoin on impulsive and premeditated aggression: Acontrolled study. J Clin Psychopharmacol 1997; 17:341–349

29. Post RM, Leverich GS, Rosoff AS: Carbamazepine prophy-laxis in refractory affective disorders: A focus on long-termfollow-up. J Clin Psychopharmacol 1990; 10:318–327

30. Gerner RH, Stanton A: Algorithm for patient management ofacute manic states: Lithium, valproate, or carbamazepine? JClin Psychopharmacol 1992; 12:57S–63S

31. Cloyd JC, Lackner TE, Leppik IE: Antiepileptics in theelderly. Pharmacoepidemiology and pharmacokinetics. ArchFam Med 1994; 3:589–598

32. Tardiff K: The current state of psychiatry in the treatment ofviolent patients. Arch Gen Psychiatry 1992; 49:493–499

33. Lewin J, Sumners D: Successful treatment of episodic dyscon-trol with carbamazepine. Br J Psychiatry 1992; 161:261–262

34. Payne SD: Carbamazepine and episodic dyscontrol. Br J Psy-chiatry 1993; 162:425–426

35. Sugarman P: Carbamazepine and episodic dyscontrol. Br JPsychiatry 1992; 161:721

36. Pourcher E, Filteau MJ, Boochard RH, Baruch P: Efficacy ofthe combinations of buspirone and carbamazepine in earlyposttraumatic delirium. Am J Psychiatry 1994; 151:150–151

37. McAllister TW: Carbamazepine in mixed frontal lobe and psy-chiatric disorders. J Clin Psychiatry 1985; 46:393

38. Fugate LP, Spacek LA, Kresty LA, Levy CE, Johnson JC,Mysiw WJ: Measurement and treatment of agitation follow-ing traumatic brain injury: II. A survey of the Brain InjurySpecial Interest Group of the American Academy of PhysicalMedicine and Rehabilitation. Arch Phys Med Rehabil 1997;78:924–928

39. Pope HG, McElroy SL, Keck PE: Valproate in the treatment ofacute mania: A placebo-controlled study. Arch Gen Psychiatry1991; 48:62–68

40. Bowden CL, Brugger AM, Swann AC: Efficacy of divalproexversus lithium and placebo in the treatment of mania. JAMA1994; 271:918–924

41. Mellow AM, Solano-Lopez C, Davis S: Sodium valproate inthe treatment of behavioral disturbance in dementia. J GeriatrPsychiatry Neurol 1993; 6:205–209

42. Wroblewski BA, Joseph AB, Kupfer J, Kalliel K: Effectivenessof valproic acid on destructive and aggressive behaviours inpatients with acquired brain injury. Brain Inj 1997; 11:37–47

43. Morris GL: Gabapentin. Epilepsia 1999; 40(Suppl 5):S63–S7044. Petroff OAC, Rothman DL, Behar KL, Lamoureax D,

Mattson RH: The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 1996;39:95–99

45. Pellock JM: Utilization of new antiepileptic drugs in children.Epilepsia 1996; 37:S66–S73

46. Meythaler JM, Yablon SA: Antiepileptic drugs. Phys MedRehabil Clin N Am 1999; 10:275–300

47. Paladin FM: Clinical experience with gabapentin (Neurontin)as monotherapy or adjunctive therapy in partial epilepsy sec-ondary to neoplastic or vascular lesions. Epilepsia 1997; 38:34

48. Shorvon S, Stefan H: Overview of the safety of newerantiepileptic drugs. Epilepsia 1997; 38:S45–S51

49. Feely M: Drug treatment of epilepsy. Br Med J 1999; 318:106–109

50. Collins TA, Petroff OAC, Mattson RH: A comparison of fournew antiepileptic medications. Seizure 2000; 9:291–293

51. Goldberg JF: Treatment of bipolar disorders. Psychiatric Clin-ics of North America Annual of Drug Therapy 2000; 7:115–149

52. Goldenberg G, Kahaner K, Basavaraju N, Rangu S:Gabapentin for disruptive behaviour in an elderly dementedpatient. Drugs Aging 1998; 13:183–184

53. Regan WM, Gordon SM: Gabapentin for behavioral agitationin Alzheimer’s disease. J Clin Psychopharmacol 1997; 17:59–60

54. Ryback R, Ryback L: Gabapentin for behavioral dyscontrol.Am J Psychiatry 1995; 152:1399

55. Childers MK, Holland D: Psychomotor agitation followinggabapentin use in brain injury. Brain Inj 1997; 11:537–540

56. Lee DO, Steingard RJ, Cesena M, Helmers SL, Riviello JJ,Mikati MA: Behavioral side effects of gabapentin in children.Epilepsia 1996; 37:87–90

57. Dichter MA, Brodie MJ: Drug therapy: New antiepilepticdrugs. N Engl J Med 1996; 334:1583–1590

58. Cheung H, Kamp D, Harris E: An in vitro investigation of theaction of lamotrigine on neuronal voltage-activated sodiumchannels. Epilepsy Res 1992; 13:107–112

59. Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J,Sinclair K, Gilliam F, Faught E: Cognitive effects of topira-mate, gabapentin, and lamotrigine in healthy young adults.Neurology 1999; 52:321–327

60. Bourgeois BF: New antiepileptic drugs. Arch Neurol 1998;55:1181–1183

61. Spina E, Pisani F, Perucca E: Clinically significant pharmacoki-netic drug interactions with carbamazepine. An update. ClinPharmacokinet 1996; 31:198–214

62. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, MonaghanE, Rudd GD: A double-blind placebo-controlled study of lam-otrigine monotherapy in outpatients with bipolar I depression.J Clin Psychiatry 1999; 60:79–88

63. Calabrese JR, Bowden CL, McElroy SL, Cookson J, AndersenJ, Jr. PEK, Rhodes L, Bolden-Watson C, Zhou J, Ascher JA:Spectrum of activity of lamotrigine in treatment-refractorybipolar disorder. Am J Psychiatry 1999; 156:1019–1023

64. Davanzo PA, King BH: Open trial lamotrigine in the treat-ment of self-injurious behavior in an adolescent with profoundmental retardation. J Child Adolesc Psychopharmacol 1996;6:273–279

65. Beran RG, Gibson RJ: Aggressive behavior in intellectuallychallenged patients with epilepsy treated with lamotrigine.Epilepsia 1998; 39:280–282

66. Privitera MD: Topiramate: A new antiepileptic drug. AnnPharmacother 1997; 31:1164–1173

67. Burton LA, Harden C: Effect of topiramate on attention.Epilepsy Res 1997; 27:29–32

68. Marcotte D: Use of topiramate, a new anti-epileptic as a moodstabilizer. J Affect Disord 1998; 50:245–251

69. van Kammen DP, Calabrese JR, Shelton MD: Topiramate insevere treatment refractory mania. Bipolar Disord 1999; 1:56

70. Kusumakar V, Yatham LN, O’Donovan C: Topiramate aug-mentation in women with refractory rapid cycling bipolar dis-order and significant weight gain from previous treatment.Bipolar Disord 1999; 1:38

71. Chengappa KNR, Rathore D, Levine J: Topiramate as add-on treatment for patients with bipolar mania. Bipolar Disord1999; 1:42–53

72. Khan A, Faught E, Gilliam F, Kuzniecky R: Acute psychoticsymptoms induced by topiramate. Seizure 1999; 8:235–237

73. Leppik IE: Tiagabine: The safety landscape. Epilepsia 1995;36:S10–S13

74. Beydoun A: Monotherapy trials of new antiepileptic drugs.Epilepsia 1997; 38:S21–S31

75. Fisher R, Blum D: Colbazam, oxcarbazepine, tiagabine, top-iramate, and other new antiepileptic agents. Epilepsia 1995;36:S105–S114

76. Brodie MJ: Tiagabine pharmacology in profile. Epilepsia 1995;36:S7–S9

77. So EL, Wolff D, Graves NM: Pharmacokinetics of tiagabineas add-on therapy in patients taking enzyme-inducingantiepilepsy drugs. Epilepsy Res 1995; 22:221–226

78. Kaufman KR: Adjunctive tiagabine treatment of psychiatricdisorders: Three cases. Ann Clin Psychiatry 1998; 10:181–184




79. Shaffer LC, Shaffer CB: Tiagabine and the treatment of refrac-tory bipolar disorder. Am J Psychiatry 1999; 156:2014–2015

80. Grunze H, Erfurth A, Marcuse A: Tiagabine appears not to beefficacious in the treatment of acute mania. J Clin Psychiatry1999; 60:759–762

81. Dodrill CB, Arnett JL, Sommerville KW, Sussman NM: Effectsof differing doses of vigabatrin (Sabril) on cognitive abilitiesand quality of life in epilepsy. Epilepsia 1995; 36:164–173

82. Gillham RA, Blacklaw J, McKee PJ, Brodie MJ: Effectsof vigabatrin on sedation and cognitive function in patientswith refractory epilepsy. J Neurol Neurosurg Psychiatry 1993;56:1271–1275

83. McGuire AM, Duncan JS, Trimble MR: Effects of vigabatrinon cognitive function and mood when used as add-on therapy

in patients with intractable epilepsy. Epilepsia 1992; 33:128–134

84. Grunewald RA, Thompson PJ, Corcoran R, Jackson GD,Duncan JS: Effects of vigabatrin on partial seizures and cog-nitive function. J Neurol Neurosurg Psychiatry 1994; 57:1057–1063

85. Sander JW, Hart YM, Trimble MR, Shorvon SD: Vigabatrinand psychosis. J Neurol Neurosurg Psychiatry 1991; 54:435–439

86. Ben-Menachem E: Vigabatrin. Epilepsia 1995; 36:S95–S10487. Post RM, Denicoff KD, Frye MA, Dunn RT, Leverich GS,

Osuch E, Speer A: A history of the use of anticonvulsants asmood stabilizers in the last two decades of the 20th century.Neuropsychobiology 1998; 38:152–166

Use of Antiepileptics in Traumatic Brain Injury: A Review for Psychiatrists

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