CURRENT REVIEW IN CLINICAL SCIENCE
`
`Psychotropic Effects of Antiepileptic
`Drugs
`
`Siddhartha Nadkarni, MD1,2, and Orrin Devinsky, MD1,2,3
`
`Departments of 1Neurology, 2Psychiatry and 3Neurosurgery,
`NYU School of Medicine, New York
`
`Antiepileptic drugs are important psychotropic agents that are com-
`monly used to treat psychiatric disorders. The behavioral effects of
`antiepileptic drugs may differ between epilepsy and psychiatric pa-
`tient populations. Randomized, double-blind, controlled data on
`the psychotropic efficacy of antiepileptic drugs are limited mainly
`to bipolar disorder.
`
`Antiepileptic drugs (AEDs) are psychotropic agents; that is,
`they act on the mind and can positively or negatively influ-
`ence behavior. This result is expected, given their mechanisms
`of action, which are to alter ion channel and neurotransmitter
`system functions and, thereby, modulate the electrochemical
`systems that underlie behavior. Behavioral effects (e.g., cogni-
`tive and mood) associated with AEDs are complex and can vary
`dramatically between patients. It is currently not possible to pre-
`dict which patient with epilepsy will tolerate an AED and which
`one will develop adverse, as opposed to positive, psychotropic
`effects.
`
`AEDs and Behavioral Effects
`
`Studies involving either adverse or beneficial effects of AEDs in
`one patient population (e.g., epileptic, psychiatric, or other clin-
`ical groups, such as patients with migraine and diabetic neuropa-
`thy) cannot be assumed to apply to another patient population.
`A spectrum of behavioral effects from these medications can be
`experienced by patients with or without epilepsy. In epilepsy pa-
`tients, suppression of seizures or interictal epileptiform activity
`may be accompanied by positive or negative behavioral effects.
`In general, sedating AEDs, such as valproic acid and carba-
`mazepine, possess anxiolytic, antimanic, and sleep-promoting
`benefits but may cause fatigue, impaired attention, and mood
`depression. Activating AEDs, such as felbamate and lamotrig-
`ine, may possess antidepressant and attention-enhancing effi-
`
`Epilepsy Currents, Vol. 5, No. 5 (September/October) 2005 pp. 176–181
`Blackwell Publishing, Inc.
`C(cid:1) American Epilepsy Society
`
`cacy but may cause anxiety, insomnia, and agitation. These
`generalizations of the effects of AEDs are limited by the wide
`variability of clinical responses.
`Even among epilepsy patients, striking differences may be
`seen in the effects of an AED, based on both individual reac-
`tions and other clinical factors. For example, in comparison to
`patients with new-onset epilepsy, refractory epilepsy patients
`may be resistant to adverse neurobehavioral effects when ad-
`ministered a new or additional AED. Studies of inpatients with
`medically refractory epilepsy who were administered felbamate
`showed that rapid escalation of the dose to 3,600 mg/day was
`often well tolerated (1). However, with outpatient populations,
`slower titrations more commonly elicited side effects, such as
`gastrointestinal, headache, insomnia, restlessness, and agitation
`(2).
`
`Epilepsy patients, in general, may be more susceptible to
`the adverse behavioral effects of AEDs than are other popula-
`tions, possibly resulting from structural or functional changes
`that increase their risk of psychiatric disorders. For example,
`affective and psychotic symptoms exhibited with levetiracetam
`administration are significantly more common among patients
`with epilepsy than among patients with cognitive or anxiety
`disorders (3). For other medications, such as ethosuximide, vi-
`gabatrin, and topiramate, a forced normalization like process
`may contribute to behavioral changes, such as psychosis (4–6).
`A hypothesis relating to this phenomenon posits that epilepti-
`form discharges may mimic electroconvulsive therapy in a focal
`area, and discharge suppression may lead to psychopathology.
`However, multiple other mechanisms are likely.
`
`Off-label Use of AEDs
`
`The vast majority of data regarding psychotropic effects as-
`sociated with AEDs show negative changes, such as anxiety,
`irritability, agitation, depression, and psychosis, possibly as an
`artifact of study designs focused on screening for adverse ef-
`fects. Many of the reports regarding positive psychotropic ef-
`fects associated with AEDs are based on small samples, often
`using retrospective, nonrandomized, or nonblinded data. As a
`result, a bias exists toward focusing on adverse effects that are
`epiphenomena of antiepileptic treatment, whereas the need for
`proactive assessment of positive effects of AEDs has not been
`met.
`
`The dramatic increase in the use of AEDs as therapy for psy-
`chiatric disorders outpaces evidence of their efficacy. Although
`behavioral effects as a side effect have been studied, large, ran-
`domized, controlled trials that directly assess behavioral effects
`
`ARGENTUM Exhibit 1115
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`Current Review in Clinical Science
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`associated with AED administration are scarce. However, stud-
`ies do provide evidence that carbamazepine, valproate, and lam-
`otrigine act both as antimanic agents and mood stabilizers in
`bipolar disorder (7). The increased off-label use of AEDs, other
`than these three, for psychiatric disorders is potentially dan-
`gerous. The data supporting the use of AEDs for psychiatric
`disorders often is based on case reports, small open-label series,
`or controlled studies that are limited by sample size and sta-
`tistical power or by methods biased toward positive findings.
`For instance, presenting topiramate as a treatment for major
`depression or anxiety that also helps with weight loss is mis-
`leading. Data solidly show that topiramate helps patients lose
`weight, but no data demonstrate a beneficial effect with affec-
`tive disorders. No AED has been shown to be efficacious for
`the treatment of depression, generalized anxiety disorder, panic
`disorder, schizophrenia, or most other psychiatric disorders (8).
`
`Frequently Used AEDs
`
`The following are commonly administered AEDs and brief de-
`scriptions of their potential psychotropic effects.
`Barbiturates. The barbiturates are rarely prescribed as psy-
`chotropic agents, although Rickels (9) and Shaffer (10) found
`that they possess anxiolytic, sedative hypnotic, and mood-
`stabilizing properties in some patients. Barbiturates can impair
`cognition and motivation; depress mental and physical energy
`as well as mood; and cause hyperactivity, irritability, aggressive
`behavior, and impotence. Brental (11) showed that barbiturates
`are most likely to cause depression and suicidal ideation in pa-
`tients with a family or personal history of affective disorder.
`With depressed, irritable, or aggressive epilepsy patients taking
`long-term barbiturate therapy, gradual conversion to a nonbar-
`biturate AED may avoid the need for prescribing a psychotropic
`medication.
`Carbamazepine. Although carbamazepine is structurally
`similar to the tricyclic antidepressant imipramine, it does not
`have antidepressant effects. DeLeon (7) demonstrated that CBZ
`effectively treats mania and stabilizes mood in bipolar disor-
`der. Uncontrolled studies support a role for CBZ in treating
`impulse-control disorders, such as borderline personality dis-
`order with aggression and episodic dyscontrol syndrome. Stein
`(12), Uhde (13), and Lima (14) showed that CBZ is not ef-
`fective in treating panic disorder or cocaine dependence. CBZ
`may cause behavioral problems. Friedman (15) showed that
`10% of patients with mental retardation, who were treated
`with CBZ for mood disorders, developed adverse behavioral
`reactions. CBZ-induced behavioral disorders usually occur in
`patients with existing behavioral difficulties.
`Ethosuximide. Ethosuximide, used to treat absence seizures,
`may cause confusion, sleep disturbances, aggressive behavior,
`
`depression, and, rarely, psychosis. Forced normalization with
`ethosuximide may cause behavioral abnormalities (4).
`Felbamate. Felbamate has stimulant properties, which can
`cause anxiety, irritability, or insomnia (16).
`Gabapentin. Pande (17) showed that social phobia and
`other forms of anxiety are effectively treated with gabapentin.
`In two double-blind studies, Pande (17) and Frye (18) revealed
`that gabapentin was ineffective for bipolar or unipolar depres-
`sive disorders, although Schaffer et al. (10) and McElroy (19)
`demonstrated that gabapentin improved mania and the depres-
`sive phase of bipolar disorder in open-label studies. Ryback
`(20) found that preliminary studies suggest a beneficial effect of
`gabapentin on behavioral dyscontrol, agitation in senile demen-
`tia (21), and self-injurious behaviors in neurologic syndromes
`(22). In uncontrolled studies with epilepsy patients, gabapentin
`improved the sense of well-being and mood dysfunction, in-
`dependent of seizure reduction (23). Notably, this effect just
`reached statistical significance (p = 0.04) in one of three de-
`pression scales. The other two depression inventories had p val-
`ues >0.57, whereas the anxiety scale had a p value >0.9. This
`study found no reduction in seizure frequency in the GBP-
`treated group (mean, 1,615 mg/day), a difference from double-
`blind placebo-controlled trials that showed efficacy of GBP at
`this dosage. GBP has minimal detrimental cognitive side effects
`with epilepsy patients (24,25) but occasionally causes irritabil-
`ity and agitation. This problem most often occurs in children
`with developmental disabilities but may affect children with
`normal intelligence and sensorimotor function as well as adults
`(26,27).
`Lamotrigine. Lamotrigine effectively treats refractory bipo-
`lar disorder (28–30). During a 1-year follow-up, McElroy (31)
`found that bipolar patients experienced sustained improvement
`in depressive symptoms. The proportion of patients achieving
`remission by week 4 of the study was 81%, and episodes of ma-
`nia/hypomania occurred less frequently than in the prior year.
`In a placebo-controlled trial of bipolar patients with recent ma-
`nia or hypomania, lithium was superior to placebo at prolong-
`ing the time to a manic, hypomanic, or mixed episode, whereas
`LTG was superior to placebo at prolonging the time to a depres-
`sive episode (32). For patients with bipolar disorder I, substitu-
`tion of LTG for other psychotropic medications was associated
`with improved cognitive function (33). Unlike some other psy-
`chotropic agents used to treat bipolar disorder, LTG does not
`destabilize mood or cause sexually adverse effects, weight gain,
`or withdrawal symptoms (32). In preliminary studies, LTG has
`demonstrated beneficial effects on unipolar depression (18),
`borderline personality disorder (34), and schizoaffective disor-
`der (35). LTG may cause mild stimulation and insomnia, which
`can be managed by shifting most of the dose to the morning or
`early afternoon.
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`Current Review in Clinical Science
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`In patients with epilepsy, LTG has a favorable cognitive
`and behavioral profile (36). Patients with developmental dis-
`abilities and epilepsy may experience both positive and negative
`psychotropic effects (37,38). Positive effects include diminished
`irritability, hyperactivity, and perseveration, as well as improved
`energy and social function. Negative effects include irritabil-
`ity, hyperactivity, and stereotypic or aggressive behavior. Serum
`LTG levels do not predict a psychotropic response.
`Levetiracetam. Nopositive psychotropic effects are estab-
`lished for LEV, although it is chemically related to the putative
`nootropic drug piracetam. Approximately 5% to 10% of adults
`and 12% to 25% of children taking LEV may exhibit irritabil-
`ity, anxiety, depression, and other behavioral disorders. These
`problems may occur more often in patients with developmen-
`tal delays (39). Among 118 patients with epilepsy and learning
`disabilities who were treated with LEV, 15 (12.7%) had be-
`havioral symptoms: 9 (7.6%), aggressive behavior; 2 (1.7%),
`affective disorder; 2 (1.7%), emotion lability; and 2 (1.7%),
`other personality changes (39).
`Phenytoin. Once promoted as an antidepressant (40), PHT
`now is rarely used as a psychotropic agent, although a controlled
`study found efficacy for mania (41). PHT has a cognitive and
`behavioral profile similar to that of CBZ (42). Some patients
`experience sedation, psychomotor slowing, mild cognitive im-
`pairment, and depression. A chronic, cumulative encephalopa-
`thy may occur after long-term exposure to high doses, perhaps
`resulting partly from cerebellar atrophy. An acute encephalopa-
`thy and seizures may develop with toxicity (blood PHT levels,
`>35 µg/mL).
`Tiagabine. Inpatients with epilepsy, tiagabine may improve
`mood or cause irritability, emotional lability, and dysphoria
`(43,44). Preliminary studies indicate that TGB is not effective
`in bipolar disorder (45).
`Topiramate. TPM may improve mania and stabilize mood
`in bipolar disorder (3). TPM may help to treat binge-eating
`disorder (46) and to reduce aggression and other behavioral
`disorders in intellectually impaired adults (47). An open-label
`study supports its use for posttraumatic stress disorder (48) and
`social phobia (49). The weight loss associated with TPM can
`benefit many patients, especially those treated with drugs pro-
`moting weight gain (e.g., antipsychotic drugs, valproate, GBP,
`and selective serotonin reuptake inhibitors).
`Cognitive and behavioral problems associated with TPM
`use are a significant concern with epilepsy patients. However,
`both cognitive and behavioral problems are less frequent and
`severe when the starting dose is low and is increased slowly (50).
`Cognitive disorders include impaired attention, word-finding,
`verbal fluency, memory, and psychomotor slowing. Behavioral
`changes include depression, irritability, and, rarely, psychosis
`(51). Among 103 patients in whom behavioral disorders de-
`
`veloped while they were being administered TPM, 46 were
`affective, 22 were aggressive, 16 were psychotic, 11 were anx-
`ious, and 8 had personality changes (46). In a study of 470 re-
`fractory epilepsy patients, behavioral side effects were the most
`common cause for discontinuation (70%), followed by men-
`tal slowing (27.6%), dysphasia (16.0%), and mood problems
`(e.g., agitation, 11.9%) (51). In a randomized, controlled trial
`of TPM, GBP, and LTG in healthy young adults, only TPM-
`treated subjects showed significant declines in attention and
`word fluency, as well as increases on an anger–hostility scale
`(24). These changes were observed with acute doses and at 2-
`and 4-week visits. In patients with Lennox–Gastaut syndrome,
`adverse events included somnolence, mood problems, nervous-
`ness, personality disorder, and language problems (52).
`Valproate. VPA effectively treats mania and stabilizes mood
`in patients with bipolar disorder (53,54). Compared with
`lithium, VPA was superior in providing a longer duration of
`successful prophylaxis and less deterioration in depressive symp-
`toms, but suicide attempt and death rates were higher with VPA
`(55). It reduces the severity of acute alcohol withdrawal and re-
`duces benzodiazepines needs (56). VPA may improve mood in
`patients with epilepsy, developmental disabilities, and schizoaf-
`fective disorder (57,58) as well as effectively treat panic disorder
`(58) and borderline personality disorder (60). Irritability, agi-
`tation, aggression, self-injurious behavior, and mood problems
`in patients with CNS disorders, such as head trauma, seizures,
`or dementia, may respond well to VPA therapy (58–60). VPA
`causes sedation and infrequently may cause cognitive impair-
`ment, irritability, depression, hyperactivity, and aggressive be-
`havior.
`Vigabatrin. Vigabatrin is an irreversible inhibitor of GABA
`transaminase, which increases GABA levels in the CNS. Vi-
`gabatrin has no established positive psychotropic effects and
`may cause depression, psychosis, and exacerbate hyperactivity
`(61,62).
`Zonisamide. Preliminary studies suggest that zonisamide
`may help treat mania in patients with bipolar and schizoaffec-
`tive disorders (63,64). However, ZNS may induce irritability,
`emotional lability, and rarely, mania, or psychosis.
`Pharmacologic properties of the frequently used AEDs are
`summarized in Table 1.
`
`Conclusion
`
`AEDs are psychotropic agents with positive, negative, or no ef-
`fect in diverse cognitive and behavioral domains. More random-
`ized, controlled, and adequately powered studies are needed to
`assess their efficacy in treating psychiatric disease. Until such
`trials are performed, off-label use of AEDs for psychiatric con-
`ditions should be judicious. Psychotropic effects in the epilepsy
`
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`Current Review in Clinical Science
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`TABLE 1. Potential Psychotropic Effects of Antiepileptic Drugs
`
`Antiepileptic Drug
`
`Beneficial Effects
`
`Harmful Effects
`
`Barbiturates
`
`Anxiety, mood stabilizing, sleep
`
`Carbamazepine
`Ethosuximide
`Gabapentin
`
`Lamotrigine
`
`Aggression, mania, mood stabilizing
`∗
`Anxiety, insomnia, social phobia,
`stabilizing
`∗
`∗
`Depression,
`
`∗
`
`mood
`
`mood stabilization,
`
`mania
`
`∗
`
`Levetiracetam
`
`Data not available
`
`Phenytoin
`Tiagabine
`Topiramate
`
`Valproate
`
`Zonisamide
`
`Mania
`Mania, mood stabilization
`Binge eating, mania, mood stabilization
`
`∗
`Agitation, aggression, irritability, mania,
`∗
`mood stabilization
`Mania
`
`Aggression, impaired cognition and attention,
`depression, irritability, sexual function and desire
`Irritability, impaired attention
`Aggression, confusion, depression, insomnia
`Irritability/agitation (usually in children with
`disabilities)
`Insomnia, irritability (usually in children with
`disabilities)
`Anxiety, depression, irritability (all appear more
`common in children)
`Depression, impaired attention
`Depression, irritability
`Depression, impaired cognition (word finding,
`memory) and attention, irritability
`Depression
`
`Aggression, emotional lability, irritability
`
`∗
`
`Signifies the existence of good, affirmative data from well-planned studies to support a beneficial effect.
`
`population are variable and unpredictable. Unfortunately, a his-
`tory of psychiatric illness may be a risk factor for negative
`psychotropic effects. Thus, beneficial psychotropic effects of
`AEDs, paradoxically, may be less relevant to epilepsy popula-
`tions. Use of sedating doses and combinations of AEDs that can
`impair cognitive and behavioral function should be avoided. Fi-
`nally, we must be wary of secondary effects of certain AEDs.
`For example, enzyme-inducing AEDs, such as CBZ, PHT, phe-
`nobarbital, and primidone, can increase sex hormone–binding
`globulin, reduce free (bioactive) testosterone, and thereby re-
`duce libido and impair sexual function. Although sexual interest
`and function are not considered psychotropic effects, perhaps
`they ought to be.
`
`References
`
`1. Devinsky O, Faught RE, Wilder BJ, Kanner AM, Kamin M,
`Kramer LD, Rosenberg A. Efficacy of felbamate monotherapy
`in patients undergoing presurgical evaluation of partial seizures.
`Epilepsy Res 1995;20:241–246.
`2. Ettinger AB, Jandorf L, Berdia A, Andriola MR, Krupp LB,
`Weisbrot DM. Felbamate-induced headache. Epilepsia 1996;37:
`503–505.
`3. Cramer JA, DeRue K, Devinsky O, Edrich P, Trimble MR. A sys-
`tematic review of the behavioral effects of levetiracetam in adults
`with epilepsy, cognitive disorders, or an anxiety disorder. Epilepsy
`Behav 2003;4:124–132.
`4. Landolt H. Serial electroencephalographic investigations during
`psychotic episodes in epileptic patients and during schizophrenic
`attacks. In: Lectures on Epilepsy (de Haas L, ed.). New York: Else-
`vier, 1958:3:91–133.
`5. Mula M, Trimble MR. The importance of being seizure free:
`
`Topiramate and psychopathology in epilepsy. Epilepsy Behav
`2003;4:430–434.
`6. Thomas L, Trimble M, Schmitz B, Ring H. Vigabatrin and be-
`haviour disorders: A retrospective survey. Epilepsy Res 1996;25:21–
`27.
`7. DeLeon OA. Antiepileptic drugs for the acute and maintenance
`treatment of bipolar disorder. Harv Rev Psychiatry 2001;9:209–
`222.
`8. Moller HJ. Non-neuroleptic approaches to treating negative
`symptoms in schizophrenia. Eur Arch Psychiatry Clin Neurosci
`2004;254:108–116.
`9. Rickels K, Pereira-Ogan JA, Chung HR, Gordon PE, Landis WB.
`Bromazepam and phenobarbital in anxiety: A controlled study.
`Curr Ther Res Clin Exp 1973;15:679–690.
`10. Schaffer LC, Schaffer CB, Carento J. The use of primidone
`in treatment of refractory bipolar disorder. Ann Clin Psychiatry
`1999;11:61–66.
`11. Brent DA, Crumrine PK, Varma R, Brown RV, Allan MJ. Pheno-
`barbital treatment and major depressive disorder in children with
`epilepsy. Pediatrics 1987;80:909–917.
`12. Stein G. Drug treatment of the personality disorders. Br J Psychi-
`atry 1992;161:167–184.
`13. Uhde TW, Stein MB, Post RM. Lack of efficacy of carba-
`mazepine in the treatment of panic disorder. Am J Psychiatry
`1988;145:1104–1109.
`14. Lima AR, Lima MS, Soares BG, Farrell M. Carbamazepine
`for cocaine dependence. Cochrane Database Syst Rev 2001;4:
`CD002023.
`15. Friedman DL, Kastner T, Plummer AT. Adverse behavioural ef-
`fects in individuals with mental retardation and mood disorders
`treated with carbamazepine. Am J Ment Retard 1992;96:541–
`546.
`16. Ketter TA, Malow BA, Flamini R, Ko D, White SR, Post RM,
`Theodore WH. Felbamate monotherapy has stimulant-like effects
`in patients with epilepsy. Epilepsy Res 1996;23:129–137.
`
`Page 00004
`
`

`
`180
`
`Current Review in Clinical Science
`
`17. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G.
`Gabapentin in bipolar disorder: A placebo-controlled trial of
`adjunctive therapy: Gabapentin Bipolar Disorder Study Group.
`Bipolar Disord 2000;2:249–255.
`18. Frye MA, Ketter TA, Kimbrell TA, Dunn RT, Speer AM,
`Osuch EA, Luckenbaugh DA, Cora-Ocatelli G, Leverich GS, Post
`RM. A placebo-controlled study of lamotrigine and gabapentin
`monotherapy in refractory mood disorders. J Clin Psychopharma-
`col 2000;20:607–614.
`19. McElroy SI, Soutulloi CA, Keck PE Jr, Kmetz GF. A pilot trial of
`adjunctive gabapentin in the treatment of bipolar disorder. Ann
`Clin Psychiatry 1997;9:99–103.
`20. Ryback R, Ryback L. Gabapentin for behavioral dyscontrol [Let-
`ter]. Am J Psychiatry 1995;152:1399.
`21. Moretti R, Torre P, Antonello RM, Cazzato G, Bava A.
`Gabapentin for the treatment of behavioural alterations in
`dementia: Preliminary 15-month investigation. Drugs Aging
`2003;20:1035–1040.
`22. McManaman J, Tam DA. Gabapentin for self-injurious behavior
`in Lesch-Nyhan syndrome. Pediatr Neurol 1999;20:381–382.
`23. Harden CL, Lazar LM, Pick LH, Nikolov B, Goldstein MA,
`Carson D, Ravdin LD, Kocsis JH, Labar DR. A beneficial ef-
`fect on mood in partial epilepsy patients treated with gabapentin.
`Epilepsia 1999;40:1129–1134.
`24. Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, Sinclair K,
`Gilliam F, Faught E. Cognitive effects of topiramate, gabapentin,
`and lamotrigine in healthy young adults. Neurology 1999;52:321–
`327.
`25. Dodrill CB, Arnett JL, Hayes AG, Garofalo EA, Greeley CA,
`Greiner MJ, Pierce MW. Cognitive abilities and adjustment
`with gabapentin: Results of a multisite study. Epilepsy Res
`1999;35:109–121.
`26. Lee DO, Steingard RJ, Cesena M, Helmers SL, Riviello JJ, Mikati
`MA. Behavioral side effects of gabapentin in children. Epilepsia
`1996;37:87–90.
`27. Ettinger AB, Barr W, Solomon S. Psychotropic properties of
`antiepileptic drugs in patients with developmental disabilities.
`In Developmental Disabilities (Devinsky O, Westbrook L, eds.).
`Boston: Butterworth-Heinemann, 2002:219–230.
`28. Kotler M, Matar MA. Lamotrigine in the treatment of resistant
`bipolar disorder. Clin Neuropharmacol 1998;21:65–67.
`29. Ghaemi SN, Gaughan S. Novel anticonvulsants: A new generation
`of mood stabilizers? Harv Rev Psychiatry 2000;8:1–7.
`30. Erfurth A, Walden J, Grunze H. Lamotrigine in the treatment of
`schizoaffective disorder. Neuropsychobiology 1998;38:204–205.
`31. McElroy SL, Zarate CA, Cookson J, Suppes T, Huffman RF,
`Greene P, Ascher J. A 52-week, open-label continuation study of
`lamotrigine in the treatment of bipolar depression. J Clin Psychi-
`atry 2004;65:204–210.
`32. Bowden CL, Asnis GM, Ginsberg LD, Bentley B, Leadbetter
`R, White R. Safety and tolerability of lamotrigine for bipolar
`disorder. Drug Saf 2004;27:173–184.
`33. Khan A, Ginsberg LD, Asnis GM, Goodwin FK, Davis KH,
`Krishnan AA, Adams BE. Effect of lamotrigine on cognitive
`complaints in patients with bipolar I disorder. J Clin Psychiatry
`2004;65:1483–1490.
`34. Pinto OC, Akiskal HS. Lamotrigine as a promising approach
`to borderline personality: An open case series without concur-
`rent DSM-IV major mood disorder. J Affect Diord 1998;51:333–
`343.
`
`35. Erfurth A, Walden J, Grunze H. Lamotrigine in the treatment of
`schizoaffective disorder. Neuropsychobiology 1998;38:204–220.
`36. Meador KJ, Baker GA. Behavioral and cognitive effects of lamot-
`rigine. J Child Neurol 1997;12:S44–S47.
`37. Beran RG, Gibson RJ. Aggressive behavior in intellectually chal-
`lenged patients with epilepsy treated with lamotrigine. Epilepsia
`1998;39:280–282.
`38. Ettinger AB, Weisbrot DM, Saracco J, Dhoon A, Kanner A,
`Devinsky O. Positive and negative psychotropic effects of lam-
`otrigine in epilepsy patients with mental retardation. Epilepsia
`1998;39:874–877.
`39. Mula M, Trimble MR, Sander JW. Psychiatric adverse events in
`patients with epilepsy and learning disabilities taking levetirac-
`etam. Seizure 2004;13:55–57.
`40. Sun M. Book touts dilantin for depression. Science 1982;215:951–
`952.
`41. Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH. Pheny-
`toin as an antimanic anticonvulsant: A controlled study. Am J
`Psychiatry 2000;157:463–465.
`42. Devinsky O. Cognitive and behavioral effects of antiepileptic
`drugs. Epilepsia 1995;36(suppl 2):46–65.
`43. Leppik IE. Tiagabine: The safety landscape. Epilepsia 1995;36:
`S10–S13.
`44. Dodrill CB, Arnett JL, Shu V, Pixton GC, Lenz GT, Sommerville
`KW. Effects of tiagabine monotherapy on abilities, adjustment,
`and mood. Epilepsia 1998;39:33–42.
`45. Carta MG, Hardoy MC, Grunze H, Carpiniello B. The use
`of tiagabine in affective disorders [Review]. Pharmacopsychiatry
`2002;35:33–34.
`46. Shapira NA, goldsmith TD, McElroy SL. Treatment of binge-
`eating disorder with topiramate: A clinical case series. J Clin Psy-
`chiatry 2000;61:368–372.
`47. Janowsky DS, Kraus JE, Barnhill J, Elamir B, Davis JM. Ef-
`fects of topiramate on aggressive, self-injurious, and disrup-
`tive/destructive behaviors in the intellectually disabled: An open-
`label retrospective study. J Clin Psychopharmacol 2003;23:500–
`504.
`study of add-on and
`JL. Prospective open-label
`48. Berlant
`monotherapy topiramate in civilians with chronic nonhalluci-
`natory posttraumatic stress disorder. BMC Psychiatry 2004;4:
`24.
`49. Van Ameringen M, Mancini C, Pipe B, Oakman J, Bennett M.
`An open trial of topiramate in the treatment of generalized social
`phobia. J Clin Psychiatry 2004;65:1674–1678.
`50. Besag FM. Behavioural effects of the new anticonvulsants. Drug
`Saf 2001;24:513–536.
`51. Dohmeier C, Kay A, Greathouse N. Neuropsychiatric complica-
`tions of topiramate therapy [Abstract]. Epilepsia 1998;39(suppl
`6):189.
`52. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger
`G. A double-blind, randomized trial of topiramate in Lennox-
`Gastaut syndrome: Topiramate YL Study Group. Neurology
`1999;52:1882–1887.
`53. Freeman TW, Clothier JL, Pazzaglia P, Lesem MD, Swann AC.
`A double-blind comparison of valproate and lithium in the treat-
`ment of acute mania. Am J Psychiatry 1992;149:108–111.
`54. Post RM, Ketter TA, Denicoff K, Pazzaglia PJ, Leverich GS,
`Marangell LB, Callahan AM, George MS, Frye MA. The place
`of anticonvulsant therapy in bipolar illness. Psychopharmacology
`1996;128:115–129.
`
`Page 00005
`
`

`
`Current Review in Clinical Science
`
`181
`
`55. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J,
`Revicki D. Suicide risk in bipolar disorder during treatment with
`lithium and divalproex. JAMA 2003;290:1467–1473.
`56. Reoux JP, Saxon AJ, Malte CA, Baer JS, Sloan KL. Dival-
`proex sodium in alcohol withdrawal: A randomized double-
`blind placebo-controlled clinical trial. Alcohol Clin Exp Res
`2001;25:1324–1329.
`57. Kastner T, Finesmith R, Walsh K. Long-term administration of
`valproic acid in the treatment of affective symptoms in people
`with mental retardation. J Clin Psychopharmacol 1993;13:448–
`451.
`58. Stoll AL, Banov M, Kolbrener M, Mayer PV, Tohen M, Strakowski
`SM, Castillo J, Suppes T, Cohen BM. Neurological factors pre-
`dict a favorable valproate response in bipolar and schizoaffective
`disorders. J Clin Psychopharmacol 1994;14:311–313.
`59. Baetz M, Bowen RC. Efficacy of divalproex sodium in patients
`with panic disorder and mood instability who have not re-
`
`sponded to conventional therapy. Can JPsy chiatry 1998;43:73–
`77.
`60. Stein DJ, Simeon D, Frenkel M, Islam MN, Hollander E. An
`open trial of valproate in borderline personality disorder. J Clin
`Psychiatry 1995;56:506–510.
`61. Ben-Menachem E, French J. Vigabatrin. In Epilepsy: A Comprehen-
`sive Textbook (Engel J, Pedley TA, eds.). Philadelphia: Lippincott-
`Raven, 1997:1609–1618.
`62. Levinson DF, Devinsky O. Psychiatric adverse events during vi-
`gabatrin therapy. Neurology 1999;53:1503–1511.
`63. Kanba S, Yagi G, Kamijima K, Suzuki T, Tajima O, Otaki J, Arata
`E, Koshikawa H, Nibuya M, Kinoshita N, et al. The first open
`study of zonisamide, a novel anticonvulsant, shows efficacy in
`mania. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:707–
`715.
`64. McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment
`of acute bipolar mania. Biol Psychiatry 2000;48:539–557.
`
`Page 00006