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Biological Therapies in Psychiatry
Alan J. Gelenberg, M.D.
Dr. Bob's
Psychopharmacology Tips

New Anticonvulsants in Bipolar and Other Psychiatric Disorders

From: Biological Therapies in Psychiatry
Date: June, 1997

Lithium is the only agent approved by the US Food and Drug Administration for the maintenance treatment of bipolar disorder. As we have noted previously, not every bipolar patient responds to lithium, nor can all tolerate it (BTP 1995; 18: 35, 1994; 17: 46-47). Some categories of patients are particularly problematic, including those with dysphoric and mixed episodes, rapid cyclers, patients with neurologic histories, and those with comorbid substance abuse. In some of these cases, anticonvulsants, singly or in combinations, often are tried. The two anticonvulsants most commonly used in bipolar patients are divalproex (Depakote), which is approved for the treatment of acute mania, and carbamazepine (Tegretol and others), which has been used longer for bipolar disorder but has been less rigorously studied. Their use has opened the door for clinicians to try two new anticonvulsants -- gabapentin (Neurontin) and lamotrigine (Lamictal) -- for bipolar patients. Both are indicated as adjunctive treatments for partial seizures in adults with epilepsy.

Gabapentin and Lamotrigine in Bipolar Disorder

Recently Schaffer and Schaffer reported on 28 patients treated in a private outpatient setting who had "refractory bipolar disorder." (1) These 4 men and 24 women, aged 21 to 56 years, had been incompletely responsive to lithium, valproate, or carbamazepine and consented to an open-label trial of gabapentin. Several patients continued to take other psychotropic drugs concomitantly. The daily doses of gabapentin were between 33 and 2700 mg with an average of 539 mg.

By global judgment of physician and patient, 18 of the 28 had a "positive response" and continued to take the drug for 1 to 9 months. Of the 10 who failed to improve, 2 were considered nonresponders and 8 discontinued gabapentin due to side effects -- most commonly sedation, activation, or increased cycling. The authors did not specify comorbidity, phase of illness, or other factors known to affect treatment response in bipolar patients.

In another cases series, five female inpatients -- three with bipolar disorder and two with schizoaffective disorder, bipolar type -- were treated with gabapentin, 600 to 2400 mg/day. (2) All were resistant to or intolerant of at least three other mood stabilizers, including valproate, carbamazepine, clozapine (Clozaril), traditional neuroleptics, and/or clonazepam (Klonopin). All took other medications concomitantly with gabapentin. Response to gabapentin was considered to be marked in three patients, moderate in one, and mild in another. Marked response was associated with higher dosages, and there were no significant side effects.

Stanton and others independently reported the successful use of gabapentin to treat mania in a 40-year-old man with bipolar disorder, alcohol dependence, and a history of bilateral frontal lobe injury from a motor vehicle accident. (3) The patient refused a trial of lithium, and doctors did not want to use valproate and carbamazepine due to his impaired hepatic function and blood coagulation factors. Starting gabapentin at a daily dose of 900 mg, they reached 3600 mg/day by the 4th day of treatment. After 10 days of taking gabapentin and no other psychotropic agents, the patient's score on the Young Mania Rating Scale decreased by half, with reductions in the full range of manic symptoms. Both the patient and his wife considered his improvement "dramatic." He had no side effects.

In an open trial, Fogelson and Sternbach treated five women and two men, aged 28 to 54 years, with lamotrigine for treatment-refractory bipolar disorder. (4) After 8 weeks of lamotrigine, 200 to 400 mg/day, three patients (all with rapid cycling) showed marked improvement, two showed moderate improvement, and two were unchanged. One patient discontinued lamotrigine after 8 weeks due to nausea.

Calabrese and coworkers describe another patient with rapid cycling bipolar disorder who responded to lamotrigine. (5) This 49-year-old man had failed to respond satisfactorily to individual trials of lithium, fluoxetine (Prozac and others), and carbamazepine. After 8 weeks of lamotrigine up to 200 mg/day, depression symptoms decreased by about 80%. He continued taking lamotrigine and remained euthymic for 11 months.

Walden and others report on a 39-year-old man with bipolar disorder who failed to improve on several different combinations of medications following hospitalization for a manic episode. (6) When lamotrigine was added to a regimen of valproic acid and trimipramine (Surmontil), the patient's condition gradually improved over several weeks. His lamotrigine dose of 150 mg/day had to be lowered to 100 mg/day when his lamotrigine blood levels increased from less than 2 ug/mL to 6.2 ug/ml, presumably as a result of an interaction with valproate.

Possible Uses in Other Psychiatric Disorders

Gabapentin might be useful in some cases of agitation in patients with organic brain syndromes. Regan and Gordan write of a 68-year-old woman with a 5-year history of Alzheimer's disease. (7) Associated agitation and violence had failed to respond to trials of buspirone (Buspar), fluoxetine, trazodone (Desyrel and others), and haloperidol (Haldol and others). After 3 weeks of treatment with gabapentin, 300 mg bid (in addition to haloperidol), the patient became calmer and easier to assist in daily activities. After 9 weeks, doctors were able to taper her daily dose of haloperidol to only 0.5 mg. Ryback and Ryback found gabapentin, 1200 mg/day, to be helpful as an adjunct to imipramine (Tofranil and others) for treating behavioral dyscontrol in an adolescent with intermittent explosive disorder, attention deficit hyperactivity disorder, and an organic mood disorder secondary to a head injury. (8) When Short and Cooke added gabapentin, 300 mg/day, to carbamazepine and lamotrigine to treat a patient with epilepsy, however, hypomanic symptoms occurred. (9)

Davanzo and King describe a favorable response to lamotrigine in an 18-year-old woman with generalized seizures and profound mental retardation. (10) Self biting had failed to respond to trials of naltrexone (Trexan), paroxetine (Paxil), and thioridazine (Mellaril and others). Carbamazepine brought excellent seizure control but failed to improve her self-injurious behavior. With lamotrigine, however, she became calmer and had much less self-injurious behavior, with benefits sustained over 1 year of treatment. Seizure control has been maintained, even though carbamazepine was tapered and discontinued. The patient's only side effect was mild to moderate constipation.

Pharmacology

Lamotrigine's mechanism of action is unknown, but animal models of self-injurious behavior suggest glutamatergic interactions, and lamotrigine may inhibit neuronal glutamate release. Following oral administration, lamotrigine is rapidly and completely absorbed with negligible first-pass metabolism. Its absolute bioavailability, which is not affected by food, is 98%. Peak plasma concentrations occur 1 to 5 hours after administration, and it is approximately 55% protein bound. Lamotrigine is metabolized primarily by glucuronic acid conjugation, its major metabolite is inactive, and its half-life is about 26 hours.

Gabapentin's mechanism of action is also unknown. It is not appreciably metabolized in humans, so all pharmacologic actions are due to the activity of the parent compound. Its elimination half-life is 5 to 7 hours. Because it is excreted intact almost entirely by the kidney, patients with renal insufficiency may require dosage adjustment, as levels can be greatly elevated. Gabapentin does not bind to plasma proteins and seems to be safe in overdose.

Adverse Reactions

There were 20 sudden and unexplained deaths during premarketing trials of lamotrigine among 4700 patients with epilepsy, and 8 such deaths out of 2203 patients taking gabapentin during premarketing development. These incidences are higher than that expected in a healthy population matched for age and sex but within the expected range for patients with epilepsy not being treated with lamotrigine or with gabapentin. Some of the deaths could have been from seizures that were not observed.

Approximately 10% of all individuals who take lamotrigine develop a rash, which usually occurs in the first 4 to 6 weeks of treatment. (11) The incidence of rash increases when lamotrigine is taken with valproate (which elevates concentrations) and may also be higher when lamotrigine is started at a higher dose or titrated more quickly. These are also risk factors for the development of a serious rash requiring hospitalization, such as the Stevens-Johnson syndrome, toxic epidermal necrolysis, or angioedema, which occur in 0.1% of adults and in 1% to 2% of pediatric patients taking this medication. (The incidence may be lower in adults not taking other medications concomitantly.) A warning has been added to lamotrigine's labeling concerning these life-threatening rashes. Patients are instructed to discontinue lamotrigine and consult a doctor at the first sign of a possible drug-related rash, as it is impossible to tell whether a rash will be severe or benign. Because of the increased risk in children, lamotrigine is not approved for patients under 16 years old. Sachs and others report a case of Stevens-Johnson syndrome associated with lamotrigine in a 30-year-old man. (12) The patient was also taking valproic acid, 2400 mg/day, and the rash developed 5 weeks after lamotrigine was added to this regimen.

Other case reports of serious adverse reactions with lamotrigine include: multiple organ failure, (13) encephalopathy, (14) fulminant hepatic failure, (15) leukopenia, (16) supraventricular extrasystoles and first-degree atrioventricular block, (17) and disabling tremor. (18) More benign side effects associated with lamotrigine treatment include dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, and vomiting. All but somnolence and headache appear to be dose related. Side effects associated with gabapentin are similar, with somnolence, dizziness, ataxia, fatigue, and nystagmus being the most common. Some physicians have found lamotrigine to be activating in some patients and gabapentin to be more sedating, (19) while others report the opposite. Serious adverse effects that have occurred in association with gabapentin include choreoathetosis, (20) an exacerbation of Lennox-Gastaut epilepsy, (21) and dystonic and myotonic movement disorder. (22)

Drug Interactions and Dosing

In a study of valproate and lamotrigine in 18 normal volunteers, Anderson and colleagues found that valproate markedly increased the half-life of lamotrigine and decreased its clearance, while lamotrigine decreased plasma concentrations of valproate to a lesser degree. (23) The authors recommend reducing lamotrigine dosages in patients taking this combination of antiepileptic drugs.

Lamotrigine is eliminated more rapidly in patients who have been taking hepatic enzyme-inducing antiepileptic drugs -- including carbamazepine, phenytoin, phenobarbital, and primidone.

For patients taking any of these anticonvulsants (not including valproate) with lamotrigine, lamotrigine should be started at 50 mg/day, increased to 50 mg bid after 2 weeks, and then increased again after 2 more weeks to 150 to 250 mg bid. For patients receiving lamotrigine in addition to enzyme-inducing antiepileptic drugs and valproate, the initial dose should be 25 mg every other day or 12.5 mg/day. This dose can be increased by 12.5 or 25 mg/day every 2 weeks. Because valproate more than doubles the elimination half-life of lamotrigine, the maximum daily dose of lamotrigine in patients taking both medications should not exceed 150 mg/day, and this should be administered in two divided doses.

The effective dose of gabapentin is 900 to 1800 mg/day in three divided doses. Titration to this level can take place rapidly: 300 mg on the first day, 300 mg bid on day 2, and 300 mg tid on day 3. Giving the first dose at bedtime may minimize side effects. Ivan Goldberg, MD, stated recently in his online psychopharmacology mailing list that it may be necessary to use as much as 900 mg tid to treat mixed states or rapid cycling bipolar disorder (written communication, April 1997). Gabapentin can be coadministered with carbamazepine or divalproex with no effect on blood drug levels.

Conclusion

Open-label studies, case series, and individual reports indicate that gabapentin and lamotrigine may be efficacious in the treatment of bipolar disorder and various other psychiatric indications. Some physicians have been using lamotrigine with success in the treatment of post-traumatic stress disorder, and we will surely hear of other uses of these new anticonvulsants as our experience with them in clinical practice grows. The manufacturer of lamotrigine is conducting several large multicenter studies in mania, bipolar depression, and maintenance treatment. We look forward to more such studies and increased information on these medications, which present therapeutic options for bipolar patients and others who have not responded to previously available treatments. For now, these novel agents should be considered as alternatives for primary or adjunctive therapy when more established treatments are ineffective or poorly tolerated. Their ultimate role in our armamentarium remains to be defined.

  1. Schaffer CB, Schaffer LC: Gabapentin in the treatment of bipolar disorder, letter to editor. Am J Psychiatry 1997; 154: 291-292.
  2. Bennett J, Goldman WT, Suppes T: Gabapentin for treatment of bipolar and schizoaffective disorders, letter to editor. J Clin Psychopharmacol 1997; 17: 141-142.
  3. Stanton SP, Keck PE Jr, McElroy SL: Treatment of acute mania with gabapentin, letter to editor. Am J Psychiatry 1997; 154: 287.
  4. Fogelson DL, Sternbach H: Treatment refractory bipolar disorder treated with lamotrigine. J Clin Psychiatry 1997; 58: 271-273.
  5. Calabrese JR, Fatemi SH, Woyshville MJ: Antidepressant effects of lamotrigine in rapid cycling bipolar disorder, letter to editor. Am J Psychiatry 1996; 153: 1236.
  6. Walden J, Hesslinger B, van Calker D, Berger M: Addition of lamotrigine to valproate may enhance efficacy in the treatment of bipolar affective disorder. Pharmacopsychiatry 1996; 29: 193-195.
  7. Regan WM, Gordon SM: Gabapentin for behavioral agitation in Alzheimer's disease, letter to editor. J Clin Psychopharmacol 1997; 17: 59-60.
  8. Ryback R, Ryback L: Gabapentin for behavioral dyscontrol, letter to editor. Am J Psychiatry 1995; 152: 1399.
  9. Short C, Cooke L: Hypomania induced by gabapentin, letter to editor. Br J Psychiatry 1995; 166: 679-680.
  10. Davanzo PA, King BH: Open trial of lamotrigine in the treatment of self-injurious behavior in an adolescent with profound mental retardation. J Child Adolesc Psychopharmacol 1996; 6: 273-279.
  11. Physicians' Desk Reference, 51st ed. Montvale, NJ, Medical Economics Company, 1997.
  12. Sachs B, Rönnau AC, Ruzicka T, Gleichmann E, Schuppe HC: Lamotrigine and toxic epidermal necrolysis, letter to editor. Lancet 1996; 348: 1597.
  13. Gregersen H, Nielsen JS, Peterslund NA: Acute porphyria and multiple organ failure during treatment with lamotrigine. Ugeskr Laeger 1996; 158: 4091-4092.
  14. Hennessy MJ, Wiles CM: Lamotrigine encephalopathy, letter to editor. Lancet 1996 347: 974-975.
  15. Makin AJ, Fitt S, Williams R, Duncan JS: Fulminant hepatic failure induced by lamotrigine. BMJ 1995; 311: 292.
  16. Nicholson RJ, Kelly KP, Grant IS: Leucopenia associated with lamotrigine. BMJ 1995; 310: 504.
  17. Steinhoff BJ, Stodieck SR, Tiecks FP, Wedel R, Polatschek B: Cardiac side effects and ECG changes with lamotrigine? -- A clinical study. Schweiz Arch Neurol Psychiatr 1994; 145: 8-12.
  18. Reutens DC, Duncan JS, Patsalos PN: Disabling tremor after lamotrigine with sodium valproate, letter to editor. Lancet 1993; 342: 185-186.
  19. Psychopharmacology online: Consultation, communication, and peer review on the information highway. An interview with Ivan K. Goldberg, M.D. Curr Affect Illness 1997; 16: 5-12.
  20. Buetefisch CM, Gutierrez A, Gutmann L: Choreoathetotic movements: A possible side effect of gabapentin. Neurology 1996; 46: 851-852.
  21. Vossler DG: Exacerbation of seizures in Lennox-Gastaut syndrome by gabapentin. Neurology 1996; 46: 852-853.
  22. Reeves AL, So EL, Sharbrough FW, Krahn LE: Movement disorders associated with the use of gabapentin. Epilepsia 1996; 37: 988-990.
  23. Anderson GD, Yau MK, Gidal BE, Harris SJ, Levy RH, Lai AA, Wolf KB, Wargin WA, Dren AT: Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 1996; 60: 145-156.

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[dr. bob] Dr. Bob is Robert Hsiung, MD, dr-bob@uchicago.edu

[dr. gelenberg] Alan J. Gelenberg, M.D.

URL: http://www.dr-bob.org/tips/split/New-anticonvulsant-bipolar.html
Original article copyright 1997 Biological Therapies in Psychiatry.
Web page copyright 1998 Robert Hsiung.