Antiepileptic Drugs, 5th Edition

Gabapentin

32

Clinical Efficacy and Use in Psychiatric Disorders

John H. Greist MD

Distinguished Senior Scientist, Madison Institute of Medicine; and Clinical Professor of Psychiatry, University of Wisconsin, Madison, Wisconsin

The utility of nonbenzodiazepine anticonvulsants in the treatment of bipolar illness has been shown in controlled studies (1). The notion that anticonvulsants may be useful in psychiatric conditions other than bipolar illness (e.g., anxiety or psychotic disorders) has not enjoyed the same benefit of controlled research. Although claims of anxiolytic effects have been made for phenytoin, carbamazepine, and valproate, little evidence exists to support such use. The improved tolerability of newer anticonvulsant agents has renewed interest in exploring their psychiatric uses.

Gabapentin was introduced in the early 1990s and is of interest for its potential psychotropic effects. Early studies in seizure disorders indicated that gabapentin possessed minimal cognition-impairing effects such as those commonly associated with the older antiepileptic drugs (2, 3, 4, 5, 6). Additionally, improvements in mood and well-being among epileptic patients who were taking gabapentin were reported in a retrospective data analysis (7) and were subsequently confirmed in a prospective study (8).

The published open-label reports to date on the utility of gabapentin for the treatment of anxiety and bipolar disorders are noted in Table 32.1. Numerous reports of patient series successfully treated with gabapentin for various psychiatric conditions have been presented at various scientific meetings but are not included here. Despite the multitude of published reports, systematic evaluation of the psychiatric uses of gabapentin has not been carried out, and gabapentin is not approved by any government agency in the United States for such uses.

ANXIETY DISORDERS

Preclinical data gathered early in the development of gabapentin showed anxiolyticlike effects in several animal models (9). Isolated anecdotal reports emerged over the years (10,11) and indicated the successful use of gabapentin to treat anxiety symptoms. Contemporaneously, we conducted two controlled clinical studies to test the hypothesis that gabapentin may be anxiolytic.

The first study (12) compared gabapentin and placebo in outpatients (n = 69) who were diagnosed with social phobia, according to the criteria of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), and who were treated for 14 weeks in a randomized, double-blind study design. Gabapentin was administered with doses given in a flexible escalating manner between the range of 900 and 3,600 mg/day. Using the Liebowitz Social Anxiety Scale as the primary measure of efficacy, this study found that patients taking gabapentin showed a significantly greater reduction in Liebowitz Social Anxiety Scale scores than those receiving placebo. The improvement seen with gabapentin was significantly greater than that observed with placebo after 1 week of treatment, and the superiority continued at each subsequent evaluation.

The second study (13) treated outpatients with DSM-IV-diagnosed panic disorder, with or without agoraphobia, in a randomized double-blind study lasting 8 weeks. Gabapentin was given in flexible doses of between 900 and 3,600 mg daily. The primary efficacy measure was the baseline to end point change in the total score of the Panic and Agoraphobia Scale (14), which is a composite measure of five domains of symptomatic and functional impairment in panic disorder. The protocol-specified analysis of efficacy did not show a difference between drug and placebo on the change in Panic and Agoraphobia Scale score. However, the same analysis on a subset of patients with at least a moderate severity of symptoms (as defined by a baseline total Panic and Agoraphobia Scale score of 20 or more) found that the drug-treated group showed a significantly greater improvement than the placebo-treated group.

The results of these studies, along with the experience of clinicians as mentioned in published case reports, provide preliminary evidence for the anxiolytic effects of gabapentin. Yet many unanswered questions remain. In addition to confirmation of the controlled trial results, a primary question centers on the dose-response curve in anxiety disorders. The doses used in the controlled trials were adjusted based on response and tolerability in the range of 900 to 3,600 mg daily given in three divided doses. Nearly two-thirds of the patients received doses >3,000 mg daily. Although these doses were well tolerated in both studies, the dose-response curve for anxiolytic effect can be definitively established only by fixed-dose studies. Anecdotal reports from experienced clinicians suggest that much smaller doses, perhaps in the range of 600 to 1,200 mg, may be sufficient to treat anxiety symptoms.

P.350

TABLE 32.1. PUBLISHED REPORTS OF UNCONTROLLED GABAPENTIN USE IN MOOD AND ANXIETY DISORDERS

Authors

Diagnosis

No. Patients

Dose/Regimen

Outcome

Ryback et al., 1997

Bipolar disorder

73

Variable, up to 3,600 mg/day

Good response in 67

Schaffer and Schaffer, 1997

Bipolar disorder

28

33-2,700 mg/day (mean, 539)

Good response in 18

Young et al., 1997

Bipolar depression

15

Flexible dosing

Full or partial response in 8

McElroy et al., 1997

Bipolar disorder (hypomanic, manic, or mixed)

9 consecutive

Adjunctive 300-4,800 mg/day

Moderate or marked improvement in 7 by 1 mo, in 1 by 3 mo; of these eight, six maintained their response at 1-7 mo follow-up

Stanton et al., 1997

Acute mania

1

3,600 mg/day

Marked improvement

Bennett et al., 1997

Bipolar disorder schizoaffective

5

Adjunctive 600-2,400 mg/day

Marked or moderate improvement in 4

Chouinard et al., 1998

Schizophrenia, schizoaffective disorder, bipolar disorder, generalized anxiety disorder

18

Adjunctive 100-4,400 mg/day

Improved sleep and reduced anxiety in all patients

Erfurth et al., 1998

Acute mania

14

1,200-4,800 mg/day alone or in combination

BRMAS 38 to 8 in add-on group (n = 6); 27 to 9 in 4/8 solo group (n = 8)

Soutullo et al., 1998

Acute mania and ADHD

1

1,500 mg/day added on to carbamazepine

Marked response within 1 mo

Ghaemi and Katzow, 1998

Bipolar or unipolar MDD

50

100-5,600 mg/day (mean 1,597 mg/day)

Moderate to marked efficacy in 15 (30%)

Knoll et al., 1998

Bipolar disorder

12

Adjunctive gabapentin, median top dose = 2,400 mg/day

Marked response in 1, moderate response in 7, mild response in 2 and no response in 2

Brown and Hong, 1999

Bipolar disorder with antidepressant-induced bruxism

1

Adjunctive

Complete resolution of bruxism

Young et al., 1999

Non-rapid-cycling bipolar disorder type I and II

37

Adjunctive, up to 6 mo

Significant reduction in manic and depressive symptoms

Grunze et al., 1999

Bipolar disorder type I

20*

1,200-4,800

BRMAS score declined significantly in patients with moderate mania, but gabapentin was not efficacious in patients with very severe mania

Cabras et al., 1999

Bipolar disorder schizoaffective

25

Adjunctive, flexible dosing (mean dose, 1,440 mg/day)

Positive response in 19 (76%)

Hatzimanolis et al., 1999

Acute mania

2

Adjunctive, flexible dosing

Moderate improvement after 2 wk of treatment

Maurer et al., 1999

MMD with somatoform pain disorder

1

Adjunctive, 1,800 mg/day

Remission of depression and pain

Perugi et al., 1999

Bipolar type I (mixed)

21

300-2,000 mg/day for 8 wk (mean dose, 1,130 mg/day)

Marked improvement in 4, moderate improvement in 6, mild worsening in 1; improvements maintained for 4-12 mo; HAMD decrease significantly

Sokolski et al., 1999

Bipolar disorder (mixed)

10

Adjunctive, flexible dosing

HAMD and BRMAS declined rapidly and significantly over 1 mo; improvement in insomnia

Hardoy et al., 1999

Schizoaffective and bipolar disorder with antipsychotic-induced movement disorder

16

Adjunctive, flexible dosing

14 patients showed improvement of movement disorders

Wang et al., 2000

Bipolar depression

23

Adjunctive, flexible dosing

60% response in mild to moderate depression, little or no response in severe depression

Vieta et al., 2000

Bipolar disorder type I and II

22

Flexible dosing (mean dose, 1,310 mg/day)

Two-point improvement on CGI-BP among 8 of 16 patients who completed 12 wk of treatment; those with anxious or depressive symptoms had the most improvement

ADHD, attention deficit/hyperactivity disorder; MDD, major depressive disorder.

P.351

 

The safety of gabapentin among patients with epilepsy is now well known (15, 16, 17, 18, 19), but the safety of the drug in anxious patients is less well described. Both the controlled studies showed a profile of adverse events consistent with that previously reported among epileptic patients. The most frequent adverse events were somnolence and dizziness that dissipated with continued treatment. Fewer data are available on adverse effects associated with cessation of gabapentin treatment. In both controlled anxiety studies, gabapentin was discontinued at the end of the trial by a rapid taper-down over 6 days. No overt withdrawal phenomena were observed, a finding suggesting that, unlike some other anxiolytics, gabapentin may not produce tolerance and withdrawal effects. One case report, however, suggested that rebound anxiety may occur after withdrawal of high-dose gabapentin among patients with obsessive-compulsive disorder (20). Until more data accrue on this issue, following the general clinical principle of withdrawing any antiepileptic agent gradually seems advisable.

MOOD DISORDERS

The data on the use of gabapentin in the treatment of bipolar disorder are more complicated. Several clinical reports first suggested that gabapentin, like other anticonvulsants, may be clinically useful in treating patients with bipolar disorder who are partially responsive to conventional mood stabilizers (21,22). Numerous case series (23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35) were subsequently reported, confirming that therapeutic benefit was associated with the addition of gabapentin to combination drug regimens in patients with bipolar illness who were refractory to other treatments (Table 32.1).

Several of these reports involve patients with acute mania treated with gabapentin alone or in combination with other drugs (36, 37, 38, 39, 40). In the treatment of acute mania, the most important contribution comes from an open-label prospective study (36,37) using gabapentin either alone or in combination with other antimanic agents. These two reports involved 20 acutely manic inpatients treated with gabapentin either alone or added to other antimanic drugs. Clinical symptom severity ratings were collected prospectively using the Bech-Rafaelsen Mania Scale. The authors of this study concluded that patients receiving gabapentin as adjunctive treatment derived greater benefit than those who received it as monotherapy. This finding may suggest that gabapentin treats some component of acute mania (e.g., comorbid anxiety, insomnia) that responds incompletely to traditional antimanic treatments. In this respect, gabapentin may be complementary to, rather than a substitute for, established antimanic agents. This idea is supported by another report of the open-label treatment of 22 patients with type I or II bipolar disorder (41). Of the 16 patients who completed 12 weeks of treatment, eight showed at least a two-point improvement on the Clinical Global Impression (Bipolar). The greatest improvement seemed to occur in patients with anxious and depressive features.

Some data suggest that the best candidates for adjunctive gabapentin treatment may be patients with bipolar depression in the mild to moderate range of severity (35). In this group, the rate of response was noted to be about 60%, whereas patients with more severe symptoms had little or no response.

Two controlled studies of gabapentin in bipolar disorder have been conducted. In a crossover design, Frye et al. (42) tested the utility of high-dose gabapentin (≤4,800 mg/day) among patients with bipolar disorder who were refractory to treatment with conventional mood stabilizer treatment (i.e., lithium, valproate, or carbamazepine). The patients were entered into a crossover study that included three randomized 6-week treatment periods with gabapentin, lamotrigine, or placebo. Only a modest benefit of gabapentin over placebo was demonstrated in the initial parallel-group portion of the study. Overall, the rate of improvement in mood symptoms on gabapentin did not differ from placebo.

Another study (43) involved patients with bipolar disorder (n = 117) treated with lithium, valproate, or the combination of the two and who were still manifesting manic, hypomanic, or mixed manic-depressed symptoms. After a 2-week single-blind placebo stabilization period to adjust the doses of lithium or valproate, patients were randomized to treatment with adjunctive gabapentin (900 to 3,600 mg/day) or placebo for 10 weeks. Their clinical status was rated using the Young Mania Rating Scale, the Hamilton Depression Rating Scale, the Internal States Scale, the NIMH-Life Chart, and the Clinical Global Impression of Change.

The results of this study were surprising in light of the previously published anecdotal reports of the beneficial effects of gabapentin in patients with bipolar disorder. Patients who received adjunctive placebo showed significantly greater reductions in the total Young Mania Rating Scale scores than those receiving adjunctive gabapentin. This difference was not explained by worsening in the gabapentin-treated group but by a larger therapeutic effect

P.352


in the placebo-treated group. Further data exploration showed that the group randomized to placebo included a large number of patients whose background therapy (mainly lithium) was adjusted during the stabilization period. It is conceivable that this treatment optimization may have produced the greater therapeutic effect seen among patients receiving placebo during the randomized treatment phase. A fuller discussion of the methodologic problems with this study has been published (43).

The discrepancy between anecdotal reports and the controlled studies on the use of gabapentin in bipolar disorder is puzzling. It is possible that the patient population selected for the two controlled studies differed in some fundamental respect from the sort of patients selected by clinicians on a case-by-case basis and included in the published case reports. Alternatively, gabapentin may have a beneficial effect on some component of the bipolar disorder symptom picture (e.g., comorbid anxiety) that is not adequately treated by agents such as lithium and valproate and that was not adequately measured in the controlled studies.

OTHER PSYCHIATRIC CONDITIONS

A few published reports discuss the use of gabapentin for the control of behavioral disorders associated with dementia (44, 45, 46, 47). This could be a valuable use for a well-tolerated drug such as gabapentin. Unfortunately, current knowledge on the use of gabapentin in this population lacks support from controlled studies.

Another promising application of gabapentin is enhancing abstinence during treatment of alcohol or cocaine abusers (48). Based on the association between postdetoxification insomnia and the risk of alcoholic relapse, it is proposed that using gabapentin to improve sleep may help to minimize resumption of drinking (49).

CONCLUSION

The data to date suggest that gabapentin is superior to placebo in reducing anxiety symptoms among patients with social phobia and in a subset of patients with panic disorder. The anxiolytic effect of gabapentin was shown in the social phobia study to be apparent as early as the first week of treatment. This speedy effect could be clinically useful, especially among patients requiring more rapid relief than that provided by the antidepressant drugs.

The efficacy of gabapentin in bipolar disorder is unclear. Anecdotal reports involving over 200 patients with bipolar disorder report therapeutic benefit on gabapentin treatment. Yet controlled studies have failed to detect such an effect. Several potential explanations exist for such a discrepancy that can only be resolved through further studies. In summary, gabapentin may be useful in the treatment of psychiatric symptoms in anxiety and other disorders, but a great deal more controlled research is required before definitive recommendations for such use can be made.

ACKNOWLEDGMENT

Atul C. Pande, MD, graciously reviewed this manuscript, and I appreciate his thoughtful criticisms.

REFERENCES

  1. Post RM, Frye MA, Denicoff KD, et al. Beyond lithium in the treatment of bipolar illness. Neuropsychopharmacology1998;19:206-219.
  2. Blum DE. New drugs for persons with epilepsy. Adv Neurol1998;76:57-87.
  3. Leach JP, Girvan J, Paul A, et al. Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy. J Neurol Neurosurg Psychiatry1997;62:372-376.
  4. Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology1999;52:321-327.
  5. Meador KJ, Loring DW, Ray PG, et al. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia1999;40:1279-1285.
  6. Mortimore C, Trimble M, Emmers E. Effects of gabapentin on cognition and quality of life in patients with epilepsy. Seizure1998;7:359-364.
  7. Dimond KR, Pande AC, Lamoreaux L, et al. Effect of gabapentin (Neurontin) [corrected] on mood and well-being in patients with epilepsy [published erratum appears in Prog Neuropsychopharmacol Biol Psychiatry1996;20:1081]. Prog Neuropsychopharmacol Biol Psychiatry 1996;20:407-417.
  8. Harden CL, Lazar LM, Pick LH, et al. A beneficial effect on mood in partial epilepsy patients treated with gabapentin. Epilepsia1999;40:1129-1134.
  9. Singh L, Field MJ, Ferris P, et al. The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine.Psychopharmacology (Berl)1996;127:1-9.
  10. Chouinard G, Beauclair L, Belanger MC. Gabapentin: long-term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders [Letter]. Can J Psychiatry1998;43:305.
  11. Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders [Letter]. Am J Psychiatry1998;155:992-993.
  12. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol1999;19:341-348.
  13. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol2000;20:467-471.
  14. Bandelow B. Assessing the efficacy of treatments for panic disorder and agoraphobia. II. The Panic and Agoraphobia Scale. Int Clin Psychopharmacol1995;10:73-81.
  15. McLean MJ. Gabapentin. Epilepsia1995;36[Suppl 2]:S73-S86.
  16. Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: a systematic review of their efficacy and tolerability. BMJ1996;313:1169-1174.
  17. Bourgeois BF. New antiepileptic drugs. Arch Neurol1998;55:1181-1183.

P.353

 

  1. Curry WJ, Kulling DL. Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin. Am Fam Physician1998;57:513-520.
  2. Shorvon S, Stefan H. Overview of the safety of newer antiepileptic drugs. Epilepsia1997;38[Suppl 1]:S45-S51.
  3. Cora Locatelli G, Greenberg BD, Martin JD, et al. Rebound psychiatric and physical symptoms after gabapentin discontinuation [Letter]. J Clin Psychiatry1998;59:131.
  4. Ryback RS, Brodsky L, Munasifi F. Gabapentin in bipolar disorder [Letter]. J Neuropsychiatry Clin Neurosci1997;9:301.
  5. Schaffer CB, Schaffer LC. Gabapentin in the treatment of bipolar disorder [Letter]. Am J Psychiatry1997;154:291-292.
  6. Young LT, Robb JC, Patelis Siotis I, et al. Acute treatment of bipolar depression with gabapentin. Biol Psychiatry1997;42:851-853.
  7. Young LT, Robb JC, Hasey GM, et al. Gabapentin as an adjunctive treatment in bipolar disorder. J Affect Disord1999;55:73-77.
  8. McElroy SL, Soutullo CA, Keck PE Jr, et al. A pilot trial of adjunctive gabapentin in the treatment of bipolar disorder. Ann Clin Psychiatry1997;9:99-103.
  9. Bennett J, Goldman WT, Suppes T. Gabapentin for treatment of bipolar and schizoaffective disorders. J Clin Psychopharmacol1997;17:141-142.
  10. Ghaemi SN, Katzow JJ, Desai SP, et al. Gabapentin treatment of mood disorders: a preliminary study. J Clin Psychiatry1998;59:426-429.
  11. Knoll J, Stegman K, Suppes T. Clinical experience using gabapentin adjunctively in patients with a history of mania or hypomania. J Affect Disord1998;49:229-233.
  12. Brown ES, Hong SC. Antidepressant-induced bruxism successfully treated with gabapentin. J Am Dent Assoc1999;130:1467-1469.
  13. Cabras PL, Hardoy MJ, Hardoy MC, et al. Clinical experience with gabapentin in patients with bipolar or schizoaffective disorder: results of an open-label study. J Clin Psychiatry1999;60:245-248.
  14. Hardoy MC, Hardoy MJ, Carta MG, et al. Gabapentin as a promising treatment for antipsychotic-induced movement disorders in schizoaffective and bipolar patients. J Affect Disord1999;54:315-317.
  15. Maurer I, Volz HP, Sauer H. Gabapentin leads to remission of somatoform pain disorder with major depression. Pharmacopsychiatry1999;32:255-257.
  16. Perugi G, Toni C, Ruffolo G, et al. Clinical experience using adjunctive gabapentin in treatment-resistant bipolar mixed states. Pharmacopsychiatry1999;32:136-141.
  17. Sokolski KN, Green C, Maris DE, et al. Gabapentin as an adjunct to standard mood stabilizers in outpatients with mixed bipolar symptomatology. Ann Clin Psychiatry1999;11:217-222.
  18. Wang PW, Winsberg ME, Santosa CM, et al. Open adjunctive gabapentin effective in bipolar depression. Biol Psychiatry2000;47[Suppl]:84S.
  19. Erfurth A, Kammerer C, Grunze H, et al. An open label study of gabapentin in the treatment of acute mania. J Psychiatr Res1998;32:261-264.
  20. Grunze H, Erfurth A, Amann B, et al. Gabapentin in the treatment of mania. Fortschr Neurol Psychiatr1999;67:256-260.
  21. Hatzimanolis J, Lykouras L, Oulis P, et al. Gabapentin as monotherapy in the treatment of acute mania. Eur Neuropsychopharmacol1999;9:257-258.
  22. Stanton SP, Keck PE Jr, McElroy SL. Treatment of acute mania with gabapentin [Letter]. Am J Psychiatry1997;154:287.
  23. Soutullo CA, Casuto LS, Keck PE Jr. Gabapentin in the treatment of adolescent mania: a case report. J Child Adolesc Psychopharmacol1998;8:81-85.
  24. Vieta E, Martinez-Arán A, Nieto E, et al. Adjunctive gabapentin treatment of bipolar disorder. Eur J Psychiatry2000;15:433-437.
  25. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol2000;20:607-614.
  26. Pande AC, Crockatt JG, Janney CA, et al. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disord2000;2:249-255.
  27. Dallocchio C, Buffa C, Mazzarello P. Combination of donepezil and gabapentin for behavioral disorders in Alzheimer's disease [Letter]. J Clin Psychiatry2000;61:64.
  28. Hawkins JW, Tinklenberg JR, Sheikh JI, et al. A retrospective chart review of gabapentin for the treatment of aggressive and agitated behavior in patients with dementias. Am J Geriatr Psychiatry2000;8:221-225.
  29. Herrmann N, Lanctot K, Myszak M. Effectiveness of gabapentin for the treatment of behavioral disorders in dementia. J Clin Psychopharmacol2000;20:90-93.
  30. Letterman L, Markowitz JS. Gabapentin: a review of published experience in the treatment of bipolar disorder and other psychiatric conditions. Pharmacotherapy1999;19:565-572.
  31. Myrick H, Malcolm R, Brady KT. Gabapentin treatment of alcohol withdrawal [Letter]. Am J Psychiatry1998;155:1632.
  32. Karam Hage M, Brower KJ. Gabapentin treatment for insomnia associated with alcohol dependence [Letter]. Am J Psychiatry2000;157:151.