Several novel approaches have been suggested for treatment-resistant bipolar maintenance (either depression or cycling) including clozapine, at either low or standard doses, and maintenance ECT.35-38 Other approaches include augmentation with hypermetabolic thyroid supplementation, diltiazem, aripiprazole, topiramate, gabapentin, mexiletine, levetiracetam, and chromium, as well as vagus nerve stimulation.19,39-46 Efficacy has also been reported for levetiracetam monotherapy and a combination of topiramate and clozapine.47,48
Bipolar disorder is associated with significant morbidity. Numerous evidence-based treatments exist for all phases of bipolar disorder, and these should be optimized and fully explored before resorting to treatments with limited evidence of efficacy. Medication dosage should be titrated to response and emergence of adverse effects.
Combinations of evidence-based treatments are often used. When a treatment has failed, careful consideration should be made about whether it should be discontinued before adding another. Comorbidities such as substance abuse that complicate treatment must be minimized. Often, lithium or an anticonvulsant is used initially and an antipsychotic is added if response is not adequate. However, antipsychotics have been shown to be efficacious in nonpsychotic moderately ill bipolar manic and depressed patients. If evidence-based treatments are truly unsuccessful, clozapine and ECT have some evidence of efficacy as an augmentation to standard treatments. If these too fail, then novel treatments may be considered.
1. Gitlin MJ. Treatment-resistant bipolar disorder. Bull Menninger Clin. 2001;65:26-40.
2. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163:217-224.
3. Sachs GS. Treatment-resistant bipolar depression. Psychiatr Clin North Am. 1996;19:215-236.
4. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004; 161:564-566.
5. Lee JH, Dunner DL. The effect of anxiety disorder comorbidity on treatment resistant bipolar disorders. Depress Anxiety. 2008;25:91-97.
6. Rush AJ, Trivedi MH, Wisniewski SR, et al; STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
7. Blanco C, Laje G, Olfson M, et al. Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry. 2002;159:1005-1010.
8. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
9. Hirschfeld RM, Keck PE Jr, Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161:1057-1065.
10. McIntyre RS, Brecher M, Paulsson B, et al. Quetiapine or haloperidol as monotherapy for bipolar mania—a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005;15:573-585.
11. Fink M. ECT in therapy-resistant mania: does it have a place? Bipolar Dis. 2006;8:307-309.
12. Suppes T, Webb A, Paul B, et al. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. Am J Psychiatry. 1999;156:1164-1169.
13. Chanpattana W. Combined ECT and clozapine in treatment-resistant mania. J ECT. 2000;16:204-207.
14. Burt T, Sachs GS, Demopulos C. Donepezil in treatment-resistant bipolar disorder. Biol Psych. 1999;45: 959-964.
15. Perugi G, Toni C, Ruffolo G, et al. Clinical experience using adjunctive gabapentin in treatment-resistant bipolar mixed states. Pharmacopsychiatry. 1999;32:136-141.
16. Vieta E, Torrent C, Garcia-Ribas G, et al. Use of topiramate in treatment-resistant bipolar spectrum disorders. J Clin Psychopharmacol. 2002;22:431-435.
17. Madhusoodanan S, Bogunovic O, Brenner R, Gupta S. Use of topiramate as an adjunctive medication in an elderly patient with treatment-resistant bipolar disorder. Am J Geriatr Psychiatry. 2002;10:759.
18. Lung FW, Liu CL, Wang CS, Tzeng DS. Adjunctive topiramate treatment for refractory familial adolescent mania. World J Biol Psychiatry. 2009;10:74-77.
19. Schaffer A, Levitt AJ, Joffe RT. Mexiletine in treatment-resistant bipolar disorder. J Affect Disord. 2000; 57:249-253.
20. Heiden A, Frey R, Presslich O, et al. Treatment of severe mania with intravenous magnesium sulphate as a supplementary therapy. Psychiatry Res. 1999;89: 239-246.
21. Zarate CA Jr, Singh JB, Carlson PJ, et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study [published correction appears in Bipolar Disord. 2007;9:932]. Bipolar Disord. 2007;9:561-570.
22. Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58:347-354.
23. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry. 2007;64: 419-426.
24. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.
25. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163:232-239.
26. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007; 164:1242-1249.
27. Kayser S, Bewernick B, Axmacher N, Schlaepfer TE. Magnetic seizure therapy of treatment-resistant depression in a patient with bipolar disorder. J ECT. 2009;25:137-140.
28. Dell’Osso B, Mundo E, D’Urso N, et al. Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression. Bipolar Disord. 2009;11:76-81.
29. Sakkas P, Mihalopoulou P, Mourtzouhou P, et al. Induction of mania by rTMS: report of two cases. Eur Psychiatry. 2003;18:196-198.
30. Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162:1805-1819.
31. Denicoff KD, Smith-Jackson EE, Disney ER, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry. 1997;58:470-478.
32. Feinman JA, Dunner DL. The effect of alcohol and substance abuse on the course of bipolar affective disorder. J Affect Disord. 1996;37:43-49.
33. Dalton EJ, Cate-Carter TD, Mundo E, et al. Suicide risk in bipolar patients: the role of co-morbid substance use disorders. Bipolar Disord. 2003;5:58-61.
34. O’Brien CP, Charney DS, Lewis L, et al. Priority actions to improve the care of persons with co-occurring substance abuse and other mental disorders: a call to action. Biol Psychiatry. 2004;56:703-713.
35. Suppes T, Ozcan ME, Carmody T. Response to clozapine of rapid cycling versus non-cycling patients with a history of mania. Bipolar Disord. 2004;6:329-332.
36. Fehr BS, Ozcan ME, Suppes T. Low doses of clozapine may stabilize treatment-resistant bipolar patients. Eur Arch Psychiatry Clin Neurosci. 2005;255: 10-14.
37. Vaidya NA, Mahableshwarkar AT, Shahid R. Continuation and maintenance ECT in treatment-resis-tant bipolar disorder. J ECT. 2003;19:10-16.
38. Tsao CI, Jain S, Gibson RH, et al. Maintenance ECT for recurrent medication-refractory mania. J ECT. 2004;20:118-119.
39. Post RM, Altshuler LL, Frye MA, et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder. J Clin Psychiatry. 2005;66:370-374.
40. Bauer M, Berghöfer A, Bschor T, et al. Supraphysiological doses of L-thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders. Neuropsychopharmacology. 2002;27:620-628.
41. Silverstone PH, Birkett L. Diltiazem as augmentation therapy in patients with treatment-resistant bipolar disorder: a retrospective study. J Psychiatry Neurosci. 2000;25:276-280.
42. Perugi G, Toni C, Frare F, et al. Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity? J Clin Psychopharmacol. 2002;22:584-591.
43. Kemp DE, Dago PL, Straus JL, et al. Aripiprazole augmentation for treatment-resistant bipolar depression: sustained remission after 36 months. J Clin Psychopharmacol. 2007;27:304-305.
44. Amann BL, Mergl R, Vieta E, et al. A 2-year, open-label pilot study of adjunctive chromium in patients with treatment-resistant rapid-cycling bipolar disorder. J Clin Psychopharmacol. 2007;27:104-106.
45. Marangell LB, Suppes T, Zboyan HA, et al. A 1-year pilot study of vagus nerve stimulation in treatment-resistant rapid-cycling bipolar disorder. J Clin Psychiatry. 2008;69:183-189.
46. Nierenberg AA, Alpert JE, Gardner-Schuster EE, et al. Vagus nerve stimulation: 2-year outcomes for bipolar versus unipolar treatment-resistant depression. Biol Psychiatry. 2008;64:455-460.
47. Kaufman KR. Monotherapy treatment of bipolar disorder with levetiracetam. Epilepsy Behav. 2004;5: 1017-1020.
48. Chen CK, Shiah IS, Yeh CB, et al. Combination treatment of clozapine and topiramate in resistant rapid-cycling bipolar disorder. Clin Neuropharmacol. 2005;28:136-138.