Evidence-Based Reviews

When bipolar treatment fails: What’s your next step?

Current Psychiatry. 2008 January;7(1):39-46

References

1. Judd JL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;61:261-9.

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 (STEPBD). Am J Psychiatry 2006;163:217-24.

3. Altschuler LL, Post RM, Leverich GS. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995;152:1130-8.

4. Osterberg L, Blaschke T. Drug therapy: adherence to medication. N Engl J Med 2005;353:487-97.

5. Kusalic M. Grade II and grade III hypothyroidism in rapid cycling bipolar patients. Biol Psychiatry 1992;25:177-81.

6. Franks RD, Dubovsky SL, Lifshitz M, et al. Long-term lithium carbonate therapy causes hyperparathyroidism. Arch Gen Psychiatry 1982;39:1074-7.

7. Allen MH, Hirschfeld RMA, Wozniak PJ, et al. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry 2006;163:272-5.

8. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially responsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002;59:62-9.

9. Pazzaglia P, Post RM, Ketter TA, et al. Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness. J Clin Psychopharmacol 1998;18:404-13.

10. Conway CR, Chibnall JT, Nelson LA, et al. An open-label trial of adjunctive oxcarbazepine for bipolar disorder. J Clin Psychopharmacol 2006;26:95-7.

11. Calabrese JR, Kimmel SE, Woyshville MJ, et al. Clozapine for treatment-refractory mania. Am J Psychiatry 1996;153:759-64.

12. Mukherjee S, Sackeim HA, Schnur DB. Electroconvulsive therapy of acute manic episodes: a review of 50 years’ experience. Am J Psychiatry 1994;151:169-76.

13. Michael N, Erfurth A. Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation. J Affect Disord 2004;78:253-7.

14. Baldessarini RJ, Leahy L, Arcona S, et al. Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv 2007;58:85-91.

15. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007;356:1711-22.

16. Cookson J, Keck PE, Jr, Ketter TA, Macfadden W. Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study. Int Clin Psychopharmacol 2007;22(2):93-100.

17. Tohen M, Vieta E, Calabrese JR, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079-88.

18. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry 2002;159:116-21.

19. Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet 2007;369:935-45.

20. Kishimoto A. The treatment of affective disorder with carbamazepine: prophylactic synergism of lithium and carbamazepine combination. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:483-93.

21. McElroy SL, Zarate CA, Cookson J, et al. A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. J Clin Psychiatry 2004;65:204-10.

22. 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;64:419-26.

23. Ketter TA, Post RM, Parekh PI, Worthington K. Addition of monoamine oxidase inhibitors to carbamazepine: preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression. J Clin Psychiatry 1995;56:471-5.

24. Himmelhoch JM, Thase ME, Mallinger AG, Houck PR. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991;148:910-6.

25. Zarate CAJ, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004;56:54-60.

26. Lam JY, Freeman MK, Cates ME. Modafinil augmentation for residual symptoms of fatigue in patients with a partial response to antidepressants. Ann Pharmacother 2007;41:1005-12.

27. 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;164:1242-9.

28. Anand A, Bukhari L, Jennings SA, et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry 2005;66:195-8.

29. 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;66:370-4.

30. Zarate CAJ, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856-64.

31. Zarate CAJ, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 2005;57:430-2.

32. Nahas Z, Kozel FA, Li X, et al. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003;5:40-7.

33. Schneck CD. Treatment of rapid-cycling bipolar disorder. J Clin Psychiatry 2006;67(suppl 11):22-7.

34. Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder, I: Association with grade I hypothyroidism. Arch Gen Psychiatry 1990;47:427-32.

35. Okuma T, Yamashita I, Takahashi R, et al. Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. Pharmacopsychiatry 1990;23:143-50.

36. Calabrese JR, Meltzer HY, Markovitz PJ. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol 1991;11:396-7.

37. Goodnick PJ. Nimodipine treatment of rapid cycling bipolar disorder. J Clin Psychiatry 1995;56:330.-

Combine mood stabilizers. After optimizing the dose of a single mood stabilizer, add a second one from a different class. In an open trial, adding oxcarbazepine, up to 2,400 mg/d, helped approximately one-third of 20 patients with refractory mood cycling.¹⁰ Lithium is generally considered less effective than anticonvulsants in rapid cycling, but at least one study showed it was equivalent to carbamazepine for this problem.³⁵ Lithium combined with other mood stabilizers may be more effective than lithium monotherapy in refractory bipolar states.

Other options to consider in combination with mood stabilizers:

an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states³⁶ (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
nimodipine, which has empiric support for complex mood cycling³⁷ and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens³⁴ (but risks of inducing hyperthyroidism make this intervention third-line).

ECT can be effective for refractory rapid cycling, but some patients need more treatments than are usually necessary for mania or depression.

Related resources

Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.

Drug brand names

Bupropion • Wellbutrin
Carbamazepine • Tegretol
Clonazepam • Klonopin
Clozapine • Clozaril
Fluoxetine • Prozac
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lithium • Lithobid, others
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Concerta, Ritalin, others
Modafinil • Provigil
Nimodipine • Nimotop
Olanzapine/fluoxetine • Symbyax
Oxcarbazepine • Trileptal
Paroxetine • Paxil
Pramipexole • Mirapex
Pregabalin • Lyrica
Quetiapine • Seroquel
Riluzole • Rilutek
Selegiline • Eldepryl
Topiramate • Topamax
Tranylcypromine • Parnate
Valproate • Depakene, Depakote
Venlafaxine • Effexor
Verapamil • Calan, Isoptin, others
Zonisamide • Zonegran

Disclosures

Dr. Mostert reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Dubovsky receives research/grant support from Eli Lilly and Company, Organon, Pfizer, UCB Pharma, anhd Forest Laboratories. He is a consultant to Oganon and Biovail Pharmaceuticals.