The problem of treatment resistance in bipolar disorder begins with its definition. Characterizing the phases of bipolar disorder as manic, mixed, hypomanic, or depressed does not do justice to the reality for many persons with this disorder. Persistent symptoms of mood elevation, irritability, and depression are all too common in the short- and long-term course of mood episodes with this illness; return to complete euthymia is rare, and recurrence and relapse are the rule rather than the exception. Unlike other psychiatric illnesses, such as major depressive disorder, the many phases of bipolar disorder make a simple description of treatment resistance difficult.
Because bipolar disorder is almost always a recurrent illness, it is not merely the lack of resolution of any single mood episode that defines treatment resistance; instead, the core goal of the treatment of bipolar disorder is the prevention of relapse and recurrence. In spite of the multitude of guidelines available to inform clinicians about treatment decisions in bipolar disorder, little is known about how to achieve and maintain long-term wellness.1-4 It may be valuable to have a realistic understanding of the course of bipolar illness in order to help clinicians, patients, and families become better able to optimize care, minimize symptoms and morbidity, and improve functioning.
It is difficult to know the precise prevalence of treatment resistance in bipolar disorder for several reasons. Large studies of acute treatments for mood episodes in bipolar disorder--primarily designed to obtain FDA approval of those compounds--are almost universally placebo-controlled trials with narrow inclusion and broad exclusion criteria, and they are of little help in defining treatment resistance. Several large observational studies, most notably the National Institute of Mental Health (NIMH)-funded Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), have examined the longitudinal course of outpatients under more or less ideal treatment conditions and are useful for helping to define treatment resistance.5 In STEP-BD during 2 years of prospective follow-up under conditions of optimal care, only 58.4% of patients who entered the study or recovered from a mood episode ultimately achieved 8 consecutive weeks of euthymia; the vast majority of these patients never recovered from a depressive episode.6
Treatment resistance in bipolar disorder is almost always characterized by persistent or relapsing depression, and it is depression that is at the core of this problem. While bipolar disorder is diagnosed by the lifetime presence of manic, mixed, or hypomanic episodes, depression and depressive symptoms are most prominent in both bipolar I and bipolar II disorders. Longitudinal data from the NIMH Collaborative Depression Study7,8 found that in about three quarters of the weeks in which patients with bipolar I disorder reported significant symptoms, their symptoms were depressive; in those with bipolar II disorder, nearly all the sick weeks were spent depressed. This finding is consistent with data from STEP-BD that showed that nearly three quarters (71.6%) of relapses were with depressed episodes, compared with about one quarter (28.4%) that were manic, mixed, or hypomanic episodes.6
Rapid cycling, a course specifier for bipolar disorder, may be the prototypical treatment-refractory state. Defined as the occurrence of 4 distinct mood episodes (either a switch from 1 pole to the opposite, or 2 episodes of the same pole separated by at least 8 weeks of partial or full recovery) in the prior 12 months, rapid cycling is becoming understood as a marker for a treatment-refractory course. It is usually diagnosed retrospectively and is rarely persistent as defined by DSM-IV when patients are followed prospectively.
In STEP-BD, 32% of the patients entering the study reported 4 or more episodes in the previous year, yet only 6% of those patients had at least 4 episodes after 1 year of prospective follow-up.9 This suggests that patients who retrospectively report multiple mood episodes may in fact be chronically and persistently ill rather than having multiple discrete episodes. (It is possible, although not likely, that treatment in STEP-BD eliminated their rapid cycling.) What is most notable about patients who reported having 4 or more episodes in the previous year is that only 12% of them had no mood episode in the prospective year of follow-up. Rapid cycling is a marker of chronicity, frequent recurrence, and lack of sustained remission.
1. Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Bipolar Disorder. Australian and New Zealand clinical practice guidelines for the treatment of bipolar disorder. Aust N Z J Psychiatry. 2004;38:280-305.
2. Yatham LN, Kennedy SH, O'Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(suppl 3):5-69.
3. American Psychiatric Association. Practice Guidelines for the Treatment of Patients With Bipolar Disorder. 2nd ed. Washington, DC: American Psychiatric Publishing, Inc; 2002.
4. Goodwin GM; the Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2003;17:149-173.
5. Sachs GS, Thase ME, Otto MW, et al. Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2003;53:1028-1042.
6. Perlis RH, Ostacher MJ, Patel J, 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.
7. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59: 530-537.
8. Judd LL, 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;60:261-269.
9. Schneck C. What is the best treatment for rapid cycling? Presented at: American Psychiatric Association Annual Meeting; May 21-26, 2005; Atlanta.
10. Perlis RH, Miyahara S, Marangell LB, et al; STEP-BD Investigators. Long-Term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004;55: 875-881.
11. Weiss RD, Ostacher MJ, Otto MW, et al; STEP-BD Investigators. Does recovery from substance use disorder matter in patients with bipolar disorder? J Clin Psychiatry. 2005;66:730-735.
12. Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2004;161:2222-2229.
13. Waxmonsky JA, Thomas MR, Miklowitz DJ, et al. Prevalence and correlates of tobacco use in bipolar disorder: data from the first 2000 participants in the Systematic Treatment Enhancement Program. Gen Hosp Psychiatry. 2005;27:321-328.
14. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case for caution. Bipolar Disorders. 2003;5:421-433.
15. Simon NM, Otto MW, Weiss RD, et al. Pharmacotherapy for bipolar disorder and comorbid conditions: baseline data from STEP-BD. J Clin Psychopharmacol. 2004;24:512-520.
16. Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163:210-216.
17. 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.
18. Calabrese JR, Shelton MD, Rapport DJ, et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid cycling bipolar disorder. Am J Psychiatry. 2005;162:2152-2161.
19. 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.
20. Frank E, Gonzalez JM, Fagiolini A. The importance of routine for preventing recurrence in bipolar disorder. Am J Psychiatry. 2006;163:981-985.
21. Colom F, Vieta E, Martinez-Aran A, et al. A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry. 2003;60: 402-407.