Pathology and Management of Treatment Resistance in Bipolar Disorder

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 Study^7,8 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.