Michael J. Ostacher, MD, MPH

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.

 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.

 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.

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

 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.

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 

 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.

 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.

How, then, do we define treatment resistance in bipolar disorder? Given that two fifths of patients in STEP-BD who entered the study during a mood episode never had 8 consecutive weeks of relative euthymia in 2 years of follow-up (ie, fully recovered from a mood episode), treatment resistance in bipolar disorder might be defined as the absence of sustained remission of at least 8 weeks in 2 years. Even as defined over such an extended period, its prevalence is remarkably high (at least in those who were referred to STEP-BD; it may be less prevalent in general psychiatric practice.)

Using this definition, it becomes clear that the outcomes reported in most randomized controlled trials of treatments for bipolar disorder, while important in terms of determining which treatments have any benefit at all, are inadequate. It is not meaningful for patients to have a 50% reduction in their symptoms or even to reach a point in which their symptoms are minimal unless that improvement is persistent; it is essential that they reach a point of sustained recovery, however elusive this goal may be.

Factors that increase the probability of treatment resistance are well known. Comorbid anxiety disorders (present in upwards of 50% of patients with bipolar I and II disorder), active and past substance use disorders (including nicotine dependence), and earlier age at onset of the mood disorder are all associated with the persistence of symptoms, more frequent episodes, and less healthy time.

 The associations between treatment resistance and disruptions in social rhythms, sleep, and environmental stress are less well documented in the literature, but it appears that regularization of sleep hours, increased contact with a support network, and adherence to a daily structure will increase well-being and improve the possibility of sustained remission.

The difficulty of treating relapsing bipolar disorder is complicated by the illness becoming refractory as a result of iatrogenic causes. These can be active or passive in their form. It is important to identify and eliminate medications and treatments that may perpetuate symptoms. Antidepressants are the most common and likely suspects, although data for determining the extent of their effect on the switch to mania and rapid cycling are limited and may be patient-specific (ie, related to patient factors rather than intrinsic to the compound).

Given the predominance and persistence of depressive symptoms in bipolar disorder, it is understandable why clinicians and patients would be eager to prescribe standard antidepressants. (What patient wants to hear, in the midst of a chronic depression, that his or her physician will not prescribe an antidepressant?) Minimizing their use, however, may hasten rather than delay recovery. Other agents, notably stimulants, should be examined for their role in the worsening of symptoms in each individual, and the myriad of medications for physical illness (eg, corticosteroids, oral contraceptives) should also be minimized. Certain psychotherapies are thought to increase anxiety and mood instability. The form and content of psychosocial approaches should be examined for their role in worsening symptoms; again, validated psychotherapeutic interventions are preferred over those not specifically studied in bipolar disorder.

Passive iatrogenic causes of persistent illness are potentially a larger problem. The inadequacy in terms of dose and duration of treatment for many illnesses, not merely bipolar disorder, is well documented in the literature but is a problem often overlooked as a cause of treatment resistance.

 The armamentarium available for the treatment of bipolar disorder is hardly benign--there is not an approved drug for any phase of bipolar disorder without a black box warning in its labeling--so it is understandable that clinicians and patients would choose medications and doses of medications perceived to be more tolerable.

STEP-BD established a consensus on adequacy of mood stabilizer treatment, and a systematic approach on the part of patients and their physicians to achieve adequate medication treatment through an effort to measure and manage care must be a cornerstone of bipolar care.

 Suggestions for adequate doses of medications are presented in the 

. Medications that have been studied in adequately powered randomized trials should always be preferred over agents without adequate data to support their use, however well tolerated they are thought to be.

A therapeutic trial of category A treatment for bipolar disorder may be defined as an adequate  dose for an adequate duration of the following agents: lithium, valproic acid, lamotrigine, carbamazepine,  olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. The dosing  and duration of treatment is dependent on the indication of the agent at the time of  prescription.

 Acute treatment indications: a treatment duration of 8 weeks is suggested as a “probably”  adequate time period for acute treatment indications such as bipolar depression, mixed  states, mania, and hypomania. A duration of at least 4 weeks may be considered “possibly”  adequate.

  Maintenance treatment indications: treatments should be evaluated over a period of at least  6 months (or 3 times the cycle interval) to determine the efficacy of maintenance treatments.  No minimum maintenance doses are suggested for atypical antipsychotics.

Prospective randomized studies examining different aspects of treatment resistance in any phase of bipolar disorder are remarkably lacking, especially given the magnitude and breadth of the problem. A recent study from STEP-BD examined the question of whether randomization to 1 of 3 open-label treatments--risperidone, lamotrigine, or inositol (a sugar alcohol)--added to a mood stabilizer would be effective in an episode of bipolar depression that was resistant to treatment with a mood stabilizer combined with at least 2 consecutive trials of standard antidepressants.

 The primary outcome measure was defined as 8 consecutive weeks of euthymia. Because of the randomization schema and small sample size, no drug was clearly more effective than another and the overall response rate was disappointingly small. Post-hoc analyses did suggest that because of a higher response rate for lamotrigine (27%)--response rates for inositol and risperidone were 18% and 4%, respectively--that drug might be of more benefit for these patients. However, because the analyses were secondary and post hoc, this benefit was not definitive. A small trial of pramipexole for refractory bipolar depression also showed potential benefit for these patients.

An important study by Calabrese and colleagues

 attempted to examine the relative benefit of lithium versus divalproex sodium for the treatment of rapid cycling. Interestingly, the randomized portion of the study did not find a difference in time to recurrence of a mood episode after prolonged stabilization on open-label treatment with both drugs. The most compelling finding of the study was that only a quarter of the patients whom the researchers attempted to stabilize on both drugs ever made it to the randomized phase; those who did not complete the study because of nonresponse were almost all unable to recover from depression. Another randomized study examined treatment of refractory patients with bipolar disorder and compared open-label clozapine added to treatment with usual care; the study found a decrease in symptoms in the patients who received clozapine.

Medication management without psychoeducation and psychosocial interventions in treatment-resistant patients is not optimum care. The importance of regularizing social rhythms and decreasing behaviors associated with mood fluctuation (ie, substance use, irregular hours of sleep, ongoing conflicts in relationships and work, poor adherence to medications, lack of regard for physical health) cannot be overly stressed; at the least, ongoing psychoeducation about the course and treatment of bipolar disorder must be part of the communication among physicians, patients, and their families.

 Behavior change may come slowly, but a focus on it must be maintained and monitored.

Ongoing management of medications, psychosocial treatments, and lifestyle interventions and the measurement of responses to changes in treatment are necessary to avoid ineffective treatment and to ensure that all aspects of care are continuously addressed. The following case of a young woman with treatment-resistant bipolar I disorder, whose treatment was adjusted and measured over time using an iterative approach to care, illustrates the time and detail that is necessary to stabilize these patients' difficult illnesses.

A 37-year-old woman, formerly employed as a financial analyst, had become disabled by symptoms of bipolar disorder. Through her 20s she had been able to progress in her career in spite of several hospitalizations for depression and multiple short manic episodes in which she would buy antiques and art, drink heavily, and have sexual liaisons with men she had recently met. She had been through multiple trials of medications--including lithium, divalproex sodium, and carbamazepine--all of which she ultimately rejected because of adverse effects. After a prolonged manic episode at age 31 that required hospital care and a leave of absence from her job, she became severely anergically depressed and did not get out of bed or bathe for days on end.

She refused treatment with the previously mentioned medications and ultimately insisted on treatment with a high-dose SSRI (citalopram), benzodiazepines, and 2 atypical antipsychotics. It was initially planned that she would discontinue olanzapine after aripiprazole was started, but she did not stop taking quetiapine because of persistent racing thoughts, irritability, and insomnia; she continued to take these medications for 2 years even though she gained 40 pounds.

Rigorous daily mood charting documented only a single 10-week period of euthymia in 5 years of prospective follow-up as she cycled through severe depression and short periods of mania or hypomania. Lamotrigine 200 mg was added to her regimen, decreasing the severity of her depressive symptoms, but she did not have a prolonged period of euthymia. Reluctantly, she agreed to taper her SSRI and have fewer periods of mood elevation. Her depressive episodes fluctuated from weeks of few symptoms to periods of paralyzing anergia and anhedonia, and she would restart her SSRI if her periods of severe symptoms lasted more than 1 week.

Ultimately she was hospitalized because of the onset of persistent wishes to die, with a plan to overdose on opiates. In the hospital, her medication history was reviewed and she agreed to restart lithium and discontinue the SSRI. Lithium had previously worsened her acne and caused a marked tremor, but the patient was willing to try a potentially helpful medication, and her dosage was increased to 900 mg/d and a serum level of 0.9 mEq/L. Aripiprazole was continued at 30 mg/d but clonaze- pam, which she had been receiving at a total daily dose of 5 mg, was tapered and discontinued.

Discharge plans included group treatment in dialectical behavior therapy for skills training and short-term individual cognitive-behavioral therapy. She found regular work in a retail store near her home; she felt that the regular hours and straightforward nature of the position would keep her interacting with others, help her earn a small income, and prevent her from retreating to her bedroom. Ultimately her depressive symptoms remitted, but she continued to have significant fatigue. Modafinil was added, raised to 400 mg in the morning, and her fatigue remitted. She no longer drinks alcohol. After 6 months without a mood episode or significant residual symptoms of depression or mania, she began a romantic relationship and is using nonhormonal contraception. She has remained episode-free for 16 months. Her current daily treatment regimen consists of 900 mg of lithium carbonate, 200 mg of lamotrigine, 30 mg of aripiprazole, and 400 mg of modafinil.

It cannot be stressed enough that the care of a vast proportion of patients with bipolar disorder must be optimized over a period of years, not weeks or months, and is effected by the application not only of medical treatments (which are a critical piece of the overall treatment) but also by the engagement of patients in an iterative process of behavioral change that includes appropriate cognitive and educational psychosocial treatments. By the rigorous measurement of responses to treatment and by managing care based on those measurements, ineffective and harmful treatments can be minimized or eliminated and effective treatments (psychopharmacologic as well as psychotherapeutic) can be used for realistic durations.

Dr Ostacher is associate medical director of the Bipolar Clinic and Research Program at Massachusetts General Hospital and an instructor in psychiatry at Harvard Medical School in Boston. He reports that he has received research support from Pfizer Inc and honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer Inc, and Concordant Rater Systems.

 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. 

 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. 

Practice Guidelines for the Treatment of Patients With Bipolar Disorder

. 2nd ed. Washington, DC: American Psychiatric Publishing, Inc; 2002.


 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. 

 Sachs GS, Thase ME, Otto MW, et al. Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD). 

 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). 

 Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. 

 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. 

 Schneck C. What is the best treatment for rapid cycling? Presented at: American Psychiatric Association Annual Meeting; May 21-26, 2005; Atlanta.


 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). 

 Weiss RD, Ostacher MJ, Otto MW, et al; STEP-BD Investigators. Does recovery from substance use disorder matter in patients with bipolar disorder? 

 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). 

 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. 

 Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case for caution. 

 Simon NM, Otto MW, Weiss RD, et al. Pharmacotherapy for bipolar disorder and comorbid conditions: baseline data from STEP-BD. 

Articles

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.

Michael J. Ostacher, MD, MPH

Articles

Pathology and Management of Treatment Resistance in Bipolar Disorder