Treatment-Resistant Bipolar Disorder - Practical Management

Practical Management
Management of patients with treatment-resistant bipolar disorder is complicated by the need to be vigilant about the possibility of affective switch, as well as the current symptomatology targeted for treatment. Self-reporting may be the only available means of evaluating the patient’s illness, yet this subjective information is itself colored by the pathological mood state. In addition, when bipolar disorder is associated with concurrent medical and psychiatric conditions, the treatment process becomes more complex. Using a systematic general approach to evaluation and treatment enables the treating psychiatrists to utilize an array of clinical tools necessary to meet the needs of these patients. These include daily charting of mood and treatments and sequencing treatments at each clinical decision point using a multiphase treatment strategy.

General Treatment Approach
Establish treatment alliance  After diagnosing bipolar illness, the single most important element is to establish a therapeutic alliance between patient and psychiatrist. Providing explicit detailed instructions and education about the illness and its treatment and discussing the anticipated problems in management will help establish this alliance.

The psychiatrist should make clear that, for the purpose of treating the mood disorder, the patient and psychiatrist are entering into a partnership. The goals of this alliance are to ensure the patient’s safety, to treat acute episodes, to attempt to prevent recurrence, and to maximize the patient’s quality of life between episodes. For most patients, these primary goals can be incorporated into an individualized written treatment contract authored by the patient with input from care providers, family, and friends. The contract sets out the parameters by which normal mood, depression, and mood elevation will be assessed and formulates a treatment plan for each phase of the illness. (Sample contracts and directions for writing treatment contracts are available at the Web site of the Harvard Bipolar Research Program,

Chart mood and treatments  Mood charting aids successful treatment and should be done by both the treating psychiatrist and the patient. All patients should be encouraged to chart their mood, sleep pattern, and treatment on a daily basis. At follow-up, psychiatrists can review the patient’s chart and incorporate this information into a monthly mood chart. The data accumulated over time in the mood charts provide a record of typical precipitants, frequency and duration of episodes, and possible seasonality of the illness. Knowledge of the individual patient’s mood cycles often enables the psychiatrist to better judge the impact of treatments and determine the most appropriate duration for the continuation phase of treatment.

Review and, if indicated, order further neuropsychiatric evaluation  Medication nonresponse may be due to other medical problems. Treatment resistance therefore calls for a review of the neuropsychiatric workup and additional studies if needed to determine if there is an organic cause of the nonresponse. Mixed episodes may arise spontaneously (simple), or they may result from the co-occurrence of a primary mood disorder and a secondary neuropsychiatric condition. The most common conditions affecting treatment outcome are alcohol/substance abuse, migraine headaches, nonparoxysmal electroencephalogram (EEG) abnormalities, ADHD, bulimia, thyroid disorders, and autoimmune disorders such as systemic lupus erythematosus and multiple sclerosis. Treatment of such secondary neuropsychiatric conditions may enhance the treatment of the mixed state (Himmelhoch and Garfinkel 1986).

To rule out general medical and neuroendocrine disease, appropriate physical examination and laboratory workup should be carried out if necessary. Thyroid disease appears to be common among patients, both as a preexisting condition and as a consequence of treatment (especially with lithium or carbamazepine). Given the association between thyroid disease (see below) and treatment-refractory conditions such as rapid cycling and mixed states, evaluation and optimization of thyroid status may be a key to improving treatment response. Unfortunately, practical management guidelines for thyroid function remain controversial because laboratory measures may vary widely and still be within the normal range. In light of this, use of a thyroid preparation for optimization of thyroid function could be recommended in two situations: 1) to achieve a normalization of thyroxine, free T4, or thyroid-stimulating hormone if these values are outside the normal range; or 2) to reestablish baseline thyroid function, if on repeated measurement one of these values has changed by 50% or more during the course of the illness, even while remaining within normal limits.

Eliminate cycle-promoting agents  Data from several studies show that the elimination of antidepressants from the treatment regimen may be the single most successful intervention for rapid cycling (Kukopulos et al. 1980; Wehr et al. 1988). These data also suggest that antipsychotics may promote cycling. Some patients improve when they discontinue antipsychotics. Discontinuation of antidepressants can have salutary effects on the cycle rate of non-rapid-cycling bipolar illness. Reduction of stimulants (including caffeine) and bronchodilators (e.g., albuterol, theophylline) also appears to be beneficial.

Encourage good mood hygiene  Improvement in treatment outcome can be achieved in some cases by educating the family and patient about the nature of the mood disorder and principles of good mood hygiene. Although studies associating the onset of episodes with environmental events demonstrate little correlation beyond the earliest episodes, many patients are able to use simple strategies to lessen conflict or avoid precipitants. Encouraging the patient to maintain a stable sleep-wake schedule and to avoid extremes in work, travel across time zones, diet, or exercise often has a salutary effect. Although there are no empirical data showing the effectiveness of these approaches in treatment-refractory bipolar disorder, the low cost and low risk associated with these commonsense strategies justify their recommendation.

Interestingly, most forms of psychotherapy seem to augment the prophylactic benefit of lithium (Cochran 1984; Hirshfeld et al. 1998; Kanas 1993; Lesser 1983; Mayo et al. 1979; Miklowitz et al. 1986, 1988; van Gent et al. 1988; Vasile et al. 1987). Although the active elements of psychotherapy remain unclear, the prophylactic efficacy of verbal therapies, as with lithium treatment, appears to require continued treatment. Many patients report beneficial experience from self-help groups such as the National Depressive and Manic Depressive Association.

Implement a specific treatment algorithm  It is often effective to offer patients choices selected from among the treatment options considered appropriate given the patients’ current diagnosis and history (individualized menu of reasonable choices). The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) arranges these options in pathways, presented in Figures

45-1 and 45-2. The algorithm for bipolar depression (see Figure 45-1) commences with the diagnosis of an acute depressive episode. The other algorithm (see

Figure 45-2) comprises mood-stabilizing treatments appropriate for rapid-cycling or other bipolar disorders with treatment-resistant cycling.

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Revision date: July 7, 2011
Last revised: by Dave R. Roger, M.D.