In addition to being complex and pleomorphic in its own right, bipolar disorder is often accompanied by a host of other medical and psychiatric comorbidities. Recent evidence suggests that the illness is not as benign as originally considered and in some academic and outpatient settings, patients remain symptomatic almost half of their lives despite naturalistic treatment in the community. Bipolar disorder has considerable morbidity and mortality, both from suicide and medically related premature death.
The number of previous episodes is a potent risk factor for poor outcome. Yet, average delay to first treatment often hovers around a decade and much morbidity and comorbidity occurs and evolves during this untreated interval. In addition, each episode of depression and mania is associated with decrements in brain-derived neurotrophic factor and increases in oxidative stress, each of which can endanger neurons and be one component of the mechanism of episode sensitization (in which the greater the number of previous episodes, the greater the incidence and shorter the time to the next relapse).
Thus, it would appear that new approaches to earlier and more concerted illness interventions are required for patients who have bipolar disorder. Treating with the intent of achieving remission is a goal desired by most patients. Aggressive approaches to minor breakthroughs may prevent more major episode occurrences as well. Given the complexity of the disorder and the goal of achieving and maintaining remission, it appears that polypharmacy and complex combination therapy are often required to fulfill this mission.
Rationale for polypharmacy
The goal of remission should not be confused with that of the achievement of monotherapy as an end in itself, because that accomplishment may run counter to the goal of remission. Given the complex nature and frequent and multiple comorbidities of the disorder, it would be unrealistic to expect monotherapy to be sufficient for most persons with bipolar illness. Moreover, the notion that monotherapy is often sufficient for the management of the illness is based on several myths and misconceptions.
First, although lithium monotherapy might appear to have a high rate of response, this medication is typically given in conjunction with other agents, such as antidepressants, antipsychotics, benzodiazepines, thyroid medications, and multivitamins. Other misconceptions derive from the FDA approval process, in which approval is based on the ability of the active drug to exceed the efficacy of placebo, not on the achievement of a preset clinically robust standard desired by most clinicians. Second, and related to this point, a success rate of 50% is used in most analyses, and only rarely is major consideration given to the desired end point of remission. Finally, FDA registration, with the sole exception of lamotrigine, has been based on approval for the acute treatment of mania rather than long-term outcome. Therefore, it is clear that approval of a drug for monotherapy is not synonymous with the establishment of sufficient efficacy against all of the therapeutic targets that one seeks for patients with bipolar disorder.
In most other chronic or recurrent medical disorders, combination treatment is not only widely practiced but also the standard of care. One need only to think about triple antiretroviral therapy for AIDS, triple antibiotic therapy for tuberculosis, or the multiple medications for cancers, heart disease, and rheumatoid arthritis to see that polypharmacy for patients with bipolar disorder is not unconventional but typical of many other disorders. Multimodal therapies are used not only to achieve the desired therapeutic goal of an excellent response or complete remission but also for the prevention of loss of efficacy because of the development of treatment resistance. There may also be multiple neurochemical systems involved in bipolar disorder and not just a single deficit, as we see with dopamine in Parkinson disease or the defect in huntington protein in Huntington chorea.
Although the positive evidence for the superiority of using complex regimens in bipolar illness is scarce, the "negative" evidence is plentiful. In a study by Calabrese and colleagues,1 two of the best and most widely used drugs—lithium and valproate—when used in combination, were sufficient to acutely stabilize only 25% of the patients with rapid cycling bipolar disorder so that they could enter a randomized monotherapy trial. Half of these patients proceeded to relapse with either monotherapy, suggesting that barely 12.5% of patients with rapid cycling are likely to respond to monotherapy, and this does not include achieving and/or maintaining remission. Whereas some might argue that rapid cycling patients make up only a small percentage of the total population with bipolar illness, in our outpatient network we found that approximately 40% of retrospectively reported and 38% of prospectively rated patients met the criteria of 4 or more episodes per year, despite treatment with an average of more than 3 drugs.2,3
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