In a study by Denicoff and colleagues,4 only about one quarter of the patients who were rapid cyclers had a good response to lithium(Drug information on lithium) or carbamazepine(Drug information on carbamazepine) monotherapy (even though each year of treatment allowed adjunctive use of antipsychotics, benzodiazepines, and antidepressants, so it was not really monotherapy). In comparison, about 50% of the patients responded to a year of combination therapy.
A final rationale for polypharmacy is perhaps a surprising one, and that is the achievement of the desired therapeutic goals in the absence of adverse effects. While the use of more drugs for fewer adverse effects might seem paradoxical, it can be easily realized when each agent is administered below the patient's adverse-effects threshold, rather than attempting to push a single drug to sufficient levels to achieve efficacy. When the latter was done with lithium therapy, better effects of lithium were achieved with higher rather than lower doses or blood level targets but at the cost of a 3-fold greater incidence of adverse effects.5
The lack of a controlled clinical database for complex combination therapy in bipolar disorder should not be used as the reason for not proceeding with the best clinical treatment options for a patient, since mental health research and, in particular, research on bipolar disorder is vastly underfunded. The needed clinical trial database is not likely to be forthcoming in the foreseeable future, but its absence cannot be used as a rationale for not proceeding on the basis of one's best clinical judgment and the patient's best clinical interests.
Principles of polypharmacy
How one proceeds to develop the best complex combination therapy for a patient is crucial to a good outcome. Each drug and the entire regimen need to be managed with great care in attempting to balance the achievement of optimal therapeutic gains with a new medication and the absence of adverse effects. A careful patient diary that includes information on mood, medication, sleep, and side effects is of great importance in this therapeutic balancing act. Arriving most rapidly at the optimal treatment regimen for a given individual often involves a compromise of academic rigor in favor of clinical expediency.
If, for example, the addition of lithium to valproate(Drug information on valproate) did not make a substantial clinical difference in symptomatic improvement yet did not engender problematic side effects, one might recommend not discontinuing lithium, but adding a new adjunctive agent to the existing lithium/valproate combination. Although lithium may not have provided the desired therapeutic effect, its withdrawal could nonetheless produce a clinical exacerbation. There may be a markedly increased rate of suicide and suicide attempts during lithium discontinuation compared with its continuation.6 The evaluation of the efficacy of the third agent would also be potentially obscured because one would be requiring the third agent to treat both the previous residual symptomatology and the potential exacerbation related to lithium withdrawal. Thus, a clearer clinical trial evaluation of the third agent may be based on a stable continuation of the lithium/valproate combination to see to what extent the new agent provided increased therapeutic effectiveness with minimal adverse effects.
With a complex illness course such as that associated with rapid cycling, or anxiety or substance abuse comorbidities, one might consider giving the patient 2 mood stabilizers, targeting different aspects of the symptomatology from the beginning rather than engaging in sequential extended monotherapy trials, each with a low likelihood of adequate effectiveness.1 In this way, if the patient were to have an inadequate response to combination treatment from the outset, one would have saved the patient from 1 of the 2 protracted monotherapy trials in addition to the third combination trial.
In rational polypharmacy, conventional doses and blood level targets are not the primary goal. Rather, maximizingtherapeutic efficacy and minimizing adverse effects of the entire regimen is the aim. It is largely because of the effects of pushing conventional dosage regimens to their maximum in clinical trials that the preliminary view of polypharmacy is that it causes more adverse effects. With a careful, individualized approach, the opposite is likely to be the result.
The choice of an initial agent should be based on the currently soft clinical and biological predictors of individual patient responses outlined in the Table. In the large percentage of patients with bipolar disorder who are overweight (50% of women and about 67% of men) or at high risk for obesity, one should consider the use of relatively weight-neutral compounds in an effort to avoid exacerbating weight-related problems.
The next agent should perhaps be targeted at the most prominent residual symptomatology or comorbidity. Of course, choosing an initial agent from the outset that may be effective for both the major presenting symptoms and the comorbidities is optimal (eg, valproate for a patient in a manic phase with a history of migraines, since valproate is FDA-approved for the prevention of migraine).