The majority of patients treated for bipolar disorder receive multiple psychotropic medications concurrently (polypharmacy), despite a lack of empirical evidence for any combination of three or more medications. Some patients benefit from the skillful management of a complex medication regimen, but iterative additions to a treatment regimen often do not lead to clinical improvement, are expensive, and can confound assessment of the underlying mood disorder. Given these potential problems of polypharmacy, this paper reviews the evidence supporting the use of multiple medications and seeks to identify patient personality traits that may put patients at a greater risk for ineffective complex chronic care. Patients with bipolar disorder (n = 89), ages 18 and older, were assessed on the Montgomery Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and the NEO Five Factor Inventory (NEO-FFI), and completed a treatment history questionnaire to report psychotropic medication use. We found that patients with lower scores on openness had significantly more current psychotropic medications than patients with higher scores on openness (3.7 ± 1.9 vs. 2.8 ± 1.8, p < 0.05). Patients with the highest lifetime medication use had significantly lower extraversion (21.8 ± 8.9 vs. 25.4 ± 7.6, p < 0.05) and lower conscientiousness (21.9 ± 8.2 vs. 27.9 ± 8.2, p < 0.01) than those reporting lower lifetime medication use. Low levels of openness, extraversion, and conscientiousness may be associated with increased psychotropic medication use. Investigating the role of individual differences, such as patient personality traits, in moderating effective polypharmacy warrants future research.