Patients were more likely to take a mood stabilizer than any other drug. About 80% of the 450 patients were taking a stable drug combination for 50% or more days. Consistent with prior research (Baldessarini et al. 2008a, b; Goldberg et al. 2009), the majority of patients were taking polypharmacy including 75% of those with a stable combination. About half the patients with a stable combination were taking an antidepressant, despite the ongoing controversy. There was no predominant treatment regimen, as the stable combinations consisted of 52 unique combinations by medication class and 231 unique combinations by specific drugs.
This study cannot distinguish whether or not patients were taking polypharmacy because they were refractory to monotherapy. In a study of US medical claims, about one third of patients with bipolar disorder received initial treatment with polypharmacy (Baldessarini et al. 2008a). Also, polypharmacy is routinely prescribed to inpatients (Greil et al. 2012; Vincenti et al. 2010; Wolfsperger et al. 2007). Recent research suggests that monotherapy with a mood stabilizer or second-generation antipsychotic is generally effective for acute mania (Goldberg et al. 2009; Grunze et al. 2009; Malhi et al. 2012; Tamayo et al. 2010), but polypharmacy is often required for acute depression, mixed states, and maintenance (Goldberg et al. 2009; Malhi et al. 2012; Tamayo et al. 2010). However, polypharmacy increases the risk of drug interactions and adverse events (Besag and Berry 2006; Mojtabai and Olfson 2010; Sandson et al. 2005). In a US national study, psychotropics were a common cause of emergency department visits for adverse drug reactions for those under age 65 (Lucado et al. 2011). The challenge of polypharmacy is that the gain in stability from adding another drug must outweigh the safety risks and side effects (Malhi et al. 2012).
In the current study, the use of more than one drug within a medication class greatly increased the drug load. Patients taking two antipsychotics, antidepressants, or benzodiazepines had about double the drug load of those taking one drug, similar to prior findings (Procyshyn et al. 2010; Tognoni 1999). This result suggests that within a medication class, increasing the dose of one drug produces a lower drug load than adding a second drug. In patients with epilepsy, anticonvulsant polypharmacy is associated with a much higher drug load than with monotherapy, and a higher drug load is associated with increased adverse events (Lammers et al. 1995; Deckers et al. 2001; Deckers 2002). In contrast to that in epilepsy, polypharmacy in bipolar disorder primarily involves drugs from more than one medication class, as with 70% of the patients taking a stable combination in this study. There are few studies of the relation between drug load as measured by the PDD/DDD ratio and adverse events for psychotropic drugs. For example, while persistent exposure to antipsychotic polypharmacy increases the risk of adverse reactions (Carnahan et al. 2006; Centorrino et al. 2004), the optimal measure to predict adverse events is unclear (Barr et al. 2010; Nosè et al. 2008). However, the drug load concept may be useful for improving tolerability of polypharmacy in bipolar disorder, and investigation of the relation between drug load and adverse reactions is indicated.
It is noteworthy that over 80% of the patients with a stable combination were taking three or less drugs. A relatively small number of drugs may facilitate long-term use, and there may be an upper limit on the number of daily drugs beyond which adherence decreases (Bauer et al. 2009; Robertson et al. 2008). Polypharmacy regimens that require frequent dosing, have dietary or time requirements, or are expensive may contribute to nonadherence (Cramer et al. 1989; Ingersoll and Cohen 2008). Patients with bipolar disorder consistently report that side effects contribute to nonadherence (Baldessarini et al. 2008b; Perlick et al. 2004). In this study, the patients without a stable combination were taking drugs, but inconsistently, with drug changes more than once a month. This finding is in agreement with prior evidence that nonadherence in bipolar disorder is typically partial or intermittent rather than complete (Baldessarini et al. 2008a; Lingam and Scott 2002).
There are many limitations to this analysis. All study patients had access to a psychiatrist and were taking medication. Furthermore, the very process of daily recording may improve medication adherence (van Berge Henegouwen et al. 1999). In clinical practice, most patients would not volunteer to keep a long-term daily record. This study may be less generalizable to other patients with bipolar disorder. With a naturalistic design, the patients in this study varied in severity, phase and course of the disease, and years of illness. The study included more females than males and more patients with bipolar I than bipolar II disorder. All data were self-reported and daily access to a computer was required. The strengths of this study include the use of prospective data from a relatively large number of patients and the entry of specific drugs and dose taken daily. However, the prescribed regimens and reasons for addition of new drugs were not known. Some drugs may be misclassified as to prescribing intent. For example, trazodone is considered an antidepressant but is frequently prescribed as a hypnotic agent. The analyses did not include other classes of psychotropic drugs such as stimulants, drugs taken for medical conditions, and over-the-counter preparations. Finally, many diverse factors that may influence medication selection such as physician prescribing habits, drug costs, regulatory influences, insurance plan formularies, pharmaceutical marketing, and patient preferences were not considered (Thistlewaite et al. 2010; Poulsen 1992).