The LiTMUS study was a longitudinal, randomized multi-site comparative effectiveness trial that examined lithium in bipolar disorder, a disorder typically associated with high rates of attrition. Despite the rigorous study design, study medication, and patient population, this study yielded a lower attrition rate than that encountered in other longer-term bipolar disorder treatment studies. We highlight six possible components of the LiTMUS design that may have contributed to minimizing attrition rates: a randomized adjunctive single-blind design, reimbursement for study-related costs, intent-to-attend procedures, quality care with limited participant burden, and target windows for study visits (see ).
Despite these substantial strengths of the study, there were also several limitations. First, we have not yet analyzed the efficacy data or the final adverse event data. Thus, it is possible that our participants had very few adverse effects, which is an important reason for attrition in most bipolar studies [6
]. It is also possible that we did not recruit a representative bipolar population. Given that participants were required to have an overall Clinical Global Illness Severity score of at least “mild” at study entry, participants must have been experiencing at least
some symptoms that prompted them to seek care. We also made several specific efforts to recruit “real-world” patients for this study. We paid for study medication (i.e., lithium) as well as OPT medication, as needed, to recruit participants from low income families and/or those without insurance.
As mentioned, it is possible that the treatment and monitoring details of this study are not feasible in community settings given that the study was conducted at bipolar, or mood disorder, specialty clinics. We believe that following empirically-supported treatment and monitoring guidelines for bipolar disorder should represent the standard of care and that disseminating this information should be an area of continued focus [9
]. However, guidelines do not address certain aspects of the treatment program included in this study, such as the bi-monthly pharmacotherapy or staff (i.e., research coordinators) assigned to follow each patient. These features of the study may have contributed to the low attrition rate, but do not mimic treatment received in community settings. Yet, these aspects are
typical for pharmacotherapy studies and yet, LiTMUS had a low attrition rate, suggesting that specific components of this study could be useful in reducing attrition and increasing retention of study participants.
LiTMUS also did not utilize a run-in phase prior to randomization which could have further minimized our attrition rates. The BALANCE (Bipolar Affective disorder: Lithium/ANti-Convulsant Evaluation) study, a longitudinal, open-label multi-site trial (N=330) to compare maintenance treatment with lithium, valproate or combined, yielded a relatively low attrition rate, or 21% [20
]. This is particularly noteworthy as BALANCE utilized a 24-month follow-up phase compared to 6-months of follow-up in LiTMUS. However, BALANCE utilized a run-in phase, or assessed treatment response over 4 to 8 weeks to ensure that only participants who “tolerated both drugs in the short term” were randomized. Of the 459 participants enrolled in BALANCE, 129 (28%) withdrew from the study during the run-in phase and prior to randomization. Given that nearly half the participants that attrited from LiTMUS, did so before week 8 (see ), such a run in phase would likely have reduced our attrition rate further [20
]. Nonetheless, BALANCE utilized several of the strategies summarized in , such as an intent-to-treat, single-blind design while providing quality clinical care with limited participant burden, which also likely explains their low attrition rate.
We also had site differences in attrition which suggests that other, non-study related factors may have impacted attrition (see ). For example, the site with the highest attrition rate (i.e., site 003) is located in a state that requires all residents to have health insurance. This requirement afforded participants at this site more treatment options, and in particular, the ability to have clinical care without participating in research. Sites with the lower attrition rates (e.g., site 004) noted that often their participants were only able to receive treatment if enrolled in a research study, due to lack of health insurance or availability of clinical care. Thus, further research is warranted to investigate other factors that may impact attrition.
In summary, several design aspects of LiTMUS, a comparative effectiveness study of bipolar disorder could be considered to limit attrition rates. Low attrition rates allow for more precise evaluations of interventions for difficult-to-treat populations and require innovative approaches for optimal study performance.