Pharmacotherapy exposure as a marker of disease complexity in bipolar disorder: Associations with clinical & genetic risk factors

Bipolar disorder (BD) is a polygenic mental illness of unknown pathogenesis and high heritability (70–90%) (Gordovez and McMahon, 2020) with a worldwide age-adjusted prevalence of 490 cases per 100,000 people (GBD 2019 Mental Disorders Collaborators, 2022). Its complex and chronic course is characterized by recurring episodes of mania or hypomania alternating with depressive episodes (McIntyre et al., 2020) and high rates of suicide (Goetz et al., 2007). Owing to its life-long burden and lack of curative interventions, BD typically requires long-term acute and maintenance pharmacotherapy. Unfortunately, even after successful acute treatment leading to symptomatic remission, relapse is common. Approximately 60% of patients relapse during the two years following recovery from a first manic episode (Kessing et al., 2018). Therefore, the goal of maintenance treatment is to decrease its functional burden by reducing relapse frequency, residual symptoms, and severity or duration of incident mood episodes (Bauer et al., 2013; Yatham et al., 2018).

A limited number of psychotropics have proven efficacious in the treatment of BD, such as lithium, antipsychotics, antiepileptics, and antidepressants, among others (Yatham et al., 2018). Notwithstanding the limited number of options, there are important nuances to pharmacotherapy in BD: some medications have mood-specific efficacy, e.g., lamotrigine is efficacious for depressive, but not manic/hypomanic, episodes (Smith et al., 2007); antidepressants increase certain patients’ risk of a manic switch (point prevalence of 14.7–23.7%) (Fornaro et al., 2018); and many psychotropics have important risks that need to be balanced against their expected benefits. The latter is especially evident for clozapine, as it has proven to be an effective treatment for BD but its use is limited to late-stage, resistant, or complex clinical scenarios due to its associated risks and side effects (Gitlin, 2006; Kapczinski et al., 2021). Still, combination pharmacotherapy has become the standard of care for BD (Frye et al., 2000; Weinstock et al., 2014).

The clinical complexity of BD is highlighted by the differences among the multiple staging models that have been proposed to classify disease progression (Salagre et al., 2018). Different models emphasize distinct illness trajectories: episode remission and relapses (Berk et al., 2007); inter-episode symptoms, cognition and overall functioning (Kapczinski et al., 2009); or developmental history with familial risk, in addition to categorizing BD within a broader psychotic-spectrum (Duffy, 2014). Nonetheless, there are overlapping common themes such as the presence of an “at-risk” state preceding disease prodrome, setting the clinical threshold at the appearance of the first or index episode, and disease progression towards a chronic course with recurrent episodes. Ultimately, these models aim to chart BD by looking at different trajectories of the disease (Salagre et al., 2018), and though they are not mutually exclusive, one model does not fit all.

On the other hand, the designation of “treatment resistance” has long been used in psychiatry to describe illness that fails to respond after adequate treatment regardless of disease progression (Gitlin, 2006). Both treatment adequacy and resistance are disease-specific, further complicated by a lack of agreement as to what constitutes either term (Howes et al., 2022). This has been a significant issue for major depressive disorder (MDD), where the many proposed definitions of treatment resistance are based on different criteria (e.g., number and duration of interventions, medication doses, or adherence) (Brown et al., 2019). For BD, in addition to the absence of a consensus definition of treatment resistant BD, efforts to define it have been sparse (Howes et al., 2022). However, defining treatment-resistance as a binary trait might not characterize the complexity or degree of overall BD treatment response—under this definition, an individual is either treatment resistant or not.

There is an unmet need to find a measure that captures disease complexity and treatment nonresponse, adapts to the heterogeneous course of BD, and can be obtained from routinely available data. As a possible solution, pharmacotherapy exposure (PE)—the number of unique medications that an individual has been exposed to during a specific time frame—has received attention in recent years due to its association with clinical characteristics of BD progression. Higher PE has been associated with later stages of disease across different models (Goi et al., 2015; Markt et al., 2021), decreased likelihood of remission (Amsterdam et al., 2016; Brancati et al., 2021), increased familial loading and comorbidities, or later age of depression onset (Parker and Graham, 2017). Nonetheless, there is variation among these studies in the time frame assessed and the individual medications or medication classes used to define PE.

To this end, in this study we quantified the PE of a well-characterized BD sample by collecting self-reported cross-sectional and lifetime exposure to individual medications and medication classes taken as treatment for BD. Four measures of PE were computed based on the: (1) cross-sectional number of medications at time of biobank enrollment; (2) cross-sectional number of medication classes at time of enrollment; (3) lifetime number of medications; and (4) lifetime number of medication classes. We then tested for associations between each PE outcome and demographic characteristics, known markers of disease severity or resistance, and psychiatric comorbidities. Finally, we explored the effect that higher genetic susceptibility to six major psychiatric disorders may have on the lifetime PE of BD patients in addition to testing whether specific medication classes may be driving this effect, if any.

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