In this study, we applied the stage model to Korean patients with BD based on comprehensive clinical information obtained from diverse sources including chart review and direct interview with patients, their caregivers and treating physicians. This approach is both intuitive and applicable in clinical practice based on a series of symptoms in light of patient’s own clinical evolution (Salagre et al. 2018).
The stage progression pattern in our study revealed several sub-populations with distinct progression patterns during the first five years after onset of bipolar illness, especially BD-I and BD-II. A prior study using the stage model (van der Markt et al. 2019) included patients with BD-I only. Our study finding corroborates previous findings that associated BD-II with chronic illness course and more frequent depressive episodes (Judd et al. 2003; Baek et al. 2011). This different clinical profile also supports differentiation of BD-I and BD-II (Gitlin andMalhi 2020; Karanti et al. 2020). In BD-II, a subset of patients reached stage 4 early in their course of illness, while others did not undergo relapse of episodes in 5 years. The interval (years) between episodes is widely distributed (Angst et al. 2005; Kurumaji et al. 2014), emphasizing heterogeneous features in the longitudinal course of BD-II.
The duration of transition shortened as patients reach higher stages. In our study, the number of years spent in later stages 3 and 4 was less than a year. This transition was faster in later stages than in the previous study (van der Markt et al. 2019), while the progression in earlier stages (1 and 2) was even slower. A previous study by Park and colleagues also reported that cumulative episodes contributed to increased recurrence (Park et al. 2018). Salvatore et al. (2014) clustered antecedents into early, intermediate, and late (prodromal) phases, and found that the mean latency among phases was reduced gradually. The mean latency between early and intermediate antecedent phases was 4.7 ± 6.9 years, and between first-episode symptoms and syndrome was 8.4 ± 14.4 weeks. Only late (prodromal) behavioral dysfunctions anticipated later mania from other (mixed, depressive, or nonaffective) major psychotic episodes (Salvatore et al. 2014). The acceleration also suggests that early BD and malignant groups manifest different illness course, which highlights the need for considering current stage in planning treatment strategies.
Notably, several studies showed different rates of stage progression patterns reflecting the progression of illness during 5 years after the onset of BD, a time frame for early intervention of the targeted population. In a previous study by van der Markt et al. (van der Markt et al.), 85% of subjects experienced stage progression in 5 years, with 7% remaining at the same stage. The rate of stage progression in our study was lower than in the previous study (53% in our study versus 85% in the study by van der Markt and colleagues, p < 0.0001), while substantial number of patients stayed in stage 2(41.5% vs. 7%, p < 0.0001). Because our study population was recruited from a BD clinic, timely and appropriate treatment might delay the progression of illness. These findings suggest the need for using a stage model in clinical practice as a prophylactic intervention against recurrent episodes.
Treatment can alter the disease course, progression and regression. Early onset and delayed medication were significant factors leading to chronic course of BD in our study, which was in line with previous studies involving subjects with cycle acceleration (Finseth et al. 2014). In a study using the stage model based on recurrent episodes, earlier age at onset and treatment with fewer psychotropic medications during patients’ lifetime were associated with higher stages (Kamali et al. 2021). Joslyn et al. (2016) also found that early age of onset is associated with factors that can negatively impact long-term outcomes. Chronic BD was shorter in duration possibly due to rapid transition. The association of gender and increased risk of stage progression was not replicated in our study (van der Markt et al. 2019). Identification of individual factors for personalized care requires assessment and adjustment of clinical interventions.
Other elements should be considered as they represent stage-specific markers (McGorry et al. 2006; Salagre et al. 2018). Previous studies have included mood symptoms such as prodromal subsyndromal depressive or manic symptoms or specific bipolar onset (van der Markt et al. 2019). In our study, we included psychiatric comorbid conditions as covariates associated with long-term bipolar illness (Singh andZarate 2006). As expected, early BD with comorbid OCD, alcohol-related disorders, or bulimia nervosa showed increased rate of transition to higher stages. Furthermore, we identified distinct factors associated with recurrent (stage 3a/3b) or malignant course (stage 3c/4). Recurrent BD is associated with better prognosis as it includes remission of episodes, whereas malignant BD is characterized by residual state without complete remission, even though these two courses have recurrent episodes in common (Judd et al. 2008). An interesting finding is that unemployment increased the risk of malignant course, but lowered the risk of episodes following remission. We can speculate that severe impairment or loss of function occurs in individuals later in the course of established BD. However, the state of being unemployed, which indicates the current work situation, may not suggest inability to work. Kapczinski et al. (2009) included psychosocial functioning as an index of illness progression.
The stage model not only enhances our understanding of BD, but also sheds light on treatments with differential value across stages. Previous studies reported mixed results involving treatment response. A study by Berk et al. (2017) pooled 12 BD studies and identified that patients in the earliest phases of the illness had a more favorable response to treatment. However, staging was not a significant factor in antidepressant response in a randomized trial (Magalhães et al. 2012). Staging did not moderate the randomized treatment effect of lithium vs. quetiapine (Kamali et al. 2021). Our study showed that current stage was associated with long-term mood stabilization in response to lithium therapy. The discrepancy in results may be attributed to the sample population. In our study, both average duration of illness and mean age were nearly 10 years earlier than in previous studies. Our sample consists of a diverse range of patients in early to chronic courses of illness. Application of this model in treatment decisions and prognosis requires determination of stage-specific pharmacological treatment.
The present study has strengths in using real world clinical data actually observed by treating physicians repeatedly. We obtained data not only from patients’ recall or electronic health records, but regular consensus meetings to improve reliability of stage definition for enhanced conceptualization and measurement of staging (Tremain et al. 2020).
Our study has several limitations. First, the small sample size might affect the study findings. Second, there could be a recall bias regarding patients’ early illness. The participants in our study were in relatively earlier course of illness compared with those in previous study, suggesting limited recall bias. In addition, we tried to re-formulate patients’ course of illness using all available information sources and repeated contacts with patients themselves, their caregivers and their treating physicians. Third, all patients were recruited and treated at the BD specialized clinic, which suggests difficulty in generalizing the study findings. Fourth, we only applied the stage model based on recurrent episodes. A recent study that integrates diverse information including laboratory data and cognitive function in the defining stage (de la Fuente-Tomás et al. 2020) showed fair validity. Descriptions of clinical stages of BD still need operationalization or consensus on terminology. For instance, whether a mixed episode meets the criteria for a certain stage can be disputed, leading to systemic error.
Within these limitations in mind, this study demonstrated the feasibility of application of the stage model based on real-world data involving Korean patients with BD. Our findings suggest that clinical staging can be used to integrate diverse courses of BD. Exacerbation of BD and resistance to treatment provide insight into illness progression at a group level ranging from early to recurrent and chronic conditions. Known variables that aggravate prognosis were confirmed, and additional variables and biomarkers are reflected in this framework.