Study Overview

Validation of dried blood spot biomarkers for identification of depressed patients with bipolar disorder misdiagnosed as having major depressive disorder

Dried blood spot collection

Background

This study aims to validate a panel of dried blood spot biomarkers that can help identify depressed patients with bipolar disorder (BD) misdiagnosed as having major depressive disorder (MDD). The study is based on our previous work on differentiating BD from MDD using blood biomarker analysis (1–10).

Challenges in diagnosing bipolar disorder

BD is a devastating psychiatric condition that is often misdiagnosed, most frequently as MDD (11,12). Currently, diagnosing BD and MDD depends on subjective evaluations of patient self-reported symptoms conducted by clinicians, which is challenging due to overlapping symptoms (13,14). Furthermore, while people with BD experience both manic and depressive episodes, they typically seek professional help only during depressive phases (15), and their awareness of manic symptoms is consistently low (12). Depressive episodes are also often the first manifestation of BD (16). Such depressive episodes of BD are virtually impossible to distinguish from those of MDD. This, coupled with brief consultation times and high workloads on medical professionals (17), makes the differential diagnosis of mood disorders difficult. Misdiagnosis of BD as MDD happens in approximately 40% of patients with BD (11,12). Such a misdiagnosis leads to inefficient and potentially harmful treatments, and to an average delay in obtaining a correct diagnosis of 5 to 7 years (18). In 2019, there were 40 million people worldwide who had been diagnosed with BD, including 0.8 million in the UK and 2.1 million in the US (19). This represents 0.5% of the global population, yet does not include those with unrecognised or misdiagnosed BD. In the UK alone, it is estimated that about 1.3 million people have BD (20), and the approximate global prevalence rates vary from 1% to 2% (21). To facilitate a timely and accurate diagnosis of BD, we are developing a blood test that can help distinguish BD from MDD in people presenting with depressive symptoms.

Solution

Our goal is to develop a user-friendly blood test that can aid in the diagnosis of BD, intended to be used in patients presenting with depressive symptoms in primary healthcare settings. Such biomarker profiling offers a complementary, objective means to facilitating an earlier and more accurate diagnosis of mood disorders. Implementing a biomarker test for BD into primary healthcare, where misdiagnoses of BD are most prevalent, would enable a more comprehensive and accurate patient assessment and inform treatment decisions early in the mental health triage process. This would ultimately lead to improved patient outcomes and more efficient use of healthcare resources.

Previous work

The study focuses on validating a panel of 17 biomarkers identified in our previous research for distinguishing BD from MDD in patients with depressive symptoms (9). The panel was discovered by analysing samples from 241 depressed patients with a previous diagnosis of MDD, of whom 67 were subsequently diagnosed as having BD. These diagnoses were made using a validated diagnostic tool developed by the World Health Organization, the Composite International Diagnostic Interview (CIDI) (22). Unique to our method was the analysis of fingerprick dried blood spot (DBS) samples self-collected by participants at home prior to diagnosis with the CIDI. The samples were analysed for 630 circulating small molecules called metabolites using a mass spectrometry-based platform in an ISO-certified laboratory. The obtained data were used to develop a diagnostic machine learning model for distinguishing BD from MDD, which correctly detected 53% of patients with BD and 76% of patients with MDD, with the overall area under the receiver operation characteristic curve (AUC) of 0.71 (i.e. fair diagnostic performance (23)). Importantly, these results validated in an independent cohort of 30 patients who were depressed at the time of sample collection and subsequently diagnosed with BD or MDD during the study’s one year follow-up period, with sensitivity of 55%, specificity of 73%, and AUC of 0.73. This diagnostic performance is comparable to that of widely used commercial blood tests such as the prostate-specific antigen test used to screen for prostate cancer (24).

Objective

The primary objective of the study is to evaluate the diagnostic performance of the previously identified panel of 17 biomarkers distinguishing BD from MDD in a new cohort of patients with a recent (within the previous 5 years) diagnosis of MDD and current depressive symptoms. This group was selected because it represents the peak incidence of BD misdiagnoses.

References

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  2. Han SYS, Tomasik J, Rustogi N, et al. Diagnostic prediction model development using data from dried blood spot proteomics and a digital mental health assessment to identify major depressive disorder among individuals presenting with low mood. Brain Behav Immun. 2020;90:184-195. doi:10.1016/j.bbi.2020.08.011
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