Major depressive disorder (MDD) and bipolar disorder (BD) are leading causes of disability worldwide, yet many people remain undiagnosed, are misdiagnosed, and/or ineffectively treated. Diagnosis relies on the clinical assessment of symptoms, and there is currently no molecular or brain-imaging diagnostic test available. Identifying and validating protein biomarkers could provide a more accurate and objective means of diagnosis. Areas covered: Proteomics is a powerful tool that enables the identification and quantification of novel candidate biomarkers of disease. In this review, we discuss the role of proteomic technologies in biomarker discovery and validation, peripheral blood as a source of protein biomarkers, statistical methods for analyzing proteomic data, and some existing challenges in the field. We also review a selection of previously published studies focused on identifying blood-based diagnostic protein biomarkers of MDD and BD within a ten-year period. Expert commentary: Proteomic studies have led to the identification of numerous potential biomarkers of MDD and BD. However, clinical validation and translation into clinical practice have not yet been achieved. Conducting large-scale validation studies and addressing various factors that limit the reproducibility of the proteomic findings are key to ensure that robust and reliable biomarker tests are developed and clinically validated.

Background Mood disorders affect hundreds of millions of people worldwide, imposing a substantial medical and economic burden. Existing diagnostic methods for mood disorders often result in a delay until accurate diagnosis, exacerbating the challenges of these disorders. Advances in digital tools for psychiatry and understanding the biological basis of mood disorders offer the potential for novel diagnostic methods that facilitate early and accurate diagnosis of patients. Objective The Delta Trial was launched to develop an algorithm-based diagnostic aid combining symptom data and proteomic biomarkers to reduce the misdiagnosis of bipolar disorder (BD) as a major depressive disorder (MDD) and achieve more accurate and earlier MDD diagnosis. Methods Participants for this ethically approved trial were recruited through the internet, mainly through Facebook advertising. Participants were then screened for eligibility, consented to participate, and completed an adaptive digital questionnaire that was designed and created for the trial on a purpose-built digital platform. A subset of these participants was selected to provide dried blood spot (DBS) samples and undertake a World Health Organization World Mental Health Composite International Diagnostic Interview (CIDI). Inclusion and exclusion criteria were chosen to maximize the safety of a trial population that was both relevant to the trial objectives and generalizable. To provide statistical power and validation sets for the primary and secondary objectives, 840 participants were required to complete the digital questionnaire, submit DBS samples, and undertake a CIDI. Results The Delta Trial is now complete. More than 3200 participants completed the digital questionnaire, 924 of whom also submitted DBS samples and a CIDI, whereas a total of 1780 participants completed a 6-month follow-up questionnaire and 1542 completed a 12-month follow-up questionnaire. The analysis of the trial data is now underway. Conclusions If a diagnostic aid is able to improve the diagnosis of BD and MDD, it may enable earlier treatment for patients with mood disorders. International Registered Report Identifier (IRRID) DERR1-10.2196/18453

The mucopolysaccharidoses (MPS) are lysosomal storage disorders that result from defects in the catabolism of glycosaminoglycans. Impaired muscle, bone, and connective tissue are typical clinical features of MPS due to disruption of the extracellular matrix. Markers of MPS disease pathology are needed to determine disease severity and monitor effects of existing and emerging new treatments on disease mechanisms. Urine samples from a small cohort of MPS-I, -II, and -VI patients (n = 12) were analyzed using label-free quantative proteomics. Fifty-three proteins including many associated with extracellular matrix organization were differently expressed. A targeted multiplexed peptide MRM LC-MS/MS assay was used on a larger validation cohort of patient samples (MPS-I n = 18, MPS-II n = 12, MPS-VI n = 6, control n = 20). MPS-I and -II groups were further subdivided according to disease severity. None of the markers assessed were altered significantly in the mild disease groups compared to controls. β-galactosidase, a lysosomal protein, was elevated 3.6-5.7-fold significantly (p < 0.05) in all disease groups apart from mild MPS-I and -II. Collagen type Iα, fatty-acid-binding-protein 5, nidogen-1, cartilage oligomeric matrix protein, and insulin-like growth factor binding protein 7 concentrations were elevated in severe MPS I and II groups. Cartilage oligomeric matrix protein, insulin-like growth factor binding protein 7, and β-galactosidase were able to distinguish the severe neurological form of MPS-II from the milder non-neurological form. Protein Heg1 was significantly raised only in MPS-VI. This work describes the discovery of new biomarkers of MPS that represent disease pathology and allows the stratification of MPS-II patients according to disease severity.