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.

With less than half of patients with major depressive disorder (MDD) correctly diagnosed within the primary care setting, there is a clinical need to develop an objective and readily accessible test to enable earlier and more accurate diagnosis. The aim of this study was to develop diagnostic prediction models to identify MDD patients among individuals presenting with subclinical low mood, based on data from dried blood spot (DBS) proteomics (194 peptides representing 115 proteins) and a novel digital mental health assessment (102 sociodemographic, clinical and personality characteristics). To this end, we investigated 130 low mood controls, 53 currently depressed individuals with an existing MDD diagnosis (established current MDD), 40 currently depressed individuals with a new MDD diagnosis (new current MDD), and 72 currently not depressed individuals with an existing MDD diagnosis (established non-current MDD). A repeated nested cross-validation approach was used to evaluate variation in model selection and ensure model reproducibility. Prediction models that were trained to differentiate between established current MDD patients and low mood controls (AUC = 0.94 ± 0.01) demonstrated a good predictive performance when extrapolated to differentiate between new current MDD patients and low mood controls (AUC = 0.80 ± 0.01), as well as between established non-current MDD patients and low mood controls (AUC = 0.79 ± 0.01). Importantly, we identified DBS proteins A1AG1, A2GL, AL1A1, APOE and CFAH as important predictors of MDD, indicative of immune system dysregulation; as well as poor self-rated mental health, BMI, reduced daily experiences of positive emotions, and tender-mindedness. Despite the need for further validation, our preliminary findings demonstrate the potential of such prediction models to be used as a diagnostic aid for detecting MDD in clinical practice.

Defining the segmental tension generated in a vertebral body tethering system for scoliosis.

Vertebral body tethering (VBT) uses a flexible tether affixed across the curve convexity with tension applied at each segment to treat scoliosis. Intraoperative tether tension may be achieved directly with a counter-tensioner or with an extension spring tube. The purpose of this study was to quantify the force generated with and without the extension spring tube using current FDA-approved VBT instrumentation, to understand the variation between surgeons using the same instrumentation, and to define the force range that is generated intra-operatively. Using a benchtop mechanical testing setup to simulate a spinal segment, we affixed the tether and applied tension using a tensioner and counter-tensioner alone (method T1) or by adding an extension spring tube (method T2). Eight orthopedic surgeons used T1 and T2 at six tensioner settings, and one surgeon completed three trials. A two-way ANOVA with a Tukey's HSD post hoc test (p < 0.05) compared the tensioner methods and testing levels. Inter- and intra-rater reliabilities were calculated using intraclass correlation coefficients (ICCs). Methods T1 and T2 exhibited linear tension-setting relationships, with high determination coefficients (R2 > 0.93). T2 consistently produced higher forces (increase of 62.1 N/setting), compared to T1 (increase of 50.6 N/setting, p < 0.05). Inter-rater reliability exhibited excellent agreement (ICC = 0.951 and 0.943 for T1 and T2, respectively), as did intra-rater reliability (ICC = 0.971).

Identification of Predictors of Mood Disorder Misdiagnosis and Subsequent Help-Seeking Behavior in Individuals With Depressive Symptoms: Gradient-Boosted Tree Machine Learning Approach.

BACKGROUND: Misdiagnosis and delayed help-seeking cause significant burden for individuals with mood disorders such as major depressive disorder and bipolar disorder. Misdiagnosis can lead to inappropriate treatment, while delayed help-seeking can result in more severe symptoms, functional impairment, and poor treatment response. Such challenges are common in individuals with major depressive disorder and bipolar disorder due to the overlap of symptoms with other mental and physical health conditions, as well as, stigma and insufficient understanding of these disorders. OBJECTIVE: In this study, we aimed to identify factors that may contribute to mood disorder misdiagnosis and delayed help-seeking. METHODS: Participants with current depressive symptoms were recruited online and data were collected using an extensive digital mental health questionnaire, with the World Health Organization World Mental Health Composite International Diagnostic Interview delivered via telephone. A series of predictive gradient-boosted tree algorithms were trained and validated to identify the most important predictors of misdiagnosis and subsequent help-seeking in misdiagnosed individuals. RESULTS: The analysis included data from 924 symptomatic individuals for predicting misdiagnosis and from a subset of 379 misdiagnosed participants who provided follow-up information when predicting help-seeking. Models achieved good predictive power, with area under the receiver operating characteristic curve of 0.75 and 0.71 for misdiagnosis and help-seeking, respectively. The most predictive features with respect to misdiagnosis were high severity of depressed mood, instability of self-image, the involvement of a psychiatrist in diagnosing depression, higher age at depression diagnosis, and reckless spending. Regarding help-seeking behavior, the strongest predictors included shorter time elapsed since last speaking to a general practitioner about mental health, sleep problems disrupting daily tasks, taking antidepressant medication, and being diagnosed with depression at younger ages. CONCLUSIONS: This study provides a novel, machine learning-based approach to understand the interplay of factors that may contribute to the misdiagnosis and subsequent help-seeking in patients experiencing low mood. The present findings can inform the development of targeted interventions to improve early detection and appropriate treatment of individuals with mood disorders.

Metabolomic Biomarker Signatures for Bipolar and Unipolar Depression.

Importance: Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) because of overlapping symptoms and the lack of objective diagnostic tools. Objective: To identify a reproducible metabolomic biomarker signature in patient dried blood spots (DBSs) that differentiates BD from MDD during depressive episodes and assess its added value when combined with self-reported patient information. Design, Setting, and Participants: This diagnostic analysis used samples and data from the Delta study, conducted in the UK between April 27, 2018, and February 6, 2020. The primary objective was to identify BD in patients with a recent (within the past 5 years) diagnosis of MDD and current depressive symptoms (Patient Health Questionnaire-9 score of 5 or more). Participants were recruited online through voluntary response sampling. The analysis was carried out between February 2022 and July 2023. Main Outcomes and Measures: Patient data were collected using a purpose-built online questionnaire (n = 635 questions). DBS metabolites (n = 630) were analyzed using a targeted mass spectrometry-based platform. Mood disorder diagnoses were established using the Composite International Diagnostic Interview. Results: Of 241 patients in the discovery cohort, 170 (70.5%) were female; 67 (27.8%) were subsequently diagnosed with BD and 174 (72.2%) were confirmed as having MDD; and the mean (SD) age was 28.1 (7.1) years. Of 30 participants in the validation cohort, 16 (53%) were female; 9 (30%) were diagnosed with BD and 21 (70%) with MDD; and the mean (SD) age was 25.4 (6.3) years. DBS metabolite levels were assessed in 241 patients with depressive symptoms with a recent diagnosis of MDD, of whom 67 were subsequently diagnosed with BD by the Composite International Diagnostic Interview and 174 were confirmed as having MDD. The identified 17-biomarker panel provided a mean (SD) cross-validated area under the receiver operating characteristic curve (AUROC) of 0.71 (SD, 0.12; P < .001), with ceramide d18:0/24:1 emerging as the strongest biomarker. Combining biomarker data with patient-reported information significantly enhanced diagnostic performance of models based on extensive demographic data, PHQ-9 scores, and the outcomes from the Mood Disorder Questionnaire. The identified biomarkers were correlated primarily with lifetime manic symptoms and were validated in a separate group of patients who received a new clinical diagnosis of MDD (n = 21) or BD (n = 9) during the study's 1-year follow-up period, with a mean (SD) AUROC of 0.73 (0.06; P < .001). Conclusions and Relevance: This study provides a proof of concept for developing an accessible biomarker test to facilitate the differential diagnosis of BD and MDD and highlights the potential involvement of ceramides in the pathophysiological mechanisms of mood disorders.

Incorporating Digital Interventions into Mental Health Clinical Practice: a Pilot Survey of How Use Patterns, Barriers, and Opportunities Shifted for Clinicians in the COVID-19 Pandemic.

Although many digital mental health interventions are available, clinicians do not routinely use them in clinical practice. In this pilot survey, we review the factors that supported the rapid transition to televisits during the COVID-19 pandemic, and we explore the barriers that continue to prevent clinicians from using other digital mental health interventions, such as mindfulness applications, mood trackers, and digital therapy programs. We conducted a pilot survey of mental health clinicians in different practice environments in the USA. Survey respondents (n = 51) were primarily psychiatrists working in academic medical centers. Results indicated that systemic factors, including workplace facilitation and insurance reimbursement, were primary reasons motivating clinicians to use televisits to provide remote patient care. The shift to televisits during the pandemic was not accompanied by increased use of other digital mental health interventions in patient care. Nine clinicians reported that they have never used digital interventions with patients. Among the 42 clinicians who did report some experience using digital interventions, the majority reported no change in the use of digital applications since transitioning to televisits. Our preliminary findings lend insight into the perspective of mental health clinicians regarding the factors that supported their transition to televisits, including institutional support and insurance reimbursement, and indicate that this shift to virtual patient care has not been accompanied by increased use of other digital mental health interventions. We contend that the same systemic factors that supported the shift toward virtual visits in the COVID-19 pandemic may be applied to support the incorporation of other digital interventions in mental healthcare. Supplementary Information: The online version contains supplementary material available at 10.1007/s41347-022-00260-8.

Learnings from user feedback of a novel digital mental health assessment.

Digital mental health interventions (DMHI) have the potential to address barriers to face-to-face mental healthcare. In particular, digital mental health assessments offer the opportunity to increase access, reduce strain on services, and improve identification. Despite the potential of DMHIs there remains a high drop-out rate. Therefore, investigating user feedback may elucidate how to best design and deliver an engaging digital mental health assessment. The current study aimed to understand 1304 user perspectives of (1) a newly developed digital mental health assessment to determine which features users consider to be positive or negative and (2) the Composite International Diagnostic Interview (CIDI) employed in a previous large-scale pilot study. A thematic analysis method was employed to identify themes in feedback to three question prompts related to: (1) the questions included in the digital assessment, (2) the homepage design and reminders, and (3) the assessment results report. The largest proportion of the positive and negative feedback received regarding the questions included in the assessment (n = 706), focused on the quality of the assessment (n = 183, 25.92% and n = 284, 40.23%, respectively). Feedback for the homepage and reminders (n = 671) was overwhelmingly positive, with the largest two themes identified being positive usability (i.e., ease of use; n = 500, 74.52%) and functionality (i.e., reminders; n = 278, 41.43%). The most frequently identified negative theme in results report feedback (n = 794) was related to the report content (n = 309, 38.92%), with users stating it was lacking in-depth information. Nevertheless, the most frequent positive theme regarding the results report feedback was related to wellbeing outcomes (n = 145, 18.26%), with users stating the results report, albeit brief, encouraged them to seek professional support. Interestingly, despite some negative feedback, most users reported that completing the digital mental health assessment has been worthwhile (n = 1,017, 77.99%). Based on these findings, we offer recommendations to address potential barriers to user engagement with a digital mental health assessment. In summary, we recommend undertaking extensive co-design activities during the development of digital assessment tools, flexibility in answering modalities within digital assessment, customizable additional features such as reminders, transparency of diagnostic decision making, and an actionable results report with personalized mental health resources.

The Delta Study - Prevalence and characteristics of mood disorders in 924 individuals with low mood: Results of the of the World Health Organization Composite International Diagnostic Interview (CIDI).

OBJECTIVES: The Delta Study was undertaken to improve the diagnosis of mood disorders in individuals presenting with low mood. The current study aimed to estimate the prevalence and explore the characteristics of mood disorders in participants of the Delta Study, and discuss their implications for clinical practice. METHODS: Individuals with low mood (Patients Health Questionnaire-9 score ≥5) and either no previous mood disorder diagnosis (baseline low mood group, n = 429), a recent (≤5 years) clinical diagnosis of MDD (baseline MDD group, n = 441) or a previous clinical diagnosis of BD (established BD group, n = 54), were recruited online. Self-reported demographic and clinical data were collected through an extensive online mental health questionnaire and mood disorder diagnoses were determined with the World Health Organization Composite International Diagnostic Interview (CIDI). RESULTS: The prevalence of BD and MDD in the baseline low mood group was 24% and 36%, respectively. The prevalence of BD among individuals with a recent diagnosis of MDD was 31%. Participants with BD in both baseline low mood and baseline MDD groups were characterized by a younger age at onset of the first low mood episode, more severe depressive symptoms and lower wellbeing, relative to the MDD or low mood groups. Approximately half the individuals with BD diagnosed as MDD (49%) had experienced (hypo)manic symptoms prior to being diagnosed with MDD. CONCLUSIONS: The current results confirm high under- and misdiagnosis rates of mood disorders in individuals presenting with low mood, potentially leading to worsening of symptoms and decreased well-being, and indicate the need for improved mental health triage in primary care.

Toward an Extended Definition of Major Depressive Disorder Symptomatology: Digital Assessment and Cross-validation Study.

BACKGROUND: Diagnosing major depressive disorder (MDD) is challenging, with diagnostic manuals failing to capture the wide range of clinical symptoms that are endorsed by individuals with this condition. OBJECTIVE: This study aims to provide evidence for an extended definition of MDD symptomatology. METHODS: Symptom data were collected via a digital assessment developed for a delta study. Random forest classification with nested cross-validation was used to distinguish between individuals with MDD and those with subthreshold symptomatology of the disorder using disorder-specific symptoms and transdiagnostic symptoms. The diagnostic performance of the Patient Health Questionnaire-9 was also examined. RESULTS: A depression-specific model demonstrated good predictive performance when distinguishing between individuals with MDD (n=64) and those with subthreshold depression (n=140) (area under the receiver operating characteristic curve=0.89; sensitivity=82.4%; specificity=81.3%; accuracy=81.6%). The inclusion of transdiagnostic symptoms of psychopathology, including symptoms of depression, generalized anxiety disorder, insomnia, emotional instability, and panic disorder, significantly improved the model performance (area under the receiver operating characteristic curve=0.95; sensitivity=86.5%; specificity=90.8%; accuracy=89.5%). The Patient Health Questionnaire-9 was excellent at identifying MDD but overdiagnosed the condition (sensitivity=92.2%; specificity=54.3%; accuracy=66.2%). CONCLUSIONS: Our findings are in line with the notion that current diagnostic practices may present an overly narrow conception of mental health. Furthermore, our study provides proof-of-concept support for the clinical utility of a digital assessment to inform clinical decision-making in the evaluation of MDD.

Personality, symptom, and demographic correlates of perceived efficacy of selective serotonin reuptake inhibitor monotherapy among current users with low mood: A data-driven approach.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are often the first-line treatment option for depressive symptoms, however their efficacy varies across patients. Identifying predictors of response to SSRIs could facilitate personalised treatment of depression and improve treatment outcomes. The aim of this study was to develop a data-driven formulation of demographic, personality, and symptom-level factors associated with subjective response to SSRI treatment. METHODS: Participants were recruited online and data were collected retrospectively through an extensive digital mental health questionnaire. Extreme gradient boosting classification with nested cross-validation was used to identify factors distinguishing between individuals with low (n=37) and high (n=111) perceived benefit from SSRI treatment. RESULTS: The algorithm demonstrated a good predictive performance (test AUC=.88±.07). Positive affectivity was the strongest predictor of response to SSRIs and a major confounder of the remaining associations. After controlling for positive affectivity, as well as current wellbeing, severity of current depressive symptoms, and multicollinearity, only low positive affectivity, chronic pain, sleep problems, and unemployment remained significantly associated with diminished subjective response to SSRIs. LIMITATIONS: This was an exploratory analysis of data collected at a single time point, for a study which had a different primary aim. Therefore, the results may not reflect causal relationships, and require validation in future prospective studies. Furthermore, the data were self-reported by internet users, which could affect integrity of the dataset and limit generalisability of the results. CONCLUSIONS: Our findings suggest that demographic, personality, and symptom data may offer a potential cost-effective and efficient framework for SSRI treatment outcome prediction.

Impact of a Web-Based Psychiatric Assessment on the Mental Health and Well-Being of Individuals Presenting With Depressive Symptoms: Longitudinal Observational Study.

BACKGROUND: Web-based assessments of mental health concerns hold great potential for earlier, more cost-effective, and more accurate diagnoses of psychiatric conditions than that achieved with traditional interview-based methods. OBJECTIVE: The aim of this study was to assess the impact of a comprehensive web-based mental health assessment on the mental health and well-being of over 2000 individuals presenting with symptoms of depression. METHODS: Individuals presenting with depressive symptoms completed a web-based assessment that screened for mood and other psychiatric conditions. After completing the assessment, the study participants received a report containing their assessment results along with personalized psychoeducation. After 6 and 12 months, participants were asked to rate the usefulness of the web-based assessment on different mental health-related outcomes and to self-report on their recent help-seeking behavior, diagnoses, medication, and lifestyle changes. In addition, general mental well-being was assessed at baseline and both follow-ups using the Warwick-Edinburgh Mental Well-being Scale (WEMWBS). RESULTS: Data from all participants who completed either the 6-month or the 12-month follow-up (N=2064) were analyzed. The majority of study participants rated the study as useful for their subjective mental well-being. This included talking more openly (1314/1939, 67.77%) and understanding one's mental health problems better (1083/1939, 55.85%). Although most participants (1477/1939, 76.17%) found their assessment results useful, only a small proportion (302/2064, 14.63%) subsequently discussed them with a mental health professional, leading to only a small number of study participants receiving a new diagnosis (110/2064, 5.33%). Among those who were reviewed, new mood disorder diagnoses were predicted by the digital algorithm with high sensitivity (above 70%), and nearly half of the participants with new diagnoses also had a corresponding change in medication. Furthermore, participants' subjective well-being significantly improved over 12 months (baseline WEMWBS score: mean 35.24, SD 8.11; 12-month WEMWBS score: mean 41.19, SD 10.59). Significant positive predictors of follow-up subjective well-being included talking more openly, exercising more, and having been reviewed by a psychiatrist. CONCLUSIONS: Our results suggest that completing a web-based mental health assessment and receiving personalized psychoeducation are associated with subjective mental health improvements, facilitated by increased self-awareness and subsequent use of self-help interventions. Integrating web-based mental health assessments within primary and/or secondary care services could benefit patients further and expedite earlier diagnosis and effective treatment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/18453.

A machine learning algorithm to differentiate bipolar disorder from major depressive disorder using an online mental health questionnaire and blood biomarker data.

The vast personal and economic burden of mood disorders is largely caused by their under- and misdiagnosis, which is associated with ineffective treatment and worsening of outcomes. Here, we aimed to develop a diagnostic algorithm, based on an online questionnaire and blood biomarker data, to reduce the misdiagnosis of bipolar disorder (BD) as major depressive disorder (MDD). Individuals with depressive symptoms (Patient Health Questionnaire-9 score ≥5) aged 18-45 years were recruited online. After completing a purpose-built online mental health questionnaire, eligible participants provided dried blood spot samples for biomarker analysis and underwent the World Health Organization World Mental Health Composite International Diagnostic Interview via telephone, to establish their mental health diagnosis. Extreme Gradient Boosting and nested cross-validation were used to train and validate diagnostic models differentiating BD from MDD in participants who self-reported a current MDD diagnosis. Mean test area under the receiver operating characteristic curve (AUROC) for separating participants with BD diagnosed as MDD (N = 126) from those with correct MDD diagnosis (N = 187) was 0.92 (95% CI: 0.86-0.97). Core predictors included elevated mood, grandiosity, talkativeness, recklessness and risky behaviour. Additional validation in participants with no previous mood disorder diagnosis showed AUROCs of 0.89 (0.86-0.91) and 0.90 (0.87-0.91) for separating newly diagnosed BD (N = 98) from MDD (N = 112) and subclinical low mood (N = 120), respectively. Validation in participants with a previous diagnosis of BD (N = 45) demonstrated sensitivity of 0.86 (0.57-0.96). The diagnostic algorithm accurately identified patients with BD in various clinical scenarios, and could help expedite accurate clinical diagnosis and treatment of BD.

A Combined Digital and Biomarker Diagnostic Aid for Mood Disorders (the Delta Trial): Protocol for an Observational Study.

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.