A multimodal approach to depression diagnosis: insights from machine learning algorithm development in primary care.

General practitioners play an essential role in identifying depression and are often the first point of contact for patients. Current diagnostic tools, such as the Patient Health Questionnaire-9, provide initial screening but might lead to false positives. To address this, we developed a two-step machine learning model called Clinical 15, trained on a cohort of 581 participants using a nested cross-validation framework. The model integrates self-reported data from validated questionnaires within a study sample of patients presenting to general practitioners. Clinical 15 demonstrated a balanced accuracy of 88.2% and incorporates a traffic light system: green for healthy, red for depression, and yellow for uncertain cases. Gaussian mixture model clustering identified four depression subtypes, including an Immuno-Metabolic cluster characterized by obesity, low-grade inflammation, autonomic nervous system dysregulation, and reduced physical activity. The Clinical 15 algorithm identified all patients within the immuno-metabolic cluster as depressed, although 22.2% (30.8% across the whole dataset) were categorized as uncertain, leading to a yellow traffic light. The biological characterization of patients and monitoring of their clinical course may be used for differential risk stratification in the future. In conclusion, the Clinical 15 model provides a highly sensitive and specific tool to support GPs in diagnosing depression. Future algorithm improvements may integrate further biological markers and longitudinal data. The tool's clinical utility needs further evaluation through a randomized controlled trial, which is currently being planned. Additionally, assessing whether GPs actively integrate the algorithm's predictions into their diagnostic and treatment decisions will be critical for its practical adoption.