Neuroinflammatory-related biomarkers and psychiatric symptom changes in substance use disorder: a South African cohort study.

Major depressive disorder (MDD) is a serious psychiatric disease that significantly impairs patients’ quality of life and social functioning. Despite the availability of various treatment options, including novel antidepressant medications, clinical outcomes remain suboptimal for many individuals, with approximately 30% of patients showing resistance to sequential antidepressant interventions []. One of the major challenges in improving treatment efficacy lies in the considerable heterogeneity of MDD, both in symptom presentation and underlying neurobiological mechanisms [, ], which has hindered progress in developing personalized, precision-based interventions. This heterogeneity in treatment response across individuals indicates that MDD likely comprises multiple neurobiological relevant stratification patterns beyond conventional diagnostic boundaries [], each probably involving distinct pathophysiological mechanisms and symptom dimensions. Numerous previous studies have made significant efforts to identify MDD subtypes using data-driven approaches [–]. However, traditional subtyping methods have primarily relied on clinical symptomatology or focused on isolated biological markers including neuroimaging [], electroencephalography [], or molecular biomarkers []. While informative, these single-domain approaches may fail to capture the complex brain-behavior relationships underlying MDD and may limit the clinical utility of subtype classifications. Currently, emerging studies have attempted to integrate both neurobiological and clinical features to subtype MDD []. However, most of these efforts have been limited by the high dimensionality of neurobiological data, which often leads to weak and unstable clustering outcomes []. Moreover, many of these studies are cross-sectional and often fail to investigate whether different MDD subtypes exhibit shared or distinct responses to therapeutic interventions. These limitations hinder our understanding of the underlying mechanisms specific to each subtype and impede the development of tailored treatment strategies for MDD. Neuromodulation approaches for treating MDD are particularly well suited for stratification-informed evaluation, as they directly engage distributed brain circuits and allow treatment effects to be tracked with objective neurophysiological markers []. Intermittent theta burst stimulation (iTBS) is a time-efficient and cost-effective form of repetitive transcranial magnetic stimulation (rTMS) []. It has attracted growing clinical interest given evidence of antidepressant efficacy comparable to standard high-frequency rTMS with markedly shorter session duration and favorable tolerability, thereby improving scalability in routine practice [, ]. However, treatment response to iTBS also varies substantially across individuals [, ], highlighting the need to identify biologically and clinically grounded stratification patterns that capture differential treatment sensitivity.