Specific immune-inflammatory profiles and neurocognitive deficits predict illness trajectories in people with type 2 diabetes mellitus or psychiatric disorders.

Introduction: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are chronic conditions that are often comorbid with each other. Neurocognitive and functional impairments are associated with numerous clinical changes during the course of illness. Immune-inflammatory dysfunction is emerging as a critical factor in the progression of these disorders. This study aimed to identify neurocognitive deficits and immune-inflammatory biomarkers that are suitable for signaling different illness trajectories from transdiagnostic and longitudinal perspectives.

Methods: Clinical status, neurocognitive and functional performance, and peripheral blood biomarkers of immune-inflammation were assessed twice a year in 165 individuals, including 30 with schizophrenia (SZ), 42 with bipolar disorder (BD), 35 with major depressive disorder (MDD), 30 with T2DM, and 28 healthy controls (HCs). Participants with chronic illness (n = 137) were stratified into quartiles, taking their years of illness duration at baseline as a reference into categories of short illness duration (SD; n = 37), middle illness duration (MD; n = 36), long illness duration (LD; n = 32), and very long illness duration (VLD; n = 32). The illness duration was used to measure the illness trajectory, and the exposure of interest was clinical progression, calculated as the difference between clinical severity at baseline (T1) and after 1 year (T2).

Results: Neurocognitive impairment was more significant in the VLD group than in the other groups, with small-moderate effect sizes (F = 2.9 to 9.3; p < 0.05-0.0001; ηp = 0.06-0.24). Moreover, the HC group showed significantly higher functional outcomes than the other groups (F = 5.8 to 6.0; p < 0.0001; ηp = 0.13-0.16). On the contrary, the HC group showed lower levels of immune-inflammatory markers (white blood cell count, absolute neutrophils, absolute monocytes, absolute basophiles, neutrophils/lymphocyte ratio, and platelets/lymphocyte ratio [PLR]) (F = 2.9 to 6.7; p < 0.05-0.0001; ηp = 0.07-0.18). In all groups, significant prospective associations were observed between cognitive function (short-term memory and processing speed), global functional scores, immune-inflammatory biomarkers (monocyte/lymphocyte ratio [MLR] and PLR), and clinical status (p < 0.05). Furthermore, a similar combination of neurocognitive deficits and immune-inflammatory alterations compounded the transdiagnostic model that best discriminated the different illness trajectories (χ = 67.4 to 78.7; p < 0.05-0.01).

Conclusions: Neurocognitive dysfunction and systemic inflammation are associated with prolonged illness trajectories in individuals with psychiatric disorders and T2DM. An immune-inflammatory profile and neurocognitive and functional performance may be valuable to differentiate individuals with different illness trajectories. These findings have potential translational utility for early transdiagnostic interventions targeting these groups.