Background: Major Depressive Disorder (MDD) is associated with accelerated ageing trajectories including functional markers of ageing, cellular ageing and markers of poor brain health. The biological mechanisms underlying these associations remain poorly understood. Chronic inflammation is also associated with advanced ageing; however, the degree to which long-term inflammation plays a role in ageing in MDD remains unclear, partly due to difficulties differentiating long-term inflammation from acute cross-sectional measures. Methods: Here, we use a longer-term measure of inflammation: a DNA methylation-based marker of C-reactive protein (DNAm CRP), in a large cohort of individuals deeply phenotyped for MDD (Generation Scotland, GS, N=804). We investigate associations between DNAm CRP and serum CRP using linear modelling with two brain ageing neuroimaging-derived phenotypes: (i) a machine learning based measure of brain-predicted age difference (brain-PAD) and (ii) white matter hyperintensities (WMH). We then examine inflammation by depression interaction effects for these brain ageing phenotypes. We sought to replicate findings in an independent sample of older community-dwelling adults (Lothian Birth Cohort 1936, LBC1936; N=615). Results: DNAm CRP was significantly associated with increased brain-PAD ({beta}=0.111, p=0.015), which was replicated in the independent sample with a similar significant effect size ({beta}=0.114, p=0.012). There were no associations between the inflammation markers and WMH phenotypes in the GS-imaging sample, however in the LBC1936 sample, DNAm CRP was significantly associated with both Wahlund infratentorial ({beta}=0.15, PFDR= 0.006) and Fazekas deep white matter hyperintensity scores ({beta}= 0.116, PFDR=0.033). There were no interaction effects between inflammation and MDD in either cohort. Conclusions: This study found robust associations between a longer-term marker of inflammation and brain ageing as measured by brain-PAD, consistent across two large independent samples. However, we found no evidence for interaction effects between inflammation and MDD on any brain ageing phenotype in these community-based cohorts. These findings provide evidence that chronic inflammation is associated with increased brain ageing, which is not specific to MDD. Future work should investigate these relationships in clinical samples including with other inflammatory biomarkers and should furthermore aim to determine causal directionality.

Objective Switching to long-acting injectable (LAI) antipsychotic maintenance treatment (AMT) represents a valuable strategy for schizophrenia. In a recovery-oriented approach, patient-reported outcomes (PROs) such as perceived disability, subjective well-being, and quality of life cannot be neglected. Methods Forty clinically stable outpatients with schizophrenia treated with oral second-generation antipsychotics were enrolled at the time of switching to the equivalent dose of LAI. 35 subjects completed this 2-year longitudinal, prospective, open-label, observational study. Patients were assessed at baseline, after 1 year, and after 2 years of LAI-AMT, using psychometric scales (Positive And Negative Syndrome Scale, PANSS; Young Mania Rating Scale, YMRS; Montgomery-angstrom sberg Depression Rating Scale, MADRS), PROs (Subjective Well-Being under Neuroleptics short form, SWN-K; Short Form-36 health survey, SF-36; 12-item World Health Organisation Disability Assessment Schedule, WHODAS 2.0), and caregiver-reported outcomes (12-item WHODAS 2.0). Results No psychotic relapses were observed. Psychopathology measures (PANSS total and subscales - excluding negative symptoms), mood symptoms (YMRS, MADRS), perceived disability (patient- and caregiver-administered WHODAS 2.0), subjective well-being (SWN-K), and quality of life (SF-36) showed a concomitant amelioration after 1 year, without further significant variations. Discussion Switching to LAI-AMT may decrease perceived impairment, and increase subjective well-being and quality of life in clinically stable outpatients with schizophrenia.