Obesity as a Risk Factor for Accelerated Brain Ageing in First-Episode Psychosis—A Longitudinal Study

Abstract

Background Obesity is highly prevalent in schizophrenia, with implications for psychiatric prognosis, possibly through links between obesity and brain structure. In this longitudinal study in first episode of psychosis (FEP), we used machine learning and structural magnetic resonance imaging (MRI) to study the impact of psychotic illness and obesity on brain ageing/neuroprogression shortly after illness onset. Methods We acquired 2 prospective MRI scans on average 1.61 years apart in 183 FEP and 155 control individuals. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants and calculated BrainAGE by subtracting chronological from the estimated brain age. Results Individuals with FEP had a higher initial BrainAGE than controls (3.39 ± 6.36 vs 1.72 ± 5.56 years; β = 1.68, t(336) = 2.59, P = .01), but similar annual rates of brain ageing over time (1.28 ± 2.40 vs 1.07±1.74 estimated years/actual year; t(333) = 0.93, P = .18). Across both cohorts, greater baseline body mass index (BMI) predicted faster brain ageing (β = 0.08, t(333) = 2.59, P = .01). For each additional BMI point, the brain aged by an additional month per year. Worsening of functioning over time (Global Assessment of Functioning; β = −0.04, t(164) = −2.48, P = .01) and increases especially in negative symptoms on the Positive and Negative Syndrome Scale (β = 0.11, t(175) = 3.11, P = .002) were associated with faster brain ageing in FEP. Conclusions Brain alterations in psychosis are manifest already during the first episode and over time get worse in those with worsening clinical outcomes or higher baseline BMI. As baseline BMI predicted faster brain ageing, obesity may represent a modifiable risk factor in FEP that is linked with psychiatric outcomes via effects on brain structure.

Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness—ENIGMA study in 2436 individuals

“…The diffuse and uniform nature of the BMI‐related brain alterations may be more congruent with cortical thinning as a consequence of obesity. The negative effects of BMI on brain structure are supported by a Mendelian randomization study, 40 several longitudinal studies, demonstrating that obesity or obesity‐related metabolic alterations precede and accelerate brain changes over time 18,41 and by improvement of brain indices following a successful treatment of obesity 42–44 …”

CoMET: a randomised controlled trial of co-commencement of metformin versus placebo as an adjunctive treatment to attenuate weight gain in patients with schizophrenia newly commenced on clozapine

“…41,42 In addition, obesity has also been found to increase risk of accelerated brain ageing in schizophrenia. 43 We found statistically significantly greater reductions in the metformin group than the placebo group for HbA1c and diastolic BP, although these reductions were not clinically meaningful. Previous studies of hypoglycaemic medications among people on clozapine have shown reductions in HbA1c 38,39 although it is possible that our findings may reflect a Type-I error associated with multiple analyses.…”

“…41,42 In addition, obesity has also been found to increase risk of accelerated brain ageing in schizophrenia. 43…”

Accelerated Global and Local Brain Aging Differentiate Cognitively Impaired From Cognitively Spared Patients With Schizophrenia

“…Fourth, the current study does not inform on molecular changes that may underlie brain aging in schizophrenia. The available literature on brain aging suggests a potential role mainly for metabolic dysfunction ( 48 ) and low-level neuroinflammation ( 49 ) that should be assessed in future studies.…”