In this study, we found that patients with SSD within the first 5 years of psychosis onset already had significantly higher AL compared to their age-matched controls, which appeared not to be driven primarily by metabolic syndrome alone. Chronic patients also showed significantly elevated AL compared with age-matched controls, and the high AL in the more chronic patients appeared to be driven more by metabolic syndrome. These results support the hypothesis that AL elevation is already present in the early years of the illness.

A study investigating AL in older (mean age 32.96 years) FEP patients showed elevated AL32. This FEP sample was unique as the patients were not on antipsychotic medications, being about 10 years older than typical FEP cohorts, and AL decreased after 12 weeks of treatment32. As the patients were acutely ill during the initial assessment, it remains to be determined whether the psychosis reduction or antipsychotic medications per se were related to the AL changes. In the current study, patients had a stringent definition of being within the first 5 years of the course of psychosis, clinically stable, and the mean age of 23.41 was more representative of the typical age range of FEP patients. Overall, these data were consistent, and suggested that AL increases can be present in the early course of psychosis.

Schizophrenia spectrum disorder patients in the US have 28.5 years of shorter lifespan compared with the general population25. After accounting for suicide and other unnatural death, 85% of the deaths were natural causes from medical illnesses25. The risks of elevated cardiovascular and metabolic diseases in schizophrenia are well-known, and are further increased in aging patients with longer illness duration19,37. Understanding the complex sources of the high rate of medical conditions and the shorter lifespan in SSD is an urgent public health issue38,39,40. In this regard, we found that abnormal cardiovascular and metabolic subcomponents alone did not stand out as more prominent than other subcomponents in explaining elevated AL. This may be consistent with some literature, which showed that while mortality rate in early schizophrenia is already very high, metabolic and cardiovascular causes may not significantly contribute to the high mortality at this stage41,42. Covarying the metabolic syndrome also did not diminish the elevated AL in the early-stage patients, suggesting that elevated cumulative stress in the early course of illness may not be driven primarily by the presence of metabolic syndrome. Instead, cardiovascular and metabolic factors, when combined with stress hormone and immune factors yielded a robust AL abnormality even in the early course of schizophrenia. Therefore, most of the AL measures showed some levels of abnormalities in early stage of the illness but by each subcomponent the findings are not as robust as the overall AL index that aggregated these multisystem measures.

AL represents the effects from a cumulative burden of stress in individuals, and therefore the entire set of biomarkers may be more valid, where elevated AL is likely due to multiple mechanisms associated with maladaptive response to stress, resulting in multisystem imbalances even at the early years of schizophrenia. The significant correlation between AL and severity of positive symptoms in the early course patients (r = 0.54, p = 0.01) may further suggest that psychosis is either directly related to greater experience of stress, or indirectly associated with the underlying mechanisms of the maladaptive response to stress. This finding is also consistent with previous studies on first episode patients and individuals with clinical high risk where greater cortisol levels are associated with more severe positive symptoms43.

Indeed, some studies showed increased cortisol levels in individuals who are at risk for psychosis and in early psychosis and in non-medicated patients8,44, but not in other studies45. In our study, neither early nor chronic patients had significantly elevated levels of overnight urinary cortisol. Rather, the composite stress hormone subcomponent consisting of overnight cortisol, epinephrine, norepinephrine, and DHEA was nominally elevated in the early-stage patient group (p = 0.04), and this finding was replicable in the chronic patient group (p = 0.01). Findings suggest that elevated stress-related hormones at the overnight resting state are a consistent finding in early to chronic courses of schizophrenia. Similarly, we also observed elevated immune subcomponent (CRP) in early stage (p = 0.005) and chronic (p = 0.03) patients. CRP is an acute phase reactant used as a non-specific global measure for inflammation. Low-grade CRP elevation is a consistent finding in both first episode and chronic schizophrenia patients that cannot be attributed to antipsychotic treatment12.

On cardiovascular measures, several recent studies suggested that first episode patients show no elevation in 10-year cardiovascular diseases or metabolic syndrome rates compared with their age-matched peers19,21. Our data also did not support that parameters of cardiovascular and metabolic risk are particularly significantly elevated in early course of the illness.

Limitations of the study included that all but four of the patients were on antipsychotic medications at the time of the study. Antipsychotics can normalize diurnal cortisol hypersecretion7,46 and decrease cortisol levels,47,48 and even a single dose of second-generation antipsychotics can reduce serum cortisol level49. However, these antipsychotic medication effects should not explain the elevated stress-related hormone subcomponent, and high AL in patients at the early years of the illness except that they may have dampened the elevations of the stress subcomponent. More specific antipsychotic medication like aripiprizole, quetiapine, and olanzapine have been studied for their specific effects on decreasing or increasing norepinephrine releases,50,51 although to what extent these effects were related to the resting overnight urinary norepinephrine levels require additional studies. The modest sample size here did not permit analysis on specific effects from each antipsychotic medication. The effect sizes of AL in the early versus later disease course patients were similar, which did not support that cumulative dose of antipsychotics was the primary reason for the high AL. Still, the use of antipsychotic medications can have effects on cardiovascular and metabolic factors52,53. Another limitation is that our data were cross-sectional, and our analysis included the first five years of the onset of psychosis. A more narrow approach could be to examine AL in the initial month(s) of psychosis onset, ideally starting in patients with no or minimal antipsychotic medication exposures, followed by longitudinal follow-up of the cases. Such an approach may provide more conclusive evidence of whether high AL begins at disease onset versus develops within the first few years of the disease.

In conclusion, this study provided new evidence of a significantly elevated AL even in the first 5 years of the illness course of SSD. We found that subcomponents separately measuring immune, stress hormone, cardiovascular or metabolic factors were only weakly to modestly elevated in schizophrenia, but the overall AL metric that aggregates these components yielded significant disease effects even with a modest sample of early-stage young patients. AL may provide a theoretically driven, empirically applicable construct for supporting early risk identification, prevention, and treatment of somatic comorbidity in patients with SSD.