Angiotensin-Converting Enzyme in Patients With Early-Stage Psychosis

Importance A major challenge in the management of psychotic disorders is the lack of objective biomarkers. While angiotensin-converting enzyme ( ACE ) has been identified as a risk gene for schizophrenia, a major knowledge gap remains regarding whether and how this genetic impact results in biological dysfunction through its protein product. Objective To compare ACE levels, enzymatic activity, and genetic variations between patients with early-stage psychosis and healthy controls and between patient subgroups with and without treatment-resistant psychosis. Design, Setting, and Participants This cross-sectional study included patients aged 13 to 35 years with early-stage psychosis (onset within the prior 2 years) who were recruited at the Johns Hopkins Schizophrenia Center in Baltimore, Maryland, between October 30, 2013, and February 9, 2018. Data were analyzed from June 1, 2018, to June 22, 2026. Exposure Early-stage psychosis. Main Outcomes and Measures The main outcomes were ACE protein levels in cerebrospinal fluid and serum, genomewide and ACE gene–specific polygenic risk scores, and ACE canonical enzymatic activity in serum. Results The study included data from 200 participants (mean [SD] age, 22.8 [4.1] years; 129 [64.5%] male), including 78 healthy controls and 122 patients with early-stage psychosis. ACE protein levels were significantly lower in both cerebrospinal fluid (Cohen d = −1.16; P = .005) and serum (Cohen d = −0.92; P < .001) in patients compared with controls, with significant correlations between biofluids ( r = 0.34; P = .04). In patients with psychosis, higher ACE genetic burden for schizophrenia was associated with lower ACE protein levels ( r = −0.35; P = .002) but not with ACE canonical (renin-angiotensin system) enzymatic activity. Patients with treatment-resistant cases had lower serum ACE protein levels than patients with non–treatment-resistant cases (Cohen d = −0.50; P = .03). There was no difference in canonical enzymatic activity between these 2 patient subgroups. Conclusions and Relevance This cross-sectional study found that ACE protein levels were significantly lower in cerebrospinal fluid and serum in patients with early-stage psychosis compared with controls. Between patient subgroups, ACE protein levels were significantly lower in serum in patients with treatment-resistant psychosis compared with those with non–treatment-resistant psychosis. A contrast was observed between ACE protein levels and catalytic function, where ACE genetic variations showed a significant correlation with protein levels but not with enzymatic activity.