An enzyme that goes down in early psychosis

Design

cross-sectional study with biofluid assay, polygenic risk scoring and enzymatic activity measurement

Population

200 participants aged 13–35 (mean 22.8 years, 64.5% male): 122 with psychosis of under two years' duration, 78 healthy controls

Primary outcome

ACE protein level in cerebrospinal fluid and serum, ACE-specific polygenic risk score, and serum enzymatic activity

Effect

lower ACE protein in patients in cerebrospinal fluid (d = −1.16, P = .005) and serum (d = −0.92, P < .001); lower still in treatment-resistant cases (d = −0.50, P = .03); no difference in canonical enzymatic activity

Psychiatry still has no blood test, and angiotensin-converting enzyme (ACE) is an odd place to look for one — it is known mainly as the target of a class of antihypertensives. But ACE is an established schizophrenia risk gene, and a cross-sectional study at the Johns Hopkins Schizophrenia Center asked what happens to the protein it codes for.

Among 200 participants aged 13 to 35 — 122 with psychosis of less than two years' duration and 78 healthy controls — ACE protein was lower in patients in both cerebrospinal fluid (Cohen d = −1.16, P = .005) and serum (d = −0.92, P < .001), and the two fluids correlated with each other. Within the patient group, a higher ACE-specific genetic burden for schizophrenia went with lower protein levels (r = −0.35, P = .002). Patients with treatment-resistant illness had lower serum ACE than those without (d = −0.50, P = .03).

The interesting detail is what did not move. Canonical renin-angiotensin enzymatic activity did not differ, either between patients and controls or between resistant and non-resistant subgroups, and did not track the genetic burden. So whatever this is, it is not straightforwardly about the blood-pressure pathway. This is research-stage work: there is no reason to send an ACE level on a patient with first-episode psychosis, and the treatment-resistance finding in particular is a small subgroup comparison that needs replicating before it means anything at the bedside.

• Do not order serum ACE in psychosis — this is not a validated test and has no established cut-off.
• Note that effect sizes here are between-group averages with overlapping distributions, not a separation of individuals.
• Remember serum ACE is raised in sarcoidosis and affected by ACE-inhibitor therapy; any future test would need those controlled for.
• Watch for replication in an independent cohort before changing how treatment resistance is assessed.
• The dissociation between protein level and enzyme activity is the finding worth following, not the levels themselves.

Why it matters

It is the first link from a known schizophrenia risk gene to a measurable protein change in living patients, and the protein moves without its enzyme activity moving.

Don't overread it

This is cross-sectional and single-centre — it cannot say whether low ACE precedes psychosis, follows it, or reflects treatment.

The statistics, in plain English

Cohen's d of −1.16 in cerebrospinal fluid is a large group difference, but a large average difference is not a diagnostic test — the two distributions still overlap substantially, which is why no sensitivity or specificity is reported. The treatment-resistance comparison (d = −0.50, P = .03) is a subgroup analysis within 122 patients and sits close to the conventional significance threshold, so it is the weakest claim in the paper. The correlation of −0.35 between genetic burden and protein level means genetics explains roughly a tenth of the variation in levels.

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