Blood Protein May Help Identify Treatment-Resistant Psychosis

Treatment-resistant psychosis remains particularly challenging because clinicians lack objective biological tests to identify patients likely to develop resistance, making it harder to tailor treatment early. New findings now suggest that angiotensin-converting enzyme may serve as a blood-based marker associated with treatment-resistant psychosis.

Researchers at Johns Hopkins Medicine identified angiotensin-converting enzyme (ACE), a protein best known for its role in blood pressure regulation, as a potential biological marker associated with treatment-resistant schizophrenia and other psychoses. ACE normally contributes to blood vessel constriction, while ACE inhibitors are widely used to treat hypertension by blocking its activity. The new findings suggest that ACE may also have a separate biological role in psychosis that is distinct from its function within the renin-angiotensin system.

The preliminary study analyzed 200 participants, including 78 healthy controls and 122 people with early-stage psychosis. Among those with psychosis, 31 had treatment-resistant disease and 91 did not. Researchers measured ACE protein levels in blood and cerebrospinal fluid, assessed ACE enzymatic activity, and analyzed genetic data related to schizophrenia risk.

ACE protein levels were significantly lower in both blood and cerebrospinal fluid among people with early-stage psychosis compared with healthy controls. Participants with treatment-resistant psychosis also had lower blood ACE levels than those without treatment resistance. However, ACE enzymatic activity did not differ significantly between the two psychosis groups, suggesting that the protein’s association with treatment resistance may involve biological functions unrelated to its established role in blood pressure regulation.

The study was published online September 9, 2026, in JAMA Psychiatry. The research involved The Johns Hopkins University and other collaborating institutions. The researchers said the findings may have applications beyond psychiatry because some proteins can perform hidden functions unrelated to their established roles, and ACE may represent another such protein.

“The new findings suggest this protein may be doing something entirely different in the context of psychosis. Our next step is to understand this additional, unrecognized function of ACE protein. If we can establish this relationship in larger and independent studies, ACE could potentially become part of a broader panel of biological markers that helps us better understand and ultimately treat psychotic disorders,” said Akira Sawa, M.D., director of the Johns Hopkins Schizophrenia Center. 

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