Johns Hopkins Medicine Researchers Identify Promising Biological Marker Linked to Treatment-Resistant Psychosis

Johns Hopkins Medicine Researchers Identify Promising Biological Marker Linked to Treatment-Resistant Psychosis

10/12/2026

Johns Hopkins researchers say they have evidence that a well-studied blood pressure regulation protein appears to also be a marker for and perhaps play a role in treatment-resistant schizophrenia and other psychoses ›

In a preliminary study using blood and spinal fluid samples from 200 people, Johns Hopkins Medicine researchers say they have evidence that a well-studied blood pressure regulation protein appears to also be a marker for and perhaps play a role in treatment-resistant schizophrenia and other psychoses.

The findings, if confirmed in larger studies, the researchers say, could eventually contribute to more objective ways of identifying people with psychosis who may need different treatment approaches.

In the federally funded study published online Sept. 9 in JAMA Psychiatry, researchers found significantly lower levels of angiotensin-converting enzyme (ACE), a protein that helps regulate blood pressure, in the blood of people with treatment-resistant psychosis compared with people with early-stage psychosis not classified as treatment resistant. Importantly, the investigators say, ACE protein levels in blood correlated with ACE levels in cerebrospinal fluid, suggesting that a simple blood test may reflect accurately what is happening in the brain.

Because ACE is known to narrow blood vessels, ACE inhibitors are widely prescribed for hypertension, blocking the protein from doing its normal job. "The new findings suggest this protein may be doing something entirely different in the context of psychosis," says Akira Sawa, M.D., director of the Johns Hopkins Schizophrenia Center. "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."

Sawa notes that previous studies identified higher than normal levels of ACE as a genetic risk for schizophrenia, although what the gene that codes for the protein actually did has been unclear.

"This study provides some evidence that genetic alterations in the gene for ACE affect the level of the protein it makes, which in turn may influence the biology of psychosis, particularly in patients whose symptoms do not respond adequately to standard treatments," says Kun Yang, Ph.D., assistant professor of psychiatry and behavioral sciences at Johns Hopkins Medicine.

Psychotic disorders, including schizophrenia, are currently diagnosed primarily through evaluation and assessment of symptoms and behaviors, including hallucinations, delusions and disordered thinking. Sawa says there are currently no objective biological blood or other tests that can determine which people with psychoses are likely to develop treatment resistance. Identifying biological differences associated with treatment resistance could help researchers develop more precise approaches to diagnosis and treatment, including the identification of new drug targets.

For the study, researchers analyzed data from 200 participants, including 78 healthy controls and 122 people with early-stage psychosis. Among the participants with psychosis, 31 had treatment-resistant psychosis and 91 did not. The researchers measured ACE protein levels in blood and cerebrospinal fluid, examined ACE enzymatic activity and analyzed genetic data related to schizophrenia risk. They found that ACE protein levels were significantly lower in both cerebrospinal fluid and blood among people with early-stage psychosis compared with healthy controls.

The researchers also found that participants with treatment-resistant psychosis had lower levels of ACE protein in their blood than patients who were not treatment resistant, but they found no significant difference in the protein's enzyme activity between the two groups.

The contrast between ACE protein levels and its enzymatic activity suggests that ACE may play a role in psychosis through biological functions unrelated to its role in regulating blood pressure, a function known as the renin-angiotensin system.

The researchers say their findings may also have applications beyond psychiatry. In recent years, scientists have discovered that some proteins "moonlight" - performing hidden functions unrelated to their established roles. A notable example is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), whose moonlighting function was discovered by Johns Hopkins Medicine researchers. Long known solely for its essential role in breaking down glucose for energy, GAPDH is now recognized to influence cell death. It's possible, they say, that ACE may be another such moonlighting protein, a discovery that could spark new lines of research in neuroscience and molecular biology.

The research was supported by grants from the National Institutes of Health and the Brain & Behavior Research Foundation.

In addition to Yang and Sawa, authors of the study are Luisa Longo, M.D.; Pasquale Di Carlo, M.D.; Max Lam, Ph.D.; Ruoyu Wang, B.S.; Semra Etyemez, M.D.; Marina Mihaljevic, M.D., Ph.D.; Nicola G. Cascella, M.D.; Frederick C. Nucifora Jr., D.O., Ph.D.; Jennifer M. Coughlin, M.D.; Gerald Nestadt, M.D.; Thomas W. Sedlak, M.D., Ph.D.; and Lindsay Hayes, Ph.D. The researchers are affiliated with The Johns Hopkins University and other collaborating institutions.