Potential New Biomarker for Psychosis Severity

Liam Davenport

June 23, 2020

Angiotensin I-converting enzyme (ACE) levels are lower in individuals with first episode psychosis (FEP) and even lower in those with resistant disease, suggesting the enzyme may be a biomarker of disease severity.

In a longitudinal cohort study, investigators found patients with FEP had significantly reduced ACE levels compared with their healthy peers.

With blood concentrations of the enzyme significantly reduced in those who were treatment-resistant, "ACE alterations appear to be already present at the disease onset" and results suggest "a possible relationship with disease severity," note the researchers, led by investigator Luisa Longo, MD, a resident in psychiatry, University of Bari Aldo Moro in Italy.

Moreover, the finding that lower ACE levels were associated with greater cognitive impairment on neuropsychological tests indicates the enzyme plays a role in "the alteration of neurocognitive abilities" in patients with FEP.

Taken together, the results "highlight ACE as a promising peripheral biomarker to identify patients at risk of treatment resistance to antipsychotics," the investigators report.

The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2020 Virtual Meeting.

Mechanisms "Poorly Understood"

Previous studies suggest ACE may play a role in neurologic and psychiatric conditions, including schizophrenia, through alterations in function or blood concentrations.

However, the molecular mechanisms underlying disease onset and response to antipsychotics in patients with FEP "remain poorly understood," the researchers note. In addition, "despite adequate antipsychotic treatment, 20% of patients have persistent symptoms."

To determine whether ACE levels are already altered in FEP patients, the investigators examined data on 138 patients with FEP and 115 healthy controls.

After measuring blood concentrations in 122 of the patients and 78 controls, they found that ACE levels were significantly lower in FEP patients (P = 4.1x10-13) after controlling for age, sex, ethnicity, duration of illness, smoking status, and chlorpromazine equivalents.

Cerebrospinal fluid (CSF) levels, which were measured in 19 patients and 18 controls, were also significantly lower in individuals with FEP (P = .01), with a strong correlation observed between blood and CSF levels (P = .0005).

Next, the team used Treatment Response and Resistance in Psychosis criteria to compare ACE levels in 32 treatment-resistant patients and 106 non­–treatment-resistant patients. Results showed that ACE blood levels were significantly lower in the treatment-resistant patients (P = .03).

Finally, the association between ACE blood levels and range of clinical and neurocognitive variables were examined across all FEP patients.

The Scale for the Assessment of Negative and Positive Symptoms was administered, along with a battery of tests looking at processing speed, working memory, verbal learning and memory, visual learning and memory, ideational fluency, and executive function. All were combined into a composite score.

While there was no association between ACE blood levels and symptom severity in the patients, there was a significant association between levels and verbal memory (P = .007) and composite cognitive score (P = .04).

Notable Finding

Commenting on the study for Medscape Medical News, Thomas W. Sedlak, MD, PhD, assistant professor of psychiatry and behavioral health, Johns Hopkins University School of Medicine, Baltimore, Maryland, said the finding that ACE levels were associated with lower cognition scores is "notable in that we don't really have any treatments for cognition."

"Antipsychotic drugs treat more of the famous symptoms of hallucinations and delusions and disordered speech, but they don't really help cognition a whole lot — and too much medicine might even make that worse," said Sedlak, who was not involved with the research.

"So it's interesting to have another biomarker that might relate a symptom of schizophrenia that we don't really have a good grip on addressing."

However, he noted that this study is "preliminary," has not looked at longitudinal changes in ACE in the same patients, and is one of "many" correlation studies.

"I like to say you can pretty much Google any chemical in the body and somebody has a claim about it and schizophrenia," Sedlak said.

Nevertheless, the current analysis is "convergent" with past studies on ACE, including those that have found associations between polymorphisms in the enzyme and schizophrenia, he noted.

Moreover, research has shown that ACE facilitates glutamate transmission, specifically via N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex, "which is probably the brain region most tied to schizophrenia abnormalities," Sedlak said.

No Tie to Inflammation

The findings do contrast, however, with the increasing body of evidence linking schizophrenia to inflammation.

Sedlak said that is not surprising, as the more that is learned about schizophrenia, "the less it is likely to be a single homogeneous entity but something more akin to intellectual disability."

"We're finding that there are different subtypes of schizophrenia, some of which might have more of an inflammatory tie and others which don't."

He added that it might be possible over the longer term to cluster patients by ACE levels and other biomarkers and then follow them long term to "see if we can predict outcomes better than purely clinical terms."

In this way, Sedlak believes that psychiatry may become more like rheumatology, "which I'd say is the area of medicine, at least in terms of making diagnoses, most similar."

The etiology of conditions such as lupus and rheumatoid arthritis is "not absolutely known" and there is "probably no single cause," with the diagnosis relying on clinical findings alongside biomarker tests.

"I think psychiatry is, long term, hoping to discover some biomarkers...that would be used together with the clinical findings to help come to more clinical agreement on how to define cases — and would be predictive long term in terms of the course of illness," Sedlak concluded.

The study had no specific funding. The study investigators and Sedlak have disclosed no relevant financial relationships.

Congress of the Schizophrenia International Research Society (SIRS) 2020: Abstract S19.

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