Blood Biomarker a ‘Promising Predictor’ of Psychosis Relapse

Copeptin, a small peptide secreted with the hormone vasopressin, appears to be one of the first promising biomarkers for predicting psychosis relapse, results of an observational study suggest.

An analysis of plasma copeptin levels in patients with schizophrenia showed those with high plasma levels of the peptide were about three times more likely to experience psychotic relapse compared with their counterparts with lower levels.

The results suggest, “copeptin could be a promising biomarker in predicting psychotic relapse in schizophrenia spectrum disorder,” said study investigator Jennifer Küster, MD, Psychiatric University Clinics Basel, Switzerland. Measuring copeptin levels upon hospital admission “could help to intensify” the care of at-risk patients, she added.

The findings were presented at the virtual Congress of the Schizophrenia International Research Society (SIRS) 2021.

Relapse Prevention Important

Two thirds of patients with schizophrenia experience at least one relapse of a psychotic episode, which in turn increases the risk of the disorder having a chronic course, Küster noted.

In addition, a psychotic relapse is associated with deterioration of function and cognition and reduced treatment response, “so relapse prevention is important,” she said.

Previous research has explored various methods of predicting schizophrenia outcomes. These include measuring inflammatory markers, catecholamines, oxytocin, and cortisol in combination with imaging markers, “but so far no reliable biomarker has been found,” Küster said.

She noted that psychotic relapse is associated with increased psychological stress — and vasopressin, which is secreted by the pituitary gland, is a known marker of stress. It is involved in sodium homeostasis and higher brain function and is also elevated in acute psychosis.

However, vasopressin “is challenging to measure because assays are complicated and unreliable,” Küster said.

As a result, the researchers turned their attention to copeptin, a more stable, more reliable surrogate marker for vasopressin. Copeptin has been shown previously to be a predictor of outcomes in somatic diseases and is also increased during psychological distress.

To measure the utility of copeptin in predicting psychotic relapse, the researchers conducted a prospective, explorative, single-center observational study involving inpatients with an acute psychotic episode diagnosed with schizophrenia spectrum disorder or affective disorder.

Baseline characteristics were collected and fasting serum copeptin levels were measured. Disease severity was measured using a range of validated assessment scales.

Predictive Factor

Among 69 patients available for analysis, 30 experienced psychotic relapse at 1-year follow-up. Relapse was defined as rehospitalization due to an acute psychotic episode.

There were no differences in baseline demographic characteristics between patients with, and without, psychotic relapse. There were also no differences in baseline psychopathology, including scores on the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Global Assessment of Function.

Küster noted that there were no overall differences between patients with and without psychotic relapse in terms of their plasma copeptin or cortisol levels at baseline.

“The only difference we saw was in diagnosis,” she reported. Patients with psychotic relapse were significantly more likely to have comorbid drug abuse — 43% in patients who relapsed vs 15% of those who did not (P = .02).

However, when the investigators calculated the area under the receiver operating characteristics curve for copeptin levels, they found there was a significant difference in relapse rates in those with copeptin levels >6 pmol/L vs those with lower levels (hazard ratio [HR], 2.3; P = .039).

When the focus was only on patients with schizophrenia spectrum disorder, the results were even more pronounced. The HR for psychotic relapse in patients with higher vs lower copeptin levels was 3.2 (P = .028).

“We also looked for other possible predicting factors,” Küster said. This included sex, age, duration of disease, reason for hospitalization, psychopathology, medication, comorbidities, and cortisol levels. “But none of these factors was associated with psychotic relapse,” she added.

The only factor positively associated with relapse was drug abuse, primarily via marijuana. However, the association with copeptin remained significant even after taking this factor into account.

In future studies, the researchers plan to examine whether copeptin levels could identify which patients at ultra-high risk will transition to first-episode psychosis, as well as to predict development of posttraumatic stress disorder, Küster said.

A Proxy for “Something Simpler”?

Commenting on the findings for Medscape Medical News, Leah H. Rubin, PhD, associate professor of neurology, Johns Hopkins University, Baltimore, Maryland, described the study as “interesting” — and noted that her own research has included measuring vasopressin in patients with untreated first-episode psychosis.

Rubin’s findings showed that levels of the hormone were associated with psychosis severity, and thus she is “not surprised that they found a marker” that may be promising in psychosis relapse prediction.

However, she took issue with the notion that vasopressin is an unreliable marker, pointing out that the work of her team demonstrates that it can be measured. Rubin added that she found it to be “pretty stable.”

In addition, because the current study had a small sample size, Rubin said she would be interested to see whether the findings can be replicated on a larger scale.

She also noted that more than two thirds of the study population were men. “Vasopressin and oxytocin are sexually dimorphic neuropeptides,” she explained, “so I think it becomes important to ensure…whether it‘s the same for men and women.”

“Just from a psychosocial perspective, what‘s going on in those folks’ lives?” Rubin asked. “Is it truly copeptin” or is it high stress levels that facilitate a relapse? Copeptin levels, she added, may be “a proxy for something simpler.”

The study authors and Rubin have disclosed no relevant financial relationships.

Congress of the Schizophrenia International Research Society (SIRS) 2021: Abstract 3007218. Presented April 19, 2021.

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