Lipid Signature May Flag Schizophrenia

A specific lipid profile can identify patients with schizophrenia, possibly paving the way for the development of the first clinically useful diagnostic test for a severe psychiatric illness, new research suggests.

Although such a test remains a long way off, investigators said, the identification of the unique lipid signature is a critical first step. However, one expert noted that the lipid signature not accurately differentiating patients with schizophrenia from those with bipolar disorder (BD) and major depressive disorder (MDD) limits the findings’ applicability.

The profile includes 77 lipids identified from a large analysis of many different classes of lipid species. Lipids such as cholesterol and triglycerides made up only a small fraction of the classes assessed.

Investigators note that some of the lipids in the profile associated with schizophrenia are involved in determining cell membrane structure and fluidity or cell-to-cell messaging, which could be important to synaptic function.

Dr Eva Schulte

“These 77 lipids jointly constitute a lipidomic profile that discriminated between individuals with schizophrenia and individuals without a mental health diagnosis with very high accuracy,” investigator Eva C. Schulte, MD, PhD, with the Institute of Psychiatric Phenomics and Genomics (IPPG) and the Department of Psychiatry and Psychotherapy at the University Hospital of Ludwig-Maximilians-University, Munich, Germany, told Medscape Medical News.

“Of note, we did not see large profile differences between patients with a first psychotic episode who had only been treated for a few days and individuals on long-term antipsychotic therapy,” Schulte said.

The findings were published online January 25 in JAMA Psychiatry.

Detailed Analysis

Lipid profiles in patients with psychiatric diagnoses have been reported previously, but those studies were small and did not identify a reliable signature independent of demographic and environmental factors.

For the current study, researchers analyzed blood plasma lipid levels from 980 individuals with severe psychiatric illness and 572 people without mental illness from three cohorts in China, Germany, Austria, and Russia.

The study sample included patients with schizophrenia (n = 478), BD (n = 184), and MDD (n = 256), as well as 104 patients with a first psychotic episode who had no long-term psychopharmacology use.

Results showed 77 lipids in 14 classes were significantly altered between participants with schizophrenia and the healthy control in all three cohorts.

The most prominent alterations at the lipid class level included increases in ceramide, triacylglyceride, and phosphatidylcholine and decreases in acylcarnitine and phosphatidylcholine plasmalogen (P < .05 for each cohort).

Schizophrenia-associated lipid differences were similar between patients with high and low symptom severity (P < .001), suggesting that the lipid alterations might represent a trait of the psychiatric disorder.

No Medication Effect

Most patients in the study received long-term antipsychotic medication, which has been shown previously to affect some plasma lipid compounds.

So, to assess a possible effect of medication, the investigators evaluated 13 patients with schizophrenia who were not medicated for at least 6 months prior to blood sample collection and the cohort of patients with a first psychotic episode who had been medicated for less than 1 week.

Comparison of the lipid intensity differences between the healthy controls group and either participants receiving medication or those who were not medicated revealed highly correlated alterations in both patient groups (P < .001).

“Taken together, these results indicate that the identified schizophrenia-associated alterations cannot be attributed to medication effects,” the investigators write.

Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were similar to those of schizophrenia but not identical.

Researchers isolated 97 lipids altered in the MDD cohorts and 47 in the BPD cohorts — with 30 and 28, respectively, overlapping with the schizophrenia-associated features and seven of the lipids found among all three disorders.

Although this was significantly more than expected by chance (P < .001), it was not strong enough to demonstrate a clear association, the investigators write.

Dr Thomas Schulze

“The profiles were very successful at differentiating individuals with severe mental health conditions from individuals without a diagnosed mental health condition, but much less so at differentiating between the different diagnostic entities,” co-investigator Thomas G. Schulze, MD, director of IPPG, told Medscape Medical News.

“An important caveat, however, is that the available sample sizes for bipolar disorder and major depressive disorder were smaller than those for schizophrenia, which makes a direct comparison between these difficult,” added Schulze, who is also a clinical professor in psychiatry and behavioral sciences at the Norton College of Medicine, SUNY Upstate Medical University, Syracuse, New York.

More Work Remains

Although the study is thought to be the largest to date to examine lipid profiles associated with serious psychiatric illness, much work remains, Schulze noted.

“At this time, based on these first results, no clinical diagnostic test can be derived from these results,” he said.

He added that the development of reliable biomarkers based on lipidomic profiles would require large prospective randomized trials, complemented by observational studies assessing full lipidomic profiles across the lifespan.

Researchers also need to better understand the exact mechanism by which lipid alterations are associated with schizophrenia and other illnesses.

Physiologically, the investigated lipids have many additional functions, such as determining cell membrane structure and fluidity or cell-to-cell messaging.

Schulte noted that several lipid species may be involved in determining mechanisms important to synaptic function, such as cell membrane fluidity and vesicle release.

“As is commonly known, alterations in synaptic function underly many severe psychiatric disorders,” she said. “Changes in lipid species could theoretically be related to these synaptic alterations.”

A Better Marker Needed

Commenting for Medscape Medical News, Steve Strakowski, MD, professor and vice chair of research in the Department of Psychiatry, Indiana University School of Medicine, Indianapolis and Evansville, noted that while the findings are interesting, they don’t really offer the kind of information clinicians who treat patients with serious mental illness need most.

“Do we need a marker to tell us if someone’s got a major mental illness compared to a healthy person?” asked Strakowski, who was not part of the study. “The answer to that is no. We already know how to do that.”

A truly useful marker would help clinicians differentiate between schizophrenia, bipolar disorder, major depression, or another serious mental illness, he said.

“That’s the marker that would be most helpful,” he added. “This can’t address that, but perhaps it could be a step to start designing a test for that.”

Strakowksi noted that the findings also do not clarify whether the lipid profile found in patients with schizophrenia predates diagnosis or whether it is a result of the mental illness, an unrelated illness, or another factor that could be critical in treating patients.

However, he was quick to point out the limitations don’t diminish the importance of the study.

“It’s a large dataset that’s cross-national, cross-diagnostic that says there appears to be a signal here that there’s something about lipid profiles that may be independent of treatment that could be worth understanding,” Strakowksi said.

“It allows us to think about developing different models based on lipid profiles, and that’s important,” he added.

The study was funded by the National Key R&D Program of China, National One Thousand Foreign Experts Plan, Moscow Center for Innovative Technologies in Healthcare, European Union’s Horizon 2020 Research and Innovation Programme, NARSAD Young Investigator Grant, German Research Foundation, German Ministry for Education and Research, the Dr. Lisa Oehler Foundation, and the Munich Clinician Scientist Program. Schulze and Schult report no relevant financial relationships. Disclosures for the other investigators are fully listed in the original article.

JAMA Psych. Published online January 25, 2023. Abstract.

Kelli Whitlock Burton is a reporter for Medscape Medical News covering psychiatry and neurology.

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