Novel CSF Biomarker and Peptide Candidate Target Cognitive Symptoms of Schizophrenia

Current schizophrenia medications address positive symptoms such as hallucinations and delusions but do little for the cognitive symptoms of the disorder, including disorganized thinking and executive dysfunction. A new study from Northwestern University, conducted in humans and mice and published in Neuron, identifies a novel cerebrospinal fluid (CSF) biomarker of schizophrenia that also functions as a candidate drug target for these cognitive deficits.¹

Schizophrenia affects approximately 0.5% of the world's population, including about 2 million people in the US. Investigators noted that unaddressed cognitive symptoms leave many patients unable to work, dependent on family for lifelong support, or at risk for homelessness and suicidal thoughts and behavior.

"A lot of people with schizophrenia cannot integrate well into society because of these cognitive deficits," said corresponding author Peter Penzes, PhD, the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences at Northwestern University Feinberg School of Medicine. "Our discovery could solve these challenges by establishing the basis of a completely novel treatment strategy through a tandem biomarker-peptide therapeutic approach."

By examining the CSF of more than 100 patients with schizophrenia and healthy controls, the investigators identified a previously unknown, freely circulating form of the calcium channel auxiliary subunit α2δ-1, encoded by the gene CACNA2D1. While this protein is typically part of a larger membrane-bound channel complex, the study found that its soluble, free-floating form specifically regulates network activity by enhancing parvalbumin-positive interneuron function and supporting excitatory/inhibitory balance. Levels of this soluble signal were significantly reduced in the CSF of patients with schizophrenia compared with controls, a deficit associated with overactive or overexcited brain circuits.

The investigators then engineered a synthetic version of the soluble protein, named SEAD1, and tested it in a genetic mouse model of schizophrenia. A single injection of SEAD1 into the brains of these animals corrected both the abnormal circuit activity and the associated behavioral deficits. The treatment did not produce observable negative effects such as sedation or reduced movement, according to the study authors.

"Our treatment reopens a crucial window to rewire connections in adult brains," said first author Marc Dos Santos, PhD, research assistant professor of Neuroscience at Feinberg. "The lack of brain plasticity is believed to be a key factor in the development of symptoms in schizophrenia. Reforming synapses could also be beneficial for other mental disorders, such as depression."

Dos Santos said the investigators do not yet know how long the therapeutic effect of a single SEAD1 injection lasts and plan to study its durability in future experiments. The team is now optimizing the SEAD1 peptide for future clinical trials in patients with 16p11.2 duplication syndrome, a genetic condition associated with a 10-fold increased risk of developing schizophrenia.

Unlike diseases such as diabetes or heart disease, which have established biomarkers like blood glucose or cholesterol, psychiatric disorders have historically lacked objective biological measures for diagnosis, according to Penzes. Many candidate psychiatric drugs also underperform in clinical trials or fail post-approval because of variability in patient biology. By pairing a validated biomarker with its corresponding therapeutic, the investigators say the approach could allow clinical trials to enroll only the subgroup of patients most likely to respond, improving trial success rates.

"The clinical trials would have much higher success rate, and the treatments would work much better because you would give the new drug to the exact people who actually could respond to that drug," Penzes said. The team's next step is to develop a blood-based version of the biomarker to identify eligible patients outside the more invasive setting of CSF sampling, which Penzes described as an eventual weekly injectable, "almost like Ozempic for schizophrenia."

The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Stanley Medical Research Institute, RUSK/S-R, and the Brain & Behavior Research Foundation.

References

1. Dos Santos M, Forrest MP, Bomba-Warczak E, et al. Soluble α2δ-1, altered in disease CSF, modulates network homeostasis and rescues deficits in a neuropsychiatric mouse model. Neuron. 2026:114(12):2128-2147.e10.

2. Schizophrenia study finds new biomarker, drug candidate to treat cognitive symptoms. News release. Northwestern University Feinberg School of Medicine. March 19, 2026. Accessed July 28, 2026. https://news.feinberg.northwestern.edu/2026/03/19/schizophrenia-study-finds-new-biomarker-drug-candidate-to-treat-cognitive-symptoms/