A large-scale analysis of postmortem brain tissue has uncovered evidence that viruses – hepatitis C, in particular – might play a role in the biology of schizophrenia and bipolar disorder.
The findings, appearing in Translational Psychiatry, suggest that the brain’s choroid plexus, a structure that filters blood into cerebrospinal fluid, might act as a covert viral reservoir that influences neural function without infecting brain cells directly.
“Our findings show that it’s possible that some people may be having psychiatric symptoms because they have an infection, and since the hepatitis C infection is treatable, it might be possible for this patient subset to be treated with antiviral drugs and not have to deal with psychiatric symptoms,” lead author and Johns Hopkins University associate professor of pediatrics Sarven Sabunciyan, Ph.D., explained in a press release.
The research team looked at the choroid plexus tissue from more than 250 cadavers: 84 with schizophrenia, 73 with bipolar disorder, 23 with major depressive disorder, and 76 without psychiatric diagnoses. Using a sensitive viral RNA sequence enrichment method, the researchers screened for more than 3,000 human and animal viruses.
Viruses showed up in the choroid plexus of nearly four dozen bodies. That’s nearly a quarter of those with schizophrenia or bipolar disorder.,The rate was far lower in controls. While several viruses surfaced, hepatitis C virus (HCV) was the only one significantly associated with these psychiatric conditions.
It’s also worth noting that multiple psychiatric cases boasted high HCV read counts, while none of control samples showed signs of the virus.
The discovery stunned the researchers since earlier research found few viral sequences in brain tissue.
The choroid plexus might help explain that disparity. As part of the blood-cerebrospinal fluid barrier, it’s more exposed to circulating pathogens than neurons. And multiple neuroimaging studies of schizophrenia have noted this inflammation.
National Data Reinforce Schizophrenia Findings
To find out whether the connection between HCV and severe mental illness extended past postmortem samples, the researchers turned to TriNetX, a database that includes more than 285 million patient records. And that’s where they found that rates of chronic HCV infection hovered near 4% among both schizophrenia and bipolar disorder patients. That’s about eight times higher than the rate among unaffected patients (0.5%). Major depressive disorder patients showed a 1.8% prevalence.
The data shows that risky behaviors (like regular IV drug use) helps drive up HCV rates, and these behaviors crop up regardless of psychiatric diagnoses.
But the researchers insist that risky behavior alone doesn’t explain the disparity. They note that depression patients, despite similar behavior, had much lower HCV rates than those with schizophrenia or bipolar disorder.
Viral RNA Without The Spread
The study also looked at whether HCV in the choroid plexus could spread into the brain. In seven HCV-positive cases with available hippocampal RNA sequencing data, the virus itself didn’t show up in the hippocampus.
However, the presence of HCV RNA in the choroid plexus lined up with consistent changes in hippocampal gene activity. More than a dozen (14) genes showed altered expression, and 185 repetitive DNA elements – mostly Alu and LINE-1 sequences – were silenced, in some cases by a median 39-fold.
Such changes could reflect an immune response to viral RNA, the authors suggest, potentially influencing brain function without any direct infection. The researchers note that similar inflammation-driven effects from other viruses could be possible.
Focusing On a Schizophrenia-Viral Hypothesis
Academics and clinicians alike have long suspected a connection between viral infections and psychiatric illness. Epidemiological patterns – such as increased schizophrenia risk after prenatal influenza exposure and the genetic overlap between immune function and mental illness – back up this premise.
But proving an active infection’s role remains challenging – especially since many viruses establish low-level, latent infections that elude standard detection.
The viral RNA enrichment technique used in this particular study skirts some of those issues, capturing a broader range of viruses. By targeting the choroid plexus, the researchers might have found the brain’s most likely viral entry point and holding zone.
Screening (and Treatment) Implications
The study’s findings carry potential clinical implications. Regulators already advise universal HCV screening for adults, but psychiatric patients – especially those living with schizophrenia and bipolar disorder – might be underdiagnosed and (as a result) undertreated. Given how easily treatable HCV is, identifying and addressing it in psychiatric populations could reduce both viral and mental health burdens.
Evidence from prior studies suggests that clearing HCV can improve cognitive symptoms and brain function. A Taiwanese cohort study even found that antiviral treatment curbed the risk of developing schizophrenia.
Consequently, the authors argue that incorporating routine HCV screening into psychiatric care could benefit hundreds of thousands worldwide.
Questions Linger
Even so, questions remain. Not all HCV-positive patients had viral RNA in the choroid plexus, suggesting that only certain infections factor into the equation.
It’s also unclear whether other viruses could trigger similar hippocampal changes, or whether inflammation from choroid plexus infection is a driver (or byproduct) of psychiatric illness.
Future research could expand virus screening to cerebrospinal fluid and other neuroepithelial structures, apply long-read sequencing to detect a wider array of pathogens, and assess whether virus-associated gene expression patterns appear in other brain regions.
Subsequent studies could also explore whether inflammatory markers in cerebrospinal fluid might distinguish psychiatric patients with underlying viral infections.
For now, the work adds weight to the recent “viral hypothesis” of psychiatric disease – one in which pathogens need not infect neurons directly to influence brain function. Instead, viruses might act from the brain’s borders, stirring immune responses that ripple inward.
Further Reading
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Antipsychotic Adherence Halves Crash Risk for Drivers with Schizophrenia
