The hallucinations get the headlines, but for many people with schizophrenia, the real devastation is the inability to feel joy from a phone call with a friend, the loss of drive to pursue hobbies, the slow disappearance of social life. These “negative symptoms” affect roughly one in 100 people worldwide and have resisted every drug on the market. Unlike delusions or paranoia, they simply don’t respond to treatment.
A study from King’s College London may finally explain why. Researchers used brain imaging to watch serotonin flood the frontal cortex of people with schizophrenia and found something unexpected: their brains release significantly more of the neurotransmitter than healthy controls. Published in JAMA Psychiatry, the work provides the first direct evidence in living patients that this chemical surge correlates with the severity of withdrawal, apathy, and emotional flattening.
The finding upends a sixty-year-old hypothesis. Scientists have long suspected serotonin played a role in schizophrenia, but they assumed levels would be too low, not too high. What the King’s team discovered instead was a system pressing too hard on the gas pedal in regions responsible for motivation and goal-directed behavior.
Tracking Invisible Surges
The study enrolled 54 adults, including 26 with schizophrenia and 28 matched healthy volunteers. Each participant underwent two PET scans using a radiotracer that binds to serotonin 2A receptors. Between scans, they received a single dose of d-amphetamine, which triggers serotonin release. By comparing how much radiotracer was displaced before and after the drug, researchers could measure how much serotonin flooded each brain region.
The frontal cortex showed the most striking difference. Everyone released more serotonin after d-amphetamine, but people with schizophrenia released far more. Among those patients, higher serotonin release tracked closely with poorer day-to-day functioning and more severe negative symptoms. People with the greatest chemical surges had the hardest time with motivation, social engagement, and independence.
“Schizophrenia is a life-altering condition that can have a dramatic impact on a person’s wellbeing. The negative symptoms that typify the illness can be extremely isolating and are a huge barrier to people getting back to the activities which are important to them like hobbies, work and family life,” Dr Martin Osugo explains.
The effect was especially pronounced in patients with deficit schizophrenia, a subtype marked by persistent negative symptoms. Importantly, the findings held even when the analysis excluded people taking antipsychotic medication, suggesting the overactive serotonin system is intrinsic to the illness rather than a side effect of treatment.
A Biological Target After Decades of Dead Ends
Current schizophrenia drugs target dopamine, which helps reduce hallucinations and delusions but does little for motivation or social withdrawal. By identifying dysregulated serotonin release as a driver of negative symptoms, the King’s study offers something rare: a concrete biological mechanism that could be addressed with future therapies.
Crucially, baseline levels of serotonin receptors were normal in people with schizophrenia. The problem isn’t how the system is built but how it behaves. That distinction matters because it points toward treatments that could regulate release without overhauling receptor density.
The researchers caution that follow-up studies will be needed to test whether safely modulating serotonin can improve symptoms without worsening other aspects of the illness. Still, the work changes the landscape. For the first time, scientists have a clear biological target linked to the symptoms that most limit quality of life. It’s a foothold where none existed before.