New Research Shows Increased Serotonin Release Could Open a New Treatment Path for Schizophrenia
Recent scientific research is shedding new light on schizophrenia, particularly on the long-standing challenge of treating its most disabling symptoms. A study conducted by researchers at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London has provided the first direct evidence that schizophrenia is linked to increased serotonin release in the brain. Even more importantly, this heightened serotonin activity appears to be closely connected to the severity of negative symptoms, which currently have no effective treatments.
Schizophrenia affects roughly 1 in 100 people worldwide and is commonly associated with hallucinations and delusions, often referred to as positive symptoms. However, for many people living with the condition, it is the negative symptoms—such as social withdrawal, loss of motivation, and inability to feel pleasure—that are most life-limiting. These symptoms frequently prevent individuals from working, maintaining relationships, or enjoying daily activities, even when other symptoms are under control.
The new findings, published in JAMA Psychiatry, suggest that serotonin, a neurotransmitter better known for its role in mood and antidepressant treatment, may play a much larger role in schizophrenia than previously proven.
What the Study Set Out to Investigate
For more than 60 years, scientists have speculated that an overactive serotonin system might contribute to schizophrenia. Despite this long-standing theory, it had never been directly tested in people living with the condition. Most prior research relied on indirect evidence, animal models, or post-mortem brain studies.
This study aimed to change that by directly measuring serotonin release in the living human brain and examining how it relates to symptom severity.
Study Design and Participants
The research involved 54 participants in total. Among them, 26 individuals had a confirmed diagnosis of schizophrenia, while 28 were healthy control participants with no history of psychiatric illness. Both groups were carefully matched to ensure reliable comparisons.
Each participant underwent two PET brain scans using a specialized radiotracer that selectively binds to serotonin receptors. PET imaging allows researchers to observe changes in brain chemistry in real time, making it particularly useful for studying neurotransmitter systems.
Between the two scans, participants received a single dose of d-amphetamine, a drug known to stimulate the release of serotonin. By comparing the scans before and after the drug was administered, researchers were able to estimate how much serotonin was released in different regions of the brain.
Key Findings: Serotonin Release Is Higher in Schizophrenia
The PET scan data revealed that d-amphetamine caused a reduction in radiotracer binding in both groups, which is expected when serotonin is released and competes with the tracer for receptor binding.
However, the most striking finding was that people with schizophrenia showed a significantly greater release of serotonin in specific brain areas compared to healthy controls. This difference was especially pronounced in the frontal cortex, a region of the brain involved in motivation, decision-making, planning, and social behavior.
These brain functions are precisely the ones most affected by negative symptoms, making the findings particularly relevant.
Connection to Negative Symptoms and Disability
The study did not stop at measuring serotonin release. Researchers also examined how these biological changes related to real-world symptoms and functioning.
They found a strong relationship between increased serotonin release and:
- Greater severity of negative symptoms
- Higher levels of functional disability, such as difficulty working or maintaining social relationships
In other words, individuals who released more serotonin in the frontal cortex tended to experience more severe motivational and social impairments.
This direct link between brain chemistry and symptom severity provides compelling evidence that serotonin is not just involved in schizophrenia, but may actively contribute to its most disabling features.
Why This Finding Matters
Current treatments for schizophrenia primarily target dopamine, another neurotransmitter involved in psychosis. While dopamine-focused medications can be effective for hallucinations and delusions, they offer little to no benefit for negative symptoms.
As a result, many people remain functionally impaired despite long-term treatment. The lack of therapies for negative symptoms has been one of the biggest unmet needs in schizophrenia care.
By identifying serotonin release as a biological process closely tied to these symptoms, the study opens the door to entirely new treatment strategies. Rather than increasing serotonin, as antidepressants often do, future therapies might focus on regulating or modulating serotonin activity in specific brain regions.
Expert Perspectives on the Findings
The researchers behind the study emphasize that schizophrenia is a deeply life-altering condition, and that negative symptoms are among the most isolating aspects of the illness. Difficulty feeling motivated or socially engaged often prevents people from returning to work, maintaining hobbies, or rebuilding family connections.
The study’s findings represent an important first step toward understanding the biological roots of these symptoms. By demonstrating a clear association between serotonin release and symptom severity, the research provides a scientific basis for future drug development.
At the same time, the researchers stress that this is early-stage evidence. More studies will be needed to confirm the findings, explore causality, and test whether altering serotonin release can actually improve symptoms in patients.
Understanding Serotonin’s Role in the Brain
Serotonin is widely known for regulating mood, emotion, sleep, and appetite, but its role in motivation and decision-making is often overlooked. In the frontal cortex, serotonin helps balance long-term planning with immediate action.
Excessive serotonin signaling in this region may interfere with goal-directed behavior, potentially contributing to apathy, reduced initiative, and emotional flatness. This offers a plausible biological explanation for why higher serotonin release might worsen negative symptoms rather than improve them.
Limitations and the Road Ahead
While the findings are significant, the study does have limitations. The sample size was relatively modest, and most participants had long-standing schizophrenia rather than early-stage illness. Additionally, PET imaging measures changes in receptor binding, which indirectly reflect serotonin release rather than measuring serotonin levels directly.
Future research will need to examine larger groups, include people earlier in the course of illness, and explore how different medications affect serotonin dynamics.
Despite these limitations, the study marks a major step forward in understanding schizophrenia at a neurobiological level.
Why This Research Brings Cautious Optimism
For decades, negative symptoms have remained largely resistant to treatment, leaving patients and clinicians with limited options. This research provides real hope that a new biological target has been identified—one that could eventually lead to therapies designed specifically to improve motivation, social engagement, and quality of life.
While much work remains, the discovery that serotonin release is directly linked to these symptoms represents a meaningful shift in how schizophrenia may be treated in the future.
Research paper reference:
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/10.1001/jamapsychiatry.2025.3430
