Higher serotonin levels are associated with schizophrenia in general and negative symptoms specifically, a neuroimaging study finds

Researchers have long believed — and the authors of a new study hypothesized — that schizophrenics have lower brain levels of the neurotransmitter serotonin, and that those lower levels are associated specifically with what are referred to as negative symptoms of schizophrenia.

Their first-of-its-kind neuroimaging study, published in JAMA Psychiatry on Dec. 10, 2025, found the opposite: participants with schizophrenia released higher levels of serotonin in response to a stimulant. Those higher levels were linked to more severe negative symptoms and poorer functioning.

The findings of the single-center case-control study conducted between 2015 and 2024 were robust. An exploratory analysis found that more serotonin was linked to even worse negative symptoms in a subgroup with deficit schizophrenia, a particularly severe and enduring syndrome defined by debilitating negative symptoms that is estimated to affect between 20% and 30% of schizophrenics worldwide.

The results suggest “the regulation of serotonin release as a target to treat negative symptoms,” write corresponding authors Martin Osugo, MBChB, Ph.D., a postdoctoral academic clinical fellow, and Oliver D. Howes, BM, BCh, Ph.D., a professor of molecular psychiatry and head of the Department of Psychosis Studies, both at King’s College London’s Institute of Psychiatry, Psychology & Neuroscience, and 14 colleagues in the U.K.

Schizophrenia is a serious mental illness, with symptoms that are defined as either negative or positive. Negative symptoms are “missings”: the lessening or absence of normal behaviors, like diminished emotional expression (flat affect), reduced speech, lack of motivation, inability to feel pleasure, and social withdrawal.

Positive symptoms are “added” to an individual’s normal experience of reality, such as hallucinations and hearing voices, delusions and paranoia.

Antipsychotics mainly work on positive symptoms. Negative symptoms are hard to treat, and they significantly worsen daily functioning and quality of life, causing difficulty in work, relationships, self-care, and goal setting.

For this study, Osugo, Howes and their colleagues divided their sample of adults into two groups: 26 people diagnosed with schizophrenia (including eight, or 31%, who met the definition for deficit schizophrenia) and 28 healthy controls. Both groups underwent PET scans before and three hours after receiving a single oral dose of D-amphetamine (also known as dextroamphetamine), a central nervous system stimulant that leads to a substantial release of serotonin in the frontal cortex.

At baseline, a key measure of serotonin release in the schizophrenia group was significantly associated with the severity of negative symptoms—but not positive symptoms — and also with poorer overall functioning and the severity of motivational negative symptoms.

‘Serotonergic dysfunction’ is a promising target

An exploratory analysis of baseline data for the subgroup with deficit schizophrenia found that they had significantly poorer overall functioning and more severe negative symptoms compared with those with nondeficit schizophrenia.

The second set of PET scans, after both groups received the neurotransmitter that increases serotonin release, found the same pattern: increased levels of serotonin in the schizophrenia group compared with healthy controls. And the exploratory analysis found significantly greater frontal cortex serotonin release in the deficit schizophrenia subgroup compared with the schizophrenia group as a whole.

“Our results suggest an overactive serotonergic system in schizophrenia, reflected by higher frontal cortex serotonin release capacity, and that this could underlie greater severity of negative symptoms," the researchers write.

As for the connection between this dysfunction and negative symptoms such as reduced motivation, the authors note that other research, much of it preclinical, has found that serotonin signaling plays a key role in certain aspects of reinforcement learning, specifically promoting waiting for a future award over acting immediately.

“Thus, serotonin overactivity may impair motivated behavior through devaluation of immediate rewards,” they write. “This is consistent with our finding that greater serotonin release was associated with more severe motivational impairments.”

They conclude that their overall findings “suggest serotonergic dysfunction in the pathophysiology of schizophrenia and identify the regulation of serotonin release and serotonin receptors as promising therapeutic targets to treat negative symptoms.”