This is perhaps the first human study to directly point the finger at 5-HT as a cause of schizophrenia and, by extension, all other mental conditions with a psychotic component such as bipolar disorder, mania, etc. As the study states, the role of 5-HT in schizophrenia was first proposed more than 60 years ago. However, at the time 5-HT was quickly becoming the darling of medicine and Big Pharma and many drugs were in the pipeline that aimed at increasing 5-HT levels and/or signalling. The (in)famous SSRI drugs are perhaps the most notable example, in widespread use to this day. Whether by idiocy or malice, medicine adopted the view back then that high DA levels/signalling is behind schizophrenia and drugs that antagonized DA were developed as treatments for this conditions. The fact that those drugs did reduce symptoms (at the cost of terrible side effects) was hailed at the time as undeniable proof that it is indeed DA that is the cause of psychotic conditions. However, what medicine and mainstream media failed to mention to the general public is that recent studies demonstrated that the flagship DA antagonist drugs for schizophrenia – haloperidol – was found to also be potent a 5-HT antagonist. Thus, the initial claim that DA is the cause of schizophrenia immediately become suspect in light of this new evidence. The study below is probably the first human one that debunks the DA hypothesis in schizophrenia directly. It found that it is increased 5-HT release, not DA release, that drives most of the symptoms associated with schizophrenia, and as such proposed that anti-serotonin treatments can be a viable treatment for the disease. In corroboration, an older smaller study found that the anti-acid drug famotidine, which also happens to powerfully lower 5-HT (to the point that it can treat a full-blown serotonin syndrome) was also able to control schizophrenia symptoms and, unlike haloperidol, famotidine does not have any known effects on the DA system, thus strongly suggesting 5-HT is the real culprit. Furthermore, every single one of the newer schizophrenia drugs known as “atypical antipsychotics” are also potent 5-HT antagonists (though not as selective as famotidine). If 5-HT ends up being proved as THE core cause of schizophrenia, it won’t be a stretch to suggest that perhaps most cases of schizophrenia are iatrogenic in origin given the widespread use of the serotonergic SSRI drugs, even among children and toddlers.
https://dx.doi.org/10.1001/jamapsychiatry.2025.3430
https://medicalxpress.com/news/2025-12-surge-serotonin-treatment-schizophrenia.html
“…An analysis of the data found that the introduction of d-amphetamine led to substantial reductions in binding of the radiotracer in both those with schizophrenia and healthy volunteers. The main finding of the study was that this release of serotonin was significantly greater in parts of the brain that are key to motivation and planning (the frontal cortex) in people with schizophrenia compared to controls. Further analysis established a close relationship between greater serotonin release and both the severity of negative symptoms and the degree of functional disability in the schizophrenia group. Dr. Martin Osugo, the study’s first author from King’s IoPPN said, “Schizophrenia is a life-altering condition that can have a dramatic impact on a person’s well-being. 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. “Our study, which provides the first evidence that serotonin release is associated with the severity of negative symptoms, is an important step forward in this field. If we can successfully regulate serotonin, then it’s possible we might be able to successfully treat negative symptoms.”
