01. Is Ondansetron Effective for Negative Symptoms in Schizophrenia?

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Efficacy and Safety of Ondansetron for Negative Symptoms

In this Quick Take, I look at a systematic review and meta-analysis that asks a practical question. Can I add something for my patient with schizophrenia who has residual symptoms, specifically negative symptoms? More specifically, what about adding ondansetron for such patients?

This paper, from colleagues in Egypt, was recently published in General Hospital Psychiatry. This may be interesting since you probably know ondansetron as an antiemetic, not as a treatment for schizophrenia.

Negative Symptoms Need Options

Here is the rationale. Residual negative symptoms are common in schizophrenia and drive disability. Lack of motivation or anhedonia—or you can also call it apathy—makes it very difficult to succeed with anything in life. Parents may use the term laziness but it’s really negative symptoms that is the problem here.

Unfortunately, antipsychotics are broadly ineffective for negative symptoms. Too much dopamine blockade that you usually get from antipsychotics can even worsen negative symptoms. So we desperately need something for our patients with negative symptoms, possibly something that does not reduce the dopamine tone in brain regions associated with motivational systems.

Ondansetron Blocks 5-HT3 Receptors

This is where ondansetron comes in. If you’re thinking, but isn’t ondansetron a medicine that is used for nausea and vomiting in the setting of cancer treatment like with chemotherapy or radiation therapy, you are correct.

But this is what makes ondansetron interesting for us in Psychiatry. Ondansetron blocks serotonin 5-HT3 receptors, which are widely distributed in the brain and periphery. One antidepressant with 5-HT3 antagonism, Mirtazapine, has shown some benefit for negative symptoms. And SSRIs have also shown some benefit for negative symptoms in some studies.

However, the exact mechanism by which ondansetron could improve negative symptoms is speculative, and I don’t want to speculate too much here. Let’s just stick with the empirical data for ondansetron and look at the study itself.

Meta-Analysis Pooled Eight Trials

The authors searched several electronic databases for randomized controlled trials where ondansetron was used in schizophrenia patients and where symptoms were evaluated with a standard scale of psychopathology, the so-called PANSS, the Positive and Negative Syndrome Scale. They selected the PANSS’ negative subscale for negative symptoms as their primary outcome measure.

They identified eight studies that they could include in their meta-analysis with a combined sample size of 533 research subjects. Most but not all studies were add-on studies where ondansetron was added to a stable antipsychotic regimen and almost all studies were relatively short lasting 12 weeks.

Negative But Not Positive Symptoms Improved

They found a statistically significant benefit for negative symptoms but not for positive symptoms. The reported effect size was a pooled mean difference of 2.96. They argued this may be clinically relevant given the magnitude.

Now, it would have been nice had the authors provided us with a Cohen’s d or even better a number needed to treat or NNT to help at least me evaluate that claim that there is not just statistical but also clinical benefit. And just to summarize the overall magnitude of their finding in more common terms if you will.

Side Effects and Limitations

With regard to side effects, only constipation was a significant side effect. Another main finding, perhaps not surprising, was heterogeneity in these trials which stem in part from the fact that they were done in a variety of countries across the world. So take this meta-analysis with a grain of salt as we are possibly combining trials that we maybe should not combine. But this is what we have.

Where does that leave us? I suspect a few of us will routinely reach for ondansetron to add it to a patient’s antipsychotic regimen. There are after all some risks like QTc prolongation particularly at a higher dose.

There is also the question of being able to cause or at least contribute to the serotonin syndrome. I believe this concern may be incorrect in practice, but you will see it in the literature and on the internet. Still, the meta-analysis suggests some patients may benefit.

GLP-1 Agonist Induced Nausea May Benefit

Let me at this point add one additional comment. There is another reason why I thought reviewing an article on ondansetron makes sense at this moment.

As more and more psychiatric patients are treated with a GLP-1 agonist to counteract the weight gain associated with antipsychotics, you may see patients who struggle to tolerate GLP-1 agonist because of nausea and vomiting, a common problem with the GLP-1 agonist particularly at the beginning of treatment. And I know that our colleagues in Primary Care or Gastroenterology use ondansetron off-label to manage these side effects, nausea and vomiting.

And in this spirit, ondansetron may not only be safe as an add-on treatment for nausea and vomiting due to GLP-1 agonist but provide the patient with a co-benefit in the sense of improving negative symptoms.

Bottom Line: Consider Ondansetron When Options Limited

If you run out of options for negative symptoms of schizophrenia, give the antiemetic ondansetron a thought.

If you want to try it, the dose in add-on trials was between 4 mg and 8 mg of ondansetron. You would be using it off-label which comes with the usual caveat and need for a good risk-benefit discussion and documentation.

Let’s also be realistic and not expect miracles. The effect size of ondansetron for negative symptoms is in my judgment going to be small and I suspect that in most patients you’re probably not even going to notice a clinical difference. So importantly, be prepared to stop it again if you do not see a good benefit.

Abstract

Purpose
It has been shown that 5-hydroxytryptamine3 (5-HT3) receptors are involved in the pathogenesis of schizophrenia. This systematic review and meta-analysis of randomized clinical trials (RCTs) evaluates the efficacy and safety of ondansetron, a potent 5-HT3 receptor antagonist, as adjunctive treatment for the management of schizophrenia, especially the negative symptoms.

Methods
A comprehensive search of electronic databases, including PubMed, Scopus, Cochrane, and Web of Science, was performed in October 2024. We included only randomized controlled trials (RCTs), and their data were extracted and analyzed using RevMan 5.4 software. The primary outcome was the PANSS (Positive and Negative Syndrome Scale) negative subscale.

Results
Eight RCTs involving 533 patients were included in the study. Ondansetron showed a statistically significant improvement in PANSS negative subscale at 12 weeks [pooled as mean difference, MD = −2.96, 95 % CI [−4.69, −1.24], P-value = 0.00007] and in general psychopathology scale [MD = −2.71, 95 % CI [−3.52, −1.90] compared to placebo. However, ondansetron and placebo did not differ in reduction of PANSS positive subscale [MD = 0.1, 95 % CI [−1.19, 1.38], P-value = 0.88], and depression scale. Ondansetron showed no significant difference regarding tardive dyskinesia between the two groups. However, constipation was significant in the ondansetron group over placebo.

Conclusion
The study findings provide valuable insights into the efficacy of ondansetron, a serotonin receptor antagonist, in managing schizophrenia, particularly negative symptoms. However, the limitations of the study highlight the need for caution in interpreting these results. Further high-quality trials are required to confirm our findings and explore the long-term impact of ondansetron in the treatment of schizophrenia.

Reference

General Hospital Psychiatry, Volume 96, 2025, Pages 37-46, ISSN 0163-8343, https://doi.org/10.1016/j.genhosppsych.2025.06.001