Vortioxetine has demonstrated effectiveness in killing glioblastoma cells in mice with an increased survival over a group taking chemo of up to 30 per cent.
In a Swiss study (1) reported in 2024, Vortioxetine, an antidepressant sold under brand names Trintellix and Brintellix, was tested with mice in two studies. First it was used against a control group and a group taking citalopram. The Vortioxetine treatment group had significantly less tumour growth and invasiveness.
In a follow up study one group of mice had standard chemo, another had a placebo and a third group had Vortioxetine. The last group had 20-30% increased survival over the chemo group, not just in the short term but in the long-term too.
A team from ETH Zurich, led by molecular biologist Sohyon Lee of ETH Zurich, first cultivated human tissue grown from samples donated by 27 GBM patients undergoing treatment surgery, and then reviewed antidepressant drugs, antipsychotics, and drugs used to treat Parkinson's disease, to see if any had benefits against the cancer.
In all, they tested 132 drugs using computer simulations and found that some antidepressant drugs were effective at suppressing the development of the GBM cells, especially one, Vortioxetine because it blocked two separate and simultaneous cascades of neural cells and cancer cells which together would inhibit GBM and explained why most antidepressant don’t work in real life - they only block one cascade.
Then the real life step - mice were given glioblastoma transplants. The control group was left untreated, while a second group of mice was treated with the SSRI antidepressant citalopram. Finally, a third group was treated with vortioxetine. In this part of the overall study, Vortioxetine, clearly inhibited growth better than the control and the citalopram group.
But when it came to the final part of the study, where vortioxetine was up against chemotherapy drugs such as TMZ, the vortioxetine showed a short term and long-term increased survival of 20-30 per cent.
Neurologist Michael Weller of the University Hospital Zurich said that the next step was to test this compound in real life humans with GBM.
Selective serotonin reuptake inhibitors (SSRIs) such as citalopram and fluoxetine have previously demonstrated antitumor effects in research on brain cancer in the laboratory, but in real life did not seem to work well.
Fluoxetine (Prozac) can cross the blood-brain barrier and has demonstrated anticancer effects in preclinical models as long ago as 2014, where it promoted AMPAR-mediated calcium-dependent apoptosis (2). It acts through multiple mechanisms: inhibiting the enzyme SMPD1, which disrupts cancer cell metabolism and reduces epidermal growth factor receptor (EGFR) signaling, and by inducing lysosomal stress and mitochondrial calcium overload (3)
When combined in the laboratory with temozolomide, fluoxetine produced massive increases in cell death and even complete tumor regression in mice (3).
Citalopram in preclinical studies (4) citalopram exhibits cytotoxic effects on various cancer cell lines, including glioblastoma and neuroblastoma. In glioblastoma models, citalopram has been shown to inhibit cell proliferation and induce apoptosis, potentially through mechanisms involving the modulation of voltage-dependent potassium channels and the inhibition of key signaling pathways like PI3K/Akt/mTOR. But, test tube promises don’t always work in real life.
A population-based study of 404 glioblastoma patients found no association between the use of antidepressants, including citalopram, and improved overall survival, even after adjusting for factors like age, tumor resection extent, and MGMT promoter methylation status (4).
Tricyclic antidepressants (TCAs) like imipramine, clomipramine and amitriptyline are another group of drugs showing promise, but this Swiss study dismissed them. They have been found to impair the malignant phenotype of glioma cells by inhibiting cellular respiration, reducing proliferation, motility, and survival, and suppressing the p65 subunit of nuclear factor-κB, which is frequently overexpressed in glioblastoma cells. Imipramine also inhibits the PI3K/Akt/mTOR signaling pathway and induces autophagic cell death in glioma cells. Long ago we covered work by a UK Professor (5) on this CANCERactive site.
It would seem that there has been a lot of interest in the use of antidepressants to increase survival in patients with brain cancer but almost all seem to fall at the hurdle of real life. Vortioxetine seems to be in a different league. Let’s hope so.
Go to: Three new approaches for brain cancer treatment
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References
1.High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity. Lee, S., Weiss, T., Bühler, M. et al. Nat Med 30, 3196–3208 (2024). https://doi.org/10.1038/s41591-024-03224-y
2. Stanford Medicine; Can Prozac fight brain cancer - Krista Conger Jan 05 2022
3. Widely-available Drug May Benefit Glioblastoma Treatment; December 17, 2021 National Brain Tumour Society
4. Antidepressant drug use in glioblastoma patients: an epidemiological view; Dorothee Gramatzki et al; Neurooncol Pract. 2020 Apr 25;7(5):514–521
5. Using Clomipramine against GBM - https://www.canceractive.com/article/using-clomipramine-to-treat-brain-tumours-1423