Treatment Approach to Depression Sees Paradigm Shift

Genetika+ uses "Brain-in-a-Dish" technology to assess a patient's unique biomarkers via a blood sample and test against over 70 approved antidepressants and drug combinations, with plans to launch testing for American MDD patients in 2024.

A common amino acid, glycine, can signal the brain to slow down, likely an operational variable in major depression, anxiety and other mood disorders, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology discovered recently.

The discovery, first reported by Science, improves understanding of the biological causes of major depressive disorder (MDD) and could speed up efforts to develop new, faster-acting medications and therapeutics for MDD, neuroscientist Kirill Martemyanov, Ph.D., author of the study, told BioSpace in an email.

“Glycine effects are non-specific," he said. “It engages a range of targets and is also a building block of proteins, hence [it's] metabolized easily." He added that there is a need for specific small-molecule drugs targeting G protein-coupled receptor 158 (GPR158), which binds to glycine.

Martemyanov’s team suspected GPR158 might play a role in the development of MDD, possibly by influencing the function of key neurotransmitter systems in the brain, such as the serotonin and dopamine system.

Soon, he led a team to publish data confirming this was the case. Once he understood the role of the gene, he investigated how sensors on brain cells receive and transmit signals.

Martemyanov said the signaling molecule wasn’t an activator in the cell as previously thought, but an inhibitor. His team found that GPR158 connected to a partnering molecule slowed signaling rather than speeding it up when bound to glycine.

His team renamed GPR158 to mGlyR, short for metabotropic glycine receptor, found to be highly active in the brain’s medial prefrontal cortex.

“We also need to understand where exactly mGlyR is engaged and how it is regulated in the brain to produce effects on mood,” he said.

Traditional Medication-Based Treatments

The World Health Organization describes MDD as an epidemic that, within two decades, will be second to cardiovascular disease in terms of global disease burden.

In 2021, the CDC estimated MDD exacts an economic burden of $326 billion annually in the U.S. Even then, this figure doesn’t wholly account for the fallout of rising diagnoses of MDD concurrent with the pandemic, wherein the WHO estimated rates of MDD increased by 25% worldwide.

Traditional medication-assisted treatment options for MDD often take weeks or months to land on a drug that works well with an individual’s body chemistry sufficiently to take effect and show efficacy.

Most traditional approaches are grouped into four categories:

• Selective serotonin reuptake inhibitors (SSRIs): increase levels of serotonin in the brain
• Serotonin-norepinephrine reuptake inhibitors (SNRIs): increase levels of serotonin and norepinephrine in the brain
• Tricyclic antidepressants (TCAs): block the reuptake of serotonin and norepinephrine, which increases the levels of these neurotransmitters
• Monoamine oxidase inhibitors (MAOIs): inhibit the action of an enzyme called monoamine oxidase, which breaks down neurotransmitters (serotonin, norepinephrine, and dopamine)

Breakthrough Therapeutics

Like Martemynanov, another expert hopes patients won’t have to rely on a “wait and see” approach as is often used in the traditional medication approach to treating MDD.

Seth Lederman, CEO of Tonix Pharmaceuticals, said finding new ways to approach MDD is imperative because of how deeply the condition affects society.

“From a societal point of view, it's hard to argue that there's any more important thing to work on, considering that brain drugs relate to suicide, homelessness and a large portion of criminality,” he told BioSpace.

Lederman and New Jersey-based-Tonix are working to re-examine drugs approved in Europe and perhaps overlooked in the U.S. in favor of the big four categories of MDD meds to revisit treatment options first broached decades ago.

He said the “dogma” about treating depression in the U.S. might hold back research into more effective approaches.

While investigating drugs to treat fibromyalgia, Lederman said he lasered in on tianeptine, a drug available in the EU and other parts of the world for decades. He’s particularly interested in how the drug can encourage dendritic arborization in a way the four major classes of MDD drugs do not.

“In the brains of depressed people … neurons shrink and undergo attrition,” he said. “There's lower connectivity in their brains.”

Lederman noted that thus far, tianeptine not only positively affects neuroplasticity by fostering arborization, but also stacks up with traditional MMD drugs in terms of efficacy, with fewer undesirable side effects, like weight gain or sexual dysfunction.

Tonix’s once-daily formulation of TNX-601 ER was designed to be bioequivalent to the three-times-a-day formulation of tianeptine sodium immediate-release tablets available overseas. No tianeptine-containing product has been approved by the FDA at this time for U.S. markets.

The drug, under the name TNX-601 ER, is currently being trialed in Phase II as a monotherapy.

“It’s a very exciting time in depression,” Lederman said of the biopharma landscape. “Part of what has made it so exciting is that people have been laboring under this cloud, this yoke, constrained by the idea that modulating neurotransmitters was the only way.”

Besides Tonix’s approach, other biopharmas are also working to flip the script on the traditional drugging paradigm.

Genetika+, based in Israel, uses blood cells and stem cell technology to assess an individual’s unique biomarkers via a blood sample. The result is a “Brain-in-a-Dish” technology, wherein the patient’s sample is tested against more than 70 approved antidepressants and drug combinations to predict which drug will be the most efficacious for each individual.

Talia Cohen Solal, the company's CEO and co-founder, told BioSpace this approach will expedite drug treatment by helping physicians make the right drug choice quickly.

“This is the first time you can take almost like a cancer biopsy, but now you can actually see what's going on,” Cohen Solal said. “In the closest model, we have the patient's brain, and then you can expose that sample to different antidepressants and see which antidepressant has the strongest impact on patients in your own population.”

She agreed with Lederman that increasing connectivity in the brain is the golden ticket to finding drugs that work—and can be delivered to the patient quickly, unlike in traditional drugging.

“When people are suffering from depression from different types of studies, you see this one can see a reduction in connectivity,” she said. “Restoring that connectivity is basically the biomarker we seek.”

What’s more, she said 67% of depression sufferers end up trying multiple medications.

“There's around 20 million people suffering from depression in the United States every year. Only 10 million get access to care. By reducing that and getting those people straight into the right medication, and out of the [health care] system, that will free up space for other people to get access to better mental health care, and really improve outcomes.”

Solal Cohen expected Genetika+’s approach to be covered by American health insurance, as with other genetic testing. The approach remains in clinical trials in the U.S. with plans to launch the testing for American MDD patients in 2024.