Novel Antidepressant Targets Key Circuits in the Brain Involved with Depression

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On February 6, 2023, Pharmacy Times also learned that the FDA just accepted a new drug application (NDA) for this treatment.

Colville Brown, MD, is the vice president of Global Medical Affairs Depression Franchise and Alliance at Sage Therapeutics, where he has been for the past 2 and a half years. Brown speaks with Pharmacy Times about the importance of innovative medicines to treat depression, which he thinks should be considered a serious medical illness.

PT Staff: Why are selective serotonin reuptake inhibitors (SSRI’s) the preferred treatment for depression?

Colville Brown, MD: What I want to highlight is that patients have been suffering and clinicians are really acknowledging that the patients with depression are struggling—they haven't had a lot of tools to date to bring patients back rapidly and quickly to wellbeing. They have been comfortable with what they have, but they are recognizing that there's a need for new treatments that can work rapidly, and bring patients back to their baselines, back to their lives. So that's the way the field is changing right now.

PT Staff: How are new treatment options paving the way for faster and more long-lasting effects compared to current offerings?

Colville Brown, MD: Yeah, it's a really good question. When you look at how depression is treated today, it can take weeks to months for the current antidepressants to work. And that means that patients aren't going to the movie theater, they're not playing with their kids, they're not seeing their friends, and they want something different. They want to have that improvement in their lives quickly. And they want to not be burdened by this side effects that are often associated with current antidepressants. And science has evolved over time. Decades ago, we thought that the monoamine hypothesis (depletion in serotonin and norepinephrine) was the reason that people develop depression. Now we're understanding that there's a more foundational and fundamental reason that patients develop depression. The leading hypothesis is that, due to a dysregulation in certain areas of the brain and how they connect, we see the symptoms of depression. And by acting on γ-Aminobutyric acid type A (GABA-A), we're able to really act on those key areas of the brain and circuits that are involved in depression. We move beyond the monoamine hypothesis, move beyond serotonin and norepinephrine—we really raised it up a level. Now [we’re] talking at the level of how different brain areas are functioning.

PT Staff: How do SSRIs differ mechanistically from depression drugs that target GABA-A receptors?

Colville Brown, MD: GABA is the major inhibitory neurotransmitter in the brain. By acting on GABA receptors, and increasing GABAergic tone, we hypothesize that you regulate these different brain networks and circuits, and they dysregulated depression. We're able to hypothesize that we regulate them by acting on the GABA A receptor.

PT Staff: What areas of the brain are affected by depression, or vice versa?

Colville Brown, MD: It's so important. Depression is a serious medical illness and it's often not considered as such. But it is a serious mental illness where you have areas of the prefrontal cortex and the limbic system, these key areas involved in that neuronal circuitry that are not functioning. And it really is connected (and underlies) some of the most common comorbidities. Depression is commonly associated with diabetes and hypertension, and it is commonly associated with other neurological diseases like dementia. And there's an interplay between depression as a serious mental illness and the illnesses that people think of every day when they think about disease, right? They think about hypertension, they think about heart disease, and heart failure. They don't think about depression the same way, but patients with depression they do. They are struggling, they're suffering. That's why having the potential for rapidly-acting agents—that can regulate these key brain areas involved in depression, we think, and we hear from health care providers (HCPs)—are going to be very valuable. And then from a clinical perspective.

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