Primary care clinicians manage much of the first-line landscape for depression and frequently coordinate care for serious mental illness. In this segment, psychiatrist Gus Alva, MD, summarizes several 2025 developments that reflect a broader shift toward novel neurobiologic targets and new care pathways that may affect referral decisions and patient questions.
The following transcript has been edited lightly for clarity and flow.
Patient Care: Looking back at 2025, what do you see as the most significant advances in mental health research that primary care physicians should know about?
Gus Alva, MD: There has been a nice settling in of the fact that we can approach different types of neuropsychiatric conditions from different angles that we've not necessarily been able to explore up to this particular point. Case in point, for example, would be major depressive disorder. And up to this point, the therapeutic modalities that we had pursued had been predominantly monoaminergic, meaning serotonin or epinephrine, dopamine. But, this last year was a good settling in of the fact that now we have phenomenal options that specifically may tap into glutamate, the main excitatory neurotransmitter in our brain, and GABA, the main inhibitory neurotransmitter in our brain. And so that, I think, becomes an important point, because if we're able to hijack a system and then specifically hone in on symptomatology a lot faster and maybe expect better outcomes, that's actually really good. So just to give you a little bit of a rendering for that, there's an intranasal form of a medication called esketamine (Spravato; NCT02418585) that this past year we saw about five years worth of data roll out that this is actually a very good option for individuals that have been somewhat treated persistent, meaning that they've not necessarily responded well to at least a couple of different antidepressants and might have suicidal ideation. And there's a GABAergic compound called xuranolone (Zurzuvae; NCT04442503), which is currently only FDA approved for postpartum depression, but that's another very important interim, because there's a lot of people in the primary care space that sometimes overlook the peripartum period, and that's specifically the sequela that might subsequently come out from that. And there's a big difference between baby blues and postpartum depression, so that's really important. And I'd say that now with an oral therapy that specifically hits glutamate pretty well dextromethorphan-bupropion (Auvelity; NCT04019704). We see results within a week, and we see really nice response and remission rates over the course of a year. It has also been a whole year now that we've had a muscarinic agent to address psychotic symptoms in adults who suffer with schizophrenia called xanomeline-trospium chloride (Cobenfy; NCT04659161), and I think that that's actually largely a very important thing. We need to move away from stigmatizing neuropsychiatric conditions, but also have different targets beyond the things that we've employed previously. And you know, we pursued data that we knew about since the 1950s and then subsequently came through with a breakthrough that helps out with targeting muscarinic 1, muscarinic 4 receptors and agonizing them, and then subsequently being able to address problems like schizophrenia without the unintended consequences of many other therapeutic modalities that we've had out there.
In the case of digital therapeutics, we now have seen also, in this past year, an entry point of an application, not just like looking up a wellness app, per se, that would just be cognitively, behaviorally therapy oriented, but a prescription digital therapeutic that helps people with major depressive disorder and has a benefit akin to another antidepressant. And depending on whether people live in a rural setting or otherwise, might not necessarily be able to engage in meaningful psychotherapeutic work. This could actually be a great aid, and the clinical studies that that we've commenced in conditions like schizophrenia have also panned out that digital therapeutics are a really interesting treatment modality that we need to be pursuing further. And then on the cognitive side of things, obviously, we now have pretty decent information that monoclonal antibodies might be very useful for individuals with mild cognitive impairment or very early Alzheimer disease. These include lecanemab (Leqembi; NCT03887455) and donanemab (Kisunla; NCT04437511). We've seen a growing evolution regards to biological parameters that might aid us in diagnosing individuals sooner. And although there is still not a cure for Alzheimer disease, if we're able to impede additional functional decline in patients and buy them more time of lucidity, that would be wonderful, right? And so that's actually really important. Those are some of the areas that I would say the past year has brought to the forefront, and they're exciting because they basically point out the fact that we continue to have fluidity in the space. It's nonstatic. There's a lot of discovery. And the important thing is getting people to have that understanding and then be able to benefit from it.
