Andrew Penn:
Welcome to Clinical Topics in Depression. I'm Andrew Penn. I'm a psychiatric nurse practitioner and associate clinical professor at UC San Francisco.

Edward Kaftarian:
And I'm Edward Kaftarian. I'm a psychiatrist and I'm on the Psych Congress Steering Committee with Andrew; and I'm the CEO of Orbit Health Telepsychiatry.

Andrew Penn:
So Ed, when it comes to depression, most of our medications target monoamine.
Serotonin and dopamine, norepinephrine. But yet those are only comprised of very small portion of the
neurotransmitters in our brain. Things such as glutamate and GABA, which are much more plentiful, are often not targeted by our current medications. But I think that's about to change. So, what I want to talk to you a little bit about today, is some of these new agents that are coming along. Some of which are already in use, such as ketamine, that target these different neurotransmitters.

Edward Kaftarian:
Yeah, I think it's helpful to think about depression treatment in multiple perspectives. So with a monoamine paradigm that we're used to, people they think serotonin, dopamine, norepinephrine, these monoamines, catecholamines. That paradigm, I think, now is going to expand into other areas. For example, the inflammatory response that has to do with depression; you have the excitatory and you have also neurotropic factors, as well. So looking at depression and the treatments, the targets for treatment, you got to look at each of these areas.

Andrew Penn:
Yeah, I mean, it's really an exciting time in our profession, right? Because this paper came out recently,
picked up by the press saying... It was a review of articles saying that, it's actually not a decrease in
serotonin that causes depression. And all of us in psychiatry, I think we're saying, "Well, yeah, we've known this for decades now." The press acted as if it was new. But this was old news that depression is not a serotonin disease. Treating serotonin can help with depression, in the same way that a headache is
not a shortage of acetaminophen disease, but treating...

Edward Kaftarian:
Right.

Andrew Penn:
... You can certainly treat a headache with acetaminophen. But really it seems like we're moving into this period where we're looking at all these different other neurotransmitters that we've neglected. So you mentioned excitatory neurotransmitter glutamate. So what do we have in our arsenal right now that actually treats glutamate?

Edward Kaftarian:
So something you're quite familiar with, esketamine treatment, that affects glutamate as well as... And
perhaps, why don't you say a few words about esketamine too. If you will, but yeah, that's one of many.

Andrew Penn:
Yeah. So esketamine and racemic ketamine, both are glutamate receptor antagonists and have increasingly been found to have these rapid antidepressant effects. Which is fantastic because, when you have depression, who wants to wait six weeks to feel better?

Edward Kaftarian:
Right.

Andrew Penn:
I mean, I always think that about our treatments. I mean, when I've had to take an antibiotic, for
example, I'm amazed that I feel markedly better within 24 hours. And I think, "Wow." If I went to my
clinician, and I had an infection, and said, "Well, you'll feel better in six weeks." I mean, I would think
that's terrible.

Edward Kaftarian:
Yeah, that doesn't inspire confidence.

Andrew Penn:
No.

Edward Kaftarian:
I mean that's the reality for the last 30 years. But we're entering a time where we don't have to settle
for just that.

Andrew Penn:
Right.

Edward Kaftarian:
Although that's a valuable tool; we have these other tools.

Andrew Penn:
Yeah, and glutamate is going to be targeted with other things, such as dextromethorphan. There's this new dextromethorphan-bupropion combination, which of course, that's a 2D6 inhibitor; and the bupropion, so it makes the dextromethorphan last longer. And that appears to have that same glutamatergic antidepressant effects as well.

Edward Kaftarian:
Don't you love when they find a medication that's been used for something else, and then they repurpose it?It's like, it's great.

Andrew Penn:
Yeah. Dextromethorphan. Cough medicine.

Edward Kaftarian:
Exactly, cough medicine, and it's not sizzurp. That's dextromethorphan done in a street way, where you
get a high off of that...

Andrew Penn: Oh. Okay.

Edward Kaftarian:
... And so we're not talking about that, but we're talking about something that does potentiate those
effects of antidepressant effects. So with ketamine, esketamine, you have an effect on glutamate. You have a glutamatergic effect. You also have effects on dopamine.

Andrew Penn:
Yeah.

Edward Kaftarian:
You have neurotropic effects. I believe that it does increase BDNF, which is brain derived neurotropic factor,
for those who are not familiar. And that's very important too. That's really exciting. BDNF.

Andrew Penn:
It's like a brain fertilizer, really.

Edward Kaftarian:
It is.

Andrew Penn:
It gets the brain... You get dendrites branching out and arborization of neurons. So yeah, you're really seeing that rapid uptick in growth.

Edward Kaftarian:
BDNF is actually really interesting, because as you said, it increases neuronal migration and connections. And it also prevents neural death, honestly. It does. It's just amazing. And one of the really interesting things, beyond medication treatment, is some interesting research coming out about intermittent fasting increasing BDNF levels.

Edward Kaftarian:
And so it reduces depression, anxiety, it increases memory. You're actually growing, as you said, fertilizer for the brain. And so, some of these treatments are also targeting that. And then you were asking me earlier about glutamate, and medications that effect that. You have amantadine, even methadone; and I don't know if there's a lot of efforts to see what we can do with methadone, other than addiction treatment.

Andrew Penn:
The S and R methadone is being developed as an antidepressant for its glutamatergic activity.

Edward Kaftarian:
Okay. So they're off and running with that too.

Andrew Penn:
Yeah, absolutely.

Edward Kaftarian:
And then you have lamotrigine, which also I believe does affect BDNF. And I think it has some glutamate effects as well.

Andrew Penn:
Yeah, yeah.

Edward Kaftarian:
So yeah, the glutaminergic possibilities are endless.

Andrew Penn:
Yeah. And then we switch the other side of the coin, which is GABA, and now we're seeing more compounds coming out that target GABA. Zuranolone, brexanolone, both having these GABAergic effects, and both of them being fairly short courses of treatment. And I think that's one of the big changes that we're seeing. Not only changing the targets of what neurotransmitters these drugs are affecting, but the duration of care is getting shorter. Or the time to affect. So instead of now where I say, "Hopefully you'll feel a little better in six weeks," we can now say, "You might be feeling better in a couple of weeks, or maybe even later this week."