Targeting the Glutamatergic System for Treatment Resistant Depression


Two experts examine the impact of targeting the glutamatergic system as therapy for treatment resistant depression.

Lisa Harding, MD: I’ll ask a question that you touched on a little earlier to get into the drugs that target the glutamatergic system. What do you think about them in fitting into this algorithm of treatment-resistant depression [TRD]?

Angelos Halaris, MD, PhD, APA, ACNP, CINP: In my practice, after I’ve determined that we’re dealing with a true TRD, not a presumptive TRD—I know I sound like a broken record—

Lisa Harding, MD: I’m with you on that broken record. I’m the other half of it.

Angelos Halaris, MD, PhD, APA, ACNP, CINP: I consider 2 options in my algorithm of choices: either TMS [transcranial magnetic stimulation], which is also very time consuming, given that the average number of sessions is about 35. It’s a minimum 3 days a week on site in the office, preferably 5 days a week. That amounts to roughly 7 or 8 weeks back to back. It also requires maintenance. The response is generally quite good. Even after the first few treatments, we can get a response, but I’ve also witnessed the loss of efficacy after termination of the initial acute treatment phase of about 35 sessions.

Lisa Harding, MD: I agree with you. I do this clinically as well, and it’s a travesty that we can’t figure out what maintenance looks like. It’s really good to hear a colleague express this as well, and that I’m not on an island by myself with these same outcomes.

Angelos Halaris, MD, PhD, APA, ACNP, CINP: Next to TMS, I consider intranasal esketamine. I’ve used it before approval by the FDA in 2019 in phase 3 clinical trials and subsequently after it was approved at our institution. I still do it. As a matter of fact, I had a maintenance patient just an hour ago, and another is coming back for maintenance intranasal esketamine right after we’re done with this discussion. It’s a very interesting approach, not so much the classic neurotransmitters or serotonin-norepinephrine-dopamine, but at the NMDA receptor blockade that involves predominantly, but not exclusively, glutamatergic transmission.

Lisa Harding, MD: Absolutely. What are your thoughts on the intravenous ketamine that is used off-label? We’ve been using that off-label since before intranasal esketamine came on the market.

Angelos Halaris, MD, PhD, APA, ACNP, CINP: Yes. I haven’t used the intravenous ketamine for the reasons you mentioned. It’s not FDA approved. It’s very costly. It is not really regulated, as intranasal esketamine is by the REMS [Risk Evaluation and Mitigation Strategy] program.

This transcript has been edited for clarity.

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