Exploring the Role of Dual-Mechanism and Multimodal Antidepressants in MDD Treatment

While traditional selective serotonin reuptake inhibitors (SSRIs) remain first-line treatment options for major depressive disorder (MDD), some patients may see greater benefit from different classes of antidepressant agents. In this video, Psych Congress Journal Clinical Editor Kristian Dambrino, DNP, PMHNP-BC, explores the role that dual-mechanism and multimodal medications may play in individualized MDD care. Dambrino equips clinicians with side effect, efficacy, and patient-specific considerations to help guide agent selection, encourage antidepressant adherence, and optimize treatment outcomes.

For more expert insights, visit the MDD Learning Library.

• SSRIs may effectively address anxiety and rumination but may be more likely to cause sexual adverse effects, particularly at higher doses.
• Serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause constipation or increased blood pressure, while norepinephrine and dopamine reuptake inhibitors (NDRIs) may have fewer sexual adverse effects and address motivation and drive but may be less effective for anxiety.
• Agents such as vortioxetine may be considered when sexual adverse effects or emotional flattening are concerns, while duloxetine may be considered in patients with comorbid conditions such as fibromyalgia.

Kristian Dambrino, DNP, PMHNP-BC: Hi I’m Kristian Dambrino, I’m a doctor of nursing practice, practicing and living in Nashville, Tenesse at Dambrino Consulting and Wellness, LLC. I'm also adjunct faculty at Belmont University College of Nursing, and I'm a Fulbright Scholar.

Psych Congress NP Institute (PCNPI): How should clinicians think about the role of SSRIs versus dual mechanism agents in MDD, and when might you choose to move beyond a traditional SSRI?

Dambrino: I like to think about medications for treatment of depression in terms of class. SSRIs are going to be, as a rule, more likely to cause sexual side effects. They're also going to be very effective in many cases in treating anxiety, that rumination, especially when you move past those antidepressant doses, which are those low to medium doses, and you start pushing higher, you're going to be treating more of that rumination and anxiety as a rule. 

But we have to think about the side effect profile, sexual side effects. A lot of these things are dose related. 

If we move on to SNRIs, we might see a little bit more constipation in that case. We might see a risk of increasing blood pressure. We see shorter half-life then, but we might see less of those sexual side effects, maybe a little bit more motivation in some cases. 

Then if we start moving past that into NDRIs, for example, we're going to be less likely to have sexual side effects, not as effective in treating anxiety, so I would not recommend them [for that]. But that motivation piece and the drive piece are going to be more effectively treated by that. 

Vortioxetine and vilazodone are examples of those multimodal agents. We're not as worried about the same degree of sexual side effects with those medications. That's because we are working on those serotonin receptors in a different way. It's not as simple as blocking the serotonin transporter, for example. So, understanding your pharmacology is very important, and always reviewing not just half-life, but what receptors are we talking about?

PCNPI: In which patient profiles might dual-mechanism or multimodal agents be most beneficial?

Dambrino: We did highlight agents like duloxetine and vortioxetine. Duloxetine is an SNRI. Many of us know in psychiatry we will have patients who have comorbid somatic manifestations of anxiety or maybe they have fibromyalgia. Duloxetine is indicated for fibromyalgia, so choosing an agent like that with that in mind—I always tell my patients I don't treat pain, I'm not practicing outside of my scope. But the book, The Body Keeps the Score, that title in and of itself, we know that to be true. We know that our patients with comorbid trauma, which we treat a lot of patients with trauma and depression, that we're thinking about that.

[For] our patients who maybe they're struggling—they’re already feeling flat at baseline, they're already feeling that profound anhedonia—maybe some SSRIs, not all of them, but some of them are going to be more likely to treat depression a little bit, but after those activating effects and when we get to steady state, there's this kind of flatness that can happen. So, I might be more likely to choose vortioxetine or a medication like that. 

We're not saying that it's impossible for [side-effects] to occur with vortioxetine, but you have that multimodal serotonergic activity that can be a little bit, I wouldn't say protective, but you're less likely to have that flattening.

Thank you so much for joining me, and please be sure to check back for updates from Psych Congress Network.

Kristian Dambrino, DNP, PMHNP-BC, is a board-certified psychiatric nurse practitioner and the founder of Dambrino Wellness, a mental health clinic in Nashville, Tennessee. She holds a Master of Science in Nursing from Vanderbilt University and a Doctor of Nursing Practice from Belmont University.

A Fulbright Scholar, she is conducting research in Indonesia and India on reducing mental health stigma through nursing capacity building, and serves as adjunct faculty at Belmont University College of Nursing, with prior faculty appointments at Michigan State University and Marian University. As a national speaker and consultant, she serves in leadership as co-chair of Psych Congress Elevate and brings her clinical and research expertise to stages and institutions across the country.

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