Megan Maroney, PharmD, BCPP: Welcome to this Drug Topics® Around the Practice® exploring the treatment landscape for treatment-resistant depression [TRD]. My name is Megan Maroney. I’m a clinical associate professor at the Ernest Mario School of Pharmacy at Rutgers University [in Piscataway, New Jersey], and a psychiatric clinical pharmacist at Monmouth Medical Center [in Long Branch, New Jersey]. Joining me today in this discussion are Dr Skolnik, Dr Thase, and Dr Cannon.

Neil Skolnik, MD: [I’m] Neil Skolnik. I’m a professor of family and community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University [in Philadelphia, Pennsylvania]. It is a pleasure to be talking about a critically important topic in primary care.

Michael Edward Thase, MD: I’m Michael Thase. I’m a professor of psychiatry at the Perelman School of Medicine [at] the University of Pennsylvania [in Philadelphia], and I’m also a member of the medical and research staff of the Corporal Michael J Crescenz Veterans Affairs Medical Center in Philadelphia.

Eric Cannon, PharmD, FAMCP: I’m Eric Cannon, chief pharmacy officer with Select Health, which is the payer of Intermountain Healthcare in Salt Lake City, Utah. I’m excited to be here today.

Megan Maroney, PharmD, BCPP: Today we’re going to talk about several topics pertaining to treatment-resistant depression including defining what treatment-resistant depression is, exploring the treatment landscape, and discussing the impact of living with treatment-resistant depression or TRD. So let’s talk about how we define TRD. Dr Skolnik, I’ll start with you. What is TRD and how do we distinguish that from major depressive disorder? Is there a universal definition?

Neil Skolnik, MD: I don’t know that there’s a universal definition because there are different definitions out there. But the most accepted one is an inadequate response to 2 or more antidepressants, usually from different classes given in an adequate dose for an adequate length of time. More important than the technical definition is the importance of us in primary care, because that’s where a lot of [management] of depression occurs. [We are] aware that many of our patients don’t respond fully. So something that’s done is we see someone who meets the criteria for major depression. We start them on first-line therapy, often an SSRI [selective serotonin reuptake inhibitor] or an SNRI [serotonin and norepinephrine reuptake inhibitor], and then we say, “We’ll see you back some time later; we’ll talk about the importance of follow-up.” And as long as they’re doing somewhat better, we continue that approach. An important thing for us all in primary care [is] to be aware of is how frequently [patients] don’t fully respond, whether that’s a partial response [with] depression and [they] warrant further intervention or [they have] TRD.

Megan Maroney, PharmD, BCPP: Would you say that the sequenced treatment alternatives to relieve depression in the STAR*D trial [NCT00021528] [affected] the definition of TRD?

Neil Skolnik, MD: [They] certainly [affected] our knowledge of how to [manage] TRD and gave us [an] evidence-based and incredibly well-done study. But some guidance about what to do was passed. So it was a rigorously done, well-done study with multiple layers of intervention for [patients] who sequentially might not have responded to initial therapy. So it advanced our knowledge a great deal.

Megan Maroney, PharmD, BCPP: And even though it was done a number of years ago, [it’s] still very relevant today. Dr Thase, what are some staging models that are used to classify the severity of TRD in practice?

Michael Edward Thase, MD: Well, the first one was the one I did with my colleague John Rush, before we began the STAR*D study. That is sometimes called the Thase-Rush [model]. It’s very simple and straightforward, and we made a hierarchy of first-line, second-line, third-line, and fourth-line treatments. When we did this model the first time, we suggested that electroconvulsive therapy [ECT] was the final common denominator. So it would be in the fourth line. Since then, we’ve had some additional treatments come in, and maybe ECT is no longer the final common denominator but a level 1 or stage 1. We had colleagues in oncology who within years of presenting this model said [that] these are levels, not stages; stages involve the pathophysiology of the illness, levels involve description. Our staging model should have been called a leveling model. So level 1 would be someone who had a good, adequate trial [with] level 1 first-line antidepressant, and level 2 would be someone who had a good trial of a second alternative treatment after the first line. There were some adjunctive treatments when we originally proposed. The adjunctive treatments are used more now than they were 20 years ago. So you could be at level 2 if sertraline didn’t work and the addition of aripiprazole didn’t work. So that could qualify you to be in level 2 of treatment resistance. As Neil said, this would be the entry to the diagnosis of TRD: 2 adequate trials in the current episode. We thought of level 3 involving the older-generation antidepressants: tricyclics [and monoamine] oxidase inhibitors. They’ve probably moved to level 4 these days. Esketamine and TMS [transcranial magnetic stimulation] could be considered the level 3 treatments that weren’t approved in 1995 when we first did this.The more vigorous [the] treatments of a more advanced nature, the more treatment-resistant the person [will be]. So it is categorical. There are categories, and it is also continuous in the sense that someone who’s had 7 strong treatments in the current episode is likely more treatment resistant than someone who’s had 2. But in the STAR*D study, the first-choice treatment got about 50% of [patients] better and the second-choice treatment got about 40% of [patients] better. But between the second and the third, there was a point of discontinuity; getting better dropped by almost 20%.This is one of the reasons [individuals] felt confident saying, “We don’t want to say treatment-resistant until somebody’s been through 2 trials of reasonable first- or second-line treatments.” And that drop-off between the second-line and the third-line treatments in STAR*D was indeed impressive. So some [individuals] sometimes criticize the 2 trials as being not rigorous enough. I think it is just rigorous enough to move on to more advanced interventions.

Megan Maroney, PharmD, BCPP: It seems like at that point, there really is differentiation for a lot of patients.

Transcript edited for clarity.