Around the Practice: Treatment-Resistant Depression

During a recent episode of Around the Practice, Megan E. Maroney, PharmD, BCPP, moderated a discussion on the treatment landscape for treatment-resistant depression (TRD). Maroney is a clinical associate professor at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, in New Brunswick and a psychiatric clinical pharmacist at Monmouth University Medical Center in Long Branch, New Jersey. Maroney was joined by Neil Skolnik, MD, a professor of family and community medicine at Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia, Pennsylvania; Michael E. Thase, MD, a professor of psychiatry at Perelman School of Medicine at the University of Pennsylvania in Philadelphia; and Eric Cannon, PharmD, FAMCP, chief pharmacy benefits officer at SelectHealth, the payer of Intermountain Healthcare, in Salt Lake City, Utah.

Defining TRD

“I don’t know that there’s a universal definition” of TRD, Skolnik said. The most accepted definition is depression that has “an inadequate response to 2 or more antidepressants, usually from different classes, given in an adequate dose for an adequate length of time,” he said. Primary care practitioners are, for many patients, the first stop for patients seeking diagnosis and treatment for depressive symptoms. When primary care providers see a patient who meets the criteria for major depression, “[w]e start them on first-line therapy, often a SSRI [selective serotonin reuptake inhibitor] or a SNRI [serotonin-norepinephrine reuptake inhibitor], and then we say, ‘We’ll see you back some time later.’…An important thing for us all in primary care to be aware of is how frequently patients don’t fully respond, whether that’s a partial response…[or whether] they warrant further intervention or have TRD.”

In clinical practice, staging models are used to classify the severity of TRD. Before beginning the phase 4 STAR*D study (NCT00021528), Thase and his colleague John Rush, MD, an adjunct professor in the Department of Psychiatry and Behavioral Sciences at Duke University School of Medicine in Durham, North Carolina, developed what is sometimes called the Thase-Rush criteria. In this straightforward model, Thase and Rush created a hierarchy of first-, second-, third-, and fourth-line depression treatments, with electroconvulsive therapy as the “fi nal common denominator,” Thase explained. Since it was created, the criteria have changed—including the language shift from stages to levels of depression—and these levels have had numerous adjunctive treatments added.

“It is categorical…and it’s 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,” Thase explained.

The results of the STAR*D study showed that first-line treatment was effective for approximately 50% of patients, whereas the second-line treatment was effective for approximately 40%. “But between the second and the third [treat-ment], there was actually a point of discontinuity, and the chance of getting better dropped almost 20%,” Thase explained. “And so this is one of the reasons [clinicians] felt confident saying, ‘We don’t want to say treatment resist-ant until somebody has been through 2 trials of reasonable first- or second-line treatments.’"

Who Is at Risk?

According to Thase, “nonadherence or intermittent adher-ence is an inherent risk factor [for TRD]. Patients who don’t adhere to treatment have less of a chance to get better.” However, Thase noted, it’s important for clinicians to ask themselves if these patients are truly treatment resistant if they haven’t adhered to their treatment.

Other risk factors include comorbidities such as substance use and abuse, either in the form of drugs or alcohol. Individuals who have an illness within the bipolar spectrum, as well as those who become suspicious, have delusional thoughts, or hear voices when they’re depressed, can also be more challenging to treat.

Although the Montgomery-Åsberg Depression Rating Scale is the “most precise 20-minute assessment scale we have for depression,” according to Thase, it is too complex to administer during the course of a typical patient visit. Instead, clinicians administer the Patient Health Questionnaire 9-item depression assessment (PHQ-9), which is filled out by the patient before the visit.

“The PHQ-9 is the only rating scale we use,” Skolnik said of his practice. “I think the greatest value in using it is being able to track someone over time. …It gives us the ability to have an objective, consistent way of tracking symptoms over time.”

The Treatment Landscape

When Thase sets out to select a treatment for a patient with TRD, he—like most standard psychiatrists—will choose an SSRI or SNRI. For patients who have not responded to 2 medi-cation trials, or to 1 medication trial of a monotherapy and a second trial with an adjunct or antidepressant combination, he turns to treatments such as esketamine, transcranial mag-netic stimulation, the newly approved combination of bupro-pion and dextromethorphan (Auvelity), or an antidepressant plus a newer-generation antipsychotic.

As with most new generation medications, cost considerations must be made. “I don’t often do newer-generation antipsychotics until the third level because of their cost and adverse effects,” Thase explained. “But they are very effective for a subset of patients.”

Skolnik often fi nds himself debating whether a certain adverse eff ect is a good eff ect. For example, in older patients who are losing weight and having trouble sleeping, mirtazapine—which has a sedating eff ect and can positively impact appetite—may be the best choice for an initial agent. For a younger patient who might be worried about weight issues, however, these adverse effects would be unwelcome.

Measuring the eff ectiveness of these treatment is also crucial and is another area where the PHQ-9 comes into play. For Skolnik, the questionnaire allows him to document whether the patient is responding—or partially responding—in a quantifi able way. “Neither I nor the patient can remember how they were doing even a month ago, never mind 6 months ago,” he said. “It gives a nice, objective way to keep track of, ‘Is the medicine working? How well is it working? Is it continuing to work? Is someone sliding back down?’”

Typically, patients should try a medication for 8 to 12 weeks to determine if the treatment is working; this can be challenging, though, when patients are struggling. In his practice, Skol-nik typically waits 4 to 6 weeks before trying something different, a benchmark with which Thase agrees. “If something has not worked at 6 to 8 weeks, it’s a mistake to go another 4 weeks longer,” he said.

When managing TRD, clinicians must also consider the patient’s level of response. Per Skolnik, a partial response occurs when a patient is feeling better—by approximately 50%—than before. A lack of response is defined as a patient who sees no improvement in their depression symptoms.

The Payer Perspective

For payers, Cannon explained, the goal is to determine how payers and physicians can collaborate in a way that allows patients to access appropriate treatments. “If you were to look at the treatment model that exists today around depression and behavioral health, we’re seeing suicide rates continue to go up. We continue to have access issues around behavioral health. And so, as we look at the implications of that, our goal really hasn’t been to restrict access to treatment,” Cannon explained. “But how do we provide broader access to treatment, and how do we do it in a unified way?”

Cannon said the goal is to avoid creating barriers to treatment. “One of the things we harp on with our teams is, ‘Make sure if you get a call from a pharmacy that you are making sure those claims go through,’” he explained. Although prior authorizations are required for some treatments, such as esketamine, prior authorizations are not required for antidepressants or antipsychotics; step therapy is required for some newer products, where a patient must try and not succeed with a medication that is less expensive. Dual therapies are also allowed, and other changes have been made to increase ease of patient access to their medications.

“I think, culturally, we sometimes aren’t as astute as we should be in [asking], ‘How do we make sure that people understand the availability of treatment and availability of options?’” Cannon said. “I worry all the time that cost is a barrier.”

For Skolnik, barriers frequently comes down to energy, stigma, and access. “Often, it’s tough when you’re depressed and you’re not getting better. And now your primary care [provider] seems to have run out of options and is sending you somewhere else,” he explained. “It takes a lot of energy to follow through on that.” He frequently sees patients who are more receptive to receiving depression treatment from a primary care provider than from a psychiatrist. “It shouldn’t be that way, but it is still a barrier,” he said.

In addition, “[there is the issue of] access, particularly for young adults or teenagers,” Skolnik said. “It’s hard to get in; there aren’t enough child psychiatrists. Even among adult psychiatrists, depending on your insurance or lack of insurance, it can be hard to find a psychiatrist with readily available appointments.”

But, Cannon explained, at the end of the day his goal is to provide care to his patients. “We have mechanisms [in place] if you can’t afford care. But all of those things together, I think, sometimes are daunting for people who may be depressed and are not familiar with the health care system.”