Experts Present Protocol for Accelerated Antidepressant Trials

The management of depression using medication continues to be a trial-and-error approach of prescribing that leaves many patients dealing with symptoms months after a diagnosis. This delay can have serious consequences, as studies show that the longer it takes for a person to respond to antidepressant therapy, the greater his or her risk of relapse and poor long-term outcomes.

At a session at this year’s Annual Meeting, experts discussed an approach designed to speed up the decision-making process for depression care called the Columbia University Accelerated Sequential Antidepressant Protocol (ASAP).

“Two dogmas have long guided antidepressant treatment guidelines,” said session speaker J. John Mann, M.D., the Paul Janssen Professor of Translational Neuroscience (in Psychiatry and in Radiology) at Columbia. “First, monotherapy is best. Second, give a medication trial at least six weeks before switching.”

Mann noted that in the STAR*D trial (a landmark clinical trial that explored different combinations of medications and/or psychotherapy in search of an optimal treatment sequence for depression) patients who received a second antidepressant following a nonresponse to the initial medication had higher remission rates than those who switched medication or received psychotherapy in addition to the initial medication.

In a similar vein, ASAP generally recommends against starting patients on popular selective serotonin reuptake inhibitors (SSRIs). Instead, the protocol suggests that physicians first try patients on antidepressants that target multiple neurotransmitters—such as serotonin-norepinephrine reuptake inhibitors (SNRIs) or bupropion, which binds norepinephrine, dopamine, and nicotine receptors. The protocol also recommends that physicians begin rational augmentation as soon as initial therapy looks unlikely to succeed—first by adding an antidepressant from a different class than the initial one, then by switching the combination or adding another medication type such as an antipsychotic, mood stabilizer, or thyroid supplements.

Mann noted that while some physicians may have concerns over potential side effects that patients may experience from taking two antidepressants, multiple studies have shown that side-effect severity and clinical trial dropout rates are comparable regardless of whether patients are taking a single antidepressant or an antidepressant augmented with another medication. He suggested that medications with different biological profiles may create effects that cancel each other out; for example, one medication may be sedating while the other is stimulating.

“Taking two medications can lead to a different range of side effects, but not necessarily a greater amount,” he said.

As for the necessity of six-week treatment windows, this timeline is primarily based on antidepressant clinical trial data. But as Mann pointed out, this reflects the time it normally takes an antidepressant to robustly separate from a placebo. “If you look purely at mood changes in responders, you can see noticeable improvements within one to two weeks,” he said. He cited a recent meta-analysis of clinical trials that found only 4% of depression patients who did not show symptom improvements after two weeks went on to achieve remission.

ASAP is built around switching medications after two to four weeks depending on the degree of symptom improvement and/or side effects, he said. The goal is that by 12 weeks—the window in which treatment response is most likely—a patient will have tried medications targeting a broad range of biological targets. If the patient is not responding at this stage, he or she may be considered treatment resistant and more aggressive interventions such as ketamine, transcranial magnetic stimulation, or electroconvulsive therapy may be advised.

Mann said ASAP could be especially valuable to primary care physicians, who are key frontline mental health providers responsible for about 80% of all antidepressant prescriptions.

And busy primary care doctors do not have to worry about memorizing long flowcharts, said fellow presenter Ravi Shah, M.D., the chief medical officer of mental health services company Geode Health. Shah presented a clinical decision support app called the Columbia Psychiatry Pathways that guides people through the ASAP process.

“We understand we have to make this process easy at the point of care,” Shah said. He explained the app assists with medication selection as well as how to properly screen for depression and suicidal ideation, how to taper medications once a patient’s symptoms have resolved, and when to consider patients for referrals.

“Our analyses show that the average time spent on the app is 40 seconds per session, so it does not disrupt valuable clinician time,” he said. Shah added that all the medications suggested by ASAP have generics, so there should be no issues with insurance authorization and/or general affordability. ■