Two recently FDA-approved medications for treatment-resistant depression may be garnering attention not for their applicability, which is currently limited, but for what they represent: the first new treatment pathways in a decade for an illness that can leave patients with limited options and disappointing results.
The first, intranasal esketamine, the S-enantiomer of ketamine, was approved by the FDA in March, and physicians are still figuring out how to implement it, or if they even want to.
Some psychiatrists, like Heidi Combs, MD, MS, associate professor of psychiatry and behavioral sciences at the University of Washington in Seattle, are waiting for long-term safety and efficacy data before prescribing esketamine for their psychiatric patients. Dr. Combs, who is medical director of inpatient psychiatry at University of Washington Medicine-Harborview Medical Center, said whether or to what degree insurance will cover the drug will also factor into her decision.
The other medication, brexanolone, was approved by the FDA in March and uses a novel mechanism to treat postpartum depression. While the drug might help someone who's really struggling, Dr. Combs said there are a lot of hurdles: 60 hours of IV treatment; side effects, including loss of consciousness, that require close monitoring; and a price tag so high her facility pharmacist said it “could buy you a Cadillac.” For patients hospitalized due to severe postpartum depression, Dr. Combs is still using electroconvulsive therapy (ECT) first.
Despite their limitations, the new drugs raise hope for the 30% of patients with depression who don't find relief after the typical first-line regimen, which involves a two-month trial of selective serotonin reuptake inhibitors (SSRIs) and/or serotonin and norepinephrine reuptake inhibitors (SRNIs), said Brian J. Mickey, MD, PhD, associate professor of psychiatry at the University of Utah in Salt Lake City. Instead of working on serotonin receptors, esketamine works on the glutamate receptor, while brexanolone works on the gamma-aminobutyric acid (GABA) receptor.
“Down the road, in addition to prescribing ketamine, we hope to leverage the knowledge we gain from understanding ketamine's mechanism of action to develop a new generation of rapid-acting antidepressants without as many side effects,” said Lawrence T. Park, MD, director of the clinical research unit at the experimental therapeutics and pathophysiology branch in the division of intramural research programs at the National Institute of Mental Health in Bethesda, Md.
For now, experts say, internists can have the greatest impact by continuing to be the first point of contact for many patients with depression symptoms, treating those with mild to moderate depression, and explaining what options may be available if those treatments fall short.
What's really new
Until this year, the FDA had approved only three new drugs for depression in the general population in the last decade: vortioxetine, levomilnacipran, and vilazodone. They've been underwhelming because they don't work differently from pre-existing treatments, don't lead to better outcomes, and aren't offered as affordable generics, Dr. Combs said.
Ketamine is not FDA-approved for depression but has shown efficacy as an off-label treatment; however, it must be administered via an IV and requires careful monitoring. The new drug, esketamine, is quickly absorbed nasally. About 50% to 75% of patients can see results within 24 hours of the first dose, with a one-year relapse rate of 25%, said John Krystal, MD, Robert L. McNeil Jr. professor of translational research and professor of psychiatry and neuroscience at Yale School of Medicine in New Haven, Conn., who has researched ketamine
Dr. Mickey, who uses IV ketamine in his practice, plans to begin offering esketamine this year. To get ready, his facility is setting up a special pharmacy and new administrative processes. Assuming insurance kicks in, “It would make a lot of sense to do as an outpatient because you won't need all the special monitoring [as brain stimulation],” he said. ECT has cognitive side effects that interfere with one's ability to function, he explained.
Intranasal esketamine treatment is intended to be used twice a week for the first four weeks, then once a week the next four weeks, then once a week or once every two weeks after that, said Dr. Park. However, not everyone is ready to offer it. Not only are the data about long-term impact underwhelming, the extensive exclusion criteria used in studies of the drug limit those who are eligible for treatment, said Dr. Combs. She said esketamine has yet to be evaluated for patients with a history of psychosis or bipolar disorder, who make up a good portion of her practice. Plus, many of the patients internists traditionally treat were also excluded: those with a history of stroke, transient ischemic attack, coronary artery bypass graft in the last 12 months, stage three or four heart failure, or hypertension greater than 140/90 mm Hg.
Moreover, concerns about abuse potential and diversion are behind the FDA's contingencies to keep administration of the new drug a strictly monitored, in-clinic process “to protect patients from developing a ketamine habit,” Dr. Krystal said.
Yet Dr. Mickey said some version of esketamine may one day be a prescription option for internists. “The company is working on oral versions … and it may make its way to the primary care physician's office as another pill,” he said.
Brexanolone, meanwhile, is considered a novel option because it's opening up a new pathway of options by working on the GABA receptor. “This might be something that will lead us to a medication that can be used in a different way with indications for the general population,” Dr. Combs said.
If patients ask about esketamine as a first-line drug, Dr. Krystal recommended putting the option into context. “Say, ‘If you've never been treated for depression before and never had psychotherapy, esketamine is limited at the moment to patients who have failed the standard treatments.’” Only after those options are exhausted, he said, may internists want to find a clinic that offers the drug.
The best practice options for internists start with routine screening. If major depressive disorder is diagnosed, cognitive behavioral therapy (CBT) or second-generation antidepressants are equally effective, as noted in ACP's 2016 guideline on treatment of the depression, said Timothy J. Wilt, MD, MPH, MACP. Dr. Wilt is core investigator and staff physician at the Minneapolis VA Center for Care Delivery and Outcomes Research, a professor of medicine at the University of Minnesota, and Chair of ACP's Clinical Guidelines Committee.
“It's unusual for a patient to call and say, ‘I'm depressed, I want to see Dr. Wilt.’ They usually come in to see me about whatever else is ailing them,” Dr. Wilt said. Patients first fill out a depression screening questionnaire, and a nurse attaches a red sticky note to the patient file if there's a positive flag. Dr. Wilt will then discuss changes in life events—death of a spouse or loss of a job, for example—as well as any physical issues that might contribute to those results.
“It's important to pay attention to circumstances that might be exacerbating [patients'] depression or putting them at higher risk for bad outcomes,” said Devan Kansagara, MD, MCR, FACP, associate professor of medicine at Oregon Health & Science University and Portland VA Medical Center in Portland and Vice-chair of ACP's Clinical Guidelines Committee.
Anything more concerning, such as mania, bipolar disorder, or suicide risk, would warrant an immediate referral to a psychiatrist, he said.
ACP's guideline, which was published Feb. 9, 2016, by Annals of Internal Medicine, said clinicians should choose between CBT or second-generation antidepressants after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with patients. “Having the ACP guidelines gave me more confidence in saying, ‘Either option is reasonable. What makes sense for you?,” Dr. Kansagara said.
If starting with medication, clinicians should consider adverse effects, treatment adherence, availability, and costs. It's also good to dovetail the treatment choice with other medical decisions. For example, Mark Dreskin, MD, primary care mental health clinical lead with the Southern California Permanente Medical Group in Los Angeles, noted that bupropion is an excellent first-line antidepressant for a patient with cardiovascular disease, since it's also used for smoking cessation.
Since side effects may occur before beneficial results, Dr. Wilt discusses them as well as expectations and benefits up front so that patients don't get discouraged or stop taking medications. Common side effects like gastrointestinal problems, headache, weight gain, heart rhythm abnormalities, and insomnia can occur in the first few weeks, while benefits may not be felt until up to eight weeks or more, he said.
A nurse follows up over the phone in two weeks, and Dr. Wilt then sees the patient again in two or three months. A patient who is improving will be seen again in six months. If there's no improvement after two months, Dr. Wilt increases the dose, changes to another medication in the same class, refers to psychotherapy, or adds a second therapy.
It's not known why patients may respond better to one SSRI or SSNI than another, said Dr. Mickey. How the drug is metabolized or works on an individual's neurochemistry may play a role, and identifying biomarkers would help more optimally manage patients. However, data still do not clearly support genetic testing, said Dr. Combs.
For individuals with a first diagnosis of depression, Dr. Wilt considers stopping treatment after four to nine months if the patient shows at least a 50% improvement on a scoring tool that asks about mood, activity, and function. For those with recurrent depressive episodes, longer or continued treatment is usually necessary. Whenever a patient stops a drug, Dr. Kansagara advises proceeding with caution to avoid withdrawal symptoms or relapse.
However, since every trial of a subsequent medication has a lower response rate, it's important to know when to refer. “I've seen people who've had three, four, five trials and have been ill for years,” Dr. Mickey said.
Dr. Wilt acknowledged that being in the VA affords him unusually easy access to psychotherapy options for his patients. There are two mental health clinicians (typically psychologists) in the clinic for every 10 internists, and they can accommodate same-day referrals. Nurse practitioners, physician assistants, or other clinicians then follow up to see how the relationships are working out and if the patient is adhering to treatment. Because psychotherapies have similar effectiveness but fewer harms compared to medications, Dr. Wilt said he typically recommends psychotherapy as first-line treatment for most of his patients.
However, in many settings, patients may struggle with limited access, community resources, and time for psychotherapy. To address those barriers, research is focusing on delivering CBT using telepsychiatry, telepsychology, and computer apps, experts said. Dr. Wilt noted that although the ACP guidelines don't address these options, they are worth exploring.
Dr. Combs said studies of computerized CBT are promising, especially when the programs have a physician on the other end. “The good news is that there's something there,” she said. “Right now [researchers] are looking at the studies to find out what is the special sauce … to boost the efficacy.”
She noted that while there are no good randomized controlled trials of smartphone apps' impact in delivering CBT, they have potential because cellphone use is so ubiquitous. Younger patients who are more accustomed to being on their phones might be particularly responsive, she noted.
Buoyed by technology, CBT or other types of therapy may be able to reach patients at earlier stages of depression, Dr. Dreskin pointed out. “This is where we can effectively intervene and prevent the condition from becoming chronic or recurrent,” he said.
Dr. Combs raised the caveat that apps, unlike HIPAA-compliant physician offices, usually don't protect data. “Patients often don't realize this,” she said. Dr. Dreskin noted that some apps, like those used by Kaiser Permanente, are HIPAA-compliant and are able to protect patients' personal information. Physician practices should determine whether an app can meet both those criteria before considering a vendor, he said.
A changing mindset
Dr. Wilt noted that it may take a second visit before a patient will talk about a mental health concern or agree to treatment, instead dismissing it as “just a phase.” Having the hard data from the depression screening questionnaire and information about the value of multiple treatment options helps open the conversation, he noted.
But Dr. Mickey noted that the stigma surrounding mental health seems to be lessening and that patients no longer ask him not to put “depression” in their chart like they used to. “That just doesn't happen anymore,” he said.
The shift is even more apparent among the younger generation, Dr. Dreskin said. He noted that teens in particular are more open to participating in groups about mental health and in discussing the issue. “That would have been taboo several years ago,” he said. “But it's not the case now.”
The next step, he said, is considering changing the lexicon to reflect newer attitudes. For example, he noted that a mental health clinic may now be called a mental “wellness” clinic. “As we get better at having options without loaded terms, patients can freely choose between traditional and nontraditional [treatment options],” he said.