Depression is a major healthcare crisis that rivals kidney disease and influenza in per capita deaths every year. Over 17 million Americans currently suffer from depression, and it’s estimated that over 280 million people are struggling with its effects worldwide.
A compounding challenge of depression is that it often accompanies preexisting health conditions. Cancer patients, stroke survivors, and heart attack victims all report significant rates of depression, and it’s been shown to have a serious adverse effect on recovery.
With proper counseling and psychiatric treatment depression can be managed, and today, 80% of people who seek treatment for depression show improvements within 4-6 weeks. However, there are still nearly 3 million patients who experience treatment-resistant depression (TRD), which is defined as depression that either never achieves remission after therapy or produces a permanent cycle of relapse.
Fortunately, in low doses, the anesthetic ketamine is demonstrating efficacy in the treatment of TRD, but the mechanism is not completely understood by researchers. Nevertheless, ketamine is fast becoming an important and promising answer in the fight against TRD.
We sat down with Kathy Gardner, a Family Nurse Practitioner (FNP), Certified Nurse Midwife (CNM), and has her Doctorate in Nursing Practice (DNP), and content creator for Premiere Education, to discuss the use of ketamine in the treatment of TRD.
Premiere Education: What is treatment-resistant depression, and have you encountered it in your practice?
Kathy Gardner: Treatment-resistant depression is commonly defined as a recurrent major depressive disorder that’s not relieved with first-line treatment, and specifically, two or more failed courses of two different antidepressants. Failure is defined as a return of debilitating symptoms and meeting criteria on the validated depression screening and symptoms tools.
3 million [people] are classified as having treatment-resistant depression, and of those, around 40% never achieve full remission. It’s a tremendous economic, social, and physical burden, and is a major contributor to suicide. There’s very few effective long-term treatments, and a great majority of persons with TRD will suffer relapses. That’s why there’s a very active research interest in rapid-acting antidepressant drugs, and ketamine is one of them.
Premiere Education: What role does ketamine play in treatment?
Kathy Gardner: Ketamine is really interesting. It’s in a class of drugs that are called glutamate receptor modulators, and it’s FDA-approved only for anesthesia.
In the early 2000s, researchers began looking at sub-anesthetic dosing with ketamine in persons with treatment-resistant depression. They found that it acts on these neurotransmitter pathways that are different from your traditional antidepressant, in the parts of the brain that release glutamate and GABA (Gamma-aminobutyric acid). The precise way in which it relieves depression isn’t that clear.
Premiere Education: What are the obstacles facing FDA approval for TRD?
Kathy Gardner: Because ketamine is an older drug that’s generically available, it never received—and will never receive—FDA approval for its use. It’s cost prohibitive to take generic drugs through the FDA approval process.
However, the early evidence [of ketamine’s] therapeutic impact on treatment-resistant depression was so compelling, that one company patented a nasal spray formulation (esketamine) in 2013. It was approved by the FDA in 2019 for treatment-resistant depression. A year later, the FDA granted approval for major depressive disorder with suicidal ideation.
Premiere Education: How do healthcare professionals administer ketamine and esketamine?
Kathy Gardner: Either drug is typically administered to patients that also take at least one oral antidepressant on a protocol schedule. Either drug is given initially twice a week for three to four weeks, and then less often—maybe about once a week for four weeks and then intermittently as needed after that. If they’re responding, they may have the option of continuing intermittent treatment.
Premiere Education: What are the side effects of ketamine and esketamine for patients?
Kathy Gardner: There are four or five different adverse effect categories: psychiatric, hemodynamic, neurologic, genitourinary, and then the drug has an abuse liability. There are significant psychiatric effects for both drugs and they’re frequent—things like agitation, confusion, hallucinations, dissociation, feeling drunk, and sensory disturbances. This is why it needs to be administered in a therapeutic clinical environment where people are trained on how to handle the effects.
Clinicians need to be very concerned about the potential for diversion and misuse and craving, and dependence withdrawal. And, you know, ketamine is known around the world as being a party drug and it stimulates the opioid receptors in the brain. All prescribing regulations and monitoring are needed.
Premiere Education: What are the challenges with access to ketamine and esketamine? Can any healthcare provider prescribe these medications?
Kathy Gardner: There are over 500 ketamine clinics in the U.S. right now, and insurance reimbursement for IV ketamine is not FDA-approved. So every ketamine infusion costs nickels and dimes, but to the patient, it’s $400-$1200.
The nasal spray is covered by insurance, and costs around $200- $400 per dose, or $3000-$5000 for an eight-week course. Only those with strong financial resources and access will be able to utilize them.
Premiere Education: What is the future of ketamine and esketamine for treating TRD?
Kathy Gardner: We really need real-world, clinically-relevant data to know the exact impact. There’s an open-arm, five-year long-term study going on right now with [esketamine], which hopefully will help answer that question, but right now, that just isn’t known.
There’s a lot of interest in these drugs, and using them for many other disorders besides depression, like personality disorders, psychotic disorders, substance use pain syndromes, seizure disorders, bipolar [disorder], obsessive-compulsive [disorder], and PTSD. Those are all still very investigational, but you’re going to see a lot coming out on [ketamine and esketamine].
