Millions of Americans live with major depressive disorder and of those, a subset of them do not respond to treatment. Psychiatrists Adrian Jacques Ambrose, MD, MPH, MBA FAPA, and Joshua Berman, MD, PhD, co-direct the Interventional Neurotherapeutic Psychiatry Program at New York-Presbyterian/Columbia where they and other mental health clinicians are using the latest therapeutic approaches to help manage patients with treatment resistant depression. Through this program, individuals with severe depression have access to a comprehensive and evidence-based suite of services to address their unrelenting symptoms. Below, Drs. Ambrose and Berman discuss the condition of treatment-resistant depression and New York-Presbyterian/Columbia’s commitment to providing cutting-edge care for those affected.
What is treatment-resistant depression?
Treatment-resistant depression is a condition that occurs when those with major depressive disorder (MDD) have tried and failed conventional treatments. A convention approach usually consists of two or more adequate trials of a conventional therapeutic agent with appropriate attempts at augmentation and plus or minus therapy to address ongoing life issues that may contribute to the situation. Nearly 30% of the more than 17 million Americans with clinical depression, or MDD, suffer from treatment-resistant depression (TRD).
Why do some people with symptoms of depression become treatment-resistant?
We think of depression as sort of a circuit problem in the brain. If some of those circuits aren’t well connected they will underperform, and people can develop symptoms that lead to depression. There are a lot of ways that the failure of connectivity can happen, but we don’t know all of them. Conventional antidepressants, like selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), tend to focus on specific neurotransmitters to fix those connections. However, patients with TRD tend to have additional complicating factors, such as, abnormalities in specific brain region, genetic predisposition, and even psychosocial difficulties. In addition, other medical comorbidities, like significant anxiety symptoms or undiagnosed hypothyroidism, can greatly increase the likelihood of a treatment resistant depressive episode. It’s important to note that TRD can be quite common – about one in three patients with MDD may have TRD.
How do you approach determining the appropriate course of treatment for these individuals?
Our first step is to evaluate and find out all the different factors that could be contributing to the condition. Are there other comorbidities, like bipolarity or concurrent medical issues? Or are there issues about styles of coping and ways of interacting with the world that need to be addressed in other ways? For many people, those things may be present, but they may not account for the difficulty in treating their depression, or those other factors may not be present at all, and they just have a more tenacious form of depression.
Since multiple conditions can have symptoms similar to depression, we want to make sure patients have comprehensive evaluation to identify any factors that may further complicate the treatments. We then consider interventional approaches that may work when conventional antidepressants don’t.
What goes into the decision-making about which interventional approaches may be most appropriate?
Deciding which interventional approach to try is very individualized for each patient. We aim to identify logical treatments and in what order they should be applied based on patients’ priorities, risk factors, and treatment history. The idea is that whatever we’re going to do, there’s always going to be something else we can try depending on the outcomes. We often have patients say that they’ve exhausted all available treatments, and they feel hopeless. As a result, one of the treatment goals is to underscore all additional treatment options with robust clinical evidence and to foster more hope for these patients. . Some of that is just when someone is depressed for a long time, it starts to seem like they’ve tried everything and nothing has worked. Many people don’t realize how many options there are to try outside of conventional therapeutics that could still elicit a response.
What we try to identify with the patients who come to the NewYork-Presbyterian/Columbia Interventional Neurotherapeutic Psychiatry Program is what is their priority– the least invasive treatment first or the thing that’s most likely to work first. Then we screen each patient to make sure that there isn’t some reason why they shouldn’t undergo a particular course of treatment. The crucial element here is we want to empower patients, so we always try to decide the interventional treatments together with the patients. Some current interventional options that we offer include intravenous ketamine, intranasal esketamine, transcranial magnetic stimulation (TMS), and electro-convulsive therapy (ECT).
What interventional approaches are you seeing success with?
Ketamine and esketamine have the chance of working the fastest and the way they work is unique. Conventional antidepressants work mainly by raising the levels of monoamine neurotransmitters like serotonin, norepinephrine, and dopamine. These approaches result in increased activity at brain circuits where monoamine neurons from the midbrain come up and meet excitatory connections in the cortex. After several weeks that can result in changes in the neurons involved that cause them to connect better to one another, and repair circuit dysfunction and depression for a lot of people.
Ketamine, on the other hand, can go directly to the synapses that get repaired through this mechanism and create rapid repairs, so you see increases in dendritic spines and changes in proteins in the endings of the axons that promote better connection. The only problem is it's not as durable, and you must give several doses of ketamine or esketamine for the changes to take hold. If you don't keep doing some kind of maintenance, for many people, those changes don't endure.
In terms of the other treatments, ECT has an edge in terms of efficacy over ketamine, and an even bigger edge over TMS. However, TMS has the most durability in treatment efficacy. We’ve seen success with all these approaches, and the key is to figure out the specific treatments that work the best for the person in front of you.
What do you think will be the next big advancement in treatment-resistant depression?
The hope is that someday we will have biomarkers that can tell us which interventional approach to use first and which patients are going to respond to different treatment options. Research in that space is critically important and will open the doors to even more personalized approaches.
In terms of the near future, we’re thinking about ways to make ketamine treatment more durable and are taking the first steps to think about how to incorporate some of the new psychedelics, like psilocybin and MDMA, into our suite of evidence-based services when they become available. We also are hoping to offer more intensive forms of TMS, including with neuroimaging to improve precision and clinical outcomes.
There are other promising new treatments that have attracted our attention. These range from treatments given in partnership with anesthesiologists such as nitrous oxide and/or inhalation anesthetics, all the way to new surgical approaches. We are always looking to learn about emerging treatments because our central philosophy is that we’re not a service that’s focused on the provision of a particular treatment, but rather at NewYork-Presbyterian/Columbia, we’re focused on identifying what our patients might need and either providing them with it or connecting them to it. Our forte is to be able to assess novel treatments and figure out how we can provide them in the safest and most effective ways to our patients. For a lot of patients, sometimes, the biggest change is to re-instill a sense of hope in them.
