Treatment-Resistant Depression Overview
Scott T. Aaronson, M.D.

Dr. Aaronson is Director of Clinical Research and a psychiatrist at the Retreat at Sheppard Pratt Health System and a clinical associate professor of psychiatry at the University of Maryland School of Medicine.

People talk about “treatment-resistant depression.” What does that mean?

To date, there isn’t a standard definition of treatment-resistant depression that is accepted by clinicians, insurers, government agencies, and people living with depression and their families. Generally speaking, when people speak of treatment-resistant depression, they’re talking about depression that has failed to respond to an adequate dose of at least two distinct approved psychiatric medications taken for at least four to six weeks.

Over the course of my practice, I have come to regard treatment-resistant as being a lack of results with at least three or four different medications. It’s known that 30-40% of patients do not respond to initial drug , so if you haven’t experienced good results with one medication, this does not necessarily mean you have treatment-resistant depression. The Star*D Study, funded by the National Institute of Mental Health, found that even when initial treatment fails, as many as one in three patients may achieve remission – an ending or near-ending of their symptoms – by continuing on with treatment and augmenting or switching medications.

One thing to note is that treatment-resistant depression is usually determined because of a lack of clinically-significant results based on medication treatment. There are other treatments that can be effective alone or in addition to medication, depending on the person and the severity and duration of the depression. When someone has tried multiple different medications without sufficient response, it may be more appropriate to think of the depression as resistant to those particular medications at those dosages, rather than the depression being untreatable.

Who typically has treatment-resistant depression?

There is no one profile of people who have treatment-resistant depression and there is no predictor of whether a person’s depression will prove hard to treat. People who come to me have generally been through several doctors and medications. They get referred to me because their doctors have run out of options or are uncomfortable with progressing with other medications, dosages, or combinations of medications. Also, in general, depression becomes more difficult to treat the longer it is left untreated.

When people with depression that has not been responsive to treatment come to you, how do you assess their treatment to date?

First, I check whether I agree with the diagnosis. Often patients who have a depression that does not respond to treatment may have a co-existing condition such as a substance use, anxiety (including a past history of trauma), or personality disorder that severely limits their ability to respond. In addition, I consider whether they might have bipolar disorder or a psychotic disorder that has not been addressed.

I also want to make sure the patient has had adequate trials of medication with regard to dosage and duration. Misdiagnosis and under-treatment need to be ruled out before concluding that the depression is “treatment-resistant.”

If a person has not achieved realistic treatment goals through medication, what additional treatment approaches are available? What is the likelihood of better outcomes?

I’m encouraged by the research, which shows potential to yield effective new drug and device development. We haven’t had much change in the way that we treat depression for the last three decades, so it’s exciting that there are so many potential treatments emerging.

Talk therapies

About 70% of the patients I see respond to a medication, but it may be a partial response and sometimes not as much as I would like. It is important to combine medication with other therapies, such as talk therapy. Talk therapies help patients change their perceptions of themselves and the world around them, and can provide strategies for managing their depression, its symptoms, and life’s challenges. It is important to consider how – and which – talk therapies might be helpful for each person.

Medications

The number of medication choices is growing. I can, for example, move a patient to a different class of medication or combine medications, such as using any of the several newer antipsychotics that have been approved for use as supplemental medications for non-psychotic depression.  The majority of medications used for depression operate through the monoamine system which include drugs that affect serotonin, norepinephrine, and dopamine. These include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs).

In 2019, the Food and Drug Administration (FDA) approved the first two antidepressant medications that do not work through the monoamine system. Brexanolone, currently available in an intravenous formulation and approved only for post-partum depression, works in a unique way to modulate gamma aminobutyric acid (GABA) receptors. Investigations are ongoing to discover if an oral form of this medication may work for the more common presentations of depression.

Another treatment in the fast-track FDA process involves a number of compounds that are NMDA antagonists (N-methyl-D-aspartate receptor antagonist). The first to get FDA approval is an intranasal form of esketamine, which has been shown to have a rapid onset of action, often within the first 24 hours after dosing. While an exciting addition, there are still questions about infrastructure, as it must be administered at a doctor’s office and there is a post-administration waiting period before the person is allowed to leave. Several other alternative medications in this class are in various stages of development and may become available in the coming months.

Brain stimulation approaches

Neurostimulation has been shown to be effective and the treatments are finally becoming more available. Non-pharmacological treatment has significant benefits as compared to medication, such as faster response to treatment and no systemic side effects, so we would like to be able to use it for the people who will benefit. We know that the brain is a combination of electrical and chemical, so there’s no reason for us to think that relying only on the chemical will provide all of the answers. Neuromodulation has shown that we can affect the brain through the use of magnets and electricity.

These are potentially promising therapies, in ascending order of invasiveness:

  • With Transcranial Magnetic Stimulation (TMS), magnetic energy is applied to the brain. I see this as something to consider as a precursor or alternative to electroconvulsive therapy. It may require daily treatment for four to six weeks. TMS treatment is covered by some insurance after prior treatment attempt requirements are met.
  • Electroconvulsive therapy (ECT) isn’t new, but may be underused even though treatment is often effective. Advances in the use of ECT have improved patients’ tolerance of the procedure and reduced some of the adverse reactions. ECT patients are anesthetized; an electrical current is passed through the brain, inducing a very short seizure that passes through the brain but not the body. Risks include prolonged seizure, memory loss, and the risks associated with general anesthesia.
  • In Vagal Nerve Stimulation (VNS), a small device is implanted to send electrical impulses to stimulate the vagus nerve for 30 seconds every five minutes throughout the day. While perhaps half of implanted patients meet response criteria of a 50% improvement or more, for many others I may see a 25% improvement in symptoms. For some patients, a 25% improvement might be considered marginal, or even a failure. But my take is that, for severely ill patients, a 25% improvement can mean the difference between being disabled and at least partially functioning. For some of my patients it has meant enjoying a hobby again or being able to return to part-time or full-time employment.After much discussion, the Centers for Medicare and Medicaid Services in 2019 rescinded their 2007 non-coverage determination and are supporting a large randomized trial of VNS in Medicare recipients with treatment resistant unipolar or bipolar depression that has failed at least four treatments. This coverage with evidence development study is currently enrolling across the country.

What can family members do to help someone with treatment-resistant depression?

As difficult as it is to support a loved one with depression, it can be even more difficult when their depression does not respond to treatment over several months. Family members need to be open to discussing their feelings. Ideally, they will have their own supports, including friends, family, and even their own therapist. Depression can be hard on everybody, so everybody needs to take care.

If someone in your family is not getting better after several months, you may want to consult with additional experts and see what treatment they might suggest. If there is a local medical school in your area, you can call for referral recommendations or you can ask your own psychiatrist or other provider. If there’s not an expert near you, try working with any hospital affiliated with a medical school and ask your health insurance customer service or behavioral health line for assistance in locating a provider, whether in person or through tele-mental health.

For a new perspective on unremitting depression, read Dr. Aaronson’s newest post

For one family’s story, read about Ronnie and his wife