What is Treatment-Resistant Depression?

Updated on November 2, 2021

Depression is one of the most common mental illnesses that can seriously impact daily life. For most individuals with depression, regular therapy, antidepressant medication, or a combination of the two are an effective treatment, and they see substantial symptom relief. However, for some patients with depression, these standard treatment options don’t alleviate symptoms. This is known as treatment-resistant depression.

This might seem like an uncommon ailment, but most forms of depression are resistant to some types of treatment. It’s common for patients with depression to try multiple treatment forms before finding the one that works for them. Up to one-third of adults with major depression continue to have serious symptoms even after trying two or more antidepressants. Approximately 10 to 15% of patients are completely resistant to all antidepressants.

It can be difficult to identify treatment-resistant depression; sometimes symptoms will resolve for a short time period before returning, only some symptoms will respond to treatment, or symptoms will lessen in severity but never fully resolve.

What causes treatment-resistant depression?

Researchers are actively looking into the causes of TRD; the answers are not clear, but some of the most common suggested causes include:

  • Misdiagnosis: An incorrect diagnosis of depression may lead an individual to believe they have treatment-resistant depression. They may be dealing with a different condition that shows similar symptoms to major depression, such as bipolar disorder. There also may be confounding conditions that make a diagnosis more complicated.
  • Metabolic disorders: Abnormalities in metabolism and nutritional deficiencies can impact an individual’s ability to respond to treatment.
  • Genetics: Researchers have yet to identify specific genetic biomarkers for TRD but there are some genetically inherited characteristics that may make individuals more resistant to medication.

Options for treatment-resistant depression

Once TRD is diagnosed, doctors should try a different approach to treatment. Typically, patients will try a different type of medication, new combinations of medications, and different dosages to attempt to find a treatment plan that works. It’s also important to consider CBT (cognitive behavioral therapy) if this isn’t already ongoing. Changing to a new therapist can sometimes have a positive impact on treatment-resistant depression.

There are also two relatively new treatment options offering promise for individuals with treatment-resistant depression: TMS and ketamine therapy.


Transcranial magnetic stimulation, or TMS, is a non-invasive process that involves administering magnetic pulses onto the scalp in order to activate neurons in a specified area of the brain associated with depression. TMS was first developed in 1985 and has been used since then as a tool in clinical trials for measuring brain activity. Its potential to treat depression has recently been discovered, and it is an extremely safe and low-risk treatment option, gaining FDA approval in 2008.

According to TMS & Brain Health, an esteemed TMS clinic, over 60% of patients see symptom relief shortly after beginning treatment, and as many as 40% see complete symptom remission. Not only that, but TMS has the potential to offer symptom relief that lasts beyond the end of the treatment period, an extremely promising alternative to relying on an antidepressant medication forever. Patients attend TMS sessions five days a week for 4 to 6 weeks, and additional sessions can be scheduled afterwards if needed. The risks of TMS are low, the most commonly reported side effects include a slight headache that dissipates shortly after treatment; TMS is not recommended for those with metal implants or a preexisting risk of seizure.


Ketamine has been used in the medical field since its discovery in 1956. Originally used as an anesthetic, ketamine is now administered at much lower doses as a treatment for depression. There are two main forms of ketamine treatment: intravenous (IV) and the esketamine nasal spray, which is now FDA-approved. Both forms of ketamine treatment are extremely safe, and show promising results, similarly to TMS. Ketamine treatment is administered a few times a week for 2 to 3 weeks.

Over half of patients see symptom relief within 5 hours of the first dose, and many patients continue to experience symptom alleviation for weeks or months after the treatment period has concluded. The most common reported side effects of ketamine therapy are a slight dizziness or lightheadedness during treatment, and a general feeling of drowsiness in the hours following a treatment session.

The right treatment for depression is different for every individual, but there are many options available for treatment-resistant depression. Any doctor or clinic should work with you to create an individualized treatment plan that suits your needs.

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