Treatment options for treatment-resistant depression

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⚡ Quick Summary

  • Treatment resistant depression (TRD) is depression that persists after at least two different courses of treatment.

  • Despite the name, there are still many treatment options for TRD, mainly divided between psychedelic medicine (ie. ketamine, psilocybin, MDMA, etc) and interventional psychiatry (ie. TMS, ECT, vagus nerve stimulation).

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What is treatment resistant depression?

See our wiki on TRD for background information.

Treatment resistant depression (TRD) is characterized by a lack of symptom improvement despite treatment with a minimum of two different courses of antidepressants. After a patient fails two antidepressants, it is likely they will fail subsequent treatments with traditional antidepressants and combinations thereof. Luckily, there are a number of other effective treatments that can help TRD patients. This article will first briefly outline the treatment algorithm of major depressive disorder (MDD) to provide some context before discussing the treatment algorithms and options for TRD.

Background and definitions

Depression rating scales are a way for clinicians to monitor patient progress by repeatedly measuring severity of symptoms with a standardized questionnaire. These scales were designed to reflect a patient’s severity of depression in an objective manner, so clinicians do not need to rely purely on subjective questions that might not accurately reflect the patient’s clinical status. There are a large number of scales, and three commonly used scales include:

  • Patient Health Questionnaire-9 (PHQ-9)
  • Hamilton Rating Scale for Depression (HRS)
  • Montgomery-Asberg Depression Rating Scale (MADRAS)

Here are some terms that are commonly used to describe patient responses to treatments. These definitions are not standardized, though most clinical studies and articles follow these guidelines. They are defined in reference to the magnitude of improvement from baseline on a depression rating scale (whichever scale is chosen in the clinical study):

  • No response: improvement <25%
  • Partial response: improvement between 25-49%
  • Response: improvement at least 50% but less than the threshold for remission
  • Remission: a score on the chosen depression rating scale less than, or equal to, a specific cutoff that defines the normal range of mental wellness. Each scale has a predetermined cutoff for remission, usually 7 or less for HRS and MADRAS and less than 5 for the PHQ-9.

There are five major classes of antidepressants [Rxlist]. These are:

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs)
  • Tricyclic antidepressants (TCAs)
  • Monoamine oxidase inhibitors (MAOIs)
  • Atypical agents

Some also characterize serotonin modulators as a sixth class of antidepressant. TCAs and MAOIs are considered older, first-generation antidepressants while the others are newer, second-generation antidepressants.

Summary of the treatment algorithm for MDD

There are many options available for the treatment of depression. The two overarching categories of treatment include pharmacotherapy (an antidepressant medication) and psychotherapy (“talk therapy”). The initial treatment of MDD may involve either or both forms of therapy. Most commonly, physicians will prescribe an antidepressant (without psychotherapy) as the initial treatment, though this differs based on physician and patient preferences, comorbidities, cost considerations, and other factors.

There is no consensus treatment algorithm for MDD in terms of which specific antidepressants to prescribe and in what order, though there are various existing guidelines and recommendations. It is most common for a physician to prescribe an SSRI first; these are the most widely prescribed class of antidepressant and include brands like Prozac, Zoloft, Celexa, Lexapro, and Paxil, among others. However, multiple studies have suggested that different types of antidepressants are roughly the same in terms of efficacy [American Psychiatric Association; Simon et al. 2020; Gartlehner et al. 2011; Malhi et al. 2013; Lester et al. 2012]. SSRIs are a common initial choice because of their more favorable side effect profile compared to other classes of antidepressants.

Regardless of which antidepressant the physician chooses as the initial treatment, the patient usually waits 4-12 weeks to see if the treatment will work. This is because antidepressants exhibit a time lag before they take effect (though some patients may feel better much faster). After four weeks the physician may decide to adjust the treatment if there has been little symptom relief. Approximately 70% of patients will not demonstrate remission [Gibbons et al. 2012]. Then, the physician must make a decision on the next step. There are a few options:

  • Increase the dose (if possible) of the current treatment
  • Add psychotherapy
  • Change the medication
  • Add another medication known as an augmenting agent (often another antidepressant or other psychiatric medication)

While there are some studies comparing these options, there is generally no accepted gold-standard treatment algorithm, nor is there a data-driven approach to optimize the right treatment pathway for a given patient. There are a very large number of combinations the provider could use in choosing a medication and dose, and deciding whether to add psychotherapy or an augmentation agent. As a result, treatment plans may come down to trial-and-error, with the patient suffering several weeks during each trial just to ascertain whether the treatment is working.

Research has shown that if a patient fails the first two antidepressants, it is likely they will not respond or achieve remission for any further combination of antidepressant, augmentation, or psychotherapy [Rush 2009]. After failing two antidepressants, a patient is considered to have TRD.

hot air balloons in the sky

Treatment options for TRD

Once a patient has failed two antidepressants, it is useful to reassess the patient’s symptoms and medical history and confirm the diagnosis of TRD. It is possible that the patient actually has a different psychiatric disorder such as bipolar disorder, substance-induced depressive disorder, or complicated grief, and therefore the treatments for MDD have been less effective. MDD is often associated with psychiatric comorbidities, i.e. psychiatric disorders that can present alongside MDD. Many MDD patients also suffer from anxiety, for example. If the patient does have a psychiatric comorbidity, the physician may opt to treat that first, instead of focusing on the depression. This is because the depression could be worsened by the other condition, and treating the other condition could lead to a better response to antidepressants.

After confirming 1) the diagnosis of TRD is correct, 2) the depression is not secondary to another illness, 3) the two initial treatments with antidepressants (possibly along with psychotherapy) both failed, and 4) the patient has maintained adherence to their medication schedule, the physician has a number of strategies to treat TRD:

  1. Augmentation (adding a treatment to the antidepressant the patient is already on). Augmentation can be performed with: A) Medication (e.g. another antidepressant, lithium, second-generation antipsychotic), B) Psychotherapy
  2. Switching the antidepressant
  3. Ketamine and esketamine
  4. Transcranial magnetic stimulation (TMS)
  5. Electroconvulsive therapy (ECT)
  6. Vagus nerve stimulation
  7. Deep brain stimulation
  8. A number of other options and combinations
  9. (Eventually, next-generation psychedelic medicines such as psilocybin-assisted psychotherapy. These are not FDA-approved yet, but are moving through clinical trials and will likely begin entering the market in a few years.)

As mentioned earlier, once a patient is determined to have TRD it is unlikely for augmentation or a switch in antidepressant (strategies #1-2 above) to result in response or remission. However, some psychiatrists and patients still prefer to continue trying strategies #1 and 2 with different combinations. As a result, some TRD patients actually end up trying various treatments without feeling better for years, sometimes even a decade or more. There are simply so many possible combinations of antidepressant, dosage, psychotherapy, and augmentation that a patient would never be able to exhaust all possible combinations. Regrettably, patients may continue to suffer intensely through this period of trial and error.

Fortunately, strategies #3-7 often work for TRD patients. These alternatives should be strongly considered for patients who are known to have TRD (but each patient should work with their provider to find the best strategy for them). Since it may be unlikely that strategies #1 and 2 will benefit many of these patients, suffering and monetary cost can be significantly reduced by jumping directly to strategies #3-7. These strategies can be divided into two buckets:

  • Psychedelic medicine – medicines using compounds that are natural psychedelics (hallucinogens) or chemically based off of psychedelics.
    • Ketamine – Small molecule drug that is FDA-approved for anesthesia and widely used off-label for TRD. Ketamine can be given for TRD in two basic models: intravenous (IV) infusion and ketamine-assisted psychotherapy. The former is simply a pharmacologic approach. The latter combines the medication with psychotherapy, and the ketamine can be given through various routes including under the tongue or injection into the muscle. Patients generally receive treatment once or twice a week for several weeks with maintenance over time.
    • Esketamine – one form of the ketamine molecule that was FDA-approved for TRD in 2019. Intranasal delivery. Generally receive treatment once or twice a week for several weeks.
    • Next-generation psychedelic medicines such as psilocybin- and MDMA-assisted psychotherapy, and many more psychedelic-inspired molecules currently being researched. MDMA is in Phase 3 clinical trials for PTSD and has received both Breakthrough Status and Expanded Access from the FDA. Psilocybin is in Phase 2 clinical trials for TRD and has also received Breakthrough Status from the FDA.
  • Interventional psychiatry – a subfield of psychiatry that focuses on brain stimulation (also known as neuromodulation).
    • TMS – FDA-approved treatment that involves the non-invasive repeated application of brief magnetic pulses to the brain. Safe, non-invasive outpatient procedure. An example of a general protocol is a roughly 40 min stimulation treatment once a day, 5 days a week, for 6 or more weeks. There are different types of TMS.
    • ECT – FDA-approved treatment that uses electrical stimulation to induce a controlled, generalized seizure while the patient is under general anesthesia. An example of a general protocol is a 60 second seizure and 10 minute unconscious anesthetized period, 3 times a week, for 4 to 20 treatments
    • Vagus nerve stimulation – FDA-approved treatment involving surgical implantation of a device (similar to a pacemaker) attached to a wire connecting the vagus nerve in the neck. Implantation of the device requires surgery.
    • Deep brain stimulation – FDA-approved for other conditions (e.g. Parkinson’s disease, OCD) and used off-label for TRD. Invasive procedure involving neurosurgery and implantation of brain electrodes connected to a pulse generator to directly modulate brain circuits and activity.

view over the fog

A detailed description of each of these treatments are given on other pages of the Official Osmind Wiki. There is no standard treatment algorithm for physicians to prioritize or choose these various treatment options. While many studies have demonstrated safety and efficacy for each of these options, there have been few high-fidelity studies that compare them head-to-head, and there are pros and cons to each approach. As a result, there are no compelling data to suggest the use of any particular treatment first. Physicians and patients generally work together to pick based off of several factors:

  • Patient preference for side effects
  • Cost and insurance coverage
  • Patient preference for treatment modality (e.g. medication versus non-invasive procedure versus invasive procedure)
  • Convenience
  • Presence of medical or psychiatric conditions that may make certain treatments inappropriate

Vagus nerve stimulation and deep brain stimulation are widely reserved as last resorts due to their invasive nature. ECT is often not viewed as the best initial option because of the suboptimal side effects and the need for the patient to undergo general anesthesia. However, ECT can be an initial option if the patient is acutely suicidal.

One general pattern that might be followed for TRD (without psychosis or acute suicidality, and not secondary to another psychiatric or medical illness) is shown below – as mentioned above, there is no rigorous evidence-based way to create a treatment algorithm based on the data that are currently available. It is important to note that the pattern provided below is general and subject to change due to numerous patient and provider specific factors. All patients should work with their physician to determine what makes the most sense for their particular situation.

Each increasing number indicates the prior therapy did not result in remission
+/- psychotherapy depending on insurance for every step

Patient starts with MDD

  1. lifestyle modifications
  2. antidepressant medication A
  3. antidepressant medication B

Patient now has TRD

  1. antidepressant medication B + augmentation medication
    *Some providers will skip step 4, while others will try step 4 many times with various combinations
  2. ketamine or esketamine
  3. TMS
  4. ECT
  5. Implanted vagal nerve stimulator
  6. deep brain stimulation

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American Psychiatric Association: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition, 2010. (Accessed on April 17, 2012).

Gartlehner G, Hansen RA, Morgan LC, et al. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med 2011; 155:772.

Gibbons RD, Hur K, Brown CH, et al. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012; 69:572.

Lester H, Gilbody S. Choosing a second generation antidepressant for treatment of major depressive disorder. BMJ 2012; 344:e1014.

Malhi GS, Hitching R, Berk M, et al. Pharmacological management of unipolar depression. Acta Psychiatr Scand Suppl 2013; :6.

Rush et al. CNS Drugs. 2009 Aug;23(8):627-47. doi: 10.2165/00023210-200923080-00001.

RxList: The Comprehensive List of Antidepressants

Simon GE, Perlis RH. Personalized medicine for depression: can we match patients with treatments? Am J Psychiatry 2010; 167:1445.