Treatment-Resistant Depression: How Psychedelic Therapy Can Help

Medically reviewed by 
Leonardo Vando, MD
Published on 
December 1, 2020
Updated on 

Psychedelic therapy for treatment-resistant depression is an exciting research area underway in the mental health field. The ability of psychedelic compounds and therapeutic experiences to successfully treat treatment-resistant depression, and help manage its symptoms, can lead to important breakthroughs for clients who haven’t responded well to other treatment modalities.

To get a deeper understanding of why this is such an exciting and promising area of research, let’s start with a definition of what treatment-resistant depression is.

Defining Treatment-Resistant Depression (TRD)

When looking for a shared definition of what constitutes TRD in the medical and clinical community, you find it can be difficult to land on a complete, thorough definition of treatment-resistant depression. However, a common definition of TRD is defined as:

A major depressive disorder with a minimum of two prior treatment failures in which there was adequate dosing and duration of these tried and failed treatments. 

To define "treatment failure":

Nierenberg and DeCecco suggested that TRD in patients who received adequate treatment could be defined based on any of 3 criteria: 
- Failure to achieve a minimum response (e.g., less than a 25% decrease from baseline HAM-D score) 
- Failure to achieve a response (e.g., less than a 50% decrease from baseline HAM-D score)
- Failure to achieve remission (e.g., a final HAM-D score of at least 7). 

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Regarding interventions, the mental health field has different modalities that are set up to help manage and mitigate depression or depressive symptoms. The most common techniques are:

  • Psychotherapeutic - Different forms of talk therapy such as cognitive behavioral therapy (CBT), in individual or group sessions 
  • Pharmacological - Prescription of antidepressants such as: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs)
  • Procedural - Treatments such as: electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or vagal nerve stimulation
  • A program combining one or more of these

For some individuals, one of these techniques alone may work, providing a reduction in symptoms or making the condition more manageable overall. In some instances, they can offer a full remission of symptoms, resolving the condition.

In others, for example, an individual may not be responsive to non-medicine based therapeutic interventions, and may not see benefits to the methods or techniques they use. For some, an addition of a pharmacological intervention may occur which can include being prescribed one, or a combination of, different medicines by a licensed clinician.

When understanding TRD, it’s helpful to point out that there is some debate on how many failed treatment attempts are required, as well as what constitutes a failed treatment response when classifying TRD. Is it two or even four different treatment trials? Is a symptom reduction by 25% or even 75% classified as a failed response?

All of this also assumes that each attempt is administered appropriately: titration to a therapeutic dose occurred and treatment was maintained for a viable amount of time to see response.

According to the STAR*D study, a frequently referenced and pivotal study on depression and its treatments, up to a third of all individuals don’t respond to any of these, and can be classified as treatment-resistant.

Here are some relevant highlights from the STAR*D study:

"Over the course of the four levels of treatment, the theoretical cumulative remission rate was 67%"
"The likelihood of remission after two vigorous medication trials substantially decreases, and remission likely requires more complicated medication regimens for which the existing evidence base is quite thin. Thus an empirically supported definition for treatment-resistant depression seems to be two antidepressant failures."
"The finding that about two-thirds of patients may be expected to reach remission with up to four treatment attempts is encouraging for this disabling illness. Continued treatment attempts, even beyond a second treatment failure, do yield results for some patients."

Working with Treatment-Resistant Depression

If someone is classified as treatment-resistant, what options are available? There are a few avenues to take:

  • Adjust Existing Medications: Modifying variables like medication dosage, or duration of medication trial can make a difference for the client. Augmenting or adding additional medications, like ketamine, that may be complementary is also an option.
  • Try or Add New Modalities: Adding on other therapeutic modalities, like psychotherapy sessions or TMS, on top of, or in addition to, existing treatments can help an individual make progress in managing and reducing depressive symptoms.
  • Lifestyle Changes: There are factors that can complicate treatments, such as recreational drug use, potentially unhealthy lifestyle/health choices, and excess stress. Working to create a more healthy internal and external environment can create a more viable space to maximize the value of various treatment modalities.

Each individual is unique: the treatment and specific protocol that works for one person may not work for another, despite similar demographic and biological fingerprints. Working with professionals to dial in treatment protocols and giving them enough time to settle in and begin taking effect is essential before claiming treatment-resistance.

Despite best efforts by an individual and their team, there still may be those who don’t respond well or tolerate the existing medical/clinical interventions available today.

Complications in Treatment-Resistant Depression Diagnosis

The mental health field is uncovering new findings daily. There are a few factors that can present complications when diagnosing and subsequently treating treatment-resistant depression.

A few factors that can complicate the process are:

  • Incorrect Diagnosis: If an individual is misdiagnosed, this can lead to an ineffective treatment plan. As an example, if a clinician has diagnosed a person with bipolar disorder when they have unipolar depression (which can look and manifest similarly at times), they may receive a treatment that does not effectively target their symptoms.
  • Genetics: Everyone's genetic makeup is unique. There are some gene variations that can impact things such as how fast a drug is metabolized, how your body processes the medicine, or whether you may be prone to side effects from a certain drug.
  • Metabolic Factors: As noted when discussing genetics  individuals may metabolize medicines differently. This can lead to a usual therapeutic dose being too low for one person while causing severe side effects or sensitivity in another.
  • Severity: More severe symptoms of depression may require higher doses of medication or augmenting with additional medications. This increases the risk of side effects and complicates care. Also, each time we change antidepressants the risk of lower efficacy with the new medication exists as well as the risk that going back on a previously effective treatment may not be as effective again.
  • Multiple Conditions: Oftentimes, mental health conditions are intertwined. An example being the unfortunate synergy between depression and anxiety. Or, depression with a chronic pain disorder. These “comorbidities,” complicate treatment plans: we must untwine the relationship one condition may have with the other, we often are then dealing with additional medications an mitigating interactions between them
  • Environmental/Lifestyle Factors: As mentioned earlier, environmental, and lifestyle factors can impact treatment in various ways. Examples include not having access to certain medications because of health insurance, a stressful home exacerbating depressive symptoms, lack of sleep or rest inhibiting mental/physical restoration, and illicit drug use which can impact mood and interact with prescribed medications.

Psychedelic Therapy for Treatment-Resistant Depression

Until recently, the psychiatric community has been limited on new methods to treat  treatment-resistant depression. However, ketamine therapy and other psychedelic medicines have shown promising results and open pathways to new approaches to treatment .

Many clients come to Mindbloom to work through symptoms of depression. Some report a remarkable difference in their experience and outcomes when using ketamine as a healing tool when compared to attempts with previous treatment modalities.

Some clients of Mindbloom with treatment-resistant depression have experienced:

  • Major reductions in depressive symptoms
  • Complete remission of the depressive symptoms, no longer meeting criteria for an active depressive disorder
  • Lifting of mood, energy levels, attitudes, and overall outlook
  • New insights or perspectives, breakthroughs, and life-changing sessions

For a number of beneficial factors —ranging from rapid-acting antidepressant (RAAD) effects, to long-term behavioral changes— ketamine therapy and other psychedelic therapies are uniquely poised to be an asset for clinicians and clients when managing and working with treatment-resistant depression.

Where other interventions and modalities have come up short for some clients, early results demonstrate that psychedelic interventions, including ketamine therapy, are viable treatment options that show promising outcomes in clinical trials.

Psychedelic treatments may not be appropriate for everyone, but when other treatment options have failed or not provided full relief, psychedelic therapy offers another option: a potential solution to find peace, for those who need it most.


This article is for informational purposes only and is not intended to be a substitute for professional medical advice. Always talk to your doctor about the risks and benefits of any treatment. If you are in a life-threatening situation, call the National Suicide Prevention Line at +1 (800) 273-8255, call 911, or go to the nearest emergency room.

Important FDA Safety Information

Ketamine is not FDA-approved for the treatment of depression or anxiety. Learn more about off-label uses here.

Side effects of ketamine treatment may include: altered sense of time, anxiety, blurred vision, diminished ability to see/hear/feel, dry mouth, elevated blood pressure or heart rate, elevated intraocular or intracranial pressure, excitability, loss of appetite, mental confusion, nausea/vomiting, nystagmus (rapid eye movements), restlessness, slurred speech, synesthesia (a mingling of the senses).

Do not proceed with ketamine treatment if any of the following apply to you:

  • Allergic to ketamine
  • Symptoms of psychosis or mania
  • Uncontrolled high blood pressure
  • CHF or other serious heart problem
  • Severe breathing problem
  • History of elevated intraocular or intracranial pressure
  • History of hyperthyroidism
  • Other serious medical illness
  • Pregnant, nursing, or trying to become pregnant

Ketamine has been reported to produce issues including, but not limited to, those listed below. However, lasting adverse side-effects are rare when medical protocols are carefully followed.

While ketamine has not been shown to be physically addictive, it has been shown to cause moderate psychological dependency in some recreational users.

  • In rare cases, frequent, heavy users have reported increased frequency of urination, urinary incontinence, pain urinating, passing blood in the urine, or reduced bladder size
  • Ketamine may worsen problems in people with schizophrenia, severe personality disorders, or other serious mental disorders.
  • Users with a personal or family history of psychosis should be cautious using any psychoactive substance, including ketamine, and discuss potential risks with your MindBloom® clinician before proceeding with treatment.
  • The dissociative effects of ketamine may increase patient vulnerability and the risk of accidents.

To promote positive outcomes and ensure safety, follow these ketamine treatment guidelines:

  • Do not operate a vehicle (e.g., car, motorcycle, bicycle) or heavy machinery following treatment until you’ve had a full night of sleep
  • Refrain from taking benzodiazepines or stimulants for 24 hours prior to treatment
  • Continue to take antihypertensive medication as prescribed
  • Avoid hangovers or alcohol intake
  • Refrain from consuming solid foods within 3 hours prior to treatment and liquids within 1 hour prior to treatment
  • Ketamine treatment should never be conducted without a monitor present to ensure your safety

Want to Tackle Depression Yourself?

Ketamine treatment has been shown effective in treating depression, use the link below to find out if this is a fit for you.

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