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). 

Retrieved from: https://www.jmcp.org/doi/pdf/10.18553/jmcp.2007.13.s6-a.2

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.

The peer-reviewed research that focuses on ketamine as an intervention for treatment-resistant depression, or as a tool in managing depression, points in a promising direction: ketamine can be an effective and viable treatment option.

But what factors contribute to making ketamine an effective tool in the treatment of depression?

Ketamine’s Dissociative & Psychedelic Properties

Ketamine’s properties make it both a dissociative and psychedelic compound. At certain doses, people can experience both the physical and psychological dissociative effects, as well as the subjective psychedelic effects.

This is a two-part experience quite unique to ketamine, and drives many of the reasons ketamine is effective in managing/treating depression.

Dissociative Properties

There is science demonstrating that the dissociative effect itself, has a direct effect on the antidepressant qualities of ketamine.

“Antidepressant effects can occur in patients who do not experience even transient dissociative effects, and vice-versa.

It is worth considering that dissociation is part of the unique effect of ketamine that is not shared by conventional antidepressants: an altered sense of self that can also lead to a new state of contentment.”

Wolfson M.D., Phil. The Ketamine Papers: Science, Therapy, and Transformation (pp. 393-394). Multidisciplinary Association for Psychedelic Studies. Kindle Edition.

Some subjective markers of dissociation, according to the CADSS scale include: 

• A feeling of moving in slow motion
• Experiencing sensations as if in a dream-like state
• A sense of being separated from the direct experiences
• An out-of-body perspective
• Feeling disconnected from the body
• Events happening at a perceived faster pace
• Disconnection from the sense of time

For someone living with depression, the felt experience of dissociation in this context can provide a respite, or the ‘breathing room’ to rest, reflect, and begin taking control again.

Psychedelic Properties

As a compliment to the dissociative effects, ketamine at certain doses can produce or give rise to an experience which also contains psychedelic properties.

“If your eyes are closed, then it’s a different visual experience. If you close your eyes even right now and actually look at what you’re seeing, it’s not just darkness or nothing—you see lights, and shapes, and colors. Most of us tend not to sit around on a daily basis with our eyes closed just watching the show, but during a ketamine infusion, you may watch the show, and it will likely be more colorful, brighter, it can have a texture to it, and you can feel like you’re travelling around in it. You’re not hallucinating—it’s really there, and it just takes on a different meaning. But this is why people sometimes describe it as psychedelic or “trippy.”

Wolfson M.D., Phil. The Ketamine Papers: Science, Therapy, and Transformation (p. 499). Multidisciplinary Association for Psychedelic Studies. Kindle Edition.

Some properties of ketamine/psychedelics include:

• Novel or altered ways of thinking or feeling, perhaps accessing alternate or mystical states of consciousness
• Visual imagery: including colors, shapes, visualizing the movement of energy, archetypal images, or watching clips of your life play back on a film real as an observer,
• New sensory patterns: including alterations in touch, smells, and physical sensations
• Increased connections in regards to memories and present circumstances

By providing a potential avenue for new insights, experiences, and connections, the ketamine experience can also provide a therapeutic compliment to the neurochemical benefits.

The dissociative and psychedelic properties of ketamine manifest themselves in the experience primarily in two ways: providing biological and phenomenological benefits, and helping generate experiential and emotional insights.

“When looking at the tools we have out there to treat depression, we have typically had to rely on the medicine to do the work. This aligns with the medical model in understanding that we take something, something happens in our mind or body, and we hopefully feel better. We are a passive participant,” Kristin Arden, Lead Clinician at Mindbloom, said. “Ketamine works in that way too, but also affords us a whole other avenue of healing potential. We are able to gain insights, perspectives, and find peace on the medicine. All in a time where our brain is primed to heal and grow thanks to the neurobiological effects of the ketamine. We can, in a way, take back a degree of self-agency in our healing process.”

Neurobiological Benefits & Experiential Insights

Biological/Neurochemical Benefits

There are a number of biological (specifically neurochemical) effects from ketamine that are helpful in treating the underlying neurobiology associated with depressive symptoms.

One of the ways depression and its symptoms manifest is through neural pathways and certain synaptic connections becoming “cemented,” promoting patterns of thinking with strong momentum carrying them. This makes depressive thoughts or feelings both routine and frequently recurring. Over time, this damages the health of the neurons themselves.

Mindbloom’s Science Director, Dr. Casey Paleos, summarizes it as such:

“The end result of all these glutamate-related neuronal changes is a brain much more predisposed to manifesting the constellation of subjective phenomena we call depression and anxiety.”

In order to address this predisposition, ketamine has 3 neurochemical benefits in particular that are beneficial:

1. Upregulating Neuronal Production: Ketamine increases the production of new neurons, supplying the brain with healthy and vital neurons, the basis for more effective and harmonious connections in the brain.
2. Upregulating Release of BDNF (brain-derived neurotrophic factor): BNDF, colloquially referred to as ‘fertilizer for the brain’ helps promote neuron growth, overall health, and ongoing maintenance. Providing both short and long-term benefits.
3. Stimulating mTOR: mTOR regulates many processes involved in cell growth and healing worn out synaptic connections, and also stimulates activity/growth in the prefrontal cortex and hippocampus, essential areas for emotional regulation.

From the biological perspective, ketamine produces a cascade of effects that are beneficial for short and long-term repair and flourishing of the cells, neurons, and synaptic connections that healthy, balanced brains need. 

These neurobiological effects create an environment primed for new programed responses to triggers, new understandings of ourselves and the world around us and emotional regulation.

The biological effects of ketamine are generally dose-dependent, and will often occur when ketamine enters the body. Although we have a great amount of science that has helped us understand how ketamine works as an antidepressant, there is still a lot to that is unknown and being actively explored.

Subjective/Experiential Benefits

Alongside its dissociative properties, at certain doses ketamine can also induce novel subjective experiences or classic psychedelic phenomenology. This sense of experience or journey can provide important insights and felt experiences that can help us manage depression in the short and long-term.

“A ketamine psychedelic experience tends to offer up the possibility for transformation of the self by isolating the mind to some extent from external sensations, altering body consciousness toward an experience of being energy without form, and by amplifying and scrambling the contents of mind in unpredictable ways—all of this generating the potentiality for changes in consciousness that may be beneficial and persistent. Coming back from a ketamine journey as a somewhat different being is quite predictable.”

Wolfson M.D., Phil. The Ketamine Papers: Science, Therapy, and Transformation (p. 646). Multidisciplinary Association for Psychedelic Studies. Kindle Edition.

There are a few ways the ketamine experience can do this:

1. Novel Insights: With dissociation comes a sense of being separate from yourself. With this perspective individuals can spot certain behavioral patterns, environmental triggers, or see how they act in a new way. These insights can catalyze short-term respite or long-term positive behavior/mood change.
2. Embodied Feelings: The ketamine experience can induce a number of embodied emotions/feelings. For those with depression, having an embodied experience of calm, joy, contentment, or elation can be a powerful reminder or positive reinforcement that these states are possible for them. This can change long term outlooks and actions.
3. Cognitive Distancing: Both during and for a brief window after a ketamine session, it’s possible that individuals may notice more ‘space’ between an external stimulus and their internal reaction to it. This space can provide the room to change behavior, remove automatic self-sabotaging habits, all of which are valuable in managing depression.

Acute Responsiveness & Long-Term Durability

Acute Responsiveness

Unlike other traditional treatment options for depression (namely psychotherapy, pharmacology, or a combination of the two), ketamine is fast-acting and acutely responsive.

Ketamine is classified as a RAAD (rapid-acting antidepressant) providing felt relief from major symptoms within hours or days, rather than weeks or months that traditional psychotherapeutic or pharmacological methods can take to demonstrate effects.

With this immediate response, it provides a foundation or “breathing room” for the patient and clinician to begin working on longer-term behavior/mood change.

Long-Term Durability

Complimentary to the acute responsiveness of ketamine are the lasting effects after a session. This is known as the “durability” of the effects.

There are a few factors that contribute to the long-term durability of ketamine therapy:

• Insights gained from the psychedelic properties can allow for long-term positive behavior/mood change with effective integration
• Insights are gained during a time the brain is primed to process these new insights thanks to things like neuroplasticity and synaptogenesis. Through integration, we work on reinforcing the new pathways and connections; helping them fire and wire together. 
• Through a series of treatments “stacked” or placed close together, we aim to build up a solid foundation of the substance in your system. This also reinforces the phenomenon of incremental and compounding improvements in baseline mood, attitude and perspective over a period of time.

Ketamine is a unique treatment in this regard, as single sessions have the potential to provide both short-term, rapid-acting relief, but also build toward long-term elevations in mood, brain health, and overall symptomatology.

These are some reasons we understand ketamine’s unique role to play in the treatment of depression, and why it is showing such promising results already. 

Given its ability to address both neurobiological and phenomenological experiences, and providing both short and long-term benefits — ketamine is uniquely positioned, and uniquely effective, to be a valuable treatment for depression.