Ketamine Therapy for the Treatment of Bipolar Depression: Three Approaches

Racemic ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist with a fast onset, short duration, and both dissociative and hallucinogenic effects. It is used off-label to treat depression, anxiety, PTSD, OCD, chronic pain, and other disorders, with or without psychotherapy. Ketamine’s range of administration routes and dosage options make it a versatile treatment, but despite this flexibility, most research on ketamine therapy for treating depression has focused on intravenous delivery routes with no psychotherapeutic component.

A study led by Raquel Bennett, PsyD, a psychologist, ketamine specialist, and founder of KRIYA Institute based in California, highlights the versatility of ketamine therapy by outlining three distinct paradigms for using the substance to treat bipolar depression.¹ The three approaches – biochemical, psychotherapeutic, and psychedelic – are described using composite clinical vignettes and show examples of what is possible with ketamine treatment. In each vignette, the authors describe the reasons for why each dosage, frequency, and route of administration were selected based on the patient’s background and current situation.

Biochemical

In the biochemical approach, the patient receives sub-psychedelic doses of ketamine and the dissociative and/or hallucinogenic reactions are treated as unwanted side effects. The authors support an asynchronous approach to psychotherapy with the biochemical approach (more on this below), noting their concern that some ketamine providers offer infusions as a stand-alone treatment.

According to Dr. Bennett, in the biochemical paradigm, “ketamine can be useful to rapidly treat the symptoms of an acute organic depressive episode.”

Psychotherapeutic

The psychotherapeutic paradigm also uses low doses of ketamine as a “lubricant” during the synchronous process of psychotherapy “to deepen and consolidate psychological insights,” explained Dr. Bennett. Patients are encouraged to explore self-reflection, and the authors noted in their paper that this approach works well for patients who have a well-established relationship with their therapist.

Psychedelic

Lastly, the psychedelic approach uses higher doses of ketamine to take advantage of the drug’s dissociative and psychedelic effects with the goal of inducing an altered state of consciousness. Specialized psychological support is required before, during, and after this type of experience, the authors wrote.

Dr. Bennett offered other examples of ways that ketamine can be helpful therapeutically. “Ketamine can be used as a tool for spiritual exploration, to help patients grapple with making meaning while living with chronic illness,” she said. “Ketamine can also be used as part of a maintenance regimen for long-term stability and wellness.”

She shared that the three paradigms described in the study could be applied to any “visionary medicine,” which includes psychedelic medicines and ketamine when used in psychedelic doses. Dr. Bennett pointed out, however, that clinicians, “need to be attentive” to the following questions:

• What is the medicine doing at a biological or cellular level?

• Does anything open up at the relational level?

• Is there anything informative to be gleaned at the psychospiritual level?

The study concluded that the three models of ketamine treatment can be applied to psychiatric disorders beyond bipolar depression. “I chose to write about this subject because it is one of my professional interests, and not much has been written about the use of ketamine with this population, but actually the main ideas could be applied to any mental health indication,” Dr. Bennett said.

Ketamine’s versatility offers many treatment possibilities, but how can clinicians decide the best path forward for each patient? The study’s three paradigms describe different doses, frequencies, and intentions for ketamine treatment to patients at different points in their illness. For Dr. Bennett, evaluating these factors can create highly individualized treatment.

“The skillful ketamine clinician recognizes that there is a spectrum of ketamine services – including multiple options for route, dose, frequency, and relational context – and matches the treatment to the patient’s individual needs,” she said. “I think that all of the different approaches to ketamine treatment are valid and should continue to be utilized. There is no single right way to work with ketamine.”

When creating her patients’ treatment plans, Dr. Bennett works closely with other medical professionals and combines their input with her clinical experience and observation. She considers “a variety of factors, including the patient’s immediate concerns and the full diagnostic picture; their current medication regimen; the depth of their relationship with the clinical team; their medical health status; and their past experiences and level of interest with respect to altered states of consciousness.”

Proper training for clinicians in ketamine treatment is essential, Dr. Bennett added. “The basics seem deceptively simple, but actually there is a lot to know. Clinicians who want to add ketamine services to their practices really need to take a comprehensive training on working with this specific medicine.”

In the study, Dr. Bennett’s team pointed out that whether psychotherapy is asynchronous or synchronous with ketamine treatment is an important distinction, but not one that is always clearly defined in research papers. Dr. Bennett says that term “concurrent psychotherapy” is confusing and ambiguous because it does not indicate whether a therapist was present in the room at the time of the ketamine administration. “As the field evolves, we need more specific language in order to communicate clearly,” she said.

The study’s three paradigms discuss the timing of psychotherapy with ketamine administration.

“If you want to offer true ketamine-facilitated psychotherapy, the psychotherapy has to be synchronous with the ketamine administration,” Dr. Bennett said. “Further, this approach works best when the ketamine is offered within the context of an ongoing therapy relationship, and where the ketamine dose is low enough for the patient to be able to engage in meaningful dialogue.”

In the case of a psychedelic ketamine journey, Dr. Bennett explained, the patient may be silent during the session, or they may be talking in a very non-linear way, and it is very important for the psychedelic journeyer to feel emotionally safe and supported throughout. “However, the bulk of the psychotherapy in the psychedelic paradigm actually takes place before and after the ketamine journey,” she said.

It is possible that a person undergoing ketamine treatment will not want or have access to synchronous psychotherapy. Dr. Bennett pointed out, “It appears that ketamine administration opens up a neuroplastic window (which is characterized by dendritic sprouting) that last about two and half days for most people. Certain kinds of learning appear to be enhanced in this window, which opens the door for asynchronous psychotherapy to be utilized.”

It is important to understand that ketamine does not work well as a stand-alone treatment, Dr. Bennett said. “The patients who stay well over time are actually using multiple modalities including psychotherapy, conventional oral medication, exercise, sleep schedule, mindfulness practices, and ketamine together. I am concerned that clinicians are creating ketamine addicts when they offer ketamine products alone.”

Something else to consider when using a “visionary medicine” such as ketamine is that “many people who have a hereditary illness grapple with feelings of defectiveness, as if they were born with something wrong with them from the start,” Dr. Bennett added, adding that ketamine can be helpful for these patients in a way that conventional medications cannot.

“When used correctly, psychedelic medicines invite an exploration of existential issues, such as, ‘Who am I at the core of my being? What can be learned from this challenge?’ This is arduous work, and it can be very meaningful,” she said.

• Kriya Ketamine Research Institute’s Ethical Guidelines for Ketamine Clinicians

• Ketamine Use in Psychedelic-Assisted Therapy. Psycom Pro. 2022.

• Op-Ed: Mind the Ketamine Education Gap — Better training can prevent adverse outcomes in psychiatric patients. Raquel Bennett, PsyD, and Christian Yavorsky, PhD. Medpage Today. 2021.

• Psy-Q: Ketamine and Esketamine Safety for Treatment-Resistant Depression. Psycom Pro. 2022.

• The Return of Personal Analysis: Clinicians Share Own Ketamine Experiences. Psycom Pro. 2022.