Ketamine-Assisted Psychotherapy (KAP)  for Treatment-Resistant Depression: When Standard Antidepressants Aren’t Working

When one antidepressant doesn’t help, it can be frustrating. When two, three, or even four antidepressants don’t bring relief, it can be downright discouraging. Treatment-resistant depression (TRD) affects roughly one in three adults with major depressive disorder. Many of the most common antidepressant medications are called selective serotonin reuptake inhibitors (SSRIs) and target primarily serotonin neurotransmitters due to a hypothesis from the 1960s that serotonin depletion may cause depression. But for many, taking SSRIs doesn’t result in symptom relief. Approximately 30-60% of patients treated with current antidepressant drugs fail to attain remission of depressive symptoms, leading to drug resistance and hopelessness that recovery can be achieved. ¹

As it becomes more clear that the serotonergic approach to treating depression isn’t the full picture, ketamine offers new hope that more comprehensive and effective treatments for TRD are possible. At our TRIP Clinics in Hollywood and Santa Monica, our KAP protocol helps increase insight, disrupt depressive cycles, and engage the brain’s capacity for change by combining ketamine, a medication that targets glutamate neurotransmitters, with psychotherapy to create a powerful, science-backed blend of pharmacological and behavioral care.

Why Do Some People Stop Responding to Antidepressants?

When SSRIs work, they increase serotonin signaling in the brain. In some people, including many who initially benefited from the drugs, the brain may gradually adapt to these signaling changes. This process is called pharmacoresistance, in which there are changes to receptor sensitivity, inflammation pathways, and other biological factors that are still not well understood. This may lead to a reduced treatment response over time, even when SSRIs are taken as prescribed.

In these cases, switching to another SSRI does not always lead to improvement. New treatments that act on different neural systems must be considered.

That’s where ketamine comes in.

The Science Behind Ketamine’s Rapid-Acting Antidepressant Effect

Unlike SSRIs, ketamine acts on the glutamate system, specifically targeting the NMDA receptors, to enhance AMPA signaling and promote synaptic growth. This process subsequently activates brain-derived neurotrophic factor (BDNF) and regulates the mTOR pathway, both of which support neuroplasticity, which is the brain’s natural ability to reorganize and form new connections.

Ketamine is not a new drug. It was FDA-approved as an anesthetic in 1970 and is still widely used in surgical settings. Over the past decade it has become increasingly used to treat TRD and other forms of mental health challenges. The science behind its mechanism of action and efficacy is still being discovered, with new research conducted and published every year. Thus far, the research shows that ketamine can provide rapid reductions in depression symptoms including significant decreases in suicidality within 24 hours of the start of ketamine treatment², reducing the need to wait weeks for relief from SSRIs or psychotherapy alone. 

How PSI Personalizes Your Ketamine Therapy Plan

At PSI’s TRIP Clinics, all our services are designed with our patient’s safety, comfort, and individualized needs in mind. Our Hollywood TRIP Clinic, formerly known as the California Center for Psychedelic Therapy, was the first mental health center in southern California focused on psychiatric and psychological treatment using psychedelics, including ketamine. As early leaders in ketamine-assisted psychotherapy in Los Angeles, we continue to refine our approach as new science and feedback from our community emerges. TRIP Clinics  provide a supportive, medically monitored environment with innovative approaches to treatment-resistant depression (TRD) delivered by board certified physicians and licensed psychotherapists.

What to expect during KAP treatment at PSI’s TRIP Clinics:

1. Comprehensive Intake evaluation:
   Treatment starts with one of PSI’s multidisciplinary teams, including a physician or advanced practice prescribing clinician and a licensed psychotherapist, for a full intake. This includes a detailed medical and mental health history, baseline assessments, and plenty of time to get questions answered to ensure ketamine therapy is right for you.
   
   
2. Personalized treatment plan:
   By the end of the intake evaluation, a collaborative treatment plan based on clinical history, symptom profile, and personal goals will be discussed. This typically includes an initial series of eight KAP sessions over four weeks, with each treatment lasting 90 minutes.
   
   
3. During the infusion:
   A licensed and experienced psychedelic psychotherapist is present throughout each treatment to support mental health and monitor before, during and after each ketamine dose. Our treatment rooms are private, calming, and offer a range of music, comfortable couches, blankets, pillows, and eye shades. A medical professional is on site at all times to address any medical needs.
   
   
4. Integration and reflection:
   For the last part of each treatment, time is available to reflect on and synthesize experiences into meaning for daily life. These periods of integration are assisted by an experienced psychotherapist and can help to reinforce insights and sustain improvements. It’s the integration of the ketamine experience, not the presence of the ketamine itself in your body, that makes ketamine therapy so unique as a treatment for TRD.  Integration therapy is included in each treatment to support ongoing insights, neuroplasticity, and cognitive flexibility.
   
   
5. Maintenance and follow-up:
   As the initial series comes to a close, our care team reviews the overall outcomes of the treatment and discusses a maintenance plan for the months following the initial series. Ketamine is an intermittent treatment for TRD and often requires between 2-10 KAP maintenance treatments per year, though some people don’t need any and others need more as part of a more comprehensive plan including other types of antidepressants and psychotherapy. The goal of KAP maintenance is to maintain a reduction in depression over time with as little additional treatment as possible. 

Learn more about our TRIP Clinics and the TRD treatment values we embody through ongoing research, clinical excellence, and patient-centered innovation.

Evidence and Outcomes: What the Research Shows

Multiple randomized controlled trials have demonstrated ketamine’s effectiveness for major depression that doesn’t respond to medication. Notably:

• Rapid response: Many patients experience meaningful symptom relief within 24 hours.³
  
  
• Durability: A series of treatments can extend benefits and early responders are likely to be able to maintain the initial responses over time with maintenance treatment.⁴
  
  
• Research Emphasis: PSI’s clinicians draw on insights from real world data and ongoing psychedelic and mental health research to continually refine dosing strategies, integration techniques, and personalized care plans aimed at improving long-term outcomes.

Access and Availability in Los Angeles

IM ketamine therapy is an off-label treatment for depression. Other common off-label drugs are: beta blockers for anxiety, botox for migraines or TMJ and metformin for PCOS. These drugs show efficacy for the purposes listed, but were FDA approved for treatment of something else, similar to how ketamine was FDA approved as an anesthetic. As a result, insurance coverage can vary.

Some insurance plans may offer reimbursement for IM ketamine therapy for treatment-resistant depression as an out-of-network mental health benefit, while others may not cover ketamine or psychotherapy at all. PSI’s Hollywood and Santa Monica TRIP Clinics can provide a detailed receipt (“superbill”) listing procedure codes, diagnosis, and fees, which then can be submitted for potential reimbursement.

PSI’s care coordinators will help you explore payment options, reimbursement possibilities, and eligibility for ongoing clinical trials that may offset treatment costs.

Schedule a TRD consultation in Santa Monica
Schedule a TRD consultation in Hollywood

A New Path Forward for Depression Care

For those with depression that hasn’t responded to traditional medications, ketamine-assisted psychotherapy offers an evidence-informed path toward relief. By targeting the brain’s glutamate system and reopening pathways for neuroplasticity, ketamine supports both rapid and sustained improvements in mood and function.

If you’re ready to explore how ketamine therapy can help you or your community finally feel relief and begin to thrive, despite treatment resistant depression, schedule a consultation at our Santa Monica or Hollywood TRIP Clinic today.

References

1. Alqahtani AM, Kumarappan C, Kumar V, Srinivasan R, Krishnaraju V. Understanding the genetic aspects of resistance to antidepressants treatment. Eur Rev Med Pharmacol Sci. 2020 Jul;24(14):7784–7795. doi:10.26355/eurrev_202007_22281. PMID: 32744705.

2. Keilp JG, Madden SP, Marver JE, Frawley A, Burke AK, Herzallah MM, Gluck M, Mann JJ, Grunebaum MF. Effects of ketamine versus midazolam on neurocognition at 24 hours in depressed patients with suicidal ideation. J Clin Psychiatry. 2021 Nov 2;82(6):21m13921.

3. Vestring S, Galuba V, Kern E, Voita S, Berens F, Nasiri D, Domschke K, Normann C. Ketamine in multiple treatment-resistant depressed inpatients: A naturalistic cohort study. J Affect Disord. 2024 Apr 1;350:895–899.

‍

FAQs

1. How effective is ketamine for treatment-resistant depression?
Studies show that about 50–70% of patients with treatment resistant depression experience improvement after a series of ketamine treatments. 

2. How long do results last?
Ketamine is an intermittent treatment that requires ongoing treatments to maintain the benefits. Most people find that the duration of the results increase as the initial series progresses. Many patients feel relief for weeks or months and require between 2-10 maintenance treatments per year to sustain those benefits over time.  Ongoing psychotherapy is indicated to help sustain antidepressant benefits.

3. Is ketamine safe long-term?
Ketamine has long been listed on the World Health Organization’s list of essential medications because its medical benefits far outweigh its psychological and physiological risks. When administered in a clinical setting, ketamine has a strong safety record. PSI does not prescribe ketamine for at-home use or offer access to the drug outside of administration by a licensed prescriber and a session with a licensed psychotherapist. Our clinicians care about our patient’s overall wellbeing and psychological health and continually monitor for signs of dependence or misuse.  

5. What happens during a session?
Our website walks through what to expect in a session here. We prioritize comfortable, medically supported mental health care at our TRIP Clinics.  

6. Where can I receive treatment in Los Angeles?
You can receive treatment at PSI’s two flagship treatment centers: TRIP Clinic Santa Monica and TRIP Clinic Hollywood, which both specialize in psychedelic medicine including person-centered ketamine-assisted psychotherapy with compassionate, collaborative medical and psychological support.