RESEARCH IN POPULATIONS THAT MAY BENEFIT FROM KAP
TREATMENT RESISTANT DEPRESSION
“Shortcomings in the effectiveness of antidepressant treatments contributes to the enormous public health burden of depression. While antidepressants such as SSRIs can be helpful for some people with depression, improvement is slow among eventual responders, and many patients relapse after having achieved a response. Further, subgroups of depressed patients, particularly those with bipolar disorder, respond poorly to traditional antidepressants, and they are treated predominately with alternative treatments.” (Duman et al., 2016; Krystal et al., 2013).
“While traditional antidepressants take weeks to kick in and side effects can be disruptive to the patient’s quality of life, even the most severely depressed patients may begin to respond to ketamine as early as a few hours after administration. Researchers also suspect it could help build a more resilient brain in the long-term, due to an increase in BDNF (brain derived neurotrophic factor) /neuronal growth.” (The Past, Present and Future of Using Ketamine to Treat Depression | Science| Smithsonian Magazine)
“Yale School of Medicine published the first randomized controlled trial to demonstrate ketamine’s antidepressant effects in 2000. ‘Led by John Krystal, now the chair of the school’s psychiatry department, the researchers showed that a single subanesthetic dose (less than what would be given for anesthesia) of ketamine improved depression—and in some cases led to a near complete recovery—in less than 24 hours.”(The Past, Present and Future of Using Ketamine to Treat Depression | Science| Smithsonian Magazine)
“Researchers have a good sense of where ketamine first binds in the higher brain centers to affect cognitive and emotional functioning. But, as with many drugs, the specific mechanisms by which it exerts its effects remain more mysterious. Researchers also think ketamine may be able to reverse the damage to the connections between brain cells caused by chronic stress. This may be why its antidepressant effects seem to last longer over consecutive doses, and suggests that it could help protect against depression relapse.” (The Past, Present and Future of Using Ketamine to Treat Depression | Science| Smithsonian Magazine)
“In 2006, the National Institute of Mental Health concluded that a single intravenous dose of ketamine had rapid antidepressant effects. Around three hundred clinical trials have since been held; the broad consensus is that ketamine relieves symptoms of depression for a period that can last days or weeks, during which time talk therapy often proves more effective than normal.” (Ketamine Therapy Is Going Mainstream. Are We Ready? | The New Yorker)
“Through a rigorous literature review, seventeen articles including 603 participants were identified. From available KAP publications, it is apparent that combined treatments can, in specific circumstances, initiate and prolong clinically significant reductions in pain, anxiety, and depressive symptoms, while encouraging rapport and treatment engagement, and promoting abstinence in patients addicted to other substances. Despite much variance in how KAP is applied (route of ketamine administration, ketamine dosage/frequency, psychotherapy modality, overall treatment length), these findings suggest psychotherapy, provided before, during, and following ketamine sessions, can maximize and prolong benefits.” (Drozdz et al., 2022)
OBSESSIVE COMPULSIVE DISORDER (OCD)
The World Health Organization ranks OCD as one of the 10 most handicapping conditions by lost income and decreased quality of life. People with OCD deal with recurring, intrusive thoughts (obsessions) and repetitive behaviors (compulsions) and often feel there is no escape. Available pharmacological treatments (selective serotonin reuptake inhibitors or SSRIs) are not fast-acting, rarely produce complete symptom remission and take 2–3 months to produce meaningful symptom relief. The gold standard for behavioral therapies is exposure and response prevention (ERP) and can be very challenging for patients to sustain and see improvement in symptoms. With medication, high SRI doses are required with increased side effect burden, and ~30–40% of OCD patients remain refractory to these treatments.
Increasing evidence indicates that disruptions in glutamate signaling may play a role in OCD symptoms. Pioneering human studies have shown that low-dose ketamine, which acts on brain glutamate receptor pathways (among others), has rapid, robust therapeutic effects in depression and other disorders. A randomized controlled clinical trial comparing a single low-dose intravenous ketamine to placebo in OCD patients showed ketamine’s therapeutic effect was rapid (within hours), and half those who received the drug reported remarkable OCD symptom relief (lasting up to 7 days).(Davis et al., 2021)
A recent study used the SAPAP3 knockout (KO) mouse model of compulsive grooming to probe mechanisms underlying ketamine’s therapeutic effect on OCD-like behaviors in mice. “Here we recapitulate the fast-acting therapeutic effect of ketamine on compulsive behavior, and show that ketamine increases activity of dorsomedial prefrontal neurons projecting to the dorsomedial striatum in KO mice. Optogenetically mimicking this increase in fronto-striatal activity reduced compulsive grooming behavior in KO mice. Conversely, inhibiting this circuit in wild-type mice increased grooming. Finally, we demonstrate that ketamine blocks the exacerbation of grooming in KO mice caused by optogenetically inhibiting frontostriatal activity”. (Davis et al., 2021)
MIGRAINES/CHRONIC PAIN
While there is limited research on the use of KAP specifically for migraines, some studies have examined its potential as a treatment for chronic pain, which overlaps with migraine symptoms and pathology. Because ketamine is a non-competitive antagonist of the NMDA receptor, it is thought to be responsible for many of its effects in acute and chronic pain, though multiple other mechanisms of action contribute. Ketamine has been recommended as an adjunct to opioids to improve analgesia and reduce overall opioid consumption. It has also been shown to produce short- and medium-term pain relief in complex regional pain syndrome, a chronic pain condition recently categorized as “nociplastic” pain. “Nociplastic pain refers to disorders that involve altered pain processing but do not conform to the nociceptive pain definition and lack a distinct nerve injury that would qualify them as neuropathic pain.”(Mojica et al., 2021)
ALCOHOL USE DISORDER
There is growing interest in the potential use of KAP as a treatment for alcohol use disorder (AUD), and several studies have investigated this approach.
Mixed Mental Health Diagnoses and Substance Use Disorders (Dore et al) surveyed 235 patients with a wide range of psychological and substance use related disorders (MDD, PTSD, ADHD, GAD, BPD, SUD, OCD) in three private psychiatric practices in Northern California and collected data from their KAP treatments. Patients were started on SL ketamine in the office and then adjusted dosage for home-use.
Afterwards, the clients received Intramuscular ketamine in-office in a safe and secure environment and received guided psychotherapy. Two therapists were present during the in office KAP session(s), which lasted approximately 3 hours. The clients were then prescribed a low dose sublingual (SL) lozenge, so they could replicate their medicine session at home, often unsupervised. Patients were given instructions for SL ketamine dosing, and told not to exceed more than 6 at home sessions over a two-week period.
KAP sessions were held in the office approximately 2 weeks apart, where psychotherapy was offered concurrently with IM (intramuscular) ketamine. The frequency of psychotherapy was determined based on patient diagnosis and the severity of presenting difficulties, with more symptomatic clients receiving a higher frequency of sessions.
Hamilton Anxiety Scale (HAMA) and the Beck Depression Inventory (BDI) showed significant decreases in symptoms. The most significant improvements were seen in those with developmental trauma (complex PTSD), severe depression, and in those who received more ketamine-assisted psychotherapy sessions. (Drozdz et al., 2022) This is optimistic in that these are often the most difficult and confounding cases that don’t respond to other treatments.
There is further exploration and analysis in evaluating whether “mystical-type” effects of ketamine are critical for clinical efficacy in alcohol-dependent individuals. In this secondary analysis, we determine if a subset of the psychoactive effects of ketamine, the so-called mystical-type experience, mediates the effect of ketamine, when combined with motivational enhancement therapy, on at-risk drinking behavior in alcohol-dependent individuals interested in treatment.
Forty alcohol dependent adults were randomized to either a 52-minute infusion of ketamine or midazolam (Versed), which they received on their designated quit-day during the second week of a five-week motivational enhancement therapy regimen. Psychoactive effects were assessed following the infusion, and alcohol use was monitored for the subsequent 3 weeks at each twice-weekly visit.
We found that ketamine leads to significantly greater mystical-type effects (by Hood Mysticism Scale) and dissociation (by Clinician Administered Dissociative States Scale) compared to the active control. Ketamine also led to significant reduction in at-risk drinking. The Hood Mysticism Scale, but not Clinician Administered Dissociative States Scale score, was found to mediate the effect of ketamine on drinking behavior. (Rothberg et al., 2021)
This trial adds evidence to the literature on the importance of mystical-type experiences in addiction treatment. Future research should continue to investigate the relationship between the psychoactive effects of psychedelic therapeutics and clinical outcomes for other substance use and mental health disorders. (Rothberg et al., 2021) Overall, the available evidence suggests that KAP may have potential as a treatment for AUD, although further research is needed to fully understand its safety and efficacy in this context.
BIPOLAR DISORDER
“Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches" by Raquel Bennett, Phd (et. all) reviews the potential use of ketamine in the treatment of bipolar depression. The authors discuss the challenges of treating bipolar depression and explore the biochemical effects of ketamine, including its rapid and long-lasting effects on glutamate neurotransmission, as well as its effects on other neurotransmitter systems. They discuss the potential mechanisms by which ketamine may have antidepressant effects, including the role of neuroplasticity and the activation of the mTOR pathway.
Ketamine treatment may be helpful in addressing the unmet needs of patients who are living with bipolar disorder. Scientific studies have demonstrated that racemic ketamine is clinically effective in reducing the symptoms of bipolar depression. Similar to treatment resistant depression patients, It works rapidly, often taking effect in a matter of minutes. It is generally well tolerated and has a short half-life, which translates into fewer side effects than traditional antidepressant medications. Most of the existing research to date on the use of racemic ketamine for depression (unipolar and bipolar) has looked at a sub-psychedelic dose of ketamine given by infusion as a stand-alone treatment, without concurrent psychotherapy. (Bennett et al., 2022)
The authors also examine the use of ketamine in psychotherapy, including its potential to enhance the therapeutic relationship and facilitate emotional processing. They discuss the potential use of ketamine in the context of a variety of psychotherapeutic approaches, including cognitive-behavioral therapy, mindfulness-based therapy, and psychodynamic therapy.
The authors also explore the use of ketamine in psychedelic therapy, including the potential for ketamine-assisted psychotherapy to facilitate profound emotional experiences and enhance therapeutic outcomes. They discuss the potential benefits and risks of using ketamine in the context of a psychedelic experience, including the potential for adverse psychological reactions.
The authors conclude that while there is still much to learn about the long-term safety and efficacy of ketamine in the treatment of bipolar depression, the available evidence suggests that it may be a promising treatment option. They suggest that a multimodal approach that combines ketamine with psychotherapy or psychedelic therapy may be the most effective way to treat bipolar depression with ketamine.
Overall, the article provides a comprehensive overview of the potential use of ketamine in the treatment of bipolar depression, considering both the biochemical and psychological mechanisms of action, as well as the potential benefits and risks of using ketamine in different therapeutic contexts.
The main takeaway of the comparison of various paradigms of KAP suggests that a patient who receives ketamine in the psychedelic dose range, benefits from the inherent biochemical effects of the medicine and ALSO receives substantial psychotherapeutic support before, during, and after the medicine session will have the most success with treatment.
One of the challenges in ketamine treatment is that the beneficial effect appears to be temporary, especially if one focuses on the “biochemical” effect alone. However, in our years of clinical practice, we have come to believe that ketamine and psychotherapy are synergistic and can potentiate each other (as described in our vignettes). It appears that the benefit of ketamine treatment can be extended in some patients by combining conventional pharmacotherapy, ketamine, and psychotherapy. The addition of psychotherapy can add a space for psychological exploration, relational healing, and learning new skills. We hope to reduce the chance of ketamine dependence by offering ketamine in combination with other interventions. (Bennett et al., 2022)
Ketamine Assisted Psychotherapy (KAP) can potentially reach our most complex clients who have a long history of comorbid pain, psychological challenges, and substance use disorders. The hope of Ketamine’s rapid antidepressant and anxiolytic effects can facilitate a greater engagement in therapy, as well as instill hope in a population that has felt despondent after multiple treatment failures. This medicine can work and create functional shifts on a biochemical, relational, emotional and spiritual level.