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An Overview of Ketamine as a Therapeutic Option for Depression, Anxiety, PTSD, Pain, and More

What is Ketamine?

  • First synthesized in 1962, then FDA approved in 1970 for anesthesia and procedural sedation.
  • The FDA has recently approved the esketamine (the S enantiomer) form for treatment-resistant depression in conjunction with another oral antidepressant.
  • Currently used for the treatment of mental disorders such as depression, anxiety, post-traumatic disorder which is considered "off-label".
  • There exists a wealth of evidence that highlights the value of ketamine in the treatment of severe pain.
  • When used for mood disorders and pain management or, sub-dissociative dosing, also referred to as low-dose ketamine, it is utilized either alone or in conjunction with other pain medications and or antidepressants.
  • On the World Health Organization’s list of Essential Medications, which includes medications such as penicillin, lidocaine, and morphine.

Indications For Ketamine

Ketamine therapy has been most extensively researched for its effectiveness in treating major depressive disorder and treatment-resistant depression. Additionally, ketamine has been explored as a treatment option for other mental disorders, such as anxiety, post-traumatic stress disorder (PTSD), and for pain management. For some individuals, ketamine might be considered an early alternative to traditional antidepressants, potentially offering a way to avoid potential unpleasant side effects such as decreased libido, weight gain, and disruptions in sleep and mood.

Depression

  • After a single infusion of ketamine, the response rate is 71% at day one (peak anti-depressant effects at 24hr) and 54% at day three.
  • Remission rate of 51% reported for depression.
  • The mean duration to relapse from another depressive episode is 17 days after a single infusion of ketamine — multiple infusions (such as series of six sessions) prolong the duration between recurrent depressive episodes.
  • There is a dose dependent relationship for anti-depressant effects.

Anxiety

  • Individuals with anxiety disorder most often have comorbid depression, thus treatment with ketamine can be helpful for both conditions.

PTSD

  • Lifetime incidence of PTSD is 6.8% or 12.9% among U.S. veterans.
  • Remission rates of upwards to 80% have been reported with repeated infusions over a short period of time for PTSD (six infusions over a twelve day period).

Suicide

  • On average, there are 132 suicides per day, or approximately one death every 11 minutes.
  • Clinical studies have demonstrated that a single ketamine infusion can significantly reduce suicidal thoughts within just one hour. Individuals who received ketamine experienced complete remission of suicidal ideation at a rate of 63% by the third day, and these high remission rates (70%) persisted even through the six-week mark. This stands in stark contrast to other acute suicide treatment methods like electroconvulsive therapy (ECT), where only 38% were free of suicidal thoughts after three treatments.

Addiction, alcoholism, and substance abuse

  • In this clinical trial, patients who were given three weekly ketamine treatments had significantly more days abstinent from alcohol compared to the placebo group at six month follow-up; 86% of participated were still sober after six months.
  • Studies suggest that a low dose, ketamine can be effective in treating alcohol use disorder (AUD), resulting in reduced alcohol cravings and intake.

Fibromyalgia and chronic pain

  • Ketamine is known to interact with specific (sigma) receptors and typically operates by reducing central sensitization, mitigating the progression of ongoing, worsening, or chronic pain, and diminishing pain memory.
  • When ketamine is specifically employed for pain treatment, the dosage may be higher than that used for mood disorders, and it may require longer infusion times.
  • In a double-blind, placebo-controlled study patients with fibromyalgia received a single dose of ketamine infusion (0.3 mg/kg), patients experienced a significant reduction (>50%) in pain intensity scores.
  • Ketamine has been known to have anti-inflammatory effects, with inflammation believing to play a big role in the pathogenesis of fibromyalgia and pain.

Who should not get ketamine

  • Uncontrolled hypertension
  • Unstable heart disease (congestive heart failure, unstable coronary artery disease, history of arrhythmias)
  • Uncontrolled thyroid disease such as hyperthyroidism given concern of tachycardia and arrhythmias
  • Active substance abuse
  • Active manic phase of bipolar disorder, schizophrenia, or history of psychosis
  • Those who have shown prior hypersensitivity to the drug
  • It is not recommended for individuals during pregnancy

Mechanism of action

  • Ketamine acts as a non-competitive antagonist at the NMDA receptor, which means that rather than competing for glutamate binding site on the NMDA receptor, ketamine inhibits receptor function by blocking the ion channel itself, preventing influx of ions and thus activation/intracellular signaling.
  • Increases level of brain derived neurotrophic factor (BDNF), a protein that plays an important role in neurogenesis, causing regrowth and strengthening of broken connections in stressed brains.
  • Recent research indicates that ketamine has the potential to reopen what are known as "critical periods" for social reward learning. Ketamine appears to induce a mental state reminiscent of youthful receptivity, rendering learning and behavioral changes more accessible and attainable. This parallels the idea that learning a new language is notably easier during one's early years when the mind seems to be more adaptable and open to embracing new concepts.
  • Anti-inflammatory effects: Ketamine has been shown to reduce pro-inflammatory molecules such as the Tumor Necrosis factor (TNF-α) that plays a role in a number of auto-immune disorders such as rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn disease), ankylosing spondylitis, and psoriasis.

The ketamine infusion experience

  • The purpose of the infusion process is to administer ketamine while ensuring the most comfortable experience possible. Some individuals may undergo a dissociative state or "trip," which is a natural part of the process.
  • It is important to understand that the healing process and antidepressant effects occur after infusions while the brain undergoes neurogenesis.
  • Some individuals find meaning in their ketamine experiences with new ideas or feelings brought up to the forefront of their mind, which offers them something to work with internally or with a therapist. Others will have an experience filled with random thoughts and imagery that is difficult to understand. Individuals are reassured that it’s okay to have unusual or random experiences, because the healing is caused by structural changing of the brain, such as neurogenesis, which happened days to weeks post infusion.
  • Some experiences will be very pleasurable, relaxing, and meditative, while others will be challenging; the ketamine experience may bring out subconscious issues such as memories or trauma that can feel overwhelming.
  • A challenging trip (rather than the term “bad" trip) can still be very therapeutic, and potentially even more can be gained and used from these tough experiences.

Different forms of ketamine

Intravenous (IV) and intramuscular (IM)

  • IV is the superior route of administration- 100% bioavailability, can titrate and stop an infusion, ability to treat side effects quickly with IV access (nausea, hypertension, tachycardia).
  • IV ketamine has predictable and consistent effects and allows for ease of adjusting dose.
  • These forms are the most commonly studied and supported form of ketamine in the scientific community.

Oral

  • Some studies reported 4 to 6 weeks to see any antidepressant effect with oral ketamine, which is similar to traditional antidepressant medications.
  • Require higher doses and more potential for side effects given its lower bioavailability of approximately 20%.

Nasal

  • Only 40% bioavailable and less predictable experience (i.e., dose is dependent on rate of absorption and other patient-specific factors).
  • No ability to stop or take back dose, rather patient must wait for effects to “run its course” and wear off.

A caution on the use of “at-home” forms of ketamine

  • Patients are not monitored, increased risk for abuse/misuse, and potentially less therapeutic.
  • Recent reports reveals more than 50% of Americans misuse at-home ketamine, oftentimes accidentally or purposefully using more than the recommended dose.

Types of responders to ketamine

Early

  • Show Improvements after 1 or 2 treatments

Standard

  • Incremental improvements within 3 or 4 treatments

Late

  • May require 5+ treatments before notice any benefits.
  • By the sixth infusion, 80% of individuals who respond to ketamine can be identified. For some, a longer course of treatment is required.

Non-responders

  • 15-20% of individuals do not experience antidepressant effects from ketamine.
  • Non-ketamine treatment alternatives for non-responders include cognitive-behavioral therapy (CBT), electroconvulsive therapy (ECT), eye movement desensitization and reprocessing therapy (EMDR), and transcranial magnetic stimulation (TMS).

Interactions with other medications and potential inhibitors

  • Benzodiazepines and lamotrigine have the potential to diminish the effectiveness of ketamine. When possible, patients are requested to refrain from taking their doses of these medications on infusion days.
  • Alcohol can also hinder the antidepressant effects of ketamine. Furthermore, certain individuals may be sensitive to other substances, such as cannabis, which might interfere with the action of ketamine.

Ketamine safety

  • Nausea may be associated with high dosages, head movement, and visual stimulation
  • Rarely some may experience anxiety given the normal emotional response from the medicine; this typically does not require pharmacological treatment, but rather reassurance and sometimes physical touch (e.g., hand holding)
  • Normal response to have slight elevation of heart rate and blood pressure
  • Non physically addictive. Chronic and frequent use of ketamine, often associated with at-home use, can lead to psychological addiction.
  • Recreational abuse of ketamine may cause bladder injury known as interstitial cystitis which is associated with daily high dosages (1+ grams); this can lead to a stiff bladder with decreased volume capacity and may require surgical intervention

The Innerbloom Ketamine Therapy approach to ketamine therapy

  • Ketamine alone is insufficient to "cure" depression or other mental disorders. In our view, integrating psychotherapy enables a more therapeutic and enduring response.
  • Ketamine is a tool or catalyst rather than a magic pill that will solve all problems
  • Ketamine may assist in interrupting negative thought patterns, maladaptive behaviors, or destructive life cycles.
  • Ketamine should not be regarded in the same way as antidepressants, which are designed for daily use. Instead, it should be administered temporarily through a series of infusions, enabling the patient to regain their footing and make healthy lifestyle changes.
  • Preparation, integration, and psychotherapy are essential for the proper and safe utilization of ketamine.

The ketamine infusion process

  • Multiple (6+) 40 minute infusions over a span of 2–6 weeks. Typically 1-2 infusions per week.
  • Boosters are available for patients who have already undergone a 6-infusion series
  • Discourage single infusions: 4–5 infusions are felt to be necessary and a fair trial to assess response to ketamine or determine if patients are non-responders
  • Sitter: Someone is always with the patient during infusions for close monitoring and support

What to expect after infusion

  • Patients will need a ride home, are encouraged to have a light day after, and should expect to be back to normal in about 3 hours (half-life of ketamine is 3 hours), but they cannot drive for at least 12 hours after infusion.
  • Rest and hydration is essential after the infusion. Some patients may find it difficult to sleep that night, while others might have a very restful slumber.
  • Patients can expect to return to work, school, and their daily routine the next day.

Preparation

  • Preparation prior to infusions appears to be beneficial for achieving the proper mindset that allows for a therapeutic response; the goal of preparation is to maximize benefits and avoid potential risks or side effects.
  • Preparation may include education, attention to set and setting, and making use of strong support systems.

Integration

  • Integration refers to what is done after infusions or in between treatment sessions; this includes plans of action and changes in lifestyle in positive ways to achieve long lasting results after ketamine therapy.
  • Ketamine therapy alone will have beneficial effects, although integration enhances the therapeutic potential of the medicine.
  • Integration include self-reflection, developing new routines and healthy daily habits along with help from a professional such as a therapist which may ultimately lead to long-term positive changes.

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