Ketamine and Esketamine

Drug Class:

NMDA Antagonist

How it works: 

Blocks a channel for a chemical in the brain called NMDA. This, in turn, increases the effects of another channel for a chemical called AMPA. This leads to increased effects of BDNF and mTOR. The increased effects of BDNF and mTOR helps the brain to rapidly form new connections between key brain cells in key areas. The route of administration changes how much medication is bioavailable and how quickly it works. For example, IV ketamine reaches a maximum in 3 minutes and is 100% bioavailable. Intranasal ketamine reaches a maximum in 10-20 minutes and is 8-45% bioavailable. While oral ketamine reaches a maximum in 30 minutes and is 17-29% bioavailable. Ketamine has extensive first-pass metabolism.

History:

Ketamine was first synthesized in 1956. It was first studied for human use at the University of Michigan to be used as an anesthetic. Ketamine has an S and R isomer. The S isomer has a higher binding affinity for NMDA receptors and produces 3-4 times greater anesthetic potency. Esketamine (S isomer) may cause less dissociative effects.

What makes it unique:

Ketamine works very differently from other antidepressants. This may open a new pathway for treatment if standard treatments are not effective. Ketamine can also cause dissociative effects and is sometimes used as a party drug. Ketamine also may decrease suicidality (which is rare for medications).

Side effects:

Ketamine produces increased blood pressures, heart rate and can cause palpitations. It does not cause respiratory depression. This is unlike opioids (pain medications) and benzodiazepines (anxiety medications) that do cause respiratory depression and can suppress breathing in overdose. Other side effects include hypersalivation, hyperreflexia, transient clonus (muscle spasm), dizziness, nausea, vomiting.  Fortunately, there is a wide therapeutic index. This means that the amount of medication that causes an effect is far from the amount that can cause a fatal overdose. A medication with a wide therapeutic index is “safer”. One of the major side effects and the reason that this medication is abused is the dissociative symptoms. These symptoms include the feeling of intoxication, perceptual alterations like visual and auditory hallucinations and depersonalization (losing the feeling of “self”).

Recreational use: 

At lower doses, ketamine causes mild dissociation with hallucinations and a distortion of time and space. Higher doses produce schizophrenia-like symptoms and perceptions that are completely separate from reality.

How effective is it:

(1) 73 patients were randomized to receive either IV Ketamine or an active control medication, the anesthetic, midazolam. The primary outcome was change in MADRS depression scale 24 hours after a single drug infusion. The ketamine group decreased depression scores by 7.95 points more than midazolam. Also, ketamine had a 64% response rate as compared to 28% in the midazolam group.

(2) A study assessed Esketamine for treatment-resistant depression in 30 patients. The patients received either an IV infusion of 0.20mg/kg, 0.40mg/kg of Esketamine, or an IV placebo. The MADRS depression scale was assessed on day 2. Esketamine 0.20mg/kg decreased scores by 16.8, Esketamine 0.40mg/kg decreased scores by 16.9 and placebo only decreased scores by 3.8.

(3) A study assessed intranasal Esketamine as an adjunctive treatment to antidepressant medications in treatment-resistant depression. Patients were randomized to receive esketamine 28mg, 56mg, 84mg or placebo twice weekly. Change in MADRS score as compared to placebo was significant for each dose. Esketamine 28mg decreased the score by 4.2, 56mg by 6.3 and 84mg by 9.0. The 56 and 84 mg strengths produced plasma levels comparable to IV esketamine 0.2mg/kg.

(4) A study looked at using intranasal esketamine for patients with depression and suicidality. The patients received esketamine 84mg or placebo twice weekly for 4 weeks. MADRS score was significantly improved in the Esketamine group at 4 hours and 24 hours but not at day 25. Significantly greater improvement in MADRS suicidal thoughts item score was seen at 4 hours, but not at 24 hours or day 25.

(5) A study looked at IV Ketamine use for treatment-resistant depression with suicidality. 26 patients were included in the study and 13 patients had clinically significant suicidal ideation. The MADRS suicidal ideation scale was used, which is a 0-6 point scale. A single infusion of ketamine decreased the score by 2.08 points 24 hours after the ketamine infusion. 62% of patients had a great response with scores of 0-1 post-infusion, 23% endorsed fleeting suicidal thoughts, while 15% continued to have high suicidal scores.

(6) A study out of Canada retrospectively looked at 22 patients with treatment-resistant depression. They had failed at least 3 antidepressant medications and transcranial magnetic stimulation. The patients then received 50mg of oral ketamine, titrated up by 25mg every 3 days. Only 18% of patients showed a 50% reduction in the Beck Depression Inventory, 14% reported partial improvement, 45% had no response and 23% showed a mild worsening.

(7) A study looked at 14 patients with treatment-resistant depression receiving hospice care. The trial looked at oral ketamine over a 28 day period. The patients had improvement in depression and anxiety scores but only 8 patients completed the study. 4 patients withdrew due to not responding.

Clinical experience: 

I haven’t personally seen its use. It is not a standard option or treatment in a hospital. This is mostly done in specialty clinics. Pharmaceuticals should never be used as the sole treatment for mental illnesses. Therapy, exercise, meditation or other treatments should always accompany prescriptions.

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References:

1. Murrough J, Iosifescu D, Chang L, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42.

2. Singh J, Fedgchin M, Daly E, et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry. 2016 Sep 15;80(6):424-431.

3. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):139-148.

4. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630.

5. Price R, Nock M, Charney D, et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol. Psychiatry. 2009;66:522–526.

6. Shirawi M, Kennedy S, Ho T, et al. Oral Ketamine in Treatment-Resistant Depression
A Clinical Effectiveness Case Series. J Clin Psychopharmacol. 2017 Aug; 37(4): 464–467.

7. Irwin S, Iglewicz A, Nelesen R, et al. Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A . 28-Day Open-Label Proof-of-Concept Trial. J Palliat Med. 2013 Aug; 16(8): 958–965.

8. Li L, Vlisides P. Ketamine: 50 years of Modulating the Mind. Front Hum Neurosci. 2016; 10: 612.

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