This is another Clinical Problems in Consultation Psychiatry (CPCP) blog from our recent case conference about Ketamine. It seems like every other week, I hear about Ketamine and often it’s praised and touted at the quick solution to depression. I’ve mentioned what researchers are doing with Ketamine as an anesthetic augmenting agent, see excerpt below and link Psychiatry Research at Iowa: Way Ahead of the Curve « The Practical Psychosomaticist: James Amos, M.D.:
I’m a clinically oriented psychiatric hospitalist at The University of Iowa Hospitals and Clinics, and I’m interested in the research going on here, which is always way ahead of the curve. One protocol that immediately caught my eye is Dr. Laurie McCormick’s “Ketamine Augmentation of Electroconvulsive Therapy (ECT) for Patients with Depression.” The description follows:
“This is a randomized controlled trial of ketamine versus anesthesia as usual during ECT procedures in unipolar or bipolar depressed patients (male or female, ages 26-60) being treated with ECT. This study involves neuropsychological testing before and after the 6th (or final) ECT treatment along with clinical assessments of depressive symptoms before, after the 6th ECT and within a week of completing a series of ECT.”
Some remarks from Dr. McCormick, MD and Dr. James Beeghly, MD were intriguing:
“Previous studies have found that ketamine may enhance the antidepressant response to ECT, possibly be neuroprotective against memory problems during ECT, and is actually quite safe. Our study here will continue for the next year before we have a large enough sample to determine whether all of these 3 factors are true. I did get several e-mails inquiring about the use of ketamine alone for the treatment of depression a few weeks ago. We’d prefer to see the results of studies comparing ketamine injections alone for depression as well as the result of our study using ketamine with ECT before considering routine use of ketamine outside of the FDA indication as an anesthetic.”
You can see another post about Ketamine at Momma Said There’d Be Days Like This « The Practical Psychosomaticist: James Amos, M.D.
However, this one by senior medical students Erin Boese and Heather Hoops is exceptionally well done and I’m pretty much pasting it below. Most of the sound bytes about Ketamine leave me wanting somebody to tell me more, and I got that. Erin is planning to do her residency in ophthalmology and Heather is targeting general surgery.
Ketamine is a phencyclidine (PCP) derivative invented in the early 1963 by Calvin Stevens, just shortly after PCP was introduced to the medical field. Ketamine was created out of the need to reduce the severe and prolonged emergence delirium and extreme hallucinations of PCP anesthesia .
The first human was given ketamine in an IV dose in 1964. The safety profile of ketamine was great; it produced a quick anesthesia without any of the respiratory depression seen with other general anesthetic drugs. The study describes gradually increasing the dose from no effect, to “spaced out”, to general anesthesia. The emergence delirium was minimal, but many of the first subjects still described experiences like floating or having no feeling in their limbs. Due to its initial success, ketamine was widely used in the Vietnam War for anesthesia and analgesia, allowing quick procedures to be done on the field without the use of respiratory support.
Around this time, many researchers became curious of the subanesthetic effects of ketamine, including an author named Marcia Moore. She administered it to herself and wrote some of the earliest literature about the psychotic-like effects . She became more tolerant to its effects after daily use, claiming that she would stay with it until “it is tamed”, but later succumbed to its dissociative effects and was found frozen in a forest near her residence . Marcia Moore was not the first researcher to abuse it, and by the early 70’s, it became clear that both PCP and ketamine were being abused by the general public. Though, theoretically it has a large safety margin, its analgesic effects, hallucinations, and co-administration with other drugs makes it extremely dangerous when used illicitly .
Due to its abuse potential, ketamine has now been mostly replaced by propofol and other short-term anesthetic agents in human anesthesia use, but still plays a large role in pediatric anesthesia, as well as in trauma and burn cases . Additionally, ketamine (along with PCP) is still widely used in veterinary anesthesia, and in research to induce schizophrenia-like disease in animal models .
- Brand names: Ketalar, Ketaject, Ketaset, and Vetalar
- Administration: Can be administered IV, PO, or rectally
- Pharmacological effects: Anesthesia, analgesia, dysphoria
- Distribution/Elimination: Distribution half life of 7 minutes, elimination half life of 2-4 hours. Eliminated in urine as hydroxylated and conjugated inactive form.
Mechanism of Action
- Non-competitive antagonist of glutamate on PCP receptors within the NMDA channels, inhibiting calcium influx.
- Prevents central sensitization in dorsal horn neurons, interfering with pain transmission down the spinal cord
- Inhibit nitric oxide synthase, decreasing NO (neurotransmitter in pain transmission)
- Low affinity to opioid receptors
- Other mechanisms, including blocking voltage-gated calcium channels, noradrenergic and seronergic reuptake inhibitors, inhibits sodium channels.
- Inhibits reuptake of catecholamines, resulting in increased heart rate and contractility (sympathomimetic)
- Blocks myocardial ATP-sensitive potassium channels
- Induces catecholamine release, stimulates beta-2 adrenergic receptors (bronchodilation)
Psychotomimetic Effects [1, 5-7]
- Dissociative anesthetic and hallucinogen
- After anesthesia, can produce an emergence delirium after anesthesia can be controlled with administration of benzodiazepine.
- Hallucinations are dose dependent and last anywhere from 1-3 hours. At low doses, hallucinations may be only seen with both eyes closed, while high doses cause intense and very vivid hallucinations. Many hallucinations are moving, and cause a sense of falling or flying. There is also a very social aspect to it with may users feeling close to others, or reporting shared delusions .
- A study was done on ketamine’s effects on the behavior of zebrafish, and found that the drug literally caused the fish to swim in circles, rather than their normal tank exploratory behavior. Additionally, ketamine significantly decreased the hypoxic stress response. Along with the strange behavior exhibited, there seems to be a decreased stress and analgesic mechanism .
In the illustration above, the behavior of zebrafish is treated with either aquaculture water (right panel) or 0.2% ketamine (left panel) for 5 minutes. Animals treated with a subtherapeutic dose of ketamine exhibit a circling behavior .
- Once the drug begins to clear the user’s system, they slowly regain awareness of their surroundings. Movement has been noted to be difficult as the drug wears off, as the user may continue to feel dissociated from their body.
- Many users do not remember the experience after the drug is out of their system. This is currently thought to be due to NMDA’s vital role in long-term potentiation.
RECREATIONAL USE [1,3]
Names: K, Bump, Cat Valium, Ket, Kit Kat, Kizzo, Special K, Super Acid, Super K, Vitamin K, Monkey Mix, Monkey Business.
Synthesis and drug market: Ketamine involves a very complicated and multi-step synthesis, making home labs a rare possibility. The vast majority of the recreational ketamine is stolen from legitimate supplies, most often veterinary supplies.
Methods of use: Most often snorted. Occasionally injected either IM or IV.
Demographics: Mostly adolescents, young adults.
- Often brought into clinic by an observer due to impaired consciousness. Some present with anxiety or chest pain.
- Hallucination symptoms resolve very quickly, and most patients are completely asymptomatic by the time they are evaluated by an ER physician.
Physical findings: White powder in or on their nose, tachycardia, hypertension.
Co-morbidities: Almost always used in combination with other illicit drugs, including ecstasy, MDMA, cocaine, and methamphetamine.
Work up: 
Ketamine generally has a large safety margin and short duration of action, and are often asymptomatic by the time they are evaluated. Work-up is therefore aimed at looking for other substance abuse, and other potential causes for extreme anxiety.
- EKG to analyze QTc and QRS for effects by co-use of other illicit drugs.
- Serum creatinine kinase and urine myoglobin if concern for rhabdomyolysis, a rare but serious side effect of ketamine.
- Detection of Use
- Excreted in urine. Look for norketamine (active metabolite)
- Can be detected and quantified in blood
- Psychotomimetic effets: reduce stimuli, avoid patient restraints if possible. Possible IV lorazepam if sedation is needed.
- Cardiovascular support: Give atropine to treat bradycardia, benzodiazepines to treat tachycardia secondary to agitation.
- Decreased consciousness: Proper positioning, suctioning, possibly anticholinergics for salivation/aspiration risk. Airway and breathing support if needed.
- Muscle rigidity side effect: Lorazepam
- Generally can be discharged after symptoms resolve in about 6 hours. No follow-up needed, unless considering drug counseling and rehabilitation.
- No role for GI decontamination, since ketamine is abused primarily through snorting and IV/IM injection routes.
- No role for haloperidol or other antipsychotic agents to treat agitation because they may prolong the QTc interval and reduce seizure threshold.
Ketamine for Depression
Multiple trials have shown that a single IV infusion of ketamine reduces depressive symptoms in patients with treatment-resistant Major Depressive Disorder (MDD) or Bipolar Disorder (BD) within hours of administration. The dose is typically 0.5mg/kg, given over an infusion of 40 minutes in an inpatient setting with at least 24 hours of monitoring afterward. Patients have often failed at least 2 adequate trials of antidepressants and some have also failed ECT. Around 75% of patients response to a one-time ketamine infusion, the antidepressant effects peak within 24 hours. However, the effects are transient and only 1/3 of patients respond after 7 days.
Prior open label and RCT studies have shown that IV ketamine infusion is effective at treating acute, severe depression in treatment-resistant patient with MDD or BD for 1-7 days. A minority of patients may get continued benefit for several weeks post-infusion. Future utility is being investigated as an adjuvant or primary anesthetic in ECT. Additionally further studies are needed to determine the safety and efficacy of ketamine infusion in the emergency department setting for actively suicidal patients. Prior studies have shown to decrease suicidal ideation but have excluded actively suicidal patients. Lastly, more wide-spread use and longer-term effectiveness of ketamine may depend on developing and validating different routes of administration such as IM or PO.
A Randomized trial of an N-Methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression 
- Study Design
- Randomized controlled trial with 18 patients
- Crossover study, patients randomized to receive one-time IV ketamine infusion (0.5mg/kg) or placebo (saline) infusion first, followed by the other with infusions 1 week apart
- Inclusion criteria
- Age 18-65
- Diagnosis of MDD
- At least 18 on Hamilton depression scale
- Previously failed 2 adequate antidepressant trials, determined by antidepressant treatment history form
- No history of bipolar or any manic or hypomanic episodes
- No other co-morbidities except generalized anxiety disorder allowed
- No history of substance abuse within last 3 months
- Outcome measures
- Primary Measure was Hamilton depression rating scale (HDRS) with measurements at different intervals up to 7 days post-infusion
- Secondary measures of Beck Depression Inventory, brief psychiatric rating scale, young mania rating scale
- Clinical response was defined as at least 50% improvement in HDRS from baseline. Remission was defined as HDRS of 7 or less
- Ketamine significantly decreased depressive symptoms compared to placebo. Effect was up to 7 days, with a peak at 24 hours. Over 70% of patients had a response at 24 hours, but only 1/3 of patients remained responsive at 7 days. Results were statistically significant (p<0.05) for 24 hours and 7 days post-infusion.
- 4 patients in ketamine first group dropped out of the study due to increased mood. 1 patient in the placebo first group dropped out due to medical illness.
- Side effects included perceptual disturbances , euphoria, derealization, depersonalization, confusion, elevated blood pressure, increased libido, dizziness, which peaked at 40 min and resolved by 110 min post-infusion
- Decreased suicidal ideation was seen in ketamine group compared to placebo control in secondary analysis.
- Figure of Results  Please see figure 2 below
Ketamine for depression: Where do we go from here? 
- Systematic review article of 5 randomized controlled trials, 10 open label trials, 10 case studies, totaling 163 patients in all. Article also examined, commented on ongoing trials with unpublished data. Response defined at >50% reduction in at least 1 depression measure
- Effect of ketamine infusion peaked at 24 hours, response rate between open label and RCT varied between 25-85%. At 72 hours the response rate dropped to 15-70%.
- NNT @ 72 hours was 3-5 for patients with MDD
- NNT @ 72 hours was 4-7 for patients with depression associated with BD, with a decreased response if patient was on valproate
- Excluded actively suicidal patients, However ketamine did rapidly decrease suicidal ideation scores on depression scales
- No other co morbidities besides generalized anxiety disorder
- Wide variation between study protocols made comparison more difficult.
- Figure of results  Please see Figure 1
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