Low-dose of ketamine infusion is relatively free of side effects for patients with treatment-resistant depression

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National Institutes of Health researchers found that a single, low-dose ketamine infusion was relatively free of side effects for patients with treatment-resistant depression.

Elia Acevedo-Diaz, M.D., Carlos Zarate, M.D., and colleagues at the NIH’s National Institute of Mental Health (NIMH) report their findings in the Journal of Affective Disorders.

Studies have shown that a single, subanesthetic-dose (a lower dose than would cause anesthesia) ketamine infusion can often rapidly relieve depressive symptoms within hours in people who have not responded to conventional antidepressants, which typically take weeks or months to work.

However, widespread off-label use of intravenous subanesthetic-dose ketamine for treatment-resistant depression has raised concerns about side effects, especially given its history as a drug of abuse.

“The most common short-term side effect was feeling strange or loopy,” said Acevedo-Diaz, of the Section on the Neurobiology and Treatment of Mood Disorders, part of the NIMH Intramural Research Program (IRP) in Bethesda, Maryland.

“Most side effects peaked within an hour of ketamine administration and were gone within two hours.

We did not see any serious, drug-related adverse events or increased ketamine cravings with a single-administration.”

This shows two brain diagrams

The researchers compiled data on side effects from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls who participated in one of five placebo-controlled clinical trials conducted at the NIH Clinical Center over 13 years. The image is credited to NIMH.

The researchers compiled data on side effects from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls who participated in one of five placebo-controlled clinical trials conducted at the NIH Clinical Center over 13 years.

While past studies have been based mostly on passive monitoring, the NIMH IRP assessment involved active and structured surveillance of emerging side effects in an inpatient setting and used both a standard rating scale and clinician interviews.

In addition to dissociative (disconnected, unreal) symptoms, the NIMH IRP assessment examined other potential side effects – including headaches, dizziness, and sleepiness.

The study did not address the side effects associated with repeated infusions or long-term use.

Out of 120 possible side effects evaluated, 34 were found to be significantly associated with the treatment.

Eight occurred in at least half of the participants: feeling strange, weird, or bizarre; feeling spacey; feeling woozy/loopy; dissociation; floating; visual distortions; difficulty speaking; and numbness. None persisted for more than four hours.

No drug-related serious adverse events, cravings, propensity for recreational use, or significant cognitive or memory deficits were seen during a three-month follow-up.

Credit: NIMH.

To overcome the limitations associated with side effects and intravenous delivery, ongoing research efforts seek to develop a more practical rapid-acting antidepressant that works in the brain similarly to ketamine.

These NIMH researchers, in collaboration with the National Institute on Aging, and the National Center for Advancing Translational Science, are planning a clinical trial of a ketamine metabolite that showed promise as a potentially more specific-acting treatment in pre-clinical studies.

Meanwhile, the U.S. Food and Drug Administration earlier this year approved an intranasal form of ketamine called esketamine, which can be administered to adults with treatment-resistant depression in a certified doctor’s office or clinic.


Background:

Severe depressive disorder is among most debilitating condition. Conventional pharmacotherapy usually takes several weeks (usually 4–12 weeks) to improve symptoms. Ketamine is an N–methyl-D aspartate receptor antagonist having rapid action on depressive symptoms.

Objectives:

The effect of subanesthetic dose of ketamine was assessed on depressive and anxiety symptoms. Illness severity and improvement were assessed after treatment with ketamine.

Materials and Methods:

Twenty-five drug-free/naïve patients of the male sex, with severe depression having no previous history of psychotic disorder, head injury, organic disorder, cardiological problem, or substance abuse were admitted for the study.

Assessments were made at baseline and injection ketamine hydrochloride was given at a subanesthetic dose of 0.5 mg/kg intravenous bolus after preparation. Assessments were repeated 1 h after the first dose. Six doses were given over 2 weeks and assessments were repeated. Final assessments were made after 1 month of the last dose.

Results:

There was a significant improvement in depression, anxiety, and the severity of illness after 2 weeks and 1 month of the last dose of ketamine. Significant improvement at 1 st h of the first dose was seen in depression and anxiety and not for illness severity. There were transient adverse effects observed in some patients which subsided within 1 h.

Conclusion:

Ketamine has a robust and rapid effect on depression, which was seen immediately after the administration of ketamine and sustained at the end of 1 month.

Key words: Depression, ketamine hydrochloride, N–methyl-D aspartate

Major depressive illness is a debilitating condition which is matter of concern worldwide affecting millions of people causing a considerable burden on health and socioeconomic status.[1] As per the World Health Organization, depression is third among global disease burden.[2] This will put tremendous pressure on societal cost due to disability. Pharmacotherapy modulating monoamine systems generally takes 4–12 weeks to start improvement. Recent studies are accepting the role of glutamate in depression, in particular, N–methyl-D aspartate (NMDA) receptors along with serotonin receptors.

They are postulated to be involved in depression.[1] Glutamate is the main excitatory neurotransmitter which has a role in neurodevelopment, neurocognitive (memory learning), and neurotrophic (nerve growth differentiation, maintenance) function.[3]

Most clinical studies accept the role of drugs modulating through NMDA receptors. Ketamine is noncompetitive voltage-dependent NMDA-receptor channel blocker whose antidepressant action is evident at low doses, and with increasing doses, it mimics psychotomimetic action and eventually leads to anesthesia in higher doses.[4]

Single dose of ketamine has rapid action on depressive symptoms, and this action persists even for a week, which suggests its possible role in neuroplasticity. Many studies showed remission of depressive symptoms 1-week postinfusion.[5]

A recent meta-analysis showed antidepressant efficacy from day 1 in patients of unipolar and bipolar depression.[6]

The neuropsychiatric effect of subanesthetic dose of ketamine helps in the management of suicidal ideation and reduces self-harm or suicide in addition to the reduction in depressive symptoms.[7] Open-label studies have shown that one-time intravenous (i.v) ketamine led to rapid improvement of treatment-resistant depression and the quickest significant antidepressant response was noted within 2 h and slowest within 4 h.[8]

Another study done in India on 27 patients of treatment-resistant depression (TRD) with single i.v dose of ketamine infusion showed short-lasting improvement in suicidal ideation and depression.[9] No significant adverse physical effects are reported in with low-dose ketamine and S-ketamine in antidepressant trials till date.[10]

Ketamine is a new and effective option in future with rapid onset of action, but studies are limited with multiple doses of ketamine which have assessed depressive and anxiety symptoms comprehensively. There are limited studies which have used i.v ketamine in bolus dose as most of the studies used it as slow i.v infusion. Hence, index study aimed to assess the efficacy of bolus i.v ketamine in patients with severe depression.


Etiology

Ketamine toxicity can result from the medical use of parenteral or intranasal ketamine or the recreational misuse of ketamine, commonly through intravenous or intramuscular injection, insufflation (snorting), oral consumption, or smoking.[8]

Epidemiology

The World Drug Report in 2015, categorized ketamine as a worldwide recreational drug, with 58 countries reporting illicit use. However, ketamine misuse occurs on a relatively small scale, and PCP derivatives constituted only 1% of “new psychoactive substances” reported to the United Nations Office of Drugs and Crime in 2014 (fact file on ketamine). Ketamine misuse often occurs in combination with other substances, including alcohol, amphetamines, MDMA, cocaine, and caffeine.

In the United States, where ketamine classifies as a C-III controlled substance since 1999, the popularity of ketamine misuse has increased since the 1980s.[9] 

However, compared to the surges in opioid and illicit cannabis misuse, ketamine misuse has occurred on a relatively small scale. Ketamine was involved in 0.033% of the United States Emergency Department visits involving illicit drugs in 2005, with this proportion increasing slightly to 0.12% in 2011 (Drug Abuse Warning Network, 2011).

Ketamine-related emergency department visits often involved other drugs, with 71.5% of ketamine-related visits in the United States in 2011 involving alcohol (Drug Abuse Warning Network, 2011). The national, survey-based ‘Monitoring the Future Study’ in the United States reported that ketamine use decreased between 2012 and 2002, from 2.5% to 1.5% and from 1.3% to 0.4%, among 12th graders and college students, respectively.

In the United Kingdom, where ketamine has been classified as a Class C drug since 2006,[9] ketamine misuse has also decreased during the 21st century. According to the World Health Organization fact file on ketamine, the percentage of United Kingdom adults and young adults who used ketamine decreased from 0.6% to 0.4% and from 1.8% to 0.8%, respectively, between 2011 and 2013.

Ketamine misuse is becoming increasingly popular as a recreational drug in Southeast Asian countries such as Taiwan, Malaysia, and China.[9] In Hong Kong, where ketamine classifies as a Schedule I drug since 2000, ketamine became the most common drug of misuse in the early 2000s.[9]

 Between 1996 and 2000, an epidemiological study involving drug-related motor vehicle collision fatalities found 9% involved ketamine use,[10] which represents a disproportionate number of fatalities compared to alcohol and opioid misuse, which are drugs in which tolerance develops more rapidly.  Surveys demonstrate that ketamine misuse is more common in southeast China than in other regions of the country.[11]Go to:

Pathophysiology

Ketamine’s main site action is as a non-competitive antagonist of the N-Methyl-D-Aspartate (NMDA) glutamate receptor, though it exhibits effects on a myriad of other receptors.  It acts as an antagonist at muscarinic and nicotinic acetylcholine receptors, blocks sodium and potassium channels, activates high-affinity D2 dopamine receptors and L-type voltage-gated calcium channels, and facilitates gamma-aminobutyric acid (GABA) inhibition. Ketamine may also increase the levels of neurotransmitters such as norepinephrine, dopamine, and serotonin in the brain.[12][13] 

As a drug that stimulates the sympathetic nervous system, tachycardia and hypertension are common with ketamine use, which masks its direct cardiac depressant effects.  However, in intensive care unit patients who are catecholamine-depleted, the use of ketamine may result in hypotension.  Although ketamine binds to mu and other opioid receptors, naloxone does not block its analgesic effects.[14]

Toxicokinetics

To date, there remains sparse information about the toxicokinetics of ketamine in the human population.

In animal studies, however, the safety ratio (defined as the proportion of the usual recreational dose to a fetal or lethal dose) has been used to evaluate the acute risk observed with ketamine.

The definition of the lethal dose (LD50) is the amount of drug that results in death in 50% of experimental animals tested. Gable et al. determined the oral ketamine safety ratio for rodents as 25,[15] and estimated that the median lethal dose averaged at 600mg/kg or 4.2g for a 70kg human.[16][17]

Ketamine has been used to provide analgesia in refractory chronic pain conditions, and even anesthesia for short surgeries.  However, the safety data is mixed regarding its toxicity when administered neuraxially in animals, with some authors suggesting that its neurotoxicity derives from preservatives.  According to the latest Polyanalgesic Consensus Conference for intrathecal drug delivery, the designation for the administration of spinal ketamine was as a 6-line adjuvant used in conjunction with other neuraxial analgesics in individuals with refractory cancer or other terminal chronic pain conditions.  There is a current ban on the publication on the study of intrathecal analgesics that lack adequate safety data in several of the top pain and anesthesia journals.[18]

History and Physical

Ketamine overdose symptoms are similar to those of PCP overdose, although the effects of ketamine tend to resolve more quickly. Physical signs and symptoms are dose-dependent through loss of consciousness.  Patients may be unable to provide a relevant history, and clinicians should seek pertinent clinical information from witnesses. Clinicians should also maintain familiarity with street names for ketamine.

The following symptoms may be present during ketamine use and intoxication: 

  • General – sedation, impaired consciousness
  • Head, Ear, Eyes, Nose, Throat – horizontal, vertical or rotary nystagmus, mydriasis, excessive salivation 
  • Cardiovascular – hypertension, tachycardia, palpitations, arrhythmias, chest pain 
  • Abdominal – abdominal pain, abdominal tenderness, nausea, vomiting 
  • Neurological – altered mental status (disorientation), paranoia, dysphoria, anxiety, confusion, slurred speech, dizziness, ataxia, dysarthria, trismus, muscular rigidity, psychomotor, psychomimetic or acute dystonic reactions
  • Genitourinary – lower urinary tract symptoms
  • Trauma – a thorough examination surveilling evidence of trauma is in order as injuries secondary to ketamine intoxication can occur due to the diminished perception of pain

Symptoms mostly unique to overdose, overly rapid infusion, or combined with other drugs: 

  • Respiratory – respiratory depression, apnea
  • Cardiovascular – hypotension, bradycardia, myocardial infarction 
  • Neurological – seizure, stupor, coma 

Symptoms mostly unique to iatrogenic, intravenous delivery[19]:

  • Respiratory – respiratory depression, laryngospasm

Evaluation

Several laboratory tests could be obtained to evaluate the degree of metabolic or cellular derangements

  • Serum PCP, acetaminophen, salicylate levels, to rule out common co-ingestions
  • ECG, to rule out conduction abnormalities and arrhythmias
  • Urine myoglobin and serum creatine kinase, to rule out the complication rhabdomyolysis
  • Imaging, to rule out other causes of altered mental status such as hemorrhage or secondary trauma
  • CSF, to rule out CNS infection such as meningitis as a cause of neuropsychiatric symptoms
  • CBC, to evaluate for leukocytosis
  • CMP, to evaluate for BUN and Cr elevation (renal compromise) or LFT elevation (hepatotoxicity)
  • Fingerstick blood glucose, which can suggest hypoglycemia as a primary cause of mental status changes, or hypoglycemia secondary to ketamine toxicity

Treatment / Management

Typically, only supportive care is necessary for patients with ketamine intoxication.  The effects of ketamine intoxication typically last between 15 minutes to several hours depending on the dose, route of administration (e.g., oral more than intravenous), metabolic capacity, and intrinsic sensitivity to the effects of the drug, which depending on genetics and several other factors.[20] Patients who are asymptomatic at presentation but report recent ketamine use should undergo observation for 6 hours. Patients who experience symptom relief after intoxication should have continuous monitoring for 1 to 2 hours after their last symptom resolves.

Monitoring includes the patient’s airway, breathing, and circulation, as ketamine can potentially cause cardiopulmonary compromise, especially when taken in combination with other drugs. If the patient vomits, the patient should be positioned to lean forward or to lie on the left side with the head facing downward, to avoid airway compromise and aspiration. Ketamine has been shown to cause bronchodilation and maintain protective airway better than other anesthetic agents used for sedation, although there have been reports of aspiration.[21]  If airway compromise occurs, intubation can provide respiratory support. The patient’s vital signs, especially temperature, should also be monitored for other symptoms, especially hyperthermia. If the patient develops severe symptoms or complications, the patient should be placed on a monitor and admitted for observation.

If ketamine was ingested, especially in large quantities or with co-ingestion of other drugs, activated charcoal could provide gastrointestinal decontamination. Activated charcoal is typically given in a 1 g/kg dose, with a dose maximum oral dose of 50 g/ng.[22] Activated charcoal should be avoided in patients with unprotected airways or absent bowel sounds.[22] Activated charcoal administration within a sufficiently brief amount of time may obviate the need for gastric lavage. Hemoperfusion and dialysis tend to be ineffective due to ketamine’s large volume of distribution.

According to the toxicology data network, there are no medications approved by the U.S. Food and Drug Administration to treat a ketamine overdose, but medications can provide management of agitation and psychosis. Benzodiazepines such as lorazepam and diazepam can alleviate agitation, psychomimetic effects, hypertension, hyperthermia, and seizures. Lorazepam is typically given 2 to 4 mg IV, or IM, and diazepam dosing generally is 5 to 10 mg IV. Butyrophenones including haloperidol have been used to treat psychotic episodes and agitation.[8] Haloperidol is typically given in doses of 5 to 10 mg IM and can be administered every 10 to 15 minutes until achieving adequate sedation. However, providers should exercise caution when using haloperidol, as lowered seizure thresholds, QT prolongation and torsades de pointes correlate with the prolonged use of haloperidol. Unnecessary stimulation should be avoided, and the patient’s room should be dim and quiet. If necessary, the health care team may provide physical restraints, to initiate IV access and secure the patient’s safety. If sedation does not adequately manage hyperthermia, evaporative cooling can decrease heat production.

Other medications can manage other symptoms. Alpha2-agonists such as clonidine can treat or prevent ketamine’s psychomimetic side effects, increase hemodynamic stability by decreasing blood pressure, and provide synergism with ketamine’s analgesic effects.[6][23][24] Clonidine is typically given at 2.5 to 5 mcg/kg in oral form, though patches are an option for long-duration inpatient infusions and IV clonidine can be used to address acute symptoms. Atropine or glycopyrrolate can prevent and treat the excess salivation associated with ketamine use, while physostigmine can address nystagmus and blurred vision. Hydration with crystalloids can improve dehydration.


Source:
NIH/NIMH
Media Contacts:
Jules Asher – NIH/NIMH
Image Source:
The image is credited to NIMH.

Original Research: Closed access
“Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression.”. Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA Jr, Park LT.
Journal of Affective Disorders doi:10.1016/j.jad.2019.11.028.



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