Ketamine for Depression and Suicidal Thoughts

Ketamine is a different kind of antidepressant.

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Ketamine has a particularly vicious reputation as an illicit drug, and this is understandable. Ketamine is similar to PCP, another dissociative anesthetic agent. When taken in toxic doses, ketamine can cause hyperactivity, including increased blood pressure, increased heart rate, sweating, and muscle rigidity. Ketamine overdose can also result in psychosis.

Despite its reputation as a drug of abuse, ketamine does have legitimate medical uses. It’s an excellent anesthetic with its own unique properties, and is used in many parts of the developing world for this reason. Furthermore, ketamine is used to treat certain types of severe pain. More recently, ketamine has proven effective at reducing suicidal thoughts.

Ketamine Explained

Ketamine is an arylcylohexylamine dissociative anesthetic agent used in both human and veterinary medicine (hence, its reputation as a ”horse tranquilizer”). Ketamine is soluble in both water and lipids (i.e., body fat), which means that it can be administered through the following routes:

  • Intravenously (IV)
  • Intramuscularly (IM)
  • Subcutaneously
  • Orally
  • Rectally
  • Transnasally
  • Transdermally

Of note, ketamine is best absorbed through the intramuscular route. Ketamine comes in three concentrations: 10 mg/mL, 50 mg/mL, and 100 mg/mL.

Ketamine has many mechanisms of action and affects several neurotransmitters in the central nervous system. These effects contribute to its broad spectrum of action, including increasing the sympathetic "fight or flight" nervous system, impacting the cardiovascular system, and the pain response. Here are some of the severe kinds of neuropathic (nerve-damage) related pain that ketamine treats:

  • Postherpetic neuralgia
  • Postamputation pain
  • Spinal ischemia
  • Brachial plexopathy
  • HIV neuropathies
  • Cancer neuropathies

Ketamine is also good at treating nociceptive pain, which arises from the stimulation of nerves. Examples of nociceptive pain include myofascial and ischemic pain.

In the medical text Poisoning & Drug Overdose, Olson and co-authors write the following regarding ketamine:

Other pharmacologic effects mediated via epigenetic modulation and expression of microRNA, inflammatory mediators, and nitric oxide synthase may mediate its sustained therapeutic effects for the management of psychiatric and mood disorders, anti-inflammatory actions, and treatment of status asthmaticus.

Here are the specific ways in which ketamine affects the body:

  • Increased heart rate
  • Increased blood pressure
  • Increased central venous pressure
  • Increased respiratory rate
  • Bronchodilation
  • Increased blood flow to the brain
  • Increased metabolic rate
  • Increased intraocular (eye) pressure
  • Possible nausea and vomiting
  • Possible delirium
  • Increased uterine tone
  • Dream-like states
  • Possible hallucinations

There are some unique properties of ketamine as an anesthetic. It doesn’t usually suppress breathing and impair the airway as much as other anesthetics do. Additionally, the fact that ketamine doesn’t lower blood pressure makes it an ideal anesthetic for those patients at risk for hypotension (i.e., low blood pressure), dehydrated patients, and patients in shock.

Ketamine for Depression and Bipolar Disorder

Researchers have had a difficult time developing new drug classes to treat depression. Decades ago, psychiatrists treated depression with drugs that blocked monoamine transporters and monoamine receptors; however, these drugs had negative side effects. The emergence of serotonin-reuptake inhibitors (SRIs) changed the field of psychiatry, and gave psychiatrists, as well as primary care physicians, safe and easily prescribed options for the treatment of depression.

Ketamine is an NMDA glutamate receptor antagonist, and is thus a glutamatergic agent. In clinical studies, the first glutamatergic agent used to treat depression was a tuberculosis antibiotic called D-cycloserine. This agent was tested on tuberculosis patients with depression in 1959, and mood improvements were quickly apparent. By the 1960s, another glutamatergic agent called amantadine had shown promise in treating Parkinson's disease, which is often accompanied by depression. Consequently, this drug was used to treat depression in a pilot study.

By the late 1980s, researchers were examining the effects of ketamine on depression. Researchers were astonished by how quickly ketamine worked to treat the symptoms of depression. Within 24 hours of treatment with one subanesthetic intravenous dose, some patients with depression were observed to go into remission.

The emergence of ketamine to treat depression elucidated a novel conceptual framework with new mechanisms of action. Traditional antidepressants often take several weeks to reach maximal efficacy. However, ketamine works much faster and results in substantial clinical improvement in mere hours.

In a 2013 article from Biological Psychiatry, Krystal and co-authors write the following:

The antidepressant effects of ketamine were not present until after the psychotigenic and euphoric effects of ketamine had disappeared. This temporal distinction first suggested that the antidepressant effects arose as a rapid neuroadaptation to the acute effects of ketamine in the brain. Across studies reported to date , antidepressant effects emerge by 2-4 hours. By 24 hours, studies report substantial improvement and response of depression symptoms in approximately 50%-80% of patients. All symptoms of depression improve, including suicidal ideation. The clinical benefits after a single ketamine dose may last as briefly as 1-2 days and may last longer than 2 weeks.

Results from a 2014 meta-analysis published in Psychopharmacology support the short-term utility of ketamine in treating both depression and bipolar disorder. Specifically, in this meta-analysis, Fond and colleagues pooled and analyzed results from studies examining the use of ketamine in major depressive disorder (MDD), bipolar depression, and resistant depression, as well as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression. The researchers found that ketamine was effective at treating depressive symptoms in each of these contexts.

Although the power of this study was limited by small sample sizes, Fond and co-authors suggest that the results of ketamine lasted between two and three days. Furthermore, evidence suggested that not only did depressive symptoms abate but suicidal thoughts lessened, too—albeit suicidal ideation was measured using only one item on depressive scales.

Importantly, Fond and colleagues note that in some patients there were transient elevations in blood pressure. Because of ketamine’s effects on the heart, the researchers warned against its use in people with heart disease.

Despite a growing body of research supporting the use of ketamine for the treatment of depression and bipolar disorder, much more research needs to be done. First, it’s unclear at what dosages ketamine should be used to treat psychiatric disease. Importantly, dissociative symptoms can appear in people taking even very low doses of ketamine. Second, antidepressants can precipitate mania in those with bipolar disorder, and although unlikely, it’s unclear whether ketamine can precipitate mania in these patients. Third, it’s unclear how often ketamine should be administered to people with psychiatric illness. Should it be administered every two or three days? Fourth, we don’t know if ketamine has any long-term adverse effects.

Ultimately, if ketamine was ever more widely used to treat depression or bipolar disorder, it would probably be an adjunctive treatment. In other words, ketamine would be used in addition to either antidepressant or mood-stabilizing medications. At this time, it’s unclear whether ketamine would need to be administered by an anesthesiologist. The intramuscular dose of ketamine may not need to be administered by an anesthesiologist and could be suitable for outpatient clinical practice.

Ketamine for Suicidal Thoughts

In recent years, the effect of ketamine on suicidal thoughts (I.e., suicidal ideation) has not been thoroughly studied. Often studies examining the effects of ketamine on mood only look at suicidal ideation as a single item on a depression rating scale.

In a December 2017 article titled ”Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial,” Grunebaum and colleagues studied the effects of ketamine in patients with major depressive disorder and suicidal ideation.

In this randomized-control trial, 80 participants were assigned to receive either ketamine or the control, midazolam. Because of its dissociative effects, no other anesthetic is comparable to ketamine. Thus, the researchers chose midazolam for a control because like ketamine, this drug has psychoactive properties. Furthermore, the half-life of both drugs is comparable, and midazolam has no antidepressant or antisuicidal effects. Both drugs were administered by a psychiatrist as one dose intravenously.

Here are some of the researchers’ findings:

  • On the day of administration, the average Scale for Suicidal Ideation (SSI) score was about five points lower in those taking ketamine, which represents a significant decrease in suicidal ideation.
  • Suicidal ideation decreased within 230 minutes of infusion.
  • Depressive symptoms improved significantly in those taking ketamine.
  • Ketamine resulted in a transient, mild-to-moderate increase in blood pressure.
  • Ketamine resulted in dissociative effects similar to those observed in other studies.
  • Improvements in suicidal ideation persisted six weeks after the initial infusion.

This study did have its limitations. For instance, this study examined people with suicidal ideation, and suicidal ideation is different from suicidal intent or behavior. Because many people have suicidal thoughts, and relatively few people commit suicide, much larger sample sizes (i.e., many more patients) would need to be included if suicidal behavior was examined. Furthermore, compared with the control group, more patients in the ketamine experimental group had borderline personality disorder.

A Word From Verywell

Between 1999 and 2015, there was a 26.5 percent increase in suicide rates in the United States. Currently, there is no good treatment for suicidal thoughts. The American Psychiatric Association states “evidence for a lowering of suicide rates with antidepressant treatment is inconclusive.” Clearly, more effective approaches to address this pressing issue are needed. Because of its rapid onset, ketamine could prove very useful at reducing suicidal thoughts.

More generally, with regard to psychiatric illness, ketamine shows promise in treating depression and bipolar disorder—especially when these illnesses are treatment resistant.

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