The drug ketamine has been used intravenously for years to rapidly treat depression, because it can take effect within hours. Unfortunately, its antidepressant effects fade in 3–5 days, and it has some unpleasant side effects. In larger doses ketamine is used as an anesthetic and sometimes as a club drug, for its ability to induce hallucinations and dissociation. It can be addictive as well.
A 2016 animal study by Todd Gould and colleagues published in the journal Nature identified a byproduct of ketamine that may be able to provide the drug’s benefits without its side effects.
When the body breaks down ketamine, it produces several chemicals that are known as ketamine metabolites. The researchers found that one of these, called hydroxynorketamine, reversed a depression-like state in mice, without producing the side effects that would be expected of ketamine.
Gould and colleagues also determined that blocking the transformation of ketamine into hydroxynorketamine prevented ketamine’s antidepressant effects.
Ketamine’s unpleasant anesthetic and dissociative effects result from the blockade of a particular receptor for the neurotransmitter glutamate (the NMDA glutamate receptor). Researchers originally thought that the NMDA blockade was linked to ketamine’s antidepressant effects, but this appears not to be the case. Instead, hydroxynorketamine seems to activate a different type of glutamate receptor, the AMPA receptor.
Gould and colleagues plan to test hydroxynorketamine in humans soon. Because it has already been present in the human body following ketamine administration, they expect it to be safe.
We have written many times before about intravenous ketamine as a fast-acting antidepressant treatment that can produce results within hours. Unfortunately, these quick results tend to fade within a few days. Current research is focused on possible ways of extending ketamine’s antidepressant effects.
A 2016 article by Jaskaran B. Singh and colleagues in the American Journal of Psychiatry reported that giving depressed patients infusions of ketamine (0.5mg/kg of body weight) twice or three times per week improved their depression compared to placebo over a period of up to 2 weeks.
Side effects included headache, anxiety, dissociation, nausea, and dizziness. The dissociation was temporary and improved with repeated dosing.
Stress increases the risk of psychiatric illnesses such as major depression and post-traumatic stress disorder. Not everyone who experiences stress goes on to develop these illnesses, though. Researchers are currently trying to find out why, exploring treatments that might increase resilience and prevent mental illnesses.
Animal research is often used to study depression. Mice exposed to certain stressors behave in ways that resemble human depression—like giving up faster when they’re forced to tread water, or withdrawing from activities they once enjoyed, like eating sucrose. In a recent study by researcher Christine Denny and colleagues, mice were injected with either saline or ketamine, a rapid-acting antidepressant, and one week later they were exposed to triggers that typically produce a depressive response. Mice who received the saline injection still got depressed when, for example, they were repeatedly forced to confront a dominant mouse. But mice who received ketamine injections did better, maintaining their motivation and not showing signs of depressive behavior following the stress. The researchers concluded that ketamine may have a protective effect against stress.
Editor’s Note: These results are remarkable because ketamine’s effects are typically short-lived.
It has been known for years that ketamine, an anesthetic at higher doses, can quickly produce anti-depressant effects when delivered intravenously. However, these effects typically last only a few days. New research is exploring how to extend the antidepressant effects of ketamine.
Researcher Ella Daly and colleagues recently compared a form of ketamine called esketamine, this time delivered intranasally, to placebo in people with tough-to-treat depression that had resisted other treatments. Daly and colleagues randomized participants to receive one of three different doses of intranasal esketamine (28mg, 56mg, or 84mg) or placebo twice a week.
All of the doses of intranasal esketamine improved participants’ depression compared to placebo, with higher doses producing more sustained improvement. After the 2-week double-blind study, participants could choose to continue (or begin) taking esketamine for another nine weeks, tapering dosage slowly from twice a week to once every other week by the end. The participants were then monitored for another eight weeks. The intranasal esketamine doses they received led to sustained improvements in depression that lasted, in some cases, through the eight weeks following their final dose.
Side effects were not severe. Ketamine can produce dissociative sensations, but these tended to dissipate with two hours of administration.
Johnson and Johnson Pharmaceuticals funded this research, which was presented at a scientific meeting in 2015, and they plan to continue researching intranasal esketamine in the hopes of getting Food and Drug Administration approval for the drug.
Studies of rodents with depression-like behaviors revealed that the combination of low (sub-therapeutic) doses of lithium and infusions of ketamine produced antidepressant-like effects. Researchers believed this might mean that in humans, lithium might have a unique effect potentiating the effects of ketamine.
In a small study by Mark J. Niciu presented at the 2015 meeting of the Society for Biological Psychiatry, patients with bipolar depression taking lithium or valproate mood stabilizers were given ketamine infusions or control infusions. In the 23 patients taking lithium and the 13 taking valproate, ketamine’s antidepressant effects were significantly better than placebo, but there was no difference between lithium and valproate with regard to these antidepressant effects. These preliminary data in a small number of subjects do not support the proposition that lithium augments the effects of ketamine in depression.
Intravenous ketamine can bring about rapid improvement in depressive symptoms among people with treatment-resistant depression. Because of its rapid effects, which can appear after only two hours, ketamine is being investigated as a treatment for people with suicidal thoughts.
At the 2015 meeting of the Society of Biological Psychiatry, Laili Soleimani and colleagues presented a poster about their recent double blind, randomized, controlled pilot study of ketamine inpatients and outpatients who scored highly on a measure of suicidal ideation. The 24 participants were randomized to receive either a single intravenous infusion of ketamine (0.5mg/kg) or a single infusion of midazolam (0.045 mg/kg), which shares ketamine’s anxiety-reducing effects but does not have antidepressant effects. They reported suicidal thoughts at 24 hours post-infusion, 48 hours, 72 hours, and 7 days. At 48 hours, those who received ketamine reported significantly reduced suicidal ideation compared to those who received midazolam, but this effect was no longer significant at the 72-hour mark.
The findings show that ketamine can briefly reduce suicidal ideation, and that the treatment is safe and tolerable for patients. This pilot study paves the way for further study of ketamine to reduce suicidal thinking in people who are at high risk for suicidal behavior.
Intravenous ketamine is known for its fast-acting antidepressant effects, which can appear within two hours of an infusion. Researchers are now investigating its use for the reduction of suicidal thoughts. In a study presented in a poster at the 2015 meeting of the Society of Biological Psychiatry, Jennifer L. Vande Voort and colleagues compared the sleep of patients whose suicidal thoughts decreased after a single ketamine infusion (0.5 mg/kg over 40 minutes) to those whose suicidal thoughts remained.
Study participants whose suicidal thoughts diminished after one infusion of ketamine had better sleep quality the following night, with fewer disruptions in sleep than among those who did not have an anti-suicidal response to ketamine. The participants who responded well to ketamine had sleep quality similar to that of healthy controls.
Vande Voort and colleagues hope that these new findings about ketamine’s effect on sleep may provide clues to the biological mechanism behind ketamine’s effect on suicidal ideation.
Ketamine, an anesthetic sometimes used intravenously in the treatment of depression, can bring about rapid onset of antidepressant effects. A new meta-analysis by researcher Michael Bloch and colleagues presented at a recent conference showed that ketamine’s maximum antidepressant effects occur within one day of administration, and its effects remain significant (compared to control conditions) one week following infusion. Ketamine’s effects were diminished in patients taking other medications. There was a trend for better response in patients with bipolar disorder than with unipolar disorder.
Bloch and colleagues analyzed eight earlier studies including a total of 180 participants. In each study, ketamine had been compared to a control condition, either an infusion of saline solution or of midazolam, which mimics ketamine’s sensory effects but does not have antidepressant effects. The researchers are calling for more meta-analyses of ketamine studies to determine which patients respond best to ketamine and how to sustain ketamine’s effects.
Editor’s Note: In another poster presented at the same conference, James Murrough reported that patients with slower processing speed responded best to ketamine. Other findings have shown that those with a history of alcohol abuse and a common genetic variant of brain-derived neurotrophic factor (BDNF), the val-66-val allele of proBDNF, are more likely to respond to ketamine.
While it can sometimes take weeks for the effects of antidepressant treatments to appear, intravenous ketamine can produce antidepressant effects in as little as two hours. However, ketamine’s effects fade after three to five days. New animal research by Chi-Tso Chiu et al. explores whether adding lithium to ketamine treatment can produce more sustained antidepressant effects.
Mice who are restrained by being placed in a tube for several hours (chronic restraint stress) exhibit a behavioral and neurochemical profile that resembles human depression. When Chiu and colleagues pretreated these stressed mice with sub-therapeutic doses of lithium (600 mg/L) in their drinking water for several weeks, a sub-therapeutic dose of ketamine (2.5 mg/kg of body weight) was enough to produce robust antidepressant effects in the mice, while neither drug alone was effective at these doses.
The combination of ketamine and lithium also restored the density of spines on the dendrites of neurons in the medial prefrontal cortex. Post-treatment with lithium (1200 mg/L) for several weeks was also successful in extending the effects of a single (50 mg/kg) ketamine injection.
Both lithium and ketamine affect the intracellular signaling pathway mTOR. Ketamine activates the pathway, increasing levels of synaptic proteins and dendritic spine density. It also increases brain-derived neurotrophic factor (BDNF) and the BDNF receptor TrkB. BDNF is important for learning and memory.
When lithium was added to the treatment of the mice with ketamine, the mTOR and BNDF pathways were further activated. Lithium also inhibits the receptor GSK-3, supporting ketamine’s rapid-acting antidepressant effects.
Ketamine treatment can produce oxidative stress, in which toxic free radicals can endanger cells, and the addition of low doses of lithium also completely prevented this neurochemical side effect.
Chiu and colleagues hope that the findings of this study in mice can eventually be applied to research in humans in the hopes of finding a clinical option that would sustain the rapid-onset antidepressant effects of ketamine for the long term.