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.
At the International College of Neuropsychopharmacology (CINP) World Congress of Neuropsychopharmacology in 2014, several presentations and posters discussed treatments that bring about rapid-onset antidepressant effects, including ketamine, isoflurane, sleep deprivation, and scopolamine.
Multiple studies, now including more than 23 according to researcher William “Biff” Bunney, continue to show the rapid-onset antidepressant efficacy of intravenous ketamine, usually at doses of 0.5 mg/kg over 40 minutes. Response rates are usually in the range of 50–70%, and effects are seen within two hours and last several days to one week. Even more remarkable are the six studies (two double-blind) reporting rapid onset of antisuicidal effects, often within 40 minutes and lasting a week or more. These have used the same doses or lower doses of 0.1 to 0.2mg/kg over a shorter time period.
Attempts to sustain the initial antidepressant effects include repeated ketamine infusions every other day up to a total of six infusions, a regimen in which typically there is no loss of effectiveness. Researcher Ronald Duman is running a trial of co-treatment with ketamine and lithium, since both drugs block the effects of GSK-3, a kinase enzyme that regulates an array of cellular functions, and in animals the two drugs show additive antidepressant effects. In addition, lithium has been shown to extend the acute antidepressant effects of one night of sleep deprivation, which are otherwise reversed by a night of recovery sleep.
Ketamine’s effects are related to the neurotransmitter glutamate, for which there are several types of receptors, including NMDA and AMPA. Ketamine causes a large burst of glutamate presumably because it blocks NMDA glutamate receptors on inhibitory interneurons that use the neurotransmitter GABA, causing glutamatergic cells to lose their inhibitory input and fire faster. While ketamine blocks the effects of this glutamate release at NMDA receptors, actions at AMPA receptors are not blocked, and AMPA activity actually increases. This increases brain-derived neurotrophic factor (BDNF), which is also required for the antidepressant effects of ketamine. Ketamine also increases the effects of mTOR, a kinase enzyme that regulates cell growth and survival, and if these are blocked with the antibiotic rapamycin, antidepressant effects do not occur.
In animal studies, ketamine increases dendritic spine growth and rapidly reverses the effects of chronic mild unpredictable stressors on the spines (restoring their mature mushroom shape and increasing their numbers), effects that occur within two hours in association with its rapid effects on behaviors that resemble human depression.
About 50–70% of treatment-resistant depressed patients respond to ketamine. However, about one-third of the population has a common genetic variation of BDNF in which one or both valine amino acids that make up the typical val-66-val allele are replaced with methionine (producing val-66-met proBDNF or met-66-met proBDNF). The methionine variations result in the BDNF being transported less easily within the cell. Patients with these poorly functioning alleles of BDNF are less likely to get good antidepressant effects from treatment with ketamine.
Ketamine in Animal Studies
Researcher Pierre Blier reviewed the effects of ketamine on the neurotransmitters serotonin, norepinephrine, and dopamine. In rodents, a swim stress test is used to measure depression-like behavior. Researchers record how quickly the rodents give up trying to get out of water and begin to float instead. Blier found that ketamine’s effects on swim stress were dependent on all three neurotransmitters. For dopamine, ketamine’s effects were dependent on increases in the number of dopamine cells firing, not on the firing rate, and for norepinephrine, ketamine’s effects were dependent on increases in burst firing patterns. Each of these effects was dependent on glutamate activity at AMPA receptors. Given these effects, Blier believes that using ketamine as an adjunct to conventional antidepressants that tend to increase these neurotransmitters may add to its clinical effectiveness.
Important Anecdotal Clinical Notes
Blier reported having given about 300 ketamine infusions to 25 patients, finding that two-thirds of these patients responded, including one-third who recovered completely, while one-third did not respond to the treatment. Patients received an average of 12 infusions, not on a set schedule, but according to when they began to lose response to the last ketamine infusion. If a patient had only a partial response, Blier gave the next ketamine treatment at a faster rate of infusion and was able to achieve a better response. These clinical observations are among the first to show that more than six ketamine infusions may be effective and well tolerated. Read more
To study depression in humans, researchers look to rodents to learn more about behavior. Rodents who are repeatedly defeated by more aggressive animals often begin to exhibit behavior that resembles depression. At the 2014 meeting of the International College of Neuropsychopharmacology (CINP), researcher Andre Der-Avakian reported that in a recent study, repeated experiences of social defeat led to depressive behavior in a subgroup of animals (which he calls susceptible), but not in others (which he calls resilient). Among many biological differences, the resilient animals showed increases in neurogenesis in the dentate gyrus of the hippocampus.
Chronic treatment of the susceptible animals with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine or the tricyclic antidepressant desipramine, which both increase neurogenesis, also reversed the depressive behavior in about half of the animals. A single injection of the anesthetic ketamine (which has rapid-acting antidepressant effects in humans) reversed social avoidance behavior in about 25% of the animals. One depression-like symptom was anhedonia (loss of pleasure from previously enjoyed activities), which researchers measured by observing to what extent the animals engaged in intracranial self-stimulation, pressing a bar to stimulate the brain pleasurably. The effectiveness of the drugs in inducing resilient behavior was related to the degree of anhedonia seen in the animals. The drugs worked less well in the more anhedonic animals (those who gave up the intracranial stimulation more easily, indicating that they experienced less reward from it.)
We reported in BNN Volume 17, Issue 6 in 2013 on researchers’ efforts to treat symptoms of post-traumatic stress disorder using the drug ketamine. This research by Adriana Feder et al. has now been published in the journal JAMA Psychiatry.
In the study of 41 patients with post-traumatic stress disorder, patients showed a greater reduction in symptoms 24 hours after receiving intravenous (IV) ketamine than after taking IV midazolam, a benzodiazepine used as an active placebo control because it produces anti-anxiety and sedating effects similar to ketamine’s. The patients ranged in age from 18 to 55 years of age and were free of other medication for two weeks before the study. Ketamine was also associated with reduction in depressive symptoms and with general clinical improvement, and side effects were minimal.
In a recent study by Ghasemi et al. published in the journal Psychiatric Research, 18 patients with unipolar depression were divided into two groups, one that received intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 minutes) three times (every 48 hours), and another that received electroconvulsive therapy (ECT) on the same schedule.
Ketamine produced antidepressant effects more quickly than ECT, and these effects were significantly better than baseline for the duration of the study, but not significantly different from those achieved through ECT by the end of the study.
Editors Note: These data continue to add to the already strong findings that ketamine produces rapid-onset antidepressant effects. When and where ketamine should be incorporated into routine clinical treatment of depression remains to be further clarified.
Brain-derived neurotrophic factor (BDNF) keeps neurons healthy and is critical for long-term memory and synapse formation. BDNF levels increase in the nucleus accumbens (the brain’s reward center) and decrease in the hippocampus during clinical depression and chronic cocaine use. In rodents, the same changes in BDNF levels occur during defeat stress (which resembles human depression).
Rodents who are repeatedly defeated by a larger rodent exhibit behaviors such as social withdrawal, lethargy, and decreased interest in sucrose. The increases in BDNF in the nucleus accumbens of these rodents could reflect the learning that takes place during the repeated defeat stress and the depression-like behaviors that follow it. Blocking the BDNF increases in the nucleus accumbens prevents these behaviors from developing.
Chadi Abdallah and other researchers at Yale University recently found that the left nucleus accumbens of patients with treatment-resistant depression is enlarged compared to normal controls, and the drug ketamine, which produces rapid-onset antidepressant effects, rapidly decreases the volume of the nucleus accumbens in the depressed patients. The mechanism by which it does so is unknown, but could reflect some suppression of the depressive learning.
Any relationship between the volume of the nucleus accumbens and its levels of BDNF is unknown, but ketamine’s effect on the size of this brain region could be linked to a decrease in the defeat-stress memories.
Brain-derived neurotrophic factor (BDNF) is a protein in the brain that protects neurons and is necessary for long-term memory and learning. Different people have different genetic variations in BDNF depending on which amino acid the gene that codes for it inserts into the protein, valine or methionine. There are three possible combinations that vary in their efficiency. The Val66Val allele of BDNF is the most efficient for secreting and transporting BDNF within the cell body to synapses on dendrites, and is also a risk factor for early onset of bipolar disorder and rapid cycling. Twenty-five percent of the population has a Met variant (either Val66Met or Met66Met), which functions less efficiently. These people have mild decrements in some cognitive processing.
Increases in BDNF are necessary to the antidepressant effects of intravenous ketamine. In animals, ketamine also rapidly changes returns dendritic spines that had atrophied back to their healthy mushroom shape in association with its antidepressant effects. Depressed patients with the better functioning Val66Val allele of BDNF respond best to ketamine, those with the intermediate functioning Val66Met allele respond less well, and those with the poorest functioning Met66Met allele virtually do not respond at all.
Researcher Ronald S. Duman of Yale University recently found that increases in BDNF in the medial prefrontal cortex are necessary to the antidepressant effects of ketamine. If antibodies to BDNF (which block its effects) are administered to the prefrontal cortex, antidepressant response to ketamine is not observed.
Duman also found that calcium influx through voltage sensitive L-type calcium channels is necessary for ketamine’s antidepressant effects. A genetic variation in CACNA1C, a gene that codes for a subunit of the dihydropiridine L-type calcium channel, is a well-replicated risk factor for bipolar disorder. One might predict that those patients with the CACNA1C risk allele, which allows more calcium influx into cells, would respond well to ketamine.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Vilma Gabbay of the Mount Sinai School of Medicine reiterated the findings from the TORDIA (Treatment of SSRI-Resistant Depression in Adolescents) study that 20% of young people with depression remained resistant to treatment, childhood-onset depression was more likely to be recurrent and more difficult than adult-onset depression in the long run, and suicide was the second leading cause of death in 12- to 17-year-olds in 2010 according to a Centers for Disease Control report in May 2013. Anhedonia (a loss of pleasure in activities once enjoyed) was the most difficult symptom to treat in adolescents.
Gabbay carefully explained some of the rationales for using ketamine in young people with depression. The presence of inflammation is a poor prognosis factor, and ketamine has anti-inflammatory effects, decreasing levels of inflammatory markers CRP, TNF-alpha, and Il-6.Given that ketamine has been widely used as an anesthetic for surgical procedures, its safety in children has already been demonstrated. Ketamine did not appear to cause behavioral sensitization (that is, increased effect upon repetition) in a report by Cho et al. in 2005 that included 295 patients.
As noted previously, Papolos et al. reported in a 2012 article in the Journal of Affective Disorders that intranasal ketamine at doses of 50 to 120 mg was well-tolerated and had positive clinical effects in 6- to 19-year-olds with the fear of harm subtype of bipolar disorder that had been highly resistant to treatment with more conventional drugs.
Gabbay reluctantly endorsed further cautious controlled trials in children and adolescents, in light of ketamine’s suggested efficacy and good safety profile, which stands in contrast to its popular reputation as a party drug or “Special K.”
Editor’s Note: The discussant of the symposium, Neal Ryan of Western Psychiatric Institute and Clinic, added an exquisitely brief discussion suggesting that ketamine should ultimately be studied in combination with behavioral and psychotherapeutic procedures to see if its therapeutic effects could be enhanced. He made this suggestion based on the data that ketamine has important synaptic effects, increasing brain-derived neurotrophic factor (BDNF), which is important for healthy cells and long-term memory, and reverting thin dendritic spines caused by stress back to their normal mushroom shape. This editor (Robert Post) could not be more in agreement.
In a recent study, ketamine performed better than an active comparator on several measures in adults with post-traumatic stress disorder (PTSD). Since ketamine has noticeable dissociative effects, researchers have looked for another drug with mind-altering effects that would be a more appropriate comparator than placebo.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Adriana Feder of Mount Sinai Hospital reported on the randomized study in those with PTSD, in which intravenous ketamine was compared to intravenous midazolam, a potent benzodiazepine that produces anti-anxiety and sedating effects. Murrough et al. previously showed that intravenous ketamine was superior to midazolam in treatment-resistant depression.
In the randomized study Feder described, the participants had suffered PTSD from a physical or sexual assault and had been ill for 12 to 14 years. Those who received ketamine improved more, in some instances for as long as two weeks (ketamine’s blood levels disappear after a few hours, and its clinical antidepressant effects usually last only a few days). Reports of side effects included three patients with blood pressure increases requiring treatment with propranolol, and four patients who each had a transient episode of vomiting.
These controlled data parallel previous open observations. When ketamine was used as a surgical anesthetic during operations on burn patients, only 26.9% subsequently reported PTSD compared to 46.4% who developed PTSD when an alternative to ketamine was used as the anesthetic.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Kyle Lapidus of Mount Sinai Hospital reviewed the literature from controlled studies on the efficacy of intravenous (IV) ketamine at a dosage of 0.5 mg/kg over a 40-minute infusion for adults with treatment-resistant depression (with consistent response rates of 50% or more), and suggested that intranasal ketamine may also be effective.
Ketamine is a strong blocker of the glutamate NMDA receptor. At high doses (6 to 12 mg/kg) it is an anesthetic, at slightly lower doses (3 to 4 mg/kg) it is psychotomimetic (causing psychotic symptoms) and is sometimes used as a drug of abuse, and at very low doses it is a rapidly acting antidepressant, often bringing about results within 2 hours. Antidepressant effects typically last 3 to 5 days, so the question of how to sustain these effects is a major one for the field.
Murrough et al. reported in Biological Psychiatry in 2012 that five subsequent infusions of ketamine sustained the initial antidepressant response and appeared to be well tolerated by the patients. Another NMDA antagonist, riluzole (used for the treatment of ALS or Lou Gehrig’s disease), did not sustain the acute effects of ketamine, and now lithium is being studied as a possible strategy for doing so.
The bioavailability of ketamine in the body depends on the way it is administered. Compared to IV administration, intramuscular (IM) administration is painful but results in 93% of the bioavailability of IV ketamine. Intranasal (IN) administration results in 25-50% of the bioavailability of IV administration, while oral administration results in only 16-20% of the bioavailability of IV administration, so Lapidus chose to study the IN route. He compared intranasal ketamine at doses of 50mg (administered in a mist ) to 0.5 ml of intranasal saline. Both were given in two infusions seven days apart. Lapidus observed good antidepressant effects and good tolerability. Papolos et al. had reported earlier that intranasal ketamine had good effects in a small open trial in treatment-resistant childhood onset bipolar disorder.
Editor’s Note: Further studies of the efficacy and tolerability of intranasal ketamine are eagerly awaited.