Meta-Analysis Shows Effectiveness of Ketamine for Bipolar and Unipolar Depression
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.
Lithium Extends Anti-Depressant Effects of Ketamine in Mice
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.
Antidepressants and Ketamine Reverse Animal Models of Anhedonia and Learned Helplessness
Researcher Tony Pitts presented a study at the 2014 meeting of the International College of Neuropsychopharmacology (CINP) that described the neurobiology of an animal model of depression in rodents. In animal models, researchers provoke depression-like symptoms in animals with the hopes of finding neurobiological clues to human depression. Pitts’ studies explored the effects of acute stressors as well as more chronic long-term stressors such as learned helplessness.
In the rodents, acute stressors caused increased cell firing in the hippocampus, which caused increases in burst firing and an increase in the number of cells firing in the ventral tegmental area, which then led to increased activity in the nucleus accumbens (the brain’s reward center). However, after the stressor was over, there was an opponent process that resulted in a much more prolonged period of inhibition in the nucleus accumbens, with associated decreases in psychomotor activity and reward seeking. The rodents lost their preference for sucrose and engaged in less intracranial self-stimulation, pressing a bar to stimulate the brain pleasurably. These and other effects suggest an analogy to anhedonia (loss of pleasure in activities that were previously enjoyed), which is a key component of human depression.
In related studies, after experiencing periods of inescapable shocks, rodents developed learned helplessness, failing to avoid the area where shocks were delivered even when an exit was readily available. Rodents who had learned helplessness showed inhibited firing of cells in the ventral tegmental area, less activity in the nucleus accumbens, and apparent anhedonia. This inhibition was mediated via messages from the infralimbic prefrontal cortex (the equivalent to the subgenual cingulate cortex in humans, important for motivation) to the amygdala and then the GABAergic ventral pallidum, which decreased the number of dopaminergic cells firing in the ventral tegmental area. Blocking the amygdala input to this inhibitory pathway reversed the low dopamine firing and the anhedonia-like behaviors.
The anesthetic ketamine (which has rapid-acting antidepressant effects in humans) produces an immediate reversal of the learned helpless behavior in the rodents and increases the number of dopamine cells firing in the ventral tegmental area. Ketamine administered directly into the nucleus accumbens induces long-term potentiation (enhanced synaptic responsivity) and reverses helpless behavior and the long-term depression of neural firing that is associated with it.
Thus, when an acute stressor is over and the opponent process emerges, or following long-term chronic stressors such as learned helplessness, the excitatory path to the ventral tegmental area is absent, while the inhibitory path to the ventral tegmental area (via the infralimbic prefrontal cortex, amygdala, and ventral pallidum) predominates. Ketamine is able to re-activate the activating pathway and increase activity in the ventral tegmental area and the nucleus accumbens, changes that are associated with the reversal of learned helplessness and anhedonia.
Editor’s Note: In the previous BNN, we reported researcher Scott Russo’s findings that input from the intralaminar nucleus of the thalamus was critical to the depression-like behaviors seen in a different animal model of depression, social defeat stress, where repeated exposure to defeat by a larger, more aggressive animal produces behaviors that resemble human depression. Here in Pitts’ research, learned helplessness is induced by inescapable shocks. Both models share the finding that firing decreases in the reward area of the brain (the nucleus accumbens). However, the key part of the brain driving the low levels of activity in the nucleus accumbens and the associated depression-like behavior appear to be different in these two different models. The intralaminar nucleus of the thalamus plays a key role in the social defeat stress model, while the infralimbic cortex and the amygdala play key roles in the learned helplessness model. These data together suggest that part of the reason depression differs from person to person may be because the illness can be driven by different brain areas as a result of different kinds of stressors.
Antidepressants and Ketamine Induce Resilience in Animals Susceptible to Depression-Like Behavior
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.)
Ketamine for Chronic PTSD
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.
IV Ketamine Produces Antidepressant Effects More Rapidly Than ECT
More and more evidence suggests that drugs such as ketamine that work by blocking the brain’s NMDA receptors can produce rapid-acting antidepressant effects in patients with depression.
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.
A Common Variant of BDNF Predicts Non-Response to IV Ketamine
Valine
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. According to research published by Gonzalo Laje and colleagues in the journal Biological Psychiatry in 2012, depressed patients with the better functioning Val66Val allele of BDNF respond best to ketamine, while those with the intermediate functioning Val66Met allele respond less well.
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.
Rationale for Using Ketamine in Youth with Treatment-Resistant Depression
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.
IV Ketamine Superior to IV Midazolam in Adults with PTSD
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.
Intranasal Ketamine May Be an Alternative to IV in Refractory Depression
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.
