New Findings On IV Ketamine For Treatment-Resistant Depression
We’ve written before about the rapid-onset antidepressant effects of ketamine, an anesthetic that is used in human and veterinary medicine. At lower doses, intravenous (IV) ketamine can induce antidepressant effects in both unipolar and bipolar depressed patients. When doses of 0.5mg/kg are infused over a period of 40 minutes, antidepressant effects appear within two hours but are short-lived, typically lasting only three to five days. Results have been consistent across studies at Yale University, the Icahn School of Medicine at Mount Sinai, and the National Institute of Mental Health. So far, clinical use has been limited by the short duration of the effects and the required presence of an anesthesiologist, which can be prohibitively expensive for many patients.
In a cover story in the January 2013 issue of Psychiatric Times, Arline Kaplan reviewed new findings about ketamine. The drug is a high-affinity, noncompetitive NMDA-glutamate receptor antagonist. It is not yet FDA-approved for use in depression.
According to a recent article by Murrough and Charney, response rates to ketamine are around 54% and the drug “appears to be effective at reducing the range of depressive symptoms, including sadness, anhedonia [the loss of ability to experience pleasure], low energy, impaired concentration, negative cognitions, and suicidal ideation.”
David Feifel, Director of the Neuropsychiatry and Behavioral Medicine Program at the University of California at San Diego (UCSD), instituted a program there in which patients can receive treatment with ketamine for clinical purposes (rather than for research) after signing detailed informed consent forms and being warned that the treatment is not yet approved for depression and that its effects may be temporary. The UCSD Medical Center’s Pharmacy and Therapeutics Committee, with the support of the anesthesiology department, agreed that nurses may administer the ketamine in an outpatient setting, making the procedure more affordable.
There is still the question of how to make ketamine’s effects last. Read more
Developing Rapid Onset Antidepressant Drugs That Act at the NMDA Receptor
For several years, researchers have been exploring potential rapid-acting treatments for unipolar and bipolar depression. Intravenous ketamine has the best-replicated results so far. A slow infusion of ketamine (0.5mg/kg over 40 minutes) produces a rapid onset of antidepressant effects in only a few hours, but the improved mood lasts only 3-5 days.
Ketamine blocks the receptors of the main excitatory neurotransmitter in the central nervous system, glutamate. Glutamate is released from nerve endings and travels across the synapse to receptors on the next cell’s dendrites. There are multiple types of glutamate receptors at the dendrites, and ketamine blocks one called the NMDA receptor, which allows calcium ions to enter the cell.
Some downsides to ketamine are the brief duration of its effectiveness and its dissociative side effects. The search is on for other drugs that are free from these side effects and that could extend the duration of rapid-onset antidepressant effects.
At the 2012 meeting of the International Congress of Neuropsychopharmacology (CINP), Mike Quirk of the pharmaceutical company AstraZeneca reviewed data on the intricacies of the glutamate NMDA receptor blockade and discussed the potential of AZD6765, an NMDA receptor blocker he and his colleagues have been researching.
The more the NMDA receptor is blocked, the more psychomimetic it becomes, meaning it produces hallucinations and delusions. For example, phencyclidine (PCP or angel dust) is a potent NMDA receptor blocker and psychosis inducer. For antidepressant purposes, a less complete or less persistent NMDA receptor blockade is desired. Read more
High Sustained Success Rate With Adjunctive Memantine (Namenda) in Treatment-Resistant Bipolar Disorder
Koukopoulos et al. published a study of the anti-Alzheimer’s drug memantine in the Journal of Affective Disorders in 2012. The study of memantine (10-30mg/day) as an add-on to patients’ regular treatment for highly treatment-resistant bipolar disorder was open (i.e. not blind, randomized or placebo-controlled), but it deserves careful attention for its noteworthy results. Of the 40 patients in the study, who had been severely ill for long periods of time, 72.5% showed a rating of much or very much improved on the Clinical Global Impressions Scale for Bipolar Disorders (CGI-BP) after both 6 months and 12 months. Among rapid cyclers, 68.4% stabilized and remitted on memantine.
Editor’s Note: Memantine is an antagonist of glutamate NMDA receptors and is approved by the Federal Drug Administration (FDA) for the treatment of Alzheimer’s dementia, but not for other indications. Nonetheless, few (if any) drugs have this high a response rate in such a difficult-to-treat population, and the researchers suggest that even based on these preliminary data (which replicate their previous observations), careful clinical trials of memantine in individual patients would be worthy of consideration.
The data are so promising that fast-track development of this drug for FDA approval would be warranted. More formal randomized controlled clinical trials are needed.
We have written before about a few treatments that have rapid-onset antidepressant effects, including intravenous (IV) ketamine (at a dose of 0.5mg over 40 minutes). Ketamine works by blocking glutamate NMDA receptors, but the rapid antidepressant effects it produces (within 2 hours of treatment) last only 3 to 4 days. Given the similar mechanisms of action of ketamine and memantine and memantine’s high success rate in this study by Koukopoulos, it is plausible that treatment with memantine could extend the rapid onset effects of IV ketamine. However, this speculation has not yet been tested. At the very least, the similarity between the mechanisms of memantine and ketamine in blocking the glutamate NMDA receptor lends additional support to the clinical rationale for treating bipolar disorder with adjunctive memantine.
Procedures with Rapid-Onset Antidepressant Effects
At a recent scientific meeting, Carlos Zarate of the National Institute of Mental Health (NIMH) discussed a variety of rapid-onset antidepressant manipulations. The talk focused on intravenous (IV) administration of the NMDA receptor antagonist ketamine and the anticholinergic drug scopolamine.
IV Ketamine
Intravenous ketamine has been administered to approximately 1000 patients at research centers at Mount Sinai Hospital in New York, Yale University, and at the NIMH in Bethesda. The results have been consistent; more than half of the patients experienced a rapid onset of antidepressant effect, usually within the first 2 hours. However, the effects of intravenous ketamine tend to disappear after 3 to 5 days.
In both unipolar and bipolar depressed patients whose illness has been highly resistant to multiple treatments, ketamine also brings about a rapid-onset decrease in suicidal ideation and intent. In some cases these positive effects have lasted a week or more. Thus intravenous ketamine could potentially be used at hospitals to treat suicidal emergencies.
Scopolamine
New data indicate that intravenous scopolamine, a selective blocker of muscarinic cholinergic receptors that is used to help ward off seasickness, brings about onset of antidepressant effects in up to one day and sometimes in a matter of hours. As with ketamine, these effects occur in both unipolar and bipolar depressed patients.
Mechanisms of Action of Ketamine
Editor’s Note: New data from animal studies may be able to explain some of the mechanisms behind the rapid onset of antidepressant effects that occurs with ketamine. Ketamine causes increases in brain-derived neurotrophic factor (BDNF), which is important for the development and health of neurons. In rodents, new synaptic proteins are created following intravenous administration of ketamine.
If animals are subjected to chronic unpredictable stress, dendritic spines (on which synapses are formed) appear to shrink. However, when ketamine is administered intravenously to these animals, not only is their behavior rapidly ameliorated, but the thin dendritic spines shift back to their more mature, mushroomed-shaped form within a few hours. (A slightly slower, less dramatic change in spines occurs with scopolamine.) A loss of dendritic volume has also been demonstrated in depressed people.
The data in animals are not only valuable for their potential application in clinical treatment and emergency situations involving suicidal ideation, but they also demonstrate a mechanism by which a single administration of intravenous ketamine or scopolamine is capable not only of reversing depressive behaviors in animals, but changing dendritic spine morphology. Given this development, it may be possible to identify other treatments that induce rapid-onset antidepressant effects using other parts of the same neurological pathways.
Other Rapid-Onset Approaches: TRH and Sleep Deprivation
Intravenous thyrotropin releasing hormone (TRH) also has rapid-onset antidepressant effects within 24 hours in depressed patients, but tolerance develops after repeated use.
Surprisingly, one night of complete sleep deprivation can also bring about dramatic onset of antidepressant effects the following day in approximately 50% of severely depressed patients.
In animal studies by Ron Duman and colleagues at Yale University, administration of brain-derived neurotrophic factor (BDNF) either into a rodent’s blood or its brain has induced rapid-onset antidepressant-like effects.
Taken together, these data indicate that there are ways to bring about rapid improvement in depression, even if conventional antidepressants usually require 2 to 4 weeks to exert their maximum antidepressant effects. Read more
Clinical Evidence May Explain the Mechanisms of Ketamine’s Rapid Acting Antidepressant Effects
At the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011, C.G. Abdallah from SUNY Downstate Medical Center reported on a study of intravenous ketamine for treatment-resistant depression. Twelve medication-free participants aged 18-65 received 0.5mg/kg ketamine over 40 minutes. There was a rapid-onset antidepressant effect, as there has been in other studies of unipolar and bipolar depressed patients. In a subgroup of 4 patients examined with magnetic resonance spectroscopy (MRS), there were rapid increases in brain GABA followed shortly thereafter by increases in brain glutamate concentrations.
Editor’s note: The rapid increases in GABA and glutamate that occur after the administration of intravenous ketamine may help account for its therapeutic effects. Other studies have shown that brain GABA is low in depressed patients, so the rapid increase in GABA with ketamine administration could partly explain the antidepressant effects of the drug. The role of the glutamate increases remains to be further explored.
Neli and associates from Yale had reported that in animals, ketamine was able to rapidly alter synapse structure and function. In an animal model of depression, rodents are exposed to chronic and unpredictable stress and develop depressive-like behavior. The mature, mushroom-shaped spines on their dendrites (the parts of neurons that receive synapses and determine the neuron’s excitability) also lose their shape, becoming straighter and spikier like immature spines. Intravenous ketamine not only improves the animals’ behavior, but also increases the number of mushroom-shaped spines within a matter of hours, rapidly improving synaptic function. This effect of ketamine was dependent on a novel intracellular pathway involving the enzyme mTOR, which if blocked prevented the re-emergence of the mature spines.
In the brains of depressed humans studied at autopsy there is reduced neural volume in the frontal cortex, which could possibly be related to dendritic atrophy and associated changes in spine shape as it appears to be in rodents. The animal data suggest the remarkable possibility that intravenous ketamine’s rapid onset of antidepressant effects could also be associated with rapid improvement in the microanatomy of the brain.
The data on ketamine’s effects in animals and the new clinical data showing that GABA and glutamate increases occurred rapidly in depressed patients administered ketamine provide further insight into the potential mechanisms of ketamine’s effect.
Ketamine Infusions May Help in Suicidal Emergencies
Intravenous ketamine has consistently been found to bring about almost immediate antidepressant effects (usually within two or three hours), which can last three to five days in duration. Typical doses are 0.5 mg/kg IV infusion over 40 minutes. A new abstract presented at the meeting of the American College of Emergency Physicians in 2010 indicated that when patients received 0.2 mg/kg ketamine infused over a period of 1-2 minutes, suicidal ideation decreased within 40 minutes. Fourteen of 15 subjects were no longer suicidal after the infusion, and in 13 of those 14 the improvement was sustained at follow-up ten days later.
Editor’s note: Such rapidly occurring, robust antidepressant/antisuicidal effects from IV ketamine continue to suggest that it is useful for emergency room therapeutic maneuvers.
Ketamine Effective in ECT-Resistant Depression
In an abstract presented at the Society of Biological Psychiatry meeting in May, Lobna Ibrahim and Carlos Zarate of the National Institute of Mental Health reported that intravenous infusions of ketamine were effective in a majority of patients with highly treatment-resistant depression, i.e. even those who had been unresponsive to a course of electroconvulsive therapy.
Editor’s note: Few treatments have been explored for this subgroup of highly treatment-resistant patients, although some have been referred for experimental protocols with intracranial deep brain stimulation (DBS) and others have been successfully treated by Mark George and colleagues at the Medical University of South Carolina with very high intensity rTMS over the left prefrontal cortex (at 130% of motor threshold, 10 Hz stimulation). Further study is needed to determine what follow-up procedures can be used to sustain an acute response to ketamine, rTMS, or ECT for the long term. Read more
