New Research on Ketamine
The drug ketamine can produce antidepressant effects within hours when administered intravenously.
Finding an Appropriate Control
Comparing ketamine to placebo has challenges because ketamine produces mild dissociative effects (such as a feeling of distance from reality) that are noticeable to patients. At the 2013 meeting of the Society of Biological Psychiatry, James W. Murrough and collaborators at the Mount Sinai School of Medicine reported their findings from the first controlled trial of intravenous ketamine in depression that uses an active control, the short-acting benzodiazepine midazolam, which has sedative effects and decreases anxiety, but is not known as an antidepressant. On virtually all measures intravenous ketamine was a more effective antidepressant following 2 infusions per week.
These data help dispel one of the criticisms of intravenous ketamine, that studies of the drug have not been sufficiently blinded (when patients and medical staff are kept from knowing which patients receive an active treatment and which are in the placebo control group) and that the lack of an appropriate active placebo contributed to the dramatic findings about ketamine’s antidepressant effects. It now appears that these criticisms have been appropriately answered and that intravenous ketamine is highly effective not only in comparison to placebo but also to an active comparator.
This research was presented as a poster at the meeting and published as abstract #442 in the meeting supplement to the journal Biological Psychiatry, Volume 73, Number 9S, and was also published in the Archives of General Psychiatry in 2013.
Slowing Down Ketamine Infusions to Reduce Side Effects
Ketamine is commonly given in 40-minute intravenous infusions. Timothy Lineberry from the Mayo Clinic reported in Abstract #313 from the meeting that slower infusions of ketamine over 100 minutes were also effective in producing antidepressant effects in patients with treatment-resistant depression. Lineberry’s research group used the slower infusion in order to increase safety and decrease side effects, such as the dissociative effects discussed above. In the 10 patients the group studied, they observed a response rate of 80% and a remission rate of 50% (similar to ketamine’s effects with 40-minute infusions).
Family or Personal History of Alcohol Dependence Predicts Positive Response to Ketamine in Depression
Mark J. Niciu and collaborators at the NIMH reported in Abstract #326 that a personal or family history of alcohol dependence predicted a positive response to IV ketamine in patients with unipolar depression.
Ketamine Acts on Monoamines in Addition to Glutamate
Ketamine’s primary action in the nervous system is to block glutamate NMDA receptors in the brain. In addition to its effects on glutamate, it may also affect the monoamines norepinephrine and dopamine. Kareem S. El Iskandarani et al. reported in Abstract #333 that in a study of rats, ketamine increased the firing rate of norepinephrine neurons in a part of the brain called the locus coeruleus and also increased the number of spontaneous firing dopamine cells in the ventral tegmental area of the brain.
Editor’s Note: These data showing that ketamine increased the activity of two monoamines could help explain ketamine’s ability to induce rapid onset of antidepressant effects, in addition to its ability to immediately increase brain-derived neurotrophic factor (BDNF, important for long-term memory and the creation of new synapses) and to restore healthy mushroom-shaped spines on the dendrites of neurons in the prefrontal cortex.
Family History Of Alcoholism Predicts Positive Response To Ketamine
The drug ketamine can bring about antidepressant effects rapidly when given intravenously, but these effects last only a few days. In a recent study, bipolar depressed patients with alcoholism or a family history of alcoholism in first-degree relatives had a more extended positive antidepressant response to IV ketamine than those without this history, and fewer adverse effects from the treatment. The study, published by David Luckenbaugh et al. from the National Institute of Mental Health in the journal Bipolar Disorders in December 2012, replicates similar findings in patients with unipolar depression, where positive family history of alcoholism also predicted better response and fewer adverse effects from IV ketamine.
Alcohol and ketamine have a common mechanism of action. They are both antagonists of the glutamate NMDA receptor, meaning they limit the effects of glutamate, the major excitatory neurotransmitter in the brain. This suggests a theoretical explanation for why a history of alcoholism might relate to ketamine response.
Editor’s Note: Family history appears to be linked to how patients respond to different mood stabilizers. Lithium works best in those patients with a positive family history of mood disorders (especially bipolar disorder). Carbamazepine works best in those without a family history of bipolar disorder among first-degree relatives. Lamotrigine works best in those with a positive family history of anxiety disorders or alcoholism.
Drugs that are effective in patients with a family history of alcoholism all target glutamate in the brain. Lamotrigine decreases glutamate release, while ketamine reduces glutamate’s effects at the receptor. Both decrease glutamate function or activity. Like lamotrigine, carbamazepine also decreases glutamate release and has good effects in those with a history of alcoholism.
Memantine is another mood-stabilizing drug that is an antagonist of the NMDA receptor, like ketamine and alcohol. It will be interesting to see whether memantine will also be successful in those with a personal or family history of alcoholism.
Intranasal Ketamine Helps Some Kids with Bipolar Disorder
The anesthetic ketamine given intranasally may help children with a certain type of bipolar disorder. In an article published in the Journal of Affective Disorders in 2013, Demetri Papolos et al. reported seeing marked improvement in a subgroup of 12 children aged 6 to 19 years of age who were nonresponsive to the usual treatment regimens of lithium, mood stabilizers, and antipsychotics. Papolos has described these children as having the “fear of harm (FOH) subtype.” In addition to having typical mood swings, these children also have a fear of aggression, separation anxiety, sleep and circadian rhythm disorders, nightmares, thermoregulatory problems, and carbohydrate craving.
Ketamine was given as an intranasal spray using an inhaler in 10mg doses. Doses were increased until the targeted symptoms remitted. Average doses ranged from 30mg to 120mg, given every 3 to 7 days. All symptom areas including depression and mania improved markedly, usually within a few hours, and this improvement lasted 3 to 4 days. Four types of aggression (measured on the Overt Aggression Scale) decreased significantly.
There were some dissociative side effects that were usually mild to moderate, but occasionally severe. They resolved spontaneously, usually within the first hour after treatment, and there appeared to be tolerance to them following repeated administration.
The authors urged caution until findings from these cases are confirmed by more controlled studies, but they concluded that the magnitude and rapidity of effects in these children with treatment resistant bipolar disorder suggested effectiveness and safety.
Ketamine for OCD
At a recent scientific meeting, researcher Carolyn Rodriguez presented a randomized controlled crossover trial of ketamine in obsessive-compulsive disorder (OCD). In contrast to a previous negative study by Block and associates at the National Institute of Mental Health (NIMH), these investigators found that intravenous (IV) infusion of ketamine (0.5 mg/kg over 40 minutes) was associated with a larger reduction in obsessive-compulsive symptoms when compared with saline infusion. These effects were rapid in onset and persisted for approximately one week in 50% of the patients with OCD who had constant intrusive thoughts.
This dose of ketamine had previously been shown to induce rapid-onset improvement in depression and suicidal ideation in those with unipolar and bipolar depression. However, the improvement in obsessive-compulsive disorder symptoms appeared unrelated to any antidepressant effect because the individuals with OCD had minimal depressive symptoms at baseline.
The traditional pharmacological treatments for OCD are selective serotonin reuptake inhibitor (SSRI) antidepressants, which require high doses and weeks to months before the onset of full effect. In contrast, Rodriguez et al. found a 90% response rate to IV ketamine within 3 hours.
Ketamine is a blocker of the glutamate NMDA receptors, and these data suggest that targeting these receptors can induce rapid onset of positive effects in OCD. However, as is the case with the acute antidepressant response to ketamine in those with depression, the best ways to extend this therapeutic effect long-term remain to be determined.
Another blocker of NMDA receptors, the anti-Alzheimer’s drug memantine (Namenda), has been reported in open studies to show improvement in those with OCD as well. N-acetylcysteine, a substance found in health-food stores, likewise appears to re-regulate a hyper-responsive glutamatergic system in the nucleus accumbens by other mechanisms, and was also shown to have efficacy as an augmenting treatment in OCD in those who are inadequately responsive to SSRIs in a 2012 article by Afshaw et al.
Editor’s Note: Taken together, the data with ketamine, memantine, and N-acetylcysteine suggest that glutamate-based mechanisms are involved in OCD and may provide an alternative target for therapeutics in addition to serotonin.
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
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
Disrupted Circadian Temperature Rhythm in Skin Temperature in Bipolar Mania
Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023
Andrea Stautland of University of Bergen studied the nocturnal temperature of sleeping participants in mania and during remission between 3:00am and 6:00am (n=12). In mania, but not in remission there were “highly significant mean changes (lack of night time decreases) between baseline and 4:30am and 6:00am, with p=0.012 and p=0.037, respectively.”
Editors Note: This data is of interest in light of the new subtype of unspecified bipolar disorder called Temperature and Sleep Dysregulation Disorder (TSDD) characterized by profound behavioral dyscontrol, marked sleep disturbance, and temperature dysregulation (red face and ears, being too hot, going out in the cold underdressed). This extremely dysfunctional syndrome responds to high dose lithium; melatonin, clonidine, and other cooling techniques; and ascending and then repeated doses of intranasal ketamine (as described by Papolos et al 2013; 2018).
“Pharmacotherapy of Bipolar Depression”
Roger McIntyre gave a talk on the “Pharmacotherapy of Bipolar Depression” at the International Society for Bipolar Disorders Conference in Chicago, June 22-25, 2023
He pointed out that, contrary to the many approved agents for mania, there were few FDA-approved drugs for depression in patients with Bipolar Disorders. These approved drugs included: cariprazine (Vraylar); lumateperone (Caplyta); lurasidone (Latuda); quetiapine (Seroquel); and the olanzapine-fluoxetine combination (Symbyax). Other non-approved agents include: lithium, lamotrigine, antidepressants, MAOIs, pramipexole, carbamazepine, ketamine, bupropion+dextromethorphan, amantadine, memantine, and possibly minocycline and celecoxib. Surprisingly, more than 3,000 bipolar depressed patients have been reported to be taking ketamine and that this was not associated with the induction of hypomania or mania.
McIntyre reported on the antidepressant (AD) effects of intra-nasal (i.n.) insulin. The insulin receptor sensitizer metformin had AD effects, but only in those who converted to insulin sensitivity.
McIntyre reported on the mixed effects of the GLP-1 agonists in the prevention of depression (Cooper et al J. Psychiatric Res, 2023). This is of interest in relationship to the bidirectional relationship of diabetes mellitus and depression.
Liraglutide appeared to have an anti-anhedonia effect. Semaglutide had AD and antianxiety effects in animal models of depression.
Recent studies have explored the antidepressant effect of psilocybin. Small studies have indicated that it has rapid onset of AD effects, and, in contrast to ketamine where rapid onset AD and anti-suicidal effects are short lived, the AD effect of psilocybin may be more prolonged.
Ketamine repairs structure and function of prefrontal cortical neurons via glutamate NMDA receptor blocking action, while psilocybin and other psychedelics act via stimulating 5HT2A receptors. One single case study suggested that blocking 5HT2A receptors with trazodone could achieve a rapid onset of AD effects of psilocybin without the psychedelic effects, a very interesting finding that requires replication.
