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Ketamine: Magic Depression Drug?

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"Depressive illness was described by Hippocrates in ancient Greece, but effective therapeutic agents did not emerge until the 1950s. Today, almost all antidepressant drugs in clinical use increase levels of certain neurotransmitters in the brain, in particular norepinephrine and serotonin. Although these medications are beneficial, a sizeable minority of patients remain resistant to their therapeutic effects. Moreover, in most patients, there is a delay of weeks to months before the drugs take full effect. As a result, there is an urgent need to develop faster-acting drugs," writes John F. Cryan, Senior Lecturer, School of Pharmacy, Department of Pharmacology and Therapeutics, Alimentary Pharmabiotic Centre, University College Cork, Ireland, in this week's journal of Science.

Major Depressive Disorder (MDD), afflicts about 17% of the population at some point in their lives, and  is frequently a disabling disorder .  Those who suffer from MDD more often than not do not get any relief from the initial medication prescribed.  Thus begins what can be a frustrating journey of side-effects and delayed relief due to the fact that most antidepressant drugs take weeks or months to produce the therapeutic effect intended. 

Ronald Duman, Professor of Psychiatry and Pharmacology Director, Division of Molecular Psychiatry and Abraham Ribicoff Research Facilities, Yale University, and senior author of a recent study, reportedly have found that a single dose of the drug ketamine can produce an antidepressant effect within hours and lasting up to a week.

Ketamine, which can produce psychotic episodes, cause damage to brain function with long-term use, and kill in high doses, is not a great candidate for ongoing therapy.  However, researchers  noted that ketamine has shown to be effective as a rapid way to treat people with suicidal thoughts; many suicidal patients respond weeks later with traditional drugs.

Yale researchers discovered that in rats, ketamine restored connections between brain cells damaged by chronic stress and quickly improved depression-like behavior.  Investigating exactly how the drug works, scientists found that ketamine activates a signaling pathway in the brain called the mammalian target of rapamycin pathway (mTOR), suggesting new therapeutic targets for antidepressant drug development. 

“The pathway is the story. Understanding the mechanism underlying the antidepressant effect of ketamine will allow us to attack the problem at a variety of possible sites within that pathway,” says George Aghajanian, Professor of Psychiatry, Yale School of Medicine.

Other antidepression drugs do not appear to activate this mTOR pathway.  Based on investigation of a few different classes, serotonin selective reuptake inhibitors (SSRI), the tricyclic antidepressants, and even electroconvulsive seizure, similar effects with those classes of antidepressants have not been evidenced.

The August 20 issue of the journal Science, report that the new findings should hasten the development of a safe and easy-to-administer form of the anti-depressant ketamine.  Ketamine use has a proven track record in remarkably effecting severelydepressed patients.

“It’s like a magic drug—one dose can work rapidly and last for seven to 10 days,” said  Duman. 

In an interview, Duman said "There are two major findings, I think, of the paper. A single dose of this NMDA, antagonist, ketamine, produces an increase in the number of connections in a part of the brain—the prefrontal cortex—that’s known to be involved in depression and treatment response. This is a really dramatic finding that a drug can increase the connections between neurons within a relatively short timeframe."

"To put that into perspective,  there are quite a few studies in the field that have demonstrated that stress and depression—models of depression in preclinical studies—produce the opposite effect – they actually cause atrophy of neurons and decrease the size of the dendritic or processes of neurons. So, here’s a drug that’s able to rapidly reverse the actions of and produce the opposite actions of what is occurring with chronic stress or depression."

He cites the second major finding, "related to the mechanism and the signaling pathways that
underlie that effect. Ketamine can rapidly increase a signaling cascade that regulates
translation of proteins at the synapse or at the contact site of neurons, that’s known to be involved in control of protein synthesis. It’s been implicated in models of learning and memory, and is required for protein synthesis–dependent long-term memory."

Duman admits that studying something like depression or any psychiatric illness in rodents is difficult.  Behavioral tests have been devised modeling certain aspects of depression, such as
helplessness or confusion enabling testing as to whether or not ketamine can produce an antidepressant response.  The mTOR pathway, is identical in all mammals, therefore the same in rats and humans.

Reporting in Science Magazine, Nanxin Li, Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry and Neurobiology, Yale University School of Medicine cites, "The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications.  Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine."

'The dissociative anesthetic effects of ketamine have also been applied within the realm of postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption as well as reports of nausea following abdominal surgery.' The Medscape Journal of Medicine (2008).

Other possible illnesses that could benefit from treatment with ketamine are bi-polar depression and post-traumatic stress disorder (PTSD). It is also used widely in veterinary medicine.

Treatment of alcohol addiction and drug addiction in Germany, using Ketamine, psychotherapy and group therapy, resulted in successful withdrawal and continued abstinence for more than one year.

Developed early in the 1960's, Ketamine was commonly used as an anaesthetic for soldiers in Vietnam.  Recreational use began as early as 1967 when it was referred to as "mean green" and "rockmesc".  Gaining in popularity and known as "K", "Ket", "Special K" and "Vitamine,  the 'party drug' use increased through the '90's, prompting it's placement in Schedule II of the United States Controlled Substance Act in August, 1999. 

Recreational use (abuse) of Ketamine produces profound psychological effects, characterised by a sense of detachment from one's physical body and external world, which mimic schizophrenia.  Psychotic reactions, intense hallucinations, perception of falling and flying and a complete dissociation from the real world occur during the state of unconsciousness. 

The effect on the mind is so dibilitating that users may not remember their own names or know they are human, or what that means.  The process of returning to reality is slow; movement is extremely difficult and recognizing their surroundings or being aware of their body can take hours.  The long term neurological damaging effects of Ketamine are not completely clear, however premature death has been linked to reacreational use of the drug.

Believing the use of this new information about how Ketamine works could be developed into a pill form of the drug, that is much safer and more convenient, for the treatment of severe depression.

Laura Lamp King

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