Researchers describe secrets of 'magic' antidepressant

August 19, 2010
The bottom slide shows regeneration of synaptic connections in group receiving ketamine, compared to control group. Credit: Courtesy of Yale University

Yale researchers have discovered how a novel anti-depressant can take effect in hours, rather than the weeks or months usually required for most drugs currently on the market. The findings, described in the August 20 issue of the journal Science, should speed development of a safe and easy-to-administer form of the anti-depressant ketamine, which has already proven remarkably effective in treating severely depressed patients.

The Yale scientists found that, in rats, not only quickly improves depression-like behaviors but actually restores connections between damaged by .

"It's like a magic drug -- one dose can work rapidly and last for seven to 10 days," said Ronald Duman, professor of psychiatry and pharmacology at Yale and senior author of the study.

Ketamine traditionally has been used as a general anesthetic for children, but a decade ago researchers at the Connecticut Mental Health Center found that, in lower doses, the drug seemed to give patients relief from depression, Duman said. In these initial clinical studies, which have been replicated at the National Institute of Mental Health, almost 70 percent of patients who are resistant to treatment with all other forms of antidepressants were found to improve within hours after receiving ketamine. However, its clinical use has been limited because it has to be delivered intravenously under medical supervision and in some cases can cause short-term . It has also been used as a recreational drug, known as "Special K" or sometimes just "K."

So Duman, colleague George Aghajanian and the Yale team set out to map the molecular action of the drug in the of rats that could lead to potential targets for a safer and more easily used drugs. The team discovered that ketamine acts on a pathway that rapidly forms new between neurons—a process called "synaptogenesis."

"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," Aghajanian said.

The team identified a critical point in the pathway, the enzyme mTOR, which controls protein synthesis required for new synaptic connections. There are already promising leads on ways to sustain the initial rapid effect of ketamine by intervening at specific downstream targets.

An estimated 40 percent of people suffering depression do not respond to medication. And many others only respond after many months or years of trying different treatments. The authors note that ketamine also has been tested as a means to rapidly treat people with suicidal thoughts, a benefit usually not seen until weeks of treatment with traditional .

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4 / 5 (3) Aug 19, 2010
Ketamine acts on the NMDA and AMPA receptors involved with the neurotransmitter glutamate. This may explain its rapid effects compared to existing antidepressants that interact with serotonin and norepinephrine receptors. Also, ketamine is racemic, and its stereoisomers exhibit different effects on the body. It seems there may be many uses of ketamine at sub-anesthetic doses.

3.7 / 5 (3) Aug 19, 2010
I have suffered with depression my whole life. When I finally tried drugs to my surprise the effect was remarkable. The side effects however are barely tolerable so I can only treat severe episodes and only until I can't tolerate the side effects any longer.

I have to wait until I spend weeks weeping until I take the drugs. And I have to stop the drugs as soon as I recover just enough emotional regulation so I can go two days in a row day without weeping.

This usually lasts about 3 months until I have to start the cycle again.

I consider myself lucky (when I'm not on a down cycle) because I have good friends who have no such luck at all.
5 / 5 (2) Aug 19, 2010
I hope Gacyclidine or GK-11 is the next candidate for such studies as being closely related to ketamine and has a lower neurotoxicity profile as well as higher neuroprotective property.
1 / 5 (1) Aug 20, 2010
Low gamma-aminobutyric (GABA) levels associated with depression are clinically improved with Yoga in 12-weeks, a potent therapy.

Fish oil also reduces psychosis after 12-weeks
1 / 5 (1) Aug 20, 2010
I heard similar stuff about MDMA(ecstasy)
2.3 / 5 (3) Aug 20, 2010
Amazing, now suicidal tendencies can be brought to the surface quickly.

I think that the real problem with anti-depressants is that they are prescribed for depression that is caused by real things. If a teen is depressed because of acne, an anti-depressant will do NOTHING. People who are depressed because of real problems do not need an anti-depressant, they need the problem fixed.
2.7 / 5 (3) Aug 20, 2010
Amazing, now suicidal tendencies can be brought to the surface quickly.

I think that the real problem with anti-depressants is that they are prescribed for depression that is caused by real things. If a teen is depressed because of acne, an anti-depressant will do NOTHING. People who are depressed because of real problems do not need an anti-depressant, they need the problem fixed.

Are you KIDDING? Our brains are complex chemical computers. It's well established science that you can make someone giggle like a school girl five minutes after you tell them their whole family has been killed in a car accident.

If you meant to say that these drugs are not long term solutions to problems then I'd have to agree with certain qualifiers, but these drugs absolutely do SOMETHING to the human brain.
4 / 5 (2) Aug 20, 2010
People who are depressed because of real problems do not need an anti-depressant, they need the problem fixed.

@Ravenrant, depression is itself a 'real problem.' Specifically, this article etc. refers to 'clinical depression,' a chemical imbalance that can cause, among other things, an emotionally depressive state. For instance, people with MS have higher rates of depression than people with other life-long diseases specifically because the brain neurons are being destroyed and thus leading to depression.
4.5 / 5 (2) Aug 21, 2010
I'm wondering how safe it is to give severely depressed and/or suicidal patients Ketamine (to be administered on their own)? The potential for abuse could be quite dangerous, unlike SSRIs or SNRIs, as Ketamine can produce PCP-like dissociative effects.
not rated yet Aug 21, 2010

Several studies of ketamine as an antidepressant(see my link above) noted that the drug was administered in an inpatient setting (and all used IV ketamine) and was titrated to sub-hallucinogenic doses. Usually it was given with a benzodiazepine as an adjunct to prevent these type of side effects. I don't really see this type of treatment being suitable for outpatient therapy. However, gacyclidine and other related compounds with potentially lessened hallucinogenic effects are being explored as possible future antidepressants (thanks for the tip, sender).

(Btw, ketamine was initially developed by Parke-Davis as a safer anesthetic alternative to PCP and was first used by battlefield medics in Vietnam.)
not rated yet Aug 23, 2010
Several studies suggesting that EPA and DHA contained in omega-3 oil (fish oil) might just be key to helping with depression. Then again there have also been studies showing not much improvement at all, but an improvement was shown.

Id say keep the diet under control, and exercise regularly. Many people do not consume enough omega-3. US diet is around 30:1 omega-6:omega-3 and the UK around 20:1.

Try hitting a 1:1 ratio. Google omegabrite.

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