The secret is out. The anesthetic drug, ketamine, can save lives for people with severe depressive disorders. It is being introduced in hospital emergency rooms as a rapid-acting antidepressant to treat people who have become suicidal. Patients can respond favorably in as little as one or two hours. By contrast, an antidepressant drug like Prozac can take weeks to work. In the hospital setting, ketamine is given intravenously (IV). The drug is infused as 0.5 mg/kg body weight over 40-45 minutes. This is a dose substantially lower than those used for anesthesia. It is also lower than what is used recreationally as “Special K’ to produce dissociative and psychotomimetic psychological effects. Some of the earliest research for the use of ketamine in depression was conducted at the NIMH division of the National Institutes of Health. It was studied as a treatment for those people with Bipolar Disorder or Major Depressive Disorder who did not respond to traditional antidepressants. It was found that a substantial number of antidepressant non-responders responded to a single ketamine infusion within a few hours. Unfortunately, the therapeutic effect disappeared within a few days to a week. Eventually, it was determined that a patient can receive booster or maintenance doses once per month. Some people can go longer. Many patients are able to return to a life without depression. Going for ketamine IV infusions once per month is inconvenient and expensive. Some doctors now offer ketamine as a nasal spray (intranasal) instead. Ketamine is very cheap. When prescribed for intranasal administration, one cannot simply have it filled at their local pharmacy. A compounding pharmacy is needed to create a liquid from the ketamine powder. As with IV ketamine, the dosage of intranasal ketamine must be well-controlled. Intranasal ketamine is often given as 40 mg doses, 5-7 days apart. However, it does happen that some people who do not respond to intranasal ketamine go on to respond to intravenous ketamine. The dosing of ketamine needs to be precise. The reason for this is that too low a dosage doesn’t work, and too high a dosage produces dissociative states and even psychosis. Pharmaceutical companies have been trying to develop other drugs that do the same thing as ketamine on a biological level, but without the dissociative psychological side effects. Like ketamine, these drugs cause a blocking of a gate on neurons (nerve cells) that normally let in a neurotransmitter messenger molecule known as glutamate. This gate is controlled by a special receptor called the NMDA (N-Methyl-D-Aspartate) receptor. It was thought that blocking the NMDA receptor was critical to the mechanism by which ketamine worked to treat depression. The drugs in development are bound to be expensive. It turns out, though, that ketamine may not depend on NMDA at all. Ketamine is broken-down (metabolized) naturally in the liver into a substance known as HNK (hydroxynorketamine). HNK does not work on NMDA receptors at all. Instead, it causes an increase in the production of BDNF (brain-derived neurotrophic factor). BDNF stimulates the brain to grow new neurons (neurogenesis) and support those that already exist (neurotrophy). New neurons are formed in the hippocampus and cortical regions of the brain. These structures have been implicated in the development of depressive disorders. This yields a very important conclusion. HNK can be used without worrying about dissociative and psychotomimetic effects. Dosing does not need to be precise, and the drug can be given orally. Ketamine doesn’t help everyone. It seems that a minority of people have a type of gene that causes BDNF to be manufactured less efficiently. Most people have the val66val gene that allows for the most efficient synthesis of BDNF. They respond almost completely to ketamine. However, others with the met66val gene respond less well, and those with met66met don’t respond at all. BDNF stimulates the growth of new neurons in the hippocampus structure of the brain. The hippocampus is responsible for regulating memory and emotions. In depression, the size of the hippocampus is reduced. When people respond to traditional antidepressants, there is an increase in neurogenesis there, and an increase in size. For now, empirical evidence supports the use of ketamine in depressive disorders. Hopefully, its therapeutic biological mechanisms will be better understood with continued study, leading to better treatments for depression with fewer side effects. The ketamine metabolite, HNK, might be the ideal alternative to ketamine.
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