Ketamine: Kan it Kure Depression?

in News
March 27th, 2013

Affective disorders are those disorders of the brain that are characterized by severe and inappropriate shifts in mood or emotion. These shifts are often to extreme ends of the emotional spectrum where an affected individual is constantly full of energy and confidence (mania) or withdrawn, fatigued, and excessively sad with little interest in usually enjoyable activities (depression). Both of these conditions have been observed and recorded in human history for thousands of years but only recently have they been recognized as brain disorders, given names like major depression and bipolar disorder, and treated as medical conditions.

In the past 150 years it has been noted that the onset of depression is occurring at higher rates and at younger ages that ever before. This data could be the result of factors including an increase in patients coming forward to be diagnosed, improved diagnoses, or simply better record keeping. Whatever the reason, it is estimated that 15 to 20% of the population is experiencing symptoms of major depression at any given time, with a greater occurrence in women than in men. Many are affected by this disorder and a cure has yet to be found. But before we continue, a distinction must be made between major depression and “reactive depression” in which a person may feel depressive symptoms because of a single event like the loss of a loved one or a failure of some kind. Major depression is a prolonged state in which an individual may display a number of symptoms including depressed mood, loss of interest in most activity, change in body weight or appetite, changes in sleep patterns, psychomotor agitation or retardation, fatigue, difficulty concentrating, feelings of worthlessness or guilt, and suicidal thoughts. Depending on the severity of the depression a patient may display many, or only a few of these possible symptoms.

Research has yet to find a definitive neurological cause for depression and other affective disorders. Studies of fraternal and identical twins have attempted to determine the role of nature versus nurture on the matter and animal models of depression as well as human studies have been used to develop drugs and other treatments for depression. Through this work different hypotheses have developed about the neurochemical basis of depression. Some are convinced a monoamine imbalance is responsible while others say it is an issue with serotonin dysfunction. These hypotheses have led to the development of different treatment methods and the utilization of a few classes of drugs. Drug classes include monoamine oxidase inhibitors, tricyclics, and selective serotonin reuptake inhibitors (SSRIs) which all have slightly different mechanisms of action in the brain when treating depression. What is most interesting is that after all this research and development none of these drugs stand out as the best treatment for depression. They all tend to improve depressive symptoms anywhere from a week to a month after drug therapy begins, and they all carry different, sometimes nasty, side effects. The main reason for the current love affair with SSRIs in the medical world is that they carry the most favorable set of undesirable side effects, not that they treat depression best.

Enter ketamine. This compound has a street reputation as a club drug and is derived from phenylcyclidine (PCP), another drug known for its powerful and potentially dangerous psychological and addictive affects. Both drugs were originally developed as alternative analgesics (pain relievers) to drugs like barbiturates that had a higher risk of respiratory depression and subsequent death. PCP and ketamine did produce analgesia, just not in the way they were originally thought to do so. Patients report feelings of detachment from their own body and reality when under the influence of these drugs. They can’t feel pain because their minds are off in another reality, essentially too distracted to feel anything. At high doses PCP and ketamine have been shown to induce schizophrenic symptoms in humans, or worsen previously existing schizophrenia, and research on schizophrenia uses ketamine to bring about a schizophrenic state in animal test subjects. So how on earth can a drug like this have any useful therapeutic application?

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Researchers at Yale University and the National Institute of Mental Health have recently found that administering a low dose of ketamine to a patient affected by major depression has been able to lift the patient’s mood and subdue the depression for about a week at a time. It is an astounding find given the known effects of ketamine on the mind. One study reported that 70% of patients treated with ketamine experienced an improvement in mood. One of the best parts about the treatment is that it takes effect immediately, unlike the other antidepressants on the market, which can take up to a month to work. It has also proven effective even to patients who have been resistant to other treatments. Ketamine is already an FDA-approved analgesic, usually used in veterinary settings, so further studies of this compound are now being developed in humans.

The mechanism of action for this drug is not yet clear but it is known that ketamine and PCP are nonselective NMDA receptor antagonists. They affect the glutamate pathways within the brain and also seem to have the remarkable affect of strengthening and restoring synaptic connections. In the human model of depression where it is thought that symptoms are caused by atrophy of neurons in various brain areas, it makes sense that ketamine is an affective treatment because it encourages neuron regrowth and connection. This may be done through the production of brain derived neurotrophic factor (BDNF) or other molecules that influence neuron health and maintenance. More work must be done to determine how this unlikely drug accomplishes its therapeutic affects. There are still dangers associated with taking ketamine, especially if it only works for a week at a time to treat depression and repeated use has already been shown to produce schizophrenic symptoms in some. It is an amazing and surprising find and hopefully it leads to more improved treatments of affective disorders like depression.

– J. Daniel Bireley


Ketamine Relieves Depression By Restoring Brain Connections – NPR

Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents – Trends in Neurosciences

Meyer, Jerrold S., and Linda F. Quenzer. Psychopharmacology: Drugs, the Brain, and Behavior. Sunderland: Sinauer Associates, 2005. Print.

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