Posts Tagged Ketamine
by Sara Adaes, PhD | June 28, 2016
Ketamine was first introduced in 1962. It was initially presented as a fast acting general anesthetic, being widely used as a battlefield anesthetic in the 1970s. Ketamine is considered a dissociative anesthetic – it creates an altered state of consciousness, distorting the perception of sound and vision, and producing a feeling of detachment from oneself and from the environment which provides pain relief, sedation, and amnesia.
In the clinic, ketamine is mainly used for starting and maintaining anesthesia. Given its fast sedative action, it is frequently used in emergency situations. Its main effects usually begin within five minutes of injection and last up to 25 minutes.
But ketamine can have some impactful psychological side-effects as the medication wears off, such as agitation, confusion, or hallucinations. The latter is the main reason for its use as a drug of abuse or recreational drug. Ketamine began to be illicitly consumed in the 1970s and, nowadays, it is equally known for its medical and recreational use. Ketamine can produce illusions or hallucinations that are enhanced by environmental stimuli, which explains its popularity as a club drug.
Ketamine is still used in medical contexts as an anesthetic, although its use has become less common and more restricted. However, in recent years, a new use for ketamine has been emerging.
Ketamine as an antidepressant drug
Recent studies have shown that ketamine has fast antidepressant actions in patients with major depressive disorder, even in those with the most treatment-resistant forms of depression. Major depressive disorder is a highly disabling condition with limited treatment options that are often ineffective. The onset of depression is poorly understood but it is thought to derive from a combination of neurochemical factors and triggering life events, such as overwhelming stress. Potential neurochemical factors include defects in the major neurotransmitters of the central nervous system, glutamate and GABA.
Glutamate is the major excitatory neurotransmitter in the central nervous system. Experimental studies in animal models of depression have associated glutamate with depression, showing that there may be altered levels of glutamate receptors; increased glutamate concentrations have also been found in the brains of patients with major depressive disorder. Since ketamine acts by blocking the action of the NMDA glutamate receptors, this is a likely mechanism for its fast action in depression.
Indeed, a single dose of ketamine has been shown to be able to normalize the activity of glutamate receptors. Importantly, the effects of ketamine occurred only at low doses, indicating that these antidepressant effects can occur without the psychological side effects associated with high doses of ketamine.
GABA, on the other hand, is the major inhibitory neurotransmitter in the central nervous system. It has also been associated with depression – mice with an impairment of GABAergic transmission exhibit behavioral signs that mimic the emotional patterns of depression, which supports the view of a causal link between GABAergic neurotransmission and depression. Major depressive disorder has been linked to reduced levels of GABA and GABA receptors, and to reduced expression of glutamic acid decarboxylase, an enzyme that converts glutamate to GABA.
These two effects may seem contradictory, but these deficits in the GABAergic system may actually lead to increased glutamate concentrations. However, some studies have also reported reduced rather than increased brain levels of glutamate. This has led to the hypothesis that depression may actually be associated with a dynamic balance between changes in GABAergic and glutamatergic transmission. The mechanisms underlying this possible relationship were mostly unknown, but a new study published on the journalBiological Psychiatry sheds light on this subject.
A matter of balance
A stable and regular functioning of neural networks relies on an ability to maintain a balance between inhibitory and excitatory neurotransmission. In the mentioned study, and with the goal of understanding how the balance between GABA and glutamate levels may be linked to depression, the consequences of GABAergic deficits on glutamatergic synapses were investigated. It was found that mice with depression associated with GABAergic deficits also showed reduced expression and function of glutamate receptors.
A decrease in the number and activity of glutamatergic synapses was also found. Treatment with a sub-anesthetic dose of ketamine led to a lasting normalization of glutamate receptor levels and glutamatergic synapse function. These results indicate that depression in mice with impaired GABAergic neurotransmission involves a balancing reduction of glutamatergic transmission that can be normalized for a prolonged period of time by the rapidly acting antidepressant ketamine.
This study thereby establishes the link between the GABAergic and glutamatergic deficits described for depression, and suggests that it may be caused by a dysregulation of the equilibrium mechanisms that act to restore the balance of excitation and inhibition. It is possible that conditions of chronic or repeated stress, which may trigger the development of depression, may do so by affecting the balance between GABA and glutamate levels, or by impairing the mechanisms that could restore that balance. Indeed, chronic stress has been shown to decrease the production of glutamate receptors and to render GABAergic inhibition ineffective.
This work also reinforced the antidepressant efficacy of ketamine. However, ketamine will always have a huge drawback due to its drug-of-abuse properties. The use of other NMDA glutamate receptor antagonists without the side-effects of ketamine has been tested with promising results, leading to similar effects as those obtained with ketamine. Here may lay the answer.
Garcia, L., Comim, C., Valvassori, S., Réus, G., Stertz, L., Kapczinski, F., Gavioli, E., & Quevedo, J. (2009). Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33 (3), 450-455 DOI:10.1016/j.pnpbp.2009.01.004
Hashimoto, K., Sawa, A., & Iyo, M. (2007). Increased Levels of Glutamate in Brains from Patients with Mood Disorders Biological Psychiatry, 62 (11), 1310-1316 DOI: 10.1016/j.biopsych.2007.03.017
Ionescu, D., Luckenbaugh, D., Niciu, M., Richards, E., Slonena, E., Vande Voort, J., Brutsche, N., & Zarate, C. (2014). Effect of Baseline Anxious Depression on Initial and Sustained Antidepressant Response to Ketamine The Journal of Clinical Psychiatry, 75 (09) DOI: 10.4088/JCP.14m09049
Jansen, K. (2011). A Review of the Nonmedical Use of Ketamine: Use, Users and Consequences Journal of Psychoactive Drugs, 32 (4), 419-433 DOI:10.1080/02791072.2000.10400244
Li, N., Lee, B., Liu, R., Banasr, M., Dwyer, J., Iwata, M., Li, X., Aghajanian, G., & Duman, R. (2010). mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science, 329 (5994), 959-964 DOI:10.1126/science.1190287
Luscher, B., Shen, Q., & Sahir, N. (2010). The GABAergic deficit hypothesis of major depressive disorder Molecular Psychiatry, 16 (4), 383-406 DOI:10.1038/mp.2010.120
Morgan, C., Curran, H., & , . (2012). Ketamine use: a review Addiction, 107 (1), 27-38 DOI: 10.1111/j.1360-0443.2011.03576.x
Niciu, M., Ionescu, D., Richards, E., & Zarate, C. (2013). Glutamate and its receptors in the pathophysiology and treatment of major depressive disorderJournal of Neural Transmission, 121 (8), 907-924 DOI: 10.1007/s00702-013-1130-x
Ren, Z., Pribiag, H., Jefferson, S., Shorey, M., Fuchs, T., Stellwagen, D., & Luscher, B. (2016). Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine TreatmentBiological Psychiatry DOI: 10.1016/j.biopsych.2016.02.009
Feb. 27, 2015 — There may be hope for hard-to-treat depression as scientists explore novel ways to help people who have the often crippling condition.
Recently, a number of studies have suggested the benefits of Botox, ketamine, and certain sometimes-unexpected means of treating depression.
“I’m excited in general, and I’m curious,” says Peter D. Kramer, MD, author of Listening to Prozac and Against Depression.
Each year, around 16 million U.S. adults battle major depression. Many of them benefit from antidepressants. But as many as a third get depressive symptoms despite medication. And side effects, which can include weight gain, nausea, and insomnia, are troublesome for some patients. That leaves many people with depression searching for alternatives.
But if Kramer is hopeful about the newer, novel ways to treat the condition, he’s also cautious. The studies backing those treatments aren’t conclusive, and none of the approaches have been approved by the FDA to treat depression (though some, such as ketamine, have been approved for other uses).
“Things are merely hopeful until they are demonstrated [safe and effective],” Kramer says. “It’s always hard to tell what’s going on, but it’s a very interesting time, and I think some of them will come through.”
Here’s a closer look at what might be used to help treat depression in years to come.
Ketamine. Already in use in certain clinics and in some emergency departments around the country, ketamine is an anesthetic most often used during surgery. It’s given through an IV, and it quickly eases symptoms of depression, often in a matter of hours. The benefit is temporary, though.
One recent study found it to be very good at helping curb suicidal thoughts in severely depressed people. But it’s expensive, still experimental as a depression treatment, and can cause hallucinations and other side effects.
“Some people are very uncomfortable with the side effects,” says Alan Manevitz, MD, a psychiatrist who specializes in treatment-resistant depression at Lenox Hill Hospital in New York City.
Nitrous oxide, or laughing gas. This is an anesthetic commonly used by dentists. A small study published last December reports that nitrous oxide improved depression symptoms within less than 2.5 hours.
SCOTTSDALE, AZ – The Valley has one of the first Ketamine clinics in the country — with the newest innovation fighting depression to help you or your family.
Ketamine is more commonly known as a horse tranquilizer. In the ’90s, crooks stole Ketamine out of veterinarian clinics to sell on the street as ‘Special K.’ It was a popular rave drug.
But, Ketamine really got its start during the Vietnam War. It was used as an anesthetic. It’s also used in emergency rooms across the country.
Today, it’s the hottest new method for treating clinical depression.
The clinic is called, Depression Recovery Centers and it is located in Scottsdale. There, patients receive small doses of the drug intravenously while being closely monitored at the clinic. “We are seeing incredible results,” said Dr. Ellen Diamond, a clinical psychologist at the clinic. “I have seen person after person come through here and their life has been changed.”
Ger Gaines is the clinic’s owner. He made his first fortune as one of the founders of Sprint PCS. Now, he’s taking on clinical depression. “Depression is very common. About 10 percent of the population has depression at any given time,” he said.
But for Gaines, it is more than just a business venture. “I suffer from bipolar disorder,” he said, “But probably more motivating, I have close relatives that also suffer from depression. And just being able to do something that can change their lives is important to me.”
Ketamine treatment for depression was found accidently. It was being used for pain relief when many of the patients noticed they weren’t depressed anymore. “We are more directly targeting the structures in the brain that control emotions,” Diamond said.
Gaines uses “dead leaves on a tree” as an analogy. “What the Ketamine does is take that unhealthy looking tree in winter and grow it back to a tree in summer in just an hour’s time.”…
Ketamine works by blocking one of the targets for the neurotransmitter glutamate in the brain, the N-methyl-D-aspartate (NMDA) glutamate receptor.
Now, a new study in Biological Psychiatry reports that enhancing, instead of blocking, that same target – the NMDA glutamate receptor – also causes antidepressant-like effects.