The Science Behind IV Ketamine Treatment for Depression

About 17% of the adult population suffers from depression. Everyone experiences changes in mood with highs and lows. However, people with major depressive disorder (MDD) chronically feel sad, distressed, unmotivated, excessively tired, and lose interest in pleasurable activities. Anhedonia is the medical term for the inability to enjoy pleasurable activities. Depression can make it difficult to work and function socially. Many patients become withdrawn and feel isolated. Only two-thirds of depressed patients ever experience adequate relief from the current FDA approved medications. These people have treatment resistant depression (TRD). These are the people who may benefit from treatment with ketamine. Ketamine has been shown to provide rapid, effective relief of depression, bipolar disorder, and suicidal ideation. It may also be effective in treatment of PTSD (post traumatic stress disorder).

The cause of depression is not fully understood. It is known that stress is one factor that can lead to depression. Recent studies have shown that depression is associated with neuronal atrophy (degeneration and loss of nerve cells) in the brain. This is felt to be due to loss of neurotrophic factors, chemicals that support growth and maintenance of healthy nerve cells. Perhaps one of the most important neurotrophic factors is BDNF, brain derived neurotrophic factor. Structural abnormalities have been found in certain areas of the brains of depressed patients. Both the prefrontal cortex, an area at the front of the brain and the hippocampus, an area deeper in the brain under the cerebral cortex, have been shown to have decreased size in patients with severe depression and in laboratory animals exposed to stress. The loss of volume of brain tissue in these areas is related to the duration of the depression. That is, the longer a person has suffered from depression, the greater the loss of volume in these areas of the brain. So not only are there neurochemical imbalances, but also structural abnormalities in the brains of severely depressed patients. When these brain cells atrophy (degenerate) these individual cells can no longer properly communicate with each other due to loss of synapses, which are connections between neurons. In theory this atrophy and loss of connections between neurons leads to decreased control of emotions and moods due to decreased ability of certain parts of the brain to communicate with other brain regions.

The good news: As astounding as it may seem, this loss of brain volume and nerve cell atrophy can be stopped and even reversed by successful treatment with ketamine. Neuronal communication can be restored using a process called synaptogenesis. Thomas Insel, director of The National Institute of Mental Health, has stated, “Recent data suggest that ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades.”

Current oral medications that are FDA approved to treat depression are separated into categories according to their actions on neurotransmitters, the chemicals that transmit signals between neurons. Serotonin specific reuptake inhibitors (SSRIs) include Celexa, Lexapro, Paxil, Prozac, Luvox, and Zoloft. Tricyclic antidepressants (TCAs) include Elavil, Anafranil, Sinequan, Tofranil, Pamelor, and Vivactil.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) include Cymbalta, Pristiq, Savella, and Effexor. Norepinephrine and dopamine reuptake inhibitors (NDRIs) include Wellbutrin and Zyban.

Mood stabilizers include lithium (Eskalith) and quetiapine (Seroquel). Monoamine oxidase inhibitors (MAOIs) include Marplan, Nardil, and Parnate. Others that fall into a miscellaneous category include Strattera, Buspar, Desyrel, Brintellix, and Triavil. This is not a complete list of all oral antidepressants.

The FDA approved oral medications to treat depression typically take weeks or months to become effective. If one is not effective others can be substituted until effective results are obtained. This may take several months or years. Eventually, about two-thirds of patients achieve adequate relief of their depression with these medications. Therefore, about one-third of depressed patients fail to achieve adequate relief from current FDA approved oral medications and are referred to as having treatment resistant depression (TRD). IV ketamine is typically reserved for these people who have not responded adequately to oral antidepressants.

There are two very exciting features of IV ketamine to treat depression. First, it is effective in about 70% of patients who have failed to respond to oral antidepressants. Secondly, IV ketamine can provide clinically significant results in hours or days rather than weeks or months. Ketamine works by an entirely different mechanism than current oral antidepressants.

Individual nerve cells (neurons) in the prefrontal cortex when viewed microscopically have an appearance somewhat similar to a tree with branches on one end, a main trunk in the center, and a root system below. These individual branches and roots are referred to as dendrites. The trunk is referred to as the axon. At the end of the axon there are also small fibers. At the ends of the dendrites and the fibers are the synapses. Nerve cells are not physically connected to each other. Instead there are small junctions between the ends of the dendrites of one neuron and the next neuron. These junctions are called synapses. There is a gap between these junctions called the synaptic cleft. In order for the signal from one neuron to reach the next, the neuron releases chemicals called neurotransmitters. The neurotransmitters cross the synaptic cleft (gap) and then attach to receptor sites on the next nerve. When these chemicals attach to the receptor sites it causes the nerve to transmit the signal. It is by means of neurotransmitters that neurons communicate with each other.

When viewed under the electron microscope, the dendrites are shown to have small bumps referred to as spines. It is thought that these so called spines are actually synapses, the areas where nerves communicate with each other. In severely depressed patients these individual spines are smaller and fewer in number. Likewise, it has been shown in laboratory rats that stress, which mimics depression in humans, also results in atrophy of neurons in the prefrontal cortex. As in humans with severe depression, microscopic examination of the brains of these lab rats also shows that individual dendrites (fibers) of such neurons have reduced numbers and sizes of spines projecting from the dendrites. Once again, these so called spines that are seen on microscopic examination are thought to actually be synapses. After exposure to ketamine, microscopic examination shows that the numbers and sizes of these spines of the damaged neurons is rapidly restored even after just a single exposure to ketamine.

This has been described as remodeling of synaptic connections or synaptogenesis. This increased size of the spines is directly related to improved function of the synapses.

Oral antidepressants do not restore spine numbers or function of the individual neurons. Ketamine does. Therefore, ketamine works by an entirely different manner than SSRIs, NSRIs, MAOIs, etc.

SSRIs and other categories of oral antidepressants affect the serotonin neurotransmitter system and slowly modulate this through a second messenger system (cAMP) and provide a delayed response. In contrast, ketamine is an NMDA (N-Methyl-D-Aspartate) inhibitor and works on so called glutamatergic sites. The glutamate neurotransmitter system provides a much more rapid and robust response and directly repairs the neurons. Glutamate works directly on NMDA and AMPA receptors and directly stimulates the production of BDNF, brain derived neurotrophic factor. BDNF is required for the growth and survival of neurons in the developing brain and is required for the survival of neurons in adults. BDNF is also required to allow proper functioning of synapses.

Research indicates that ketamine blocks the NMDA receptor site on so-called inhibitory neurons. By blocking the function of the inhibitory neurons this allows release of glutamate by other neurons. Glutamate, in turn, attaches to the glutamate receptor sites, which stimulates release of large amounts of BDNF. BDNF rapidly repairs the synapses of neurons that have atrophied in severely depressed patients. While the FDA approved antidepressants improve the effect of BDNF, they do not cause the release of BDNF. Ketamine does cause release of BDNF. Since ketamine causes a large release of BDNF this explains how ketamine can provide such a rapid and dramatic relief of depression.

In 2000, researchers at Yale School of Medicine, Berman, et al, demonstrated that a single dose of IV ketamine given to treatment resistant depressed patients lead to a significant reduction in depression after just four hours. A larger study in 2006 by Zarate, et al, at the National Institute of Mental Health, confirmed these findings even at just two hours after a single IV dose of ketamine. Not only that, but even after a single IV dose of ketamine the antidepressant effect continued for seven days. In 2012 Zarate, et al, demonstrated a similar effect in treatment of patients with bipolar disorder.

Studies in 2009 by Price, et al, and in 2012 by Larkin and Beautrais, showed a single dose of IV ketamine could rapidly reverse suicidal ideation for patients presenting to the emergency room following a suicide attempt and was effective for up to ten days. This is particularly important when one realizes that, according to the CDC, 36,000 people die from suicide each year, which is twice as many as people who die from homicide. Ronald Duman, PhD, a reacher at Yale, has stated that “The discovery that ketamine produces rapid antidepressant effects in treatment resistant depressed patients, by a novel mechanism (NMDA receptor blockade), is arguably the most significant advance in the field in over fifty years”.

Certain people have an abnormal genetic factor, which decreases the ability of their neurons to release BDNF.

Such people are at risk of developing depression if exposed to stress early in life. This abnormal genetic factor may explain why some individuals with depression do not respond to ketamine. This genetic factor is called the Val66Met allele and its presence can be used in the lab to identify patients who respond or do not respond to ketamine.

For those who would like to learn more about the technical aspects of ketamine in treating depression, please refer to the excellent YouTube videos by Ronald S. Duman, PhD of Yale School of Medicine: “Neurobiology of Stress, Depression, and Antidepressants: Remodeling Synaptic Connections”, “New Mechanisms Elicited with Ketamine in Treatment-Resistant Depression”, and finally “Ronald Duman, PhD, on NMDA Receptor Antagonists”. Another good YouTube video is by Carlos Zarate, MD of the National Institute of Mental Health entitled “Ketamine and Next Generation Therapies-Carlos Zarate, MD”.