KETAMINE AND ESKETAMINE. A NEW ERA IN PSYCHIATRY
In 2019, the U.S. Food and Drug Administration approved the nasal spray esketamine for management of treatment-resistant depression and major depression with imminent risk of suicide. Esketamine is a variation of ketamine developed by Janssen Pharmaceutical Companies of Johnson & Johnson and sold under the brand name Spravato. Both ketamine and esketamine are glutamate receptor modulators, which help to restore synaptic connections damaged by stressful psychiatric conditions such as Major Depression and associated anxiety conditions. This mechanism of action is totally different than standard SSRI/SNRI antidepressants. Combined, the two can often break the grip of depression and anxiety.
Frequently Asked Questions
Ketamine has been shown in multiple studies across decades to help depression and anxiety. Esketamine has passed the ‘gold standard’ of studies – a double blind trial which led to U.S. FDA approval. With either, the treatments are two hours in duration, and our proven protocol is: twice a week for a month, then once a week for a month, then every other week for a month, then done. No hospitalization is required. The treatments are typically relaxing, pleasant experiences.
Ketamine is a prescription medication that doctors can prescribe off-label to treat depression, anxiety, chronic pain, PTSD, OCD, and other mental health-related conditions. It has safely been used as an FDA-approved anesthetic since 1970. At lower doses, ketamine can move you beyond the superficial layers of your day-to-day mind, heal unhealthy neural pathways, and help you achieve the clarity you need to live the life you deserve.
Ketamine is a breakthrough medicine of the mind. It can rapidly—often within an hour or two—lift the symptoms of anxiety, depression, PTSD, OCD, and other conditions. For most people, the action of a single small dose of ketamine lasts for a week and possibly longer; after a short series of repeated doses, this effect typically extends out for weeks to months. In addition, the subjective effects on consciousness and the psyche often lead to profound emotional and psychological insights.
Knowing about Neurons
The neuron is the fundamental cell of the brain. Each neuron has a cell body (soma) that contains the nucleus, where the cell’s DNA is located; the nucleus regulates all the processes in the neuron. The cell body also contains other organelles, such as ribosomes, needed to make proteins such as neurotransmitters, and mitochondria, the miniature power plants that provide energy in the cell.
Leading off the cell body are two specialized extensions. At one end is the axon, a single long, thin nerve fiber that transmits messages from the body of the neuron to the dendrites of other neurons. Branching off from the neuron at the other end are the dendrites, a dense, bushy cluster of nerve fibers that receive messages from the axons of other neurons and send them on to the cell body. The dendrites branch out to form a large surface area that connects with many nearby neurons.
In the cerebral cortex alone, the most highly developed part of the brain, you have somewhere between 14 and 16 billion neurons. Every moment of every day, all those neurons are making billions of connections with each other, firing together to form pathways involved in planning, learning, memory, speech, and emotion.
The Role of Neurotransmitters
Neurons communicate with each other by passing impulses (also called action potentials) from the axon of one neuron to the dendrites of another. The junction where an axon meets a dendrite is called the synapse. The axons and dendrites don’t actually touch, however—a tiny gap called the synaptic cleft separates them.
Getting the nerve impulse across the synaptic cleft is the job of neurotransmitters: chemicals that act as messengers between neurons. Neurotransmitters are manufactured in the neurons and stored in tiny sacs called vesicles at the tips of axons.
The cell membranes of neurons are studded with receptors that are binding sites for specific neurotransmitters. Each receptor is a precise match for that particular chemical messenger. The neurotransmitters attach to the receptors, fitting like keys into locks and opening channels into the cell.
When a nerve impulse travels down the axon and reaches the very end, it makes calcium channels in the cell open. The positively charged calcium ions flow in and make the synaptic vesicles fuse with the cell membrane (exocytosis). The neurotransmitters stored in the vesicles then pour into the synaptic cleft. They diffuse across the gap and bind to their matching receptors in the membrane of the postsynaptic neuron (the target neuron). The binding opens the channels leading into the cell interior and calcium, sodium, magnesium, and other ions flow in.
The flow of incoming ions such as calcium and sodium depolarizes the cell membrane, creating less negative charge inside the cell. If the depolarization threshold for making the neuron fire is reached, the impulse is transmitted through the cell, down its axon, and on to the next neuron in the chain.
What happens to the neurotransmitters once they’ve done their job of opening the channels? Your body is frugal and efficient. Reuptake receptors on the presynaptic (sending) cell membrane capture the used neurotransmitters and carry them back into the cell, where they can be repackaged into new synaptic vesicles to await another cycle.
When the neurotransmitters are re-absorbed, the synapse turns off. The whole process of shuttling an impulse through one neuron and on to the next takes only about seven milliseconds. It’s happening in your brain billions of times every second, around the clock.
Types of Neurotransmitters
Different neurotransmitters affect neurons in different ways. Excitatory transmitters excite the postsynaptic neurons, making the neuron more likely to fire an impulse. Inhibitory transmitters slow the neuron, making it less likely to fire an impulse. And just to confuse things, the neurotransmitter dopamine can be both excitatory and inhibitory, depending on which receptors are present.
In the brain, the neurotransmitters glutamate and dopamine are excitatory. The inhibitory neurotransmitters are GABA (gamma-aminobutyric acid), serotonin, and dopamine (sometimes).
The release, removal, and reuptake of neurotransmitters is tightly regulated. Too much or too little of any excitatory or inhibitory neurotransmitter, or being too sensitive or insensitive to them, can disrupt the balance.
Glutamate is the most common excitatory neurotransmitter in the brain. It plays a particularly important role in neuroplasticity (the brain’s ability to form new synapses and neural connections over a lifetime), learning, and forming memories. When there’s too much glutamate in the brain, the postsynaptic neurons can become hyperexcited; when there’s way too much glutamate in the brain, it can damage neurons or even cause neuron death.
Stress, Glutamate and Damaged Neurons
Long-lasting stress takes a toll on the neurons of the cortex. Constant high levels of the stress hormone cortisol can make neurons atrophy—they shrivel and shrink. The dendrites go from large numbers of dense, spreading branches to smaller numbers of shorter, stubby branches that make fewer connections to other neurons. The axons shrink and get thinner. Intense stress can also change glutamate signaling and make the neurons less responsive and less able to connect with other neurons. Brain imaging shows that in depressed people, the prefrontal cortex is reduced in size. Shriveled connections in the cortex mean the neural pathways that control memory, decision-making, emotions, and attention don’t work as well.
The end result of all these glutamate-related neuronal changes is a brain much more predisposed to manifesting the constellation of subjective phenomena we call depression and anxiety.
This is where ketamine comes in. The drug company researchers who developed ketamine as an anesthetic in the 1960s knew it worked by triggering glutamate release into the synapse. Later researchers studying the roots of depression discovered that in people with depression, something was going wrong in the glutamate receptors. By the 1990s, they knew enough to start looking for a drug that would target the glutamate system. They didn’t have to look far. Ketamine, well studied by that point for its effects on neurons, had already been accidentally found to lift depression. Researchers at Yale began using very small doses of ketamine to treat people with severe depression who weren’t helped by standard antidepressant drugs. The results were startlingly successful.
Ketamine and Glutamate
Research into the full pharmacological action of ketamine is revealing just how complex the response to this drug is. We know that ketamine also modulates additional receptor types, but the glutamate receptors seem to play the most important role.
Neurons have a number of different binding sites for glutamate, but when it comes to ketamine, two are of particular interest: the NMDA (N-methyl-D-aspartate) receptor and the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor.
Glutamate activates the ion channels in both NMDA and AMPA receptors. When glutamate binds NMDA receptors, they open up to allow calcium ions into the cell. When glutamate binds AMPA receptors, they open up to allow sodium ions into, and potassium ions out of, the cell. No matter what type of ion enters the cell, the neuron is depolarized and the action potential “jumps” from the presynaptic cell to the postsynaptic cell. What happens after the propagation of the action potential depends on whether the neuron inhibits or excites downstream targets and the function of the neural circuit it’s in.
At the very low dose shown to have an antidepressant effect, ketamine appears to increase the release of glutamate from the presynaptic neuron into the synaptic cleft. The ketamine then preferentially blocks glutamate at the NMDA receptors of the postsynaptic cell but doesn’t block glutamate binding to adjacent AMPA receptors. The net effect is to increase AMPA activation. The effect is magnified by the way ketamine induces the neuron to make additional AMPA receptors and move them into the membrane of the synapse area.
Evolving research is revealing more about the mechanism of action for ketamine. One additional potential mechanism for ketamine is the NMDA receptors on a type of neuron called the parvalbumin interneuron. These neurons are small and relatively rare in the brain, but they’re key to synchronizing electrical activity in the brain. They work by inhibiting activity in the neurons around them. When a subunit of the NMDA receptors on these neurons is blocked by ketamine, the cells don’t get as much glutamate, and their inhibitory effect is reduced. The parvalbumin interneurons act like a brake on brain activity. Ease up on the brake and all the brain circuits become more active. The brain wakes up and becomes more responsive.
While ketamine binds strongly to NMDA and AMPA receptors, it’s also taken up, to a much smaller degree, by other neuroreceptors. Ketamine can trigger increased release of the neuromodulators dopamine and noradrenaline; it also binds weakly to nicotinic and opioid receptors. Exactly what role these receptors play in the antidepressant effect is still largely unknown and even contradictory. For example, some studies seem to show that ketamine binds to opiate receptors in a way that could create addiction; other studies show that the potential for addiction is very low.
Another possible mechanism for ketamine is its action on structures within the neuron. Some studies suggest that ketamine accumulates in lysosomes (organelles that contains digestive enzymes) and synaptic vesicles, which might then trigger mTOR signaling. Ketamine could also affect the endoplasmic reticulum (tubules within the cell that are involved with protein and lipid synthesis) and the Golgi bodies (organelles that sort, process, and transport proteins). The mechanisms are complex and still being unraveled.
Ketamine and Connectivity
The impacts of stress and depression on the brain aren’t just at the molecular and cellular level. Depression impacts connectivity at the brain macro level as well. By using functional magnetic resonance imaging (fMRI), researchers have been able to see how people with depression seem to have weaker connections within larger neural networks, such as the prefrontal cortex. This portion of the brain is the seat of higher-level cognitive processes, including executive function—the ability to control short-term behaviors in favor of self-control, planning, decision-making, problem-solving, and long-term goals. When the subregions of the prefrontal cortex aren’t communicating well, as is the case in depression, executive function can be dysfunctional. Ketamine seems to help improve global connectivity in this portion of the brain and improve the linkages among the subregions.
Ketamine, given intravenously or by intramuscular injection (we only use it by intramuscular injection), has been shown in multiple studies to provide a robust and rapid antidepressant effect within hours of treatment. Ketamine blocks a certain kind of brain receptor in a manner that unleashes a chain of biochemical events that prompts brains damaged by stressful conditions such as depression and anxiety to regrow the connections between brain cells.
Ketamine is a mixture consisting of two molecular forms, R- and S-ketamine. Esketamine, which consists only of the more biologically-active S- form of ketamine, has the same antidepressant effects of ketamine. For the sake of this discussion consider it to be a more highly distilled and somewhat more potent (milligram to milligram) version of ketamine.
Ketamine has been used as an anesthetic for more than 40 years, but the observational clinical trials to explore its power against depression and anxiety are much more recent. Because of ketamine’s age, it is generic. Because it is generic there has not been, is not, and never will be any financial incentive to conduct a double-blind clinical trial to prove its efficacy beyond all doubt. Such clinical trials cost millions of dollars to perform. Esketamine, on the other hand, was derived from ketamine at least in part to allow it to be patented, therefore providing a financial incentive to perform a ‘gold standard’ double-blind clinical trial. That clinical trial proved the power of esketamine beyond all doubt, and based on that trial it received U.S. FDA approval in 2019. And with FDA approval came insurance coverage. Meanwhile, original ketamine is not covered by insurances for treatment of depression and anxiety. It can only be used “off label” for those purposes by doctors, and therefore patients are liable for the full cost of those treatments. As they say, don’t hate the player, hate the game.
Research published May 2019 in the American Journal of Psychiatry supported the effectiveness and safety of esketamine nasal spray in treating depression in people who have not responded to previous treatment. That is one of the key studies that led the U.S. FDA to approve the use of esketamine nasal spray, in conjunction with an oral antidepressant, for use in people with treatment-resistant depression.
Multiple studies tested various ways to give ketamine (intravenous, intramuscular, nasal, and oral) at various doses to people diagnosed with treatment resistant depression. The majority of those ketamine studies reported no serious adverse events regardless of how or how much of the medication was given. The most commonly observed adverse events following ketamine administration in anti-depressive doses were related to sensory distortion, out of body experiences, and changes in blood pressure. The documented side effects were mild or at worst moderate in severity, well-tolerated, and brief.
Specifically, the side effects of ketamine treatment (and therefore, esketamine treatment also) may include: altered sense of time; anxiety; blurred vision; diminished ability to see/hear/feel; dry mouth; elevated blood pressure or heart rate; elevated intraocular or intracranial pressure; excitability; loss of appetite; mental confusion; nausea/vomiting; nystagmus (rapid eye movements); restlessness; slurred speech;and synesthesia (a mingling of the senses).
Do not proceed with ketamine treatment if any of the following apply to you:
Allergic to ketamine
Symptoms of psychosis or mania
Uncontrolled high blood pressure
CHF or other serious heart problem
Severe breathing problem
History of elevated intraocular or intracranial pressure
History of hyperthyroidism
Other serious medical illness
Pregnant, nursing, or trying to become pregnant
Ketamine has been reported to produce issues including, but not limited to, those listed below. However, lasting adverse side-effects are rare when medical protocols are carefully followed.
While ketamine has not been shown to be physically addictive, it has been shown to cause moderate psychological dependency in some recreational users.
In rare cases, frequent, heavy users have reported increased frequency of urination, urinary incontinence, pain urinating, passing blood in the urine, or reduced bladder size
Ketamine may worsen problems in people with schizophrenia, severe personality disorders, or other serious mental disorders.
Users with a personal or family history of psychosis should be cautious using any psychoactive substance, including ketamine, and discuss potential risks with your clinician before proceeding with treatment.
The dissociative effects of ketamine may increase patient vulnerability and the risk of accidents. All Zen Psychiatric Services clients treated with ketamine or esketamine, regardless of means of administration, are required to have a driver to and from treatment. Clients must take no oral food for at least two hours prior to treatment. They remain under close observation of Zen Psychiatric staff for at least120 minutes, during which time they have their vital signs checked at least three times: before, once during, and then after treatment.
We greatly prefer first contact to be made by a referring medical or psychological provider. However, we will gladly answer direct calls from prospective patients, and if that discussion indicates that our services may help your symptoms then we may schedule an evaluation appointment without direct referral. Even in that case, to be eligible for ketamine or esketamine treatment through Zen Psychiatric Services all incoming patients must allow us to contact a referring medical provider for records. Initial psychiatric evaluations are approximately one hour in length and will focus on current/recent symptoms and treatment history. We welcome referrals solely for evaluation and are happy to serve as a psychiatric consultation resource for our colleagues in the community. Initial evaluations are billed to insurance, or at a rate of $150 for self-paying patients.