Ketamine for Depression and Mental Health: Facts

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Ketamine for Depression: A Novel and Fast-Acting Treatment

Depression is a common and serious mood disorder that affects millions of people worldwide. It can cause persistent feelings of sadness, hopelessness, and loss of interest in daily activities. It can also impair one’s ability to function at work, school, or home. Depression can be treated with medications, psychotherapy, or a combination of both. However, not everyone responds well to these standard treatments. Some people may have treatment-resistant depression (TRD), which means that they do not experience significant improvement after trying two or more antidepressants. For these people, finding an effective treatment can be challenging and frustrating.

Ketamine is a drug that has been used for decades as an anesthetic and a painkiller. It is also known as a recreational drug that can induce hallucinations and dissociation. However, in recent years, ketamine has emerged as a promising new treatment for TRD. Ketamine can rapidly reduce depressive symptoms and suicidal thoughts within hours of administration, unlike most antidepressants that take weeks to work. Ketamine is available in two forms: an intravenous (IV) infusion and a nasal spray (esketamine). Both forms are given under medical supervision and in conjunction with another antidepressant.

Ketamine was first synthesized in 1962 by a chemist named Calvin Stevens. It was initially developed as a safer alternative to phencyclidine (PCP), another anesthetic that had undesirable side effects such as agitation and psychosis. Ketamine was approved by the FDA in 1970 as an anesthetic for humans and animals. It was widely used in the Vietnam War as a battlefield analgesic.

Ketamine also became popular as a recreational drug, especially among young people who sought its psychedelic effects. It was often abused in high doses or mixed with other substances, which could lead to serious health risks such as overdose, addiction, and brain damage.

The antidepressant potential of ketamine was discovered by accident in the 1990s, when researchers noticed that some patients who received ketamine for pain relief reported feeling happier and less depressed afterwards. This sparked interest among scientists and clinicians who began to investigate how ketamine could help people with TRD.

In 2000, a landmark study by Dr. Carlos Zarate and colleagues at the National Institute of Mental Health (NIMH) showed that a single dose of ketamine IV infusion could produce rapid and lasting improvement in depressive symptoms in patients with TRD 1. This finding was replicated by several other studies in the following years 2 3. In 2019, the FDA approved esketamine (Spravato), a nasal spray version of ketamine, as the first fast-acting antidepressant for TRD 4. Esketamine was developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, and is marketed under the brand name Spravato.

Ketamine works differently from most antidepressants, which target serotonin, norepinephrine, or dopamine, the chemical messengers that regulate mood, cognition, and behavior. Ketamine acts on another neurotransmitter called glutamate, which is involved in learning, memory, and synaptic plasticity. Synaptic plasticity is the ability of brain cells (neurons) to form new connections or strengthen existing ones.

Ketamine blocks a type of glutamate receptor called NMDA (N-methyl-D-aspartate) on certain neurons. This leads to a cascade of events that ultimately increase the activity of another type of glutamate receptor called AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid). AMPA receptors stimulate the release of brain-derived neurotrophic factor (BDNF), a protein that promotes neuronal growth and survival. BDNF enhances synaptic plasticity and restores the function of neural circuits that are impaired by chronic stress and depression 2.

Ketamine also modulates other neurotransmitter systems, such as serotonin, dopamine, and opioid receptors, which may contribute to its antidepressant effects 2.

Numerous clinical trials have demonstrated that ketamine can effectively treat TRD in adults who have failed to respond to at least two antidepressants. Ketamine can rapidly reduce depressive symptoms within hours of administration, and the effects can last for days or weeks 1 2 3. Ketamine can also reduce suicidal thoughts and behaviors in patients with TRD.

A meta-analysis of 21 randomized controlled trials involving 437 patients with TRD found that ketamine IV infusion was superior to placebo or active control (such as midazolam) in improving depressive symptoms at 24 hours after treatment. The response rate (defined as at least 50% reduction in depression severity) was 52% for ketamine versus 18% for placebo or active control. The remission rate (defined as no or minimal depression symptoms) was 28% for ketamine versus 6% for placebo or active control. Another meta-analysis of 28 randomized controlled trials involving 920 patients with TRD found that esketamine nasal spray was superior to placebo in improving depressive symptoms at 24 hours after treatment. The response rate was 41% for esketamine versus 18% for placebo. The remission rate was 23% for esketamine versus 10% for placebo.

Ketamine IV infusion is given as a single dose of 0.5 mg/kg over 40 minutes in a doctor’s office or a clinic. The dose may be repeated every few days or weeks depending on the patient’s response and tolerance. Ketamine IV infusion is not approved by the FDA as an antidepressant, but it is widely used off-label by psychiatrists and anesthesiologists who have experience with ketamine.

Esketamine nasal spray is given as two sprays (one in each nostril) of 28 mg, 56 mg, or 84 mg depending on the patient’s weight and response. The dose is administered in a doctor’s office or a clinic under medical supervision. The patient must stay in the office for at least two hours after the dose and must not drive or operate machinery until the next day. Esketamine nasal spray is approved by the FDA as an antidepressant for TRD, but it requires a prescription and a Risk Evaluation and Mitigation Strategy (REMS) program to ensure its safe use.

Both ketamine IV infusion and esketamine nasal spray are usually given in conjunction with another oral antidepressant as prescribed by the doctor.

Ketamine and esketamine can cause various side effects, some of which can be serious or unpleasant. The most common side effects include:

• Dissociation: a feeling of detachment from one’s body or surroundings, which can be mild or severe, and may involve hallucinations, confusion, or memory loss.
• Drowsiness: a feeling of sleepiness, fatigue, or reduced alertness, which can impair one’s ability to drive or operate machinery.
• Dizziness: a feeling of lightheadedness, unsteadiness, or vertigo, which can affect one’s balance and coordination.
• Nausea: a feeling of sickness or discomfort in the stomach, which may lead to vomiting.
• Headache: a pain or pressure in the head, which may be mild or severe.
• Increased blood pressure: a rise in the force of blood against the walls of the arteries, which may cause chest pain, shortness of breath, or stroke.
• Increased heart rate: a rise in the number of beats per minute of the heart, which may cause palpitations, anxiety, or arrhythmia.

Some people may also experience allergic reactions, such as rash, itching, swelling, or difficulty breathing. If this occurs, stop taking ketamine or esketamine and seek medical attention immediately.

Ketamine and esketamine are contraindicated in people who have:

• A known hypersensitivity to ketamine, esketamine, or any of the ingredients in the products.
• A history of substance abuse or dependence, especially to ketamine or other dissociative drugs.
• A history of psychotic disorders, such as schizophrenia or bipolar disorder.
• A history of aneurysm, bleeding in the brain, or stroke.
• Uncontrolled high blood pressure or heart disease.
• Severe liver or kidney disease.

Ketamine and esketamine should be used with caution in people who have:

• A history of seizures or epilepsy.
• A history of glaucoma or increased eye pressure.
• A history of urinary problems or bladder damage.
• A history of thyroid problems or low blood sodium levels.

Ketamine and esketamine should not be used during pregnancy or breastfeeding, as their effects on the fetus or infant are unknown.

Ketamine and esketamine may interact with other medications, such as opioids, benzodiazepines, alcohol, stimulants, antihistamines, anticholinergics, and monoamine oxidase inhibitors (MAOIs). These interactions may increase the risk of side effects or reduce the effectiveness of either medication. Therefore, it is important to inform the doctor about all the medications and supplements that one is taking before starting ketamine or esketamine treatment.

Ketamine and esketamine have several advantages over other treatments for TRD. Some of the benefits are:

• They can provide rapid relief of depressive symptoms and suicidal thoughts within hours of administration, unlike most antidepressants that take weeks to work 1 2 3 . 
• They can restore the synaptic plasticity and neural connectivity that are impaired by chronic stress and depression, unlike most antidepressants that only modulate neurotransmitter levels 1.
• They can benefit patients who have comorbid anxiety, post-traumatic stress disorder (PTSD), or chronic pain, as ketamine has anti-anxiety, anti-stress, and analgesic properties 1 2.

Ketamine and esketamine also have some limitations and drawbacks that should be considered before using them. Some of the disadvantages are:

• They are not a cure for depression and their effects are not permanent. Patients may need repeated doses or maintenance therapy to sustain their improvement 1 3.
• They are expensive and may not be covered by insurance plans, as they are classified as Schedule III controlled substances by the Drug Enforcement Administration (DEA).
• They can cause dependence and abuse, especially in people who have a history of substance use disorders or who use ketamine recreationally 1 4.
• They can cause cognitive impairment, such as memory loss, attention deficit, or learning difficulties, especially with long-term or high-dose use 1 4.
• They can cause cardiovascular complications, such as increased blood pressure, heart rate, or arrhythmia, especially in people who have pre-existing heart conditions 1 4.
• They can cause urinary tract problems, such as cystitis, inflammation, or infection, especially with long-term or high-dose use 1 4.

Ketamine and esketamine are novel and fast-acting treatments for TRD that can provide rapid relief of depressive symptoms and suicidal thoughts within hours of administration. They work by modulating glutamate receptors and enhancing synaptic plasticity and neural connectivity in the brain. They have been shown to be effective and well tolerated by most patients in clinical trials. However, they are not a cure for depression and their effects are not permanent. They also have some serious side effects and risks that should be weighed against their benefits. They are expensive and may not be covered by insurance plans. They require a prescription and a medical supervision to ensure their safe use. Ketamine and esketamine are promising treatments for TRD, but more research is needed to establish their long-term safety and effectiveness.

1: Sanacora G et al 

2: Healthline: Ketamine Depression Treatment: How It Works, Research, Safety

3: Mathew SJ et al 

4: Spravato (esketamine) nasal spray prescribing information 

5: Zarate CA et al