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Ketamine Could Be a Miracle for Treatment-Resistant Depression

Ketamine, known as ‘special K’ in the illicit drug realm, is commonly used as an anesthetic or sedative agent in human and animal medicine. Another beneficial use of the drug has emerged - helping manage treatment-resistant depression.

Key takeaways:

For the 33% of the population where standard medication and additional therapies do not resolve signs of depression, ketamine therapy may be a great option, minimizing symptoms and lessening the risk of suicide.


The World Health Organization (WHO) once recognized depression as the third leading cause of disability globally; now, in the post-COVID-19 era, it is the first. Depression, when left untreated or treated ineffectively, can lead to suicide. A combination of psychotherapy, medications and behavior modifications may be warranted to treat depression.

Recently, the use of ketamine to treat complicated depression or depression that fails to respond to common treatments has provided an option for some when all hope has been lost. More research is ongoing about how ketamine specifically works within the body in states of depression, refining treatment protocols and criteria for use.

Signs of depression

Recognizing signs and symptoms of depression in yourself or others may help identify those needing treatment sooner rather than later. Clinical signs of depression naturally will wax and wane as life’s situations and stressors change, ebb, and flow. Symptoms may include:

  • Feelings of sadness.
  • Moodiness.
  • Loss of interest or pleasure gained from activities/social interactions.
  • Decreased concentration.
  • Self-loathing.
  • Hopelessness.
  • Sleep disorders.
  • Appetite changes (up or down).
  • Weight changes (up or down).
  • Decreased energy.
  • Trouble with relationships.
  • Pain.
  • Feelings of guilt.
  • Slowed thoughts or movements (psychomotor agitation).
  • Suicidal thoughts/ideations.
  • Weakness.

Treating depression

Treating depression can be challenging, and what works for you may not work for your friend or family member. For some, the first drug tried does the trick. Others bounce from one drug to another, combining them with cognitive behavioral therapy (CBT) or other therapy modalities, but still cannot find balance or resolution of signs.

Current drug therapies for depression include drugs targeting various monoamine neurotransmitters in the body, including norepinephrine, serotonin, and dopamine. But are there options when these therapies fail to produce results?

Are there options for treatment-resistant depression?

If you are in the 33% of the population with treatment-resistant depression (TRD), perhaps ketamine may be right for you. When depression doesn’t respond to multiple therapeutic combinations, it may become severe enough to create a significant disability. Challenges with work and social relationships and suicidal thoughts and behaviors may develop if depression is left untreated. Ketamine may be a viable option for this subset of depression sufferers.

While TRD doesn’t have a universal definition, it is generally recognized when a patient fails to respond to at least two appropriate trials of different antidepressant classes given for an appropriate duration (a minimum of 6–8 weeks). Those with TRD fail to experience remission or a minimum of 50% mood modulation.

The problem with standard drug therapies is they take time, and intranasal or IV doses of ketamine act faster and may provide more immediate sustainable relief in patients who fail to respond to the more traditional therapies.

What is ketamine?

Ketamine, a schedule III controlled drug by the Drug Enforcement Agency (DEA), is approved for use in animals and people for procedures needing sedation or general anesthesia. It is used for pain management, as an anesthetic, and as an amnestic (makes you forget). It is classified as a dissociative drug with the potential for abuse. These drugs distort one’s appreciation for sound and sight and create dissociation (detachment, out-of-body-like experiences) from one’s surroundings.

How ketamine helps depression

Ketamine works differently than other typical antidepressants by increasing levels of glutamate. Glutamate is the most abundant neurotransmitter and a crucial one in the brain, creating many beneficial effects. This chemical helps with emotion regulation and pain perception and plays a role in learning and memory abilities.

Glutamate helps form connections in the brain, especially associated with injury and learning. Further, this neurotransmitter permits brain cells to interact and adjust the signal strength throughout the brain. With depression, the part of the brain that is flexible and establishes new connections (neuroplasticity) decreases. With fewer connections, one’s ability to function lessens. Ketamine increases glutamate and improves these connections.

Ketamine infusion or nasal spray

Ketamine isn’t an option for everyone, but those with TRD have two possibilities, Spravato® nasal spray or racemic ketamine infusions (IV injections). While the infusion form has been around for years, the nasal spray is an approved medication specifically for TRD. Thus, insurance companies have historically not covered the infusion form since it is being used off-label. As new research and studies further demonstrate the benefits, this may change. While many patients pay out of pocket for the infusions, some insurance companies may reimburse if claims are submitted after treatment.

Off-label prescribing means a drug approved for a different purpose or disease state is used to treat something else. It doesn’t mean that the research doesn’t show benefits. In the case of ketamine, it is already legally approved for use as a sedative/anesthetic. Drug companies just don’t want to spend money to obtain FDA labeling for treating TRD. Off-label medication use is extremely common and often necessary in medicine.

Spravato® (esketamine) 28 mg nasal spray

Spravato® is an FDA-approved nasal spray consisting of esketamine. It is prescribed in combination with an antidepressant taken by mouth (such as Prozac®, Effexor®, and Zoloft®, among others). The nasal spray is labeled solely for use against TRD. Because the intranasal route of administration would put the drug outside the realm of a hospital or clinical setting, concern for this type of delivery for abuse development or misuse exists.

Ketamine infusion

The injectable form of ketamine commonly used in anesthesia in animals and humans is given as an infusion lasting about 40 minutes for TRD therapy Treatment protocols vary. Some may receive the initial injection and never need another dose, while others may need maintenance injections at different intervals over time.

Ketamine research clearly shows efficacy in reducing depression in those with TRD. Starting with the first clinical trial in 2000, followed by a larger study by Zarate et al. in 2006, researchers began to demonstrate the positive effects of a 40-minute infusion of ketamine and improvement within 110 minutes of the infusion, lasting 7 days. Further studies evaluated dosing protocols and dose ranges. Additional studies assessed and continue to look at ketamine’s ability to decrease suicidal thoughts and inclinations. Finally, investigations with varying protocols ensued, looking at using repeat doses of infusions. See additional resources for further study information.

IV vs. Intranasal, what do the experts say?

Providing the strongest evidence in favor of ketamine use for TRD, a 2022 systematic review and meta-analysis by Bahji et al compared the use of esketamine (intranasal) and racemic (intravenous) ketamine for depression. Based on this comprehensive review, they conclude that IV ketamine outperforms intranasal esketamine in managing TRD. Both options are used in conjunction with traditional antidepressant therapy and generally in cooperation with a psychiatric professional.

How long does each ketamine treatment last?

When talking about the infusions, most people notice a benefit within the first one to three treatment sessions, though each individual is different. After an initial series of injections (six to eight, generally over 2 weeks, though it varies with each center), people typically receive maintenance injections. For subsequent injections, patients may obtain them every three to six weeks or less often. However, in a 2021 detailed review of the literature by McIntyre et al., they emphasize that studies looking at the appropriate dosing interval for maintenance therapy are still lacking.

Ketamine may help minimize suicidal thoughts

Several studies have reported that ketamine reduces suicidal thoughts for up to seven days. Those receiving repeat-dose injectable ketamine may have fewer thoughts of suicide for up to six weeks. These effects may occur by different mechanisms of action that are working to minimize depression symptoms. Additional studies are needed to determine further significance beyond six weeks past the last dose.

Pros and cons of ketamine

There are always pluses and minuses when trying any therapy. For some, results may be miraculous, while for others, the side effects outweigh the benefits. Side effects and benefits may vary depending on the form of ketamine used (nasal spray vs. infusion). Positive and negative effects also vary depending on the dose of the medication used.

The pros of ketamine for treatment-resistant depression include:

  • Rapid onset of depression symptom relief versus other therapies, which can take several weeks to show benefits.
  • Decreased anxiety.
  • Decreased suicidal thoughts versus traditional therapies, which may increase these ideations.
  • One of only two FDA treatments for treatment-resistant depression.

According to Johns Hopkins, additional ketamine benefits may include decreasing the negative effects stress can cause on the brain and nerve cells, even promoting cell growth, and improving brain function.

Cons for ketamine use, however, also must be considered. Ketamine side effects can occur and can be dose-dependent.

  • Elevated blood pressure.
  • Elevated heart rate.
  • Elevated breathing rates.
  • Nausea (upset stomach).
  • Drunk feeling.
  • Problems with urination.
  • Dizziness/spinning feeling.
  • Anxiousness.
  • Increased temperatures.
  • Sleepiness.
  • Headache.
  • Decreased energy or the opposite reaction with excitement or happiness.
  • Numbness (decreased overall sensitivity.

Additional concerns include inappropriate use of the drug and the abuse potential. Those with previous addictions, such as alcohol or substance abuse, should discuss possible concerns with healthcare professionals before selecting this therapy. Finally, some patients with underlying health conditions, such as those affecting the heart or liver, may not be eligible for this therapy due to possible health risks.

What do patients think about ketamine?

One patient, Jonathan H. truly appreciates the benefits of ketamine therapy. He has been receiving ketamine infusions for over four years. Jonathan H describes the benefits as hard to define. Still, he states that “ketamine helps to lift the heaviness of the depression. It is like it is not as acute, and I feel lighter and less down. It helps improve my overall motivation. Though this benefit slowly ebbs over time, within about three to four weeks, I feel that heaviness creep back in and know I will need an injection shortly.”

Ketamine provides Jonathan with an improved quality of life. He attributes ketamine therapy to giving him a new lease on life. In conjunction with therapy and traditional antidepressants, he has risen above depression and doesn’t let it define him.

Is ketamine right for your depression?

Ketamine isn’t for everyone, and insurance companies may not always cover this therapy. Additionally, you must meet the criteria to qualify for a trial with this drug. Finally, research continues to determine the most effective doses and administration methods (infusion vs. intranasal vs. oral or other means). Further research is ongoing to establish the right quantity, product, and delivery method to minimize the risk potential of abuse and enhance the benefits of treating depression. Current abuse risks are not readily evident in existing literature, but studies are ongoing.

If you think you may benefit from ketamine therapy, talk to your psychiatrist or primary care physician for more information and to direct you on the best place to go and who to speak with about your options.

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Starli Brighton
prefix 1 year ago
How interesting that you talk about how long a ketamine treatment can take to start to work. My son has been suffering from depression for a year now. We will find him an excellent place for depression counseling for this locally.