woman getting intravenous ketamine treatment for depression
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Depression is one of the most common mental health disorders in the U.S. and around the world. The symptoms of depression can cause significant emotional pain and distress, disrupt personal relationships, and impair the ability to fully participate in work, academic, and social activities. In addition, a diagnosis of clinical depression – called major depressive disorder (MDD) – is a risk factor for various negative physical, emotional, and behavioral conditions, including:

  • Obesity
  • Cardiovascular disease
  • Type 2 diabetes
  • Cancer
  • Anxiety disorders
  • Substance use disorders
  • Suicidal behavior

The traditional, standard approaches to treatment for MDD include:

  • Medication, such as antidepressants
  • Psychotherapy, including:
    • Cognitive behavioral therapy (CBT)
    • Dialectical behavior therapy (DBT)
    • Acceptance and Commitment therapy (ACT)
  • Education, including:
    • The science of depression and depression treatment
    • Symptom management
    • Stress management
    • Life skills training
    • Vocational training
  • Complementary supports and lifestyle changes, including:
    • Mindfulness activities
    • Healthy eating
    • Exercise
    • Peer support groups

The approaches listed above work alone or in combination for a majority of people with MDD and other depressive disorders. However, evidence shows that for around one third of people diagnosed with a depressive disorder, these standard treatments are not effective, whether alone or in combination. That’s why a relatively recent development in depression treatment – the discovery of the antidepressant properties of ketamine – is more than a simple step forward in depression treatment. It’s a legitimate breakthrough: evidence shows that ketamine can help relieve symptoms of depression for people who don’t respond to the traditional, first-line therapies we mention above.

In this article, we’ll discuss a recent peer-reviewed study that explains exactly what ketamine is and how it works to treat depression.

First, though, we’ll share the latest statistics on depression in the U.S.

Depression: Facts and Figures

Every year, the National Institutes of Health (NIH), in partnership with the Substance Abuse and Mental Health Services Administration (SAMHSA), publish the National Survey on Drug Use and Health (NSDUH). The NSDUH is a nationwide survey that includes information from over 70,000 people about their mental health, drug use, and various related topics, including the prevalence of major mental health and substance use disorders, treatment for mental health and substance use disorders, and other various related topics.

The large sample size – over 70,000 participants per year – make the NSDUH a valuable tool for understanding the rates of these disorders at the population level. Let’s take a look at the latest data on depression, as published in the 2021 NSDUH.

Depression Among Adults in the U.S.: 2020

Major Depressive Episode (MDE):

*MDE is defined as the presence depressive symptoms every day for more than two weeks*

  • Adults 18+: 8.3% (21.0 million)
  • 18-25: 18.6% (6.2 million)
  • 26-49: 9.3% (9.5 million)
  • 50+: 4.5% (5.3 million)

MDE With Severe Impairment:

*MDE with severe impairment is defined as the presence depressive symptoms every day for more than two weeks, and the symptoms prevent the individual from participating in the most basic activities of daily life, including going to work, going to school, and engaging in simple self-care such as personal hygiene*

  • Adults 18+: 5.7% (14.5 million)
  • 18-25: 13.3% (4.4 million)
  • 26-49: 6.5% (6.6 million)
  • 50+: 2.9% (3.4 million)

Adults with MDE: Received Treatment

  • Adults 18+ with MDE:
    • 61.0% (12.6 million) received treatment
  • Adults 18+ with MDE with severe impairment:
    • 64.8% received treatment
    • 18-25: 56.7% received treatment
    • 26-49: 66.6% received treatment
    • 50+: 71.8% received treatment

Those statistics tell us at least three important things. First, millions of people in the U.S. have depression and many of those have depression that prevents them from leading a full and fulfilling life. Second, of the people with depression, over half get professional treatment: that’s a good thing. However, among those people who get treatment, we know that roughly a third of them don’t respond to treatment, meaning their symptoms don’t improve.

If we use the figures above, that means that among the 14.5 million people with MDE with severe impairment, over 4.3 million engage in treatment without success.

That’s why ketamine is considered a breakthrough: it might help these 4.3 million people achieve relief.

Now that we know the scope of the problem and why ketamine is important, let’s take a look at that peer-reviewed study we mention in the introduction of this article.

Ketamine for Depression: Essential Facts

Published in March 2022, the paper “Mechanisms Of Ketamine and its Metabolites as Antidepressants” offers a detailed examination how ketamine works to relieve symptoms of depression. The study authors begin by explaining why ketamine received approval by the Food and Drug Administration (FDA) in 2019 to support patient with treatment-resistant depression.

Here’s the data they cite:

Studies also showed that ketamine not only relieved symptoms quickly, but that symptom relief persisted for up to two weeks after a single treatment.

That brings us to the two primary therapeutic differences between ketamine and traditional antidepressant medications:

  1. Traditional antidepressants often take several weeks of daily ingestion to relieve the symptoms of depression
  2. Traditional antidepressants stop working when a patient stops taking them

We’ll reiterate: the therapeutic effects of ketamine can appear within hours, and symptom relief may persist for weeks after one treatment. Ketamine has been in use for close to five years now, and researchers and clinicians have devised protocols for ketamine therapy – most patients participate in multiple sessions over several weeks – that result in symptom relief that may persist for several months.

Now let’s take a look at how ketamine works to treat depression, as compared to traditional antidepressants.

Ketamine Compared to Standard Antidepressants: Mechanisms of Action

Most standard antidepressants belong to one of the five following categories:

Selective serotonin reuptake inhibitors (SSRIs):

  • These medications work on the theory that depressive symptoms result from a deficit of serotonin in the brain, and work to increase levels of serotonin in key brain areas. SSRIs include fluoxetine, paroxetine, sertraline, citalopram, and escitalopram.

Serotonin and norepinephrine reuptake inhibitors (SNRIs):

  • These medications also increase the amount of norepinephrine present in key brain areas.
  • SNRIs include duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran

Tricyclic antidepressants (TCAs):

  • Like SSRIs and SNRIs, these medications increase the amount of serotonin and norepinephrine in the brain. Unlike SSRIs and SNRIs, they also block the action of muscarinic receptors, histamine receptors, and alpha-adrenergic receptors
  • TCAs include imipramine, nortriptyline, amitriptyline, doxepin, desipramine
  • Due to the number of negative side-effects, TCAs are not first line treatments, but may be prescribed in SSRIs or SNRIs fail to relieve symptoms

Monoamine oxidase inhibitors (MAOIs):

  • These medications are also a second-line treatment for depression. They work by blocking the action of a chemical in the brain that breaks down norepinephrine, serotonin, and dopamine.
  • MAOIs have serious side effects, and can be dangerous when ingested alongside specific foods. Therefore, MAOIs are not common.
  • Examples of MAOIs include, but are not limited to tranylcypromine, phenelzine, and isocarboxazid

Atypical Antidepressants:

  • Like the medications listed above, atypical antidepressants affect levels of serotonin, dopamine, and norepinephrine in the brain, but in various different ways that are not the same as SSRIs, SNRIs, TCAs, or MAOIs.
  • Atypical antidepressants include trazodone, mirtazapine, vortioxetine, vilazodone, and bupropion

Ketamine does not work like any of those medications. Research shows ketamine and its metabolites, including esketamine – the medication in intranasal spray – works on the following neurotransmitter and neurotransmitter-related systems in the human brain.

Ketamine Mechanism(s) of Action:

  • NMDA system and receptors
  • Opioidergic system and receptors
  • Monoaminergic system receptors
  • Glutaminergic system and receptors
  • Muscarinic system and receptors
  • Brain derived neurotrophic factor

Let’s discuss that information for a moment.

What we can see is that ketamine and its metabolites, including esketamine, exert an influence on more brain areas related to depression than all the other antidepressants. In addition, some standard antidepressants may increase risk of suicide in adolescent and adult patients. While some researchers contest the initial FDA warnings about suicide risk and antidepressants, two recent studies – read them here and here – confirm the suicide risk associated with some antidepressants.

Although there are side-effects associated with ketamine, most fade within an hour of treatment, and they do not include increased risk of suicidal ideation, suicidal behavior, or suicide attempts. In fact, research shows ketamine is effective in reducing suicidal behavior. A recent study showed that in patients in suicidal crisis in an emergency care situation, ketamine therapy led to full remission of suicidal thoughts within three days.

Implications for Depression Treatment

The study we discuss above is important because it explains how ketamine works to relieve depression: in contrast to previous antidepressants, it exerts an influence over a broader range of neurotransmitter systems in the human brain. This may explain why ketamine leads to symptom relief faster than most antidepressants, and may explain why the significant symptom relief associated with ketamine may persist for days after one treatment, and months after a series of treatments.

Those two facts are part of what makes ketamine a breakthrough discovery: the quick action and the persistent effect. But another aspect of ketamine may be even more important: its effect on treatment-resistant depression (TRD). People with TRD may go through years of treatment without experiencing symptom relief, which can compound depressive symptoms and exacerbate the severity of depression overall. However, one of the studies that led to FDA approval for ketamine showed that out of a group of 101 adults with treatment-resistant depression, 70 reported symptom relief with a combination of ketamine and a standard antidepressant.

For people with TRD, that’s major news: there may finally be a medication that helps them return to a full and fulfilling life, rather than one dictated by the symptoms of their depressive disorder. For treatment professionals, this is also major news. When a person with TRD comes to them and asks, “Is there anything that can help?” They can now answer with confidence, “Yes, I think we have a medication that may work for you.”