Can Ketamine Therapy Treat Depression Better Than SSRIs?

Reviewed By: Brian Pilecki, Ph.D.

If you’re curious about ketamine for depression, you might have heard how quickly it works. People often report improvements in their symptoms within one day, and results can last anywhere from one to two weeks. Meanwhile, conventional antidepressants like SSRIs can take several weeks to take effect.

However, the effects of ketamine also tend to wear off more quickly and require ongoing maintenance. On the other hand, conventional antidepressants typically require a daily dose.

It’s too simplistic to say that ketamine is in and SSRIs are out. Ketamine treatment might be an option for people with depression that doesn’t respond to other forms of treatment. But depression is complicated, and one treatment isn’t necessarily better than the other.

Ketamine and SSRIs work via different biological mechanisms, and their effects are worlds apart. Here’s a high-level overview of the difference between SSRIs and ketamine therapy for depression. Talk to your doctor before making any changes to your medication.

What Are SSRIs?

SSRIs (selective serotonin reuptake inhibitors) are antidepressant medications that generally increase serotonin levels in the brain.

Your brain uses neurotransmitters to send chemical messages between nerve cells. Serotonin is a central neurotransmitter that helps regulate your mood, among other behaviors and systems in your body (like memory, stress, and sleep). 1

Nerve cells usually reabsorb (or reuptake) serotonin once it reaches its destination. SSRIs block reuptake, which leads to a net increase of serotonin that is associated with the positive effects that are seen with these drugs.

It’s important to remember that more serotonin doesn’t “fix” depression. In fact, it’s not clear what causes depression in the first place. One theory is that diminished serotonin activity causes depression symptoms. However, this theory is overly simplistic and no longer relevant. 2 It’s also based on faulty logic.

For example, if SSRIs increase serotonin and improve depression, does that mean that depression is due to low serotonin? That would be like saying: Ibuprofen improves headaches, so headaches are caused by low ibuprofen. The causes of depression are much more complex, nuanced, and not fully understood.

In a paper published in World Psychiatry, the authors suggest that serotonin doesn’t cause symptoms of depression. 3 Still, there is a relationship between serotonin and depression, and low serotonin levels might make it harder for people to maintain recovery from depression.

One thing is clear: SSRIs produce an antidepressant response that can help some people feel better, even though we don’t totally know how these drugs work.

What is Ketamine?

Ketamine is a dissociative drug that makes people feel disconnected from their bodies and environments. The FDA approved ketamine as a surgical anesthetic in 1970, but its antidepressant properties weren’t reported until 2000. 4

Ketamine is often grouped into the “psychedelic” category, but it’s not the same as other drugs like LSD or psilocybin. These “classical” psychedelics work on the brain’s 5-HT receptors, which interact with serotonin. At therapeutic doses, ketamine causes effects like dissociation, euphoria, hallucinations, and relaxation.

Unlike SSRIs, which increase serotonin levels, ketamine works on many different parts of the brain at once. (But like SSRIs, it’s not clear how ketamine works. Notice a pattern here?) One prevailing theory is that ketamine’s antidepressant effects stem from its effects on the neurotransmitter glutamate.

Glutamate plays a role throughout your central nervous system. Glutamate binds to NMDA receptors to deliver its messages. Ketamine temporarily blocks those receptors, which causes glutamate levels to increase. 5

This effect contributes to ketamine’s dissociative effects, as well as the activation of pathways in the brain that support healthy brain cells and connectivity.

What is ketamine therapy?

There are two main forms of ketamine treatment: ketamine infusions or ketamine-assisted psychotherapy.

Ketamine infusions, or IV treatment, involve receiving a drug dose via IV at a ketamine clinic or outpatient facility. No therapeutic support is offered because this form of treatment is based on the idea that ketamine’s effects are due to the drug itself. Ketamine infusion therapy typically lasts about one to two hours, and the psychedelic effects subside after about an hour.

Ketamine-assisted psychotherapy takes a different approach. Ketamine is administered via various methods (IV, injection, lozenges), along with therapeutic support. The psychological experience is important with this type of treatment. This model resembles the model used for other psychedelics, such as psilocybin or MDMA. Greater attention is given to the environment, like ensuring the room is comfortable and private.

In either case, treatment frequency varies. People generally receive a series of treatments over two to three weeks. During your initial consultation with a medical professional, you’ll get a better idea of what to expect from your ketamine treatment.

How Does Ketamine Work for Depression?

A body of research suggests that glutamate is dysregulated in the brains of depressed patients. 6,7 Ketamine’s ability to increase glutamate levels may activate other parts of the brain that support brain health and connectivity, like BDNF and mTOR pathways.

Ketamine might also indirectly enhance the activity of other neurotransmitters. 8 Combined, these actions may contribute to ketamine’s antidepressant effects.

What’s more, ketamine works quickly—within a few hours. This doesn’t mean ketamine cures depression; the drug’s antidepressant effects can taper off after one week (or a little over two weeks after repeated infusions). 5

However, ketamine’s speedy effects may help relieve depressive symptoms more effectively in certain situations (such as an acute crisis) than other medications. And with that relief, people feel more receptive to and hopeful about other forms of depression treatment, like talk therapy, mindfulness, and exercise.

In other words, having temporary relief from symptoms can motivate people to seek out more lasting forms of treatment.

How Does Ketamine Differ From SSRIs?

Ketamine acts on different biological mechanisms
Ketamine causes psychedelic effects
Ketamine acts quickly

Ketamine acts on different parts of the brain

Ketamine acts on NMDA receptors and causes glutamate levels to increase in the brain. Its antidepressant effects might also be attributed to the way it affects other parts of the brain, although more human research is needed.

In comparison, SSRIs work via serotonin pathways. (That’s what the “selective” in “selective serotonin reuptake inhibitors” refers to.)

Ketamine causes psychedelic effects

In ketamine therapy, dosages are far lower than what a person would receive as a surgical anesthetic. At these low doses, ketamine can cause psychedelic effects like dissociation, euphoria, hallucinations, numbness, and relaxation.

SSRIs affect your mood, but they don’t cause psychedelic effects. SSRIs can make a person feel less depressed, more content, and able to accomplish everyday tasks.

Ketamine acts quickly

Ketamine’s effects kick in within a few hours. The effects can last anywhere from days to weeks after treatment, depending on the frequency of treatment and how a person responds to ketamine therapy. 5

SSRIs take about six to eight weeks before they achieve full effect, and even then, some people need to experiment with different combinations and dosages until they find what works best for them.

A patient will need to work with their doctor to find a prescription that delivers the best reduction of depression symptoms and the fewest side effects, but it can take time to find that combination.

Is Ketamine Safer for Depression Than SSRIs?

Ketamine isn’t inherently safer than SSRIs for depression.

As a Schedule III controlled substance, ketamine can only be prescribed and administered by a licensed clinician. In clinical contexts, ketamine is considered safe to use.

However, it’s associated with side effects, such as anxiety, allergic reactions, increased heart rate and blood pressure, nausea, and vomiting. Additionally, it’s possible to abuse and become addicted to ketamine. It’s also important to know that taking ketamine, like other psychedelics, can bring up memories of trauma or difficult memories from the past.

SSRIs are also associated with side effects, such as anxiety, changes in eating behaviors, difficulty sleeping, nausea, reduced libido, and weight gain or loss. Both ketamine and SSRIs aren’t recommended for use in people with a history of bipolar disorder or cardiac problems.

There’s a lot we don’t know about depression. What we do know is that it’s complicated. In an interview with The Microdose, psychology professor Eiko Fried said a person’s mental health state is shaped by “biological, psychological, and social factors, and your current stress, your personality, life events, adverse experiences, brains, genes, hormones.” 9

In other words, many different factors can impact a person’s depression, and it’s too simplistic to say that one form of therapy is better than the other. SSRIs are helpful for some people, and ketamine works better for others. We don’t know why (yet), but both forms of treatment are generally considered safe and can be essential parts of an overall treatment plan.

Frequently Asked Questions

Is ketamine addictive when used for depression?

It’s possible to become addicted to ketamine when it’s abused. However, the risk is low in a clinical setting because you receive a low dose in a limited amount of time under medical supervision.

If you or someone you know are struggling with substance use or addiction, reach out to the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-4357 for information about support and treatment facilities in your area.

Can I use ketamine and SSRIs at the same time?

Talk to your doctor before you combine any medications. Using ketamine and SSRIs may increase side effects like dizziness, drowsiness, confusion, and slow breathing.

Currently, there isn’t evidence that SSRIs dampen the effects of ketamine (or vice versa). However, one small study in 2020 found that another type of antidepressant medication, benzodiazepine, reduces ketamine’s antidepressant effect. 10

Is esketamine better than SSRIs?

Esketamine (brand name Spravato) rapidly improves symptoms of depression when other medications, like SSRIs, have failed to work. Esketamine is a nasal spray and FDA-approved antidepressant medication that’s related to ketamine.

Like ketamine, esketamine has a high affinity for the NMDA receptor. It blocks these receptors and increases glutamate levels. Because it operates via a different mechanism, esketamine might work better for some people than SSRIs.

However, a growing body of research suggests ketamine is more effective at reducing depression. 11

Is Ketamine a Miracle Drug for Depression?

In a word, no. Ketamine can help reduce symptoms in depressed people with treatment-resistant depression, but it doesn’t work for everyone.

As ketamine research continues to develop, we may learn more about ketamine’s effectiveness for depression compared to SSRIs. For now, ketamine is an effective alternative to traditional antidepressants because of its different biological mechanisms.

Ketamine therapy is just one treatment option in an overall plan to manage depression, along with therapy, mindfulness, and holistic lifestyle changes like exercise, sleep hygiene, and nutrition. Talk to your doctor if you’re interested in ketamine therapy.

Dr. Brian Pilecki is a clinical psychologist at Portland Psychotherapy specializing in psychedelic-assisted therapy and treating anxiety disorders, trauma, and PTSD. He graduated from Fordham University and completed a postdoctoral fellowship at the Warren Alpert Medical School of Brown University.