Is Ketamine a Last Resort for Depression? When to Consider It

Depression is a labyrinth. For many, it feels like wandering endlessly through a fog with no clear exit. Traditional treatments, SSRIs, SNRIs, therapy, light the way for some. But others remain stuck in the dark, no matter how many medications they try or how long they spend in therapy. For those individuals, ketamine has emerged as a striking, controversial, and fast-acting alternative.

But is it a last resort? Or simply misunderstood?

Understanding Ketamine’s Origin Story

Originally developed as an anesthetic in the 1960s, ketamine found its way into operating rooms and battlefields. For decades, it was known primarily for its use in surgery and emergency medicine.

Later, it became infamous as a party drug, often referred to by street names like "Special K." Yet, beneath its recreational and medical use was something remarkable: ketamine had an unexpected side effect—it made people feel better. Emotionally better. Sometimes dramatically so.

By the early 2000s, researchers began to notice ketamine’s powerful effects on depression. What caught their attention wasn’t just that it worked—it was how fast it worked. Some patients reported relief within hours. Not weeks. Not months. Hours.

The Problem with Traditional Treatments

Before diving into when ketamine should be considered, it’s important to understand the landscape of current depression treatment.

For mild to moderate depression, first-line treatments such as selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) are effective for many people.

But they come with caveats. Antidepressants can take four to six weeks, sometimes longer, to show results. And for some patients, the side effects outweigh the benefits. Others don’t respond at all.

This condition, known as treatment-resistant depression (TRD), affects roughly 30% of those diagnosed. These individuals often cycle through a carousel of medications and therapeutic modalities, sometimes for years, without finding lasting relief.

For them, ketamine may not be just another option—it may be the only one that brings light into a dark tunnel.

How Ketamine Works Differently

Ketamine doesn’t operate like conventional antidepressants. Most antidepressants target the brain's serotonin system. Ketamine takes a completely different route: it affects glutamate, the most abundant neurotransmitter in the brain.

Specifically, it acts on NMDA receptors and increases brain-derived neurotrophic factor (BDNF), which supports neural growth and repair.

This mechanism doesn’t just mask symptoms; it may help to reset dysfunctional brain circuits involved in mood regulation. Think of it less as a temporary bandage and more like rebooting a glitching computer.

And while most antidepressants have to build up in your system over weeks, ketamine often works within hours. For people in crisis, especially those with suicidal thoughts, that kind of speed can be lifesaving.

Is It a “Last Resort”?

Calling ketamine a “last resort” is both accurate and misleading. On one hand, it is typically reserved for those who haven’t responded to traditional treatments.

That’s partly due to cost, partly due to stigma, and partly due to medical caution.

The FDA has approved a form of ketamine called esketamine (Spravato) for treatment-resistant depression. It’s administered as a nasal spray in a clinical setting and is tightly controlled.

Intravenous (IV) ketamine infusions, though not FDA-approved for depression, are offered by a growing number of clinics across the U.S. and beyond, based on accumulating off-label evidence.

Still, it’s not the first thing a psychiatrist reaches for. And that’s not because it doesn’t work, but because it’s complex.

Ketamine treatment requires close supervision. Dosing is critical. The effects are intense. It can cause dissociation, temporary hallucinations, and increases in blood pressure.

The high potential for misuse and the unknowns around long-term effects make it a treatment that demands respect, not recklessness.

So yes, ketamine is often used after other options have failed. However, as more research accumulates, some clinicians are beginning to question whether it should be relegated to last-line status.

In some cases, earlier intervention with ketamine might prevent years of suffering.

When to Consider Ketamine for Depression

Not every person with depression is a candidate for ketamine. It’s important to weigh both the severity of the illness and the response to past treatments. Here are some scenarios where ketamine may be appropriate:

1. You’ve Tried Multiple Antidepressants Without Success

If you’ve cycled through several medications without finding relief, ketamine might be a viable next step.

2. You’re Experiencing Suicidal Thoughts

Because of its rapid onset, ketamine is sometimes used in emergency psychiatric settings to reduce acute suicidal ideation.

3. Therapy and Lifestyle Changes Aren’t Enough

While therapy, exercise, and diet can have powerful effects, they’re not always sufficient—especially when biochemical factors dominate.

4. You’re Seeking Alternatives to ECT

Electroconvulsive therapy (ECT) is highly effective but carries significant stigma and potential side effects. Ketamine may offer similar efficacy with fewer drawbacks.

5. You’re Informed and Committed to Supervised Use

Ketamine is not a casual option. Patients must be fully informed of the risks, monitored during treatment, and willing to engage in follow-up care.

Risks and Limitations

While ketamine offers hope, it’s not a miracle drug. Some patients don’t respond. Others experience unpleasant side effects like nausea, dizziness, or disturbing dissociative episodes.

There’s also the issue of temporary relief. The effects of a single ketamine infusion may only last a few days to a week.

To maintain improvement, patients often need a series of treatments and potentially maintenance doses afterward. This makes cost a significant barrier—many insurance plans still don’t cover ketamine therapy for depression.

Then there’s the elephant in the room: addiction.

Ketamine has addictive potential. Used improperly, it can lead to dependency and cognitive issues. That’s why strict medical oversight is essential.

The Future of Ketamine in Psychiatry

As the stigma around mental health continues to recede and as more research supports ketamine’s effectiveness, its place in psychiatry is slowly evolving.

Researchers are exploring related compounds and alternative dosing strategies that may reduce side effects while preserving antidepressant benefits.

We may even see a future where ketamine isn’t a last resort but a first-line option for specific subtypes of depression, particularly those marked by acute suicidal ideation or inflammation-driven brain dysfunction.

Is ketamine a last resort?

For now, in most cases, yes. But that label may be more about tradition and caution than about science. What we do know is this: for people living in the shadow of relentless depression, ketamine can offer a glimpse of sunlight. And sometimes, that’s enough to begin again.

If you or someone you love is battling treatment-resistant depression, ketamine may be worth a conversation with your psychiatrist, with your therapist, with yourself. Not out of desperation, but out of a desire to reclaim life from the grip of despair.

Relief might not be as far away as it seems.