How Does Ketamine Work for Depression?

Depression remains one of the most challenging mental health disorders to treat — especially in cases where standard treatments fall short. The emergence of Ketamine as a rapid‑acting treatment offers new hope, but also raises important questions: how exactly does it work, how well does it work, and who is it for?

Why is Ketamine Getting Attention?

First, some context. Conventional antidepressants — such as selective serotonin reuptake inhibitors (SSRIs) — often take weeks to produce meaningful improvement and still leave up to one‑third of patients with inadequate relief. For example, in large studies of so‑called treatment‑resistant depression (where people have failed two or more standard treatments), the need for novel options is clear.[1]

Ketamine stands out because it acts much faster than traditional treatments.[2,3]

• One news summary noted that after just three infusions over 11 days, 52% of participants with severe depression achieved remission.
• A large recent study concluded that 55 % of ketamine‑treated patients and 41 % of those receiving electroconvulsive therapy (ECT) had at least a 50 % improvement in depressive symptoms over six months.

Given this speed and efficacy, ketamine has shifted from being a fringe therapy to one more widely studied in specialized settings.

What is Ketamine and How is it Used?

Ketamine is an anesthetic with dissociative properties that’s been used since the 1970s in surgery and emergency medicine. For depression, it’s typically administered at much lower (“sub‑anesthetic”) doses, either via intravenous infusion or intranasal delivery, in medically supervised settings.

In the U.S., the drug Esketamine (a specific isomer of ketamine) is formally approved (by the Food and Drug Administration) for treatment‑resistant depression. Still, the broader use of racemic ketamine remains “off‑label.”

Because of its rapid onset and unique properties, ketamine is often considered when patients have not responded to multiple standard antidepressants or are at high risk (for example, suicidal ideation) and need a faster‑acting intervention.

How Ketamine Works in the Brain — the Current Understanding

Here’s where things get interesting (and somewhat complex). The exact mechanism by which ketamine reduces depression is still under investigation, but several key processes have emerged.

NMDA receptor antagonism and glutamate surge

Ketamine is known to block (antagonise) the NMDA (N‑methyl‑D‑aspartate) receptor, which is one of the brain’s glutamate receptors. Glutamate is the major excitatory neurotransmitter in the brain — in essence, a “go” signal for many brain functions.

By blocking NMDA receptors, particularly on inhibitory neurons, ketamine may lead to a surge of glutamate release and activation of other receptors (like AMPA receptors). Some researchers believe this glutamate surge prompts rapid synaptic changes — more on that below.

Promoting synaptic connectivity and neuroplasticity

One of the most important findings is that ketamine appears to promote synaptic growth (i.e., the connections between neurons) in brain regions implicated in depression. For example, when you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow.

This suggests that, unlike many antidepressants, which simply shift neurotransmitter levels over time, ketamine may actually help reverse some of the structural/functional decline seen in depressed brains.

Rapid onset of antidepressant effect

Because of the above mechanisms, ketamine can produce antidepressant effects within hours. Some studies report measurable mood improvement within 24 hours of infusion. That speed is a major advantage in acute situations (e.g., suicidal risk) where waiting weeks for a traditional antidepressant to work may not be safe.

Additional mechanisms and opioid system involvement

Research from Stanford Medicine suggests that the antidepressant effect of ketamine may require activation of opioid receptors in the brain.[4] This unexpected finding suggests that the mechanism is multifaceted and not solely related to NMDA/glutamate pathways.

There’s also emerging interest in ketamine’s metabolites (e.g., hydroxynorketamine) and their role in mood regulation.

What the Research Says: Effectiveness and Durability

So, how well does ketamine perform in clinical settings? Here are some of the key numbers:[3,5,6,7]

• In a retrospective analysis of intravenous ketamine induction in treatment‑resistant depression, the response rate was 53.6% and remission rate 28.9%.
• In another large comparison with ECT, 55 % of ketamine patients achieved ≥ 50% symptom reduction.
• However, durability is a challenge. Many studies report that effects begin to fade after a week or two, although maintenance protocols can extend the benefit.
• Fast facts from the University of Utah Health point out that ketamine is often used when other treatments fail, but long‑term safety and optimal dosing remain areas of research.
  

In summary, ketamine shows impressive early response rates, especially in hard‑to‑treat depression, but the challenge is maintaining those gains over time.

Who May Benefit — and Who Should Exercise Caution

Likely candidates for ketamine depression treatment include:

• Individuals with major depressive disorder (MDD) who have failed two or more conventional antidepressant treatments (i.e., treatment‑resistant depression).
• Patients needing rapid relief (for instance, in the context of suicidal thoughts) where waiting weeks is not safe.
• Patients in clinical settings already experienced with administering ketamine under supervision.

Important cautions and considerations:

• Ketamine is not a first‑line treatment. Due to cost, specialized settings, and monitoring requirements, it is usually considered after other options have failed.
• It is administered in controlled medical environments because of potential side effects: dissociation, elevated blood pressure, nausea, confusion during the dose, and other risks.
• Long‑term safety data remain limited. Because ketamine has a history of recreational misuse and known risks (e.g., bladder issues, cognitive effects with chronic high‑dose use), clinicians approach with caution.
• Patient monitoring and structured protocols are essential. Clinics typically require patients to remain observed for a period after treatment.
• Not everyone responds. As the research indicates, a sizeable portion will not achieve remission or may relapse relatively quickly.

How Does Ketamine Treatment Work?

Here’s a simplified breakdown of how ketamine treatment is often structured in a clinical setting (bear in mind variations exist):

1. Screening and baseline assessment: Evaluate depression severity, prior treatments, physical health, and suitability for ketamine.
2. Initial dose/infusion: Often intravenous ketamine at ~0.5 mg/kg over about 40 minutes (in many protocols) or intranasal/esketamine in approved settings.
3. Observation period: Patients are monitored during and after the infusion for dissociation, blood pressure changes, and other side effects.
4. Follow‑up dosing/maintenance: If initial response is positive, repeated doses may be scheduled (e.g., once or twice a week) and then tapered or maintained at longer intervals. Some clinics pair ketamine with psychotherapy to maximize durability.
5. Monitoring and adjustment: Depression symptoms, side effects, cognitive functioning, and physical health (especially in repeated dosing) are tracked.
   

Clinicians emphasise that ketamine is part of a broader treatment plan — including psychotherapy, lifestyle modifications, and other medications — not a stand‑alone “magic bullet.”

Strengths, Limitations, and What Remains to be Answered

The strengths of ketamine treatment include:

• Rapid onset of effect: unlike many antidepressants, ketamine can relieve symptoms within hours.
• Efficacy in treatment‑resistant populations: Many standard medications fail in this group, so ketamine offers a valuable alternative.
• Potential for neuroplasticity‑based treatment: the idea that we can “rewire” or restore neural connectivity is compelling.

Limitations and unanswered questions:

• Durability: How long do the effects last? What is the optimal maintenance schedule? Some relapses happen quickly. 
• Safety: What are the long‑term effects of repeated low‑dose ketamine for depression? While short‑term use appears safe in controlled settings, the long‑term data are sparse.
• Mechanism clarity: As noted, the full mechanism remains unclear — excursions into opioid receptor involvement, metabolites, and neural network changes complicate the picture.
• Cost and access: Because dosing is specialised and requires monitoring, cost and accessibility may limit wide uptake.
• Patient selection: Who is likely to respond, and how can clinicians predict response versus non‑response? Some promising biomarker research is underway.

Get Connected to Ketamine Treatment for Depression

Ketamine represents a major shift in how we think about depression treatment — not just as a slow adjustment of mood chemicals, but as a means to rapidly reboot brain connectivity and function. For patients whose depression has not responded to conventional therapies, ketamine may offer a powerful option. But it’s not without complexity: the rapid relief it can provide needs to be balanced with careful patient selection, monitoring, and thoughtful maintenance planning.

If you or someone you know is considering ketamine therapy, it’s vital to do so under the supervision of a qualified psychiatrist or mental‑health specialist experienced in its use. As research advances and our understanding deepens, ketamine’s role will likely become clearer — but for now, it stands as a promising, but not yet fully understood, tool in the depression‑treatment toolbox.

If you have treatment-resistant depression or suffer from suicidal ideation, ketamine treatment might be right for you. At 1st Step Behavioral Health, we can help you overcome depression and regain control over your life. Contact us today for more information on how we can help you.

FAQ: Ketamine for Depression

1. Is ketamine therapy covered by insurance?

Coverage varies widely. FDA-approved esketamine (Spravato) is more likely to be covered by insurance, particularly when prescribed for treatment-resistant depression under strict protocols. However, off-label racemic ketamine infusions are typically not covered, meaning patients may have to pay out of pocket. Costs can range from $400 to $800 per session, with some clinics offering payment plans.

2. Can ketamine therapy be done at home?

Currently, at-home ketamine use is not recommended or widely supported by medical organizations. While some telehealth startups advertise mail-order ketamine lozenges or tablets, experts caution that without professional supervision, the risks of misuse, side effects, and insufficient monitoring increase significantly. Most reputable providers still require on-site administration and post-dose observation.

3. Is ketamine addictive or habit-forming?

Ketamine does carry addictive potential — particularly at high doses or frequent, unsupervised use. While controlled, intermittent use in clinical settings has not shown significant dependence risk, repeated or recreational use can lead to tolerance, urinary tract damage, and cognitive impairments. That’s why ketamine treatment is only offered under strict guidelines with mental health evaluations.

4. How does ketamine interact with other antidepressants or medications?

Ketamine is often used alongside other psychiatric medications, including SSRIs, SNRIs, or mood stabilizers. In many cases, patients remain on their current meds during ketamine treatment. However, certain drug interactions — such as with benzodiazepines or stimulants — may reduce effectiveness or increase side effects. It’s essential to review your full medication list with your prescribing physician before beginning treatment.

5. Can ketamine help with anxiety, PTSD, or other mental health conditions?

Yes, emerging research suggests that ketamine may benefit generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). However, these uses are currently considered experimental and are not FDA-approved. Clinical trials are ongoing, and patients should discuss the evidence and risks with a provider experienced in these conditions.

6. How do I find a reputable ketamine clinic?

Look for clinics that:

• Are overseen by licensed psychiatrists or anesthesiologists
• Conduct thorough screening and informed consent
• Provide in-session monitoring (blood pressure, mental status)
• Offer follow-up care and integration therapy

You can check registries like the American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP3) or ask your psychiatrist for referrals. Avoid providers who minimize the risks or offer unsupervised home use without oversight.

References:

1. Time: New Hope for Depression
2. University of Michigan: Ketamine’s promise for severe depression grows, but major questions remain
3. The Harvard Gazette: Ketamine found effective in treating severe depression
4. Stanford Medicine: Ketamine’s effect on depression may hinge on hope
5. Science Direct: A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings
6. The National Library of Medicine (NLM): Efficacy of ketamine therapy in the treatment of depression
7. University of Utah: Fast Facts About Ketamine for Depression