Why Ketamine Works When 2+ Antidepressants Have Failed

You've done everything your doctors asked. You took the first antidepressant faithfully for six weeks and felt nothing change. You tried a second — maybe a third or fourth — each time enduring the side effects, the waiting, and the slow disappointment. You've adjusted doses, combined medications, maybe added therapy. And still, the weight of depression is there.

If this is your story, what you're experiencing has a name — treatment-resistant depression — and it affects roughly one in three people with major depressive disorder. But here's what your experience is also telling you: your depression likely operates through biological pathways that serotonin-based medications don't adequately reach.

This is where ketamine enters the picture — not as a last resort, but as a treatment specifically suited to the neurobiology that standard antidepressants miss.

The Fundamental Difference: Glutamate vs. Serotonin

To understand why ketamine can work when SSRIs and SNRIs have failed, you first need to understand that these treatments are targeting entirely different systems in the brain.

How SSRIs and SNRIs work

Conventional antidepressants focus on the monoamine neurotransmitters — primarily serotonin, and in the case of SNRIs, norepinephrine. They block the reabsorption of these chemicals, increasing their availability between neurons. This approach helps many people, but it operates on a theory of depression (the monoamine hypothesis) that we now know is incomplete.

How ketamine works

Ketamine works through the glutamate system — the brain's primary excitatory neurotransmitter network, which is far more extensive than the serotonin system. Specifically, ketamine is an NMDA receptor antagonist. By temporarily blocking NMDA receptors, it triggers a cascade of downstream effects that are fundamentally different from anything SSRIs can accomplish:

AMPA receptor activation increases, leading to a surge of glutamate signaling through alternative pathways
Brain-derived neurotrophic factor (BDNF) release is stimulated — BDNF is sometimes called "fertilizer for the brain" because of its critical role in neuronal growth and survival
mTOR signaling is activated, which drives the formation of new synaptic connections
Synaptic density increases in key brain regions, particularly the prefrontal cortex

In plain terms: while SSRIs try to make better use of the serotonin you have, ketamine helps your brain grow new connections and repair damaged neural circuitry. For a deeper dive into this mechanism, see our page on how ketamine works or our detailed post on the science behind ketamine therapy.

BDNF and Neuroplasticity: Rebuilding What Depression Broke

One of the most significant discoveries in depression research over the past two decades is that chronic depression causes measurable structural damage to the brain. Neuroimaging studies show reduced volume in the prefrontal cortex and hippocampus, along with decreased synaptic density — the connections between neurons literally wither.

This synaptic atrophy helps explain why depression feels so immovable. It's not just a chemical imbalance — it's a structural one. And restoring structure requires more than adjusting neurotransmitter levels. It requires neuroplasticity — the brain's ability to form new connections and pathways.

This is where ketamine's effect on BDNF becomes so important:

BDNF levels are consistently found to be lower in people with depression, especially treatment-resistant depression
Ketamine rapidly increases BDNF expression, often within hours of administration
Higher post-treatment BDNF levels correlate with greater symptom improvement, suggesting this mechanism is directly tied to clinical outcomes
The new synaptic connections formed through BDNF-driven neuroplasticity may help explain the sustained benefits some patients experience beyond the drug's immediate effects

SSRIs may modestly increase BDNF over time (which could partially explain their delayed onset of action), but ketamine's effect on this pathway is far more rapid and pronounced.

Rapid Onset: Hours Instead of Weeks

Perhaps the most striking clinical difference between ketamine and conventional antidepressants is speed.

SSRIs and SNRIs typically require 4 to 8 weeks to show full effects. During this waiting period, patients continue to suffer — and in severe cases, this delay can be dangerous.
Ketamine can produce noticeable improvements in mood and suicidal ideation within hours to days of the first treatment.

This rapid onset isn't just a convenience — it can be lifesaving. For individuals with severe depression and active suicidal thoughts, weeks of waiting for a medication to possibly work is an unacceptable timeline. Ketamine's ability to provide rapid relief fills a critical gap that has existed in psychiatry for decades.

Why is ketamine so much faster?

The speed difference comes back to mechanism. SSRIs work indirectly — they increase serotonin availability, and then the brain gradually adapts over weeks. Ketamine, by contrast, directly triggers the molecular cascade (AMPA activation, BDNF release, synaptogenesis) that leads to symptom improvement. The process of building new synaptic connections begins almost immediately after administration.

What the Research Shows

The evidence supporting ketamine for treatment-resistant depression has grown substantially over the past two decades:

Response rates in clinical studies of ketamine for TRD generally range from 50% to 70% — a remarkable figure for a population that, by definition, has already failed multiple treatments
Multiple randomized controlled trials have demonstrated ketamine's superiority over placebo in reducing depressive symptoms
Research published in leading journals including the American Journal of Psychiatry, JAMA Psychiatry, and Biological Psychiatry has consistently supported ketamine's efficacy
Studies show particular effectiveness in reducing suicidal ideation, with some research demonstrating significant reductions within 24 hours
A growing body of real-world clinical data supports the findings from controlled trials, with many patients experiencing meaningful improvement in daily functioning

It's important to note that ketamine doesn't work for everyone, and response rates vary across studies depending on dosing protocols, patient populations, and how "response" is defined. But for a treatment being used specifically in patients who haven't responded to anything else, these results represent a genuine breakthrough.

Who Is a Candidate for Ketamine Therapy?

Ketamine therapy for depression is generally considered appropriate for adults who meet specific criteria:

Diagnosis of major depressive disorder or bipolar depression (depressive episodes)
Failure of at least two adequate antidepressant trials — this is the standard threshold for treatment-resistant depression, though some providers may consider ketamine after fewer trials in certain circumstances
No active substance use disorders that would contraindicate treatment (a thorough screening is always conducted)
No uncontrolled hypertension or certain cardiovascular conditions
No active psychosis or history of psychotic disorders
Medical clearance from a qualified provider

At Discreet Ketamine, every patient undergoes a comprehensive medical evaluation before treatment begins. Our goal is to ensure that ketamine is both safe and appropriate for your specific situation. You can check whether you might be a candidate by visiting our eligibility page.

What to Expect From Ketamine Treatment

Understanding what the treatment process actually looks like can help reduce anxiety about starting something new.

The treatment protocol

Initial phase: Most protocols involve a series of treatments over two to three weeks to establish a therapeutic response. This initial loading phase is important for building the neuroplastic changes that underlie ketamine's benefits.
Maintenance phase: After the initial series, treatments are typically spaced further apart — weekly, biweekly, or monthly — based on individual response.
At-home treatment: With Discreet Ketamine, treatments are administered at home under medical supervision and guidance, providing comfort and privacy during the experience.

During a session

Sessions typically last one to two hours including monitoring time
You may experience altered perceptions, a feeling of floating, or mild dissociation — these effects are temporary and are actually part of how the treatment works
Most patients describe the experience as calm, introspective, and manageable
You should not drive or operate heavy machinery for the remainder of the day after treatment

After treatment

Many patients notice initial improvements in mood, energy, or thought patterns within the first few sessions
Benefits often build and consolidate over the course of the initial treatment series
Ongoing maintenance treatments help sustain the neuroplastic changes

For a complete walkthrough, visit our what to expect page.

Ketamine as Part of a Comprehensive Approach

Ketamine is powerful, but it works best as part of a broader treatment strategy. The neuroplastic window that ketamine opens — the period of enhanced synaptic flexibility following treatment — is an ideal time to reinforce positive changes through:

Psychotherapy, particularly cognitive behavioral therapy (CBT) or other evidence-based modalities
Lifestyle modifications including exercise, sleep hygiene, and stress management
Ongoing medical management with your treatment team
Mindfulness and integration practices to process and build on insights from treatment sessions

Think of ketamine as creating the conditions for change — new neural pathways, restored connectivity, renewed capacity for positive thought patterns — and these complementary approaches as helping to solidify those changes into lasting recovery.

Why At-Home Treatment Matters

For people with treatment-resistant depression, the logistics of getting to a clinic can be a genuine barrier. Depression saps motivation, energy, and the ability to manage even basic tasks — let alone scheduling and traveling to repeated appointments.

At-home ketamine therapy through Discreet Ketamine removes that barrier. You receive treatment in the comfort and privacy of your own space, with medical oversight and support from Dr. Ben Soffer and our clinical team. This isn't a lesser version of in-clinic treatment — it's a thoughtful adaptation that recognizes the realities of living with severe depression.

Taking the Next Step

If you've tried two or more antidepressants without adequate relief, you're not out of options — you may simply need a treatment that works through a different mechanism. Ketamine's ability to target the glutamate system, promote BDNF-driven neuroplasticity, and deliver rapid symptom relief makes it a scientifically grounded option for treatment-resistant depression.

You don't have to keep waiting for the next SSRI to maybe work. Check your eligibility today and find out if ketamine therapy through Discreet Ketamine could be the different approach your brain has been waiting for.

Learn more about ketamine for depression or explore the history and science of ketamine therapy.

Disclaimer: This article is for informational and educational purposes only and does not constitute medical advice. It is not intended to diagnose, treat, cure, or prevent any disease or condition. Individual results may vary, and ketamine therapy is not appropriate for everyone. Always consult with a qualified healthcare provider before beginning any new treatment. If you are experiencing a mental health crisis, please call 988 (Suicide & Crisis Lifeline) or go to your nearest emergency room.

Why Ketamine Works When 2+ Antidepressants Have Failed