Ketamine for Treatment-Resistant Depression

How Ketamine Works for Treatment-Resistant Depression

Up to one‑third of people with depression have treatment-resistant depression, where at least two trials of traditional antidepressant medications were not effective. Research has shown that appropriate doses of ketamine, administered in a controlled medical setting, can be helpful in treating TRD.

Instead of working on serotonin or norepinephrine like most antidepressants, ketamine acts on the brain’s glutamate system. Ketamine sets off a chain reaction in the brain to help rebuild and strengthen connections between brain cells to improve neuroplasticty—the brain’s ability to adapt, repair, and form new pathways. This means ketamine allows you to think differently and approach your mental health struggles in a new way.

Ketamine vs Traditional Antidepressants

Traditional antidepressants such as SSRIs and SNRIs primarily work on serotonin and norepinephrine and often require 4–6 weeks or longer to show meaningful improvement. Even then, a sizable portion of patients either do not respond or experience only partial relief.
Ketamine differs from these medications in several key ways:

• Mechanism: Traditional antidepressants work on serotonin, norepinephrine, or dopamine, while ketamine targets the glutamate system and NMDA receptors, to enhance neuroplasticity.
• Speed of Action: Ketamine can reduce depressive symptoms and suicidal thoughts within hours to days, compared with weeks for most antidepressants.
• Effectiveness in TRD: In clinical trials of IV ketamine, response rates (meaning at least 50% reduction in symptoms) were seen in 45% to 65% of patients within 24 hours. Another study performed by Murrough et al., showed response rates of 70.8% at the conclusion of their study.

Traditional antidepressants are usually taken daily at home, while IV ketamine is given intermittently in a monitored clinic, which allows for close observation and individualized adjustments. Many patients continue their existing antidepressant or psychotherapy while adding ketamine as an adjunctive treatment, although the exact plan is tailored to each person.

Benefits of Ketamine Therapy for Treatment-Resistant Depression

For individuals with treatment-resistant depression, ketamine therapy can offer several important benefits. The most frequently described advantages include rapid relief, improved functioning, and the potential to engage more fully in psychotherapy and daily life.

Many patients report decreased emotional heaviness, better ability to think clearly, and increased motivation after a series of ketamine treatment sessions, even when multiple traditional medications have failed in the past. In addition, patients report an overall increase in a positive outlook on life. Real‑world studies have found that ketamine is often associated with improved scores not only for depression, but also for anxiety symptoms and self‑harm or suicidal thoughts.

From a treatment‑planning perspective, ketamine can:

• Create a “window of opportunity” to make lifestyle changes or re‑engage in therapy.
• Allow for breakthroughs in therapy that have been previously hard to achieve.
• Offer an alternative for individuals who cannot tolerate side effects of other medications.
• Provide an urgent option when waiting weeks for standard antidepressants is not safe or acceptable.

Side effects are typically short‑lived and may include mild increases in blood pressure, dissociation, nausea, or dizziness during or shortly after treatment. For this reason, patients are monitored throughout each session and need a ride home.

Ketamine’s Impact on Suicidal Ideation

One of the most important and well‑studied benefits of ketamine is its rapid impact on suicidal thoughts. In a randomized controlled trial of adults with depression and significant suicidal ideation, a single ketamine infusion produced a significantly greater reduction in suicidal thinking within 24 hours compared with an active placebo.^[1]

Larger clinical cohorts of people receiving repeated ketamine infusions for treatment-resistant depression have also shown substantial decreases in self‑harm and suicidal ideation scores over several weeks. In one such study, about 50% reduction in suicidal ideation scores was observed within 6 weeks, and around half of patients who reported suicidal thoughts at baseline no longer had them after six infusions.^[2]

A 2024 meta‑analysis focusing on patients with depression and suicidal ideation found that ketamine significantly reduced suicidal thoughts, with some patients showing a level of improvement after a single day of treatment comparable to the natural remission that might otherwise take nearly a month. While ketamine is not a stand‑alone solution and must be paired with ongoing psychiatric care and safety planning, its ability to quickly reduce suicidal distress makes it a vital option in modern depression treatment.^[3]

Effectiveness of Ketamine for Treatment-Resistant Depression

Effectiveness is usually described in terms of “response” (commonly a 50% or greater reduction in depression rating scores) and “remission” (symptoms reduced to a minimal or near‑normal level). Across studies and real‑world clinics, response rates for ketamine in treatment-resistant depression often fall around 40–70%, with remission rates in the 20–40% range after a full induction series of infusions or intranasal sessions.

For example, in a large clinical sample of adults receiving IV ketamine for TRD, researchers observed a 50% response rate and 20% remission rate within six weeks based on PHQ‑9 depression scores. After additional maintenance infusions, response and remission rates increased to approximately 72% and 38%, respectively, and there was also a 50% reduction in suicidal ideation scores. These results highlight that while ketamine is not effective for everyone, it can offer substantial and sustained relief for many individuals who have not improved with multiple previous medications.^[2]

Ketamine’s benefits often extend to related issues such as anxiety, cognitive sluggishness, and ability to function at work or in relationships. Although individual experiences vary, ongoing research is exploring optimal dosing schedules, predictors of response, and long‑term safety, including how best to maintain gains with “booster” sessions, psychotherapy, and lifestyle changes over time.

Depression Symptom Relief Timeline

Depression symptoms with IV ketamine often begin to lift within hours to a few days of the first infusion, with the full pattern becoming clearer over the first 2–4 treatments. For many people, the benefit from a single infusion lasts about 3–14 days, and a multi-infusion series builds a more lasting impact.

Typical Ketamine Therapy Treatment Timeline
Phase	Timeframe	Common Symptom Pattern
Immediate	During–24 hours	Floaty sensations, lightening of mood, and possible brief lift in heaviness/suicidality.
Early response	24–72 hours	Clear mood improvement, less anxiety, and more energy.
Treatment series	Weeks 1–3	A cumulative reduction in depression severity.
Post-treatment	Weeks 2–4+	Many patients continue to report improvement in overall depression severity.
Maintenance	Months 2–6+	If there is a relapse in depression symptoms, intermittent booster sessions can be tailored to your personal depression relapse pattern.

First Infusion (Within Hours to First 3 Days):

• During and right after the first ketamine infusion, many patients feel dissociation or “floaty” sensations, along with possible brief lightening of mood. These acute drug effects usually resolve within about 1–3 hours.
• Noticeable antidepressant effects commonly emerge within 4–72 hours including improved mood, less emotional heaviness, reduced suicidal thinking, better sleep, and more energy or motivation.

Second Through Fourth Infusions (Days 3–14):

• If ketamine is going to help, most clinics expect a clear trend (some symptom relief, not necessarily full remission) by about the 2nd–4th infusion.
• A typical induction series is 6 infusions over 2–3 weeks (often 2–3 per week), during which benefits tend to accumulate and many patients report substantial depression improvement by the end of the series.

Duration of Benefits After an Infusion:

• After a single IV ketamine treatment, antidepressant effects often last roughly 3–10 days, with some sources stretching this window to about 1–3 weeks before symptoms gradually return.
• With a full induction series, the average duration of improvement from the final infusion is longer, and some patients maintain a much better baseline for several weeks or more before needing any change in treatment.

Maintenance and “Booster” Phase:

• Once a stable response is achieved, “boost” infusions are offered to individuals. If and when these are needed vary for each individual. Your healthcare team at ResetRestore MD will help create an individualized plan that is right for you!
• Over time, intervals of “boost” infusions may be adjusted to lengthen the gap between boosters based on the long-term effectiveness for the individual.

References:

1. https://pubmed.ncbi.nlm.nih.gov/29202655
2. https://pubmed.ncbi.nlm.nih.gov/36112599
3. https://www.nature.com/articles/s41398-024-02973-1
4. pms.ncbi.nlm.nih.gov/articles/PMC3725185