In a retrospective study by Schwenk and colleagues,184 discontinuation of ketamine infusions secondary to adverse effects was unrelated to the maximum infusion rate, which further questions the notion that adverse effects at low doses are dose related. These findings come from a review of 12 systematic reviews and meta-analyses comparing ketamine and esketamine for depression. Instead, these conclusions are drawn from separate placebo-controlled trials where each treatment was tested independently. The degree of difference varied across studies, but IV ketamine repeatedly showed far greater symptom reduction and higher response rates.
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You’re comparing it to 20%—the remission rate for SSRIs in treatment-resistant depression. Ketamine infusion therapy has been hailed as a transformative treatment because of its high rate of response. Ketamine, originally developed as anesthesia, was first discovered to work similarly to antidepressants as early as 1975.
In contrast, in an acute pain setting, ketamine dosages are titrated to effect, carefully balancing analgesia with adverse effects, the latter of which may require a reduction in dosage. After sufficient animal toxicity testing, phencyclidine was given to humans undergoing surgery. Phencyclidine proved to be a relatively safe anesthetic in humans, as it had been with monkeys. However, some patients developed severe and prolonged postsurgery emergence delirium.14 The first human was given ketamine via an IV subanesthetic dose on August 3, 1964. Guenter Corssen, MD, an anesthesiologist at the University of Alabama at Birmingham and author on that pivotal first manuscript,10 subsequently increased the dose in a stepwise fashion from no effect to “conscious but spaced out” and finally to a dose sufficient to produce general anesthesia.
Fast-Acting Relief: Why Ketamine Works When Nothing Else Does
- During the Vietnam War, it became a widely used anesthetic in theaters of operation where concerns about hemodynamic instability are paramount in wounded service members and has now been in clinical use for more than 50 years.
- The 23-year-old was brought to the ground by three officers and was given two carotid holds.
- Patients relapsed (some symptoms returned) on an average of 19 days after, but some did not relapse for more than three months.
- Ketamine may open a temporary “therapeutic window”—a period of heightened neuroplasticity and emotional openness—when therapy hits harder and sticks longer.
Although the FDA has not approved the use of ketamine in treating pain, some professional medical organizations have for certain conditions. The American Society of Anesthesiologists, American Society of Regional Anesthesia and Pain Medicine, and the American Academy of Pain Medicine have guidelines that support ketamine infusions for CRPS, chronic neuropathic pain and short-term acute pain. After following over 1,000 pain patients who received ketamine infusions, researchers concluded the infusions are safe and effective for people with chronic pain. The randomised trial was developed to assess antidepressant efficacy, safety, cost-effectiveness, and quality of life during and after serial ketamine infusions when compared to a psychoactive comparison drug midazolam. Trial participants were randomised to receive up to eight infusions of either ketamine or midazolam, given over four weeks, in addition to all other aspects of usual inpatient care. Graphical depiction of the relationship between ketamine dose and duration of analgesic benefit in randomized placebo-controlled trials that evaluated IV ketamine for chronic pain with a minimum of 48 hours’ follow-up.117,123,155,160–162,164 A trend line is been plotted to indicate the nature of this relationship.
Clinical Implications
The use of ketamine has skyrocketed for chronic pain and depression, but many questions remain unanswered. The most prominent among these revolve around durability of benefit and implications of repeated administrations (ie, the development of pharmacodynamic, metabolic, and behavioral tolerance leading to tachyphylaxis and loss of analgesic benefit), standardization of treatment (ie, optimum dosages and infusion parameters), and acute and chronic adverse effects, including remote neuropsychiatric effects. Given the poor translational reproducibility and validity of preclinical chronic pain research to humans, only robust clinical trials with long-term follow-up will provide answers to these questions. Although the APA consensus statement did not find any cases of clinically relevant respiratory depression at the low dosages given for depression, they did mention several instances of patients becoming unresponsive, putting them at risk of aspiration. An appropriately trained health care provider246 can monitor the patient receiving ketamine infusion in subanesthetic doses and change the infusion rate based on directions from the responsible physician who, for single-day infusions, should be immediately available. Across four systematic reviews published between 2020 and 2024, combining ketamine with psychotherapy showed signs of improving outcomes, especially for people who initially responded well to ketamine.
- Differences not only in disease features but also patient characteristics, and practice settings and capabilities, further highlight the need for dosing flexibility.
- That’s compared to other remedies for depression, like Prozac and Zoloft, that often take weeks to ease the condition and don’t work for every patient.
- One such novel treatment is the dissociative anaesthetic ketamine when given intravenously in low sub-anaesthetic doses.
Health
During maintenance phases, patients experience minimal symptom increases for up to one year post-induction, particularly when combined with appropriate therapeutic support. – Systematic reviews emphasized the slower onset of oral ketamine’s antidepressant effects compared to IV formulations, raising questions about its usefulness for patients needing rapid relief. The median remission rate was 29%, typically measured after just one or two IV ketamine infusions. Some studies reported even higher remission rates (up to 40%) with “serial” infusions, though the exact number of treatments varied and wasn’t always clearly defined (Brain Sciences, 2023).
Primarily, patients who actively engage in these lifestyle modifications alongside their ketamine treatment show more sustained improvements. Subsequently, the combination of proper maintenance scheduling, therapeutic support, and lifestyle changes creates a comprehensive approach to long-term wellness. Studies demonstrate that ketamine’s ability to increase neuroplasticity creates an optimal window for therapeutic intervention. Initially, this combination helps patients process difficult emotional material more effectively. Thereafter, the enhanced brain plasticity supports the formation of new neural pathways, making behavioral changes more sustainable.
In four systematic reviews published between 2020 and 2024, oral ketamine showed moderate antidepressant effects—but unlike IV ketamine, which often works within 24 hours, oral forms typically take 2 to 6 weeks to show any meaningful improvement (Journal of Clinical Psychiatry, 2019; Psychopharmacology Bulletin, 2020). Finally, in addition to preventing the chronification of acute pain, another top National Institutes of Health chronic pain research priority is the establishment of registries. Unlike placebo-controlled clinical trials, which gauge efficacy in small, well-selected populations, registries can provide a better measure of effectiveness in large populations treated under real-life conditions and may provide important information regarding who is likely to benefit from a specific treatment (ie, phenotyping or precision medicine).
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Findings from a randomized and blinded clinical trial investigating repeated ketamine infusions for treating depression have revealed no extra benefit for ketamine when added onto standard care for people admitted to hospital for depression. One of the biggest questions surrounding ketamine is whether the drug can prevent the transition from acute to chronic pain by virtue of its NMDA antagonist and opioid-sparing properties. Given the high prevalence rates of surgery and acute pain, and the growing use of ketamine in the context of posttraumatic (including postsurgical) pain, designing large, multicenter studies should be given high priority. The Ketamine Guidelines Committee was charged with preparing guidelines on the use of ketamine as an analgesic that would enhance patient selection and safe practice, guide institutional protocol development, serve as a resource for information, and function as a template for regulatory bodies and payers.
Several reviews highlight improved outcomes with multiple infusions, especially when spaced over two to four weeks. Serial infusions led to remission rates of up to 40%, though most reviews did not specify exactly how many infusions these protocols included. Based on the source ketamine infusion therapy effectiveness studies referenced, the vast majority involved just one or two infusions.
In late 2017, the completed document was sent to the American Society of Anesthesiologists’ Committees on Pain Medicine and Standards and Practice Parameters, after which additional modifications were made. Panel members were selected by the committee chair and both boards of directors based on their expertise in evaluating clinical trials, past research experience, and clinical experience in developing protocols and treating patients with ketamine. Questions were developed and refined by the committee, and the groups responsible for addressing each question consisted of modules composed of 3 to 5 panel members in addition to the committee chair. Once a preliminary consensus was achieved, sections were sent to the entire panel, and further revisions were made. In addition to consensus guidelines, a comprehensive narrative review was performed, which formed part of the basis for guidelines.
If you are thinking about receiving ketamine infusion therapy, you’ll want to consider some side effects beforehand. Also, if you’re dealing with a mental health condition, you might not be eligible to receive this kind of therapy. Before his death, he’d been undergoing ketamine infusion therapy for depression and anxiety, though that treatment couldn’t have killed him, the medical examiner concluded last year.
Intravenous (IV) infusion provides the highest bioavailability and most precise dosage control. Intramuscular (IM) injections offer similar rapid onset with easier administration, while nasal sprays provide a convenient FDA-approved option. Additionally, sublingual and oral forms are available for at-home use under professional guidance. But a systematic review or meta-analysis gathers all the studies on a topic, weeds out the weak ones, and looks at the overall pattern.
