Ketamine Overview

Ketamine has a checkered history of use. It has been used illegally as a dance club drug with risk for abuse and dependence known as “Special K”, but also legally by veterinarians and physicians as an anesthetic for surgery.¹ More recent research has also shown that small or subanesthetic doses of ketamine can provide relief from treatment-resistant depression, suicidal thoughts, and pain symptoms. Ketamine effects occur rapidly (within 24 hours), contrasting with standard antidepressants that rely on gradual effects over several weeks to months. Consequently, ketamine therapy is gaining traction amongst psychiatrists and other providers in treating mental illness and pain acutely. The exact mechanism of action for ketamine in relieving depressive or pain symptoms is uncertain, but it is known that it acts as an NMDA receptor antagonist, opioid receptor agonist, and activates AMPA receptors.² 

Ketamine therapy has shown varying level of success in treating the following conditions, but only the first two in bold have received FDA approval as of 2019:

The most consistent evidence for ketamine treatment is often limited to short term response (eg 24 hours up to one week) and there is need for repeated administration of ketamine to maintain longer response (eg 1-2 months). Longer term data is less robust and what is available does not show ongoing response if stopping ketamine. Many studies to date regarding ketamine use also do carry some risk for bias and the best strategies for dosing short and long term remain unclear. Ketamine and Esketamine are also schedule III medications with risk for abuse, tolerance, and dependence.

In the pivotal trial that garnered FDA approval for use of Spravato in this patient population, the results were modest. Patients received Spravato in addition to a new antidepressant or standard of care and a new antidepressant. After 28 days of treatment, patients receiving Spravato twice weekly had a 4 point better improvement on the depression rating scale utilized in the study to measure response, compared to patients not receiving Spravato¹². This equates to only a 7% better improvement. Response and remission rates were quite high at 69.3% and 52.5%, respectively, but the control group with no Spravato treatment was also quite high at 52% and 31%, respectively. In addition, there was also a maintenance phase to the trial that looked at relapse rates if continuing Spravato beyond 16 weeks of treatment for patients that achieved remission with use of Spravato plus an antidepressant. Patients that weaned off Spravato after 16 weeks were at least twice as likely to relapse as those who continued treatment, providing further evidence that ketamine treatment needs to be continued indefinitely to maintain response.¹³

Use of off-label IV ketamine (and other formulations less commonly) has been in practice for a number of years, however. The positive results from this practice are what spurred the maker of Spravato, Janssen, to pursue formulation of this nasal spray and to acquire FDA approval. Many of these studies also point to rapid and robust response with ketamine or esketamine treatment in various modes of delivery (eg IV, nasal, etc). 

In one recent randomized controlled trial involving use of IV ketamine, 25% of participants achieved antidepressant response and 5% achieved remission after their first IV infusion at 24 hours. As in previous studies, antidepressant response only lasted for about 1 week before repeat infusions were needed. Participants then received thrice weekly infusions over the next 2 weeks to gauge repeat response with more consistent dosing. These participants experienced 59% response and 23% remission. At this point, responders were then dropped to once weekly infusions for a month in a maintenance phase to see if this would hold prior benefits. At the end of this month, 91% of participants who previously had a response, maintained this response.¹⁴

Read more: TMS therapy success rate →

Other ketamine trials (most commonly utilizing IV administration) have shown similar results. Correia-Melo et al. (2017) treated 27 patients with Major or Bipolar Depression with a single infusion of IV ketamine and found response and remission rates of 59% and 41% at 24 h follow-up, 52% and 37% at 72 h follow-up,and finally 48% and 37% at 7 days follow-up.¹⁵ Looking further out, a study by Singh et al. (2016) found response rates of 53.8-68.8% and remission rates of 23.1-37.5% using twice to thrice weekly infusions at the end of two weeks. The twice weekly infusion rate actually delivered better results than thrice weekly.¹⁶

TMS Overview

Transcranial Magnetic Stimulation (TMS) was FDA approved for the treatment of treatment resistant Major Depressive Disorder in 2008. TMS utilizes magnetic pulses, similar to an MRI, to indirectly stimulate electrical activity within the brain. Depending on the type and location of stimulation that is administered, TMS can ‘wake up’ sleepy neurons that are low in electrical activity (such as in depression) or inversely ‘calm’ agitated neurons that are overactive (such as in anxiety or PTSD). The exact process by which this takes place is complex and has not been fully described, but involves what is called synaptic plasticity, with either long term potentiation or long term depression of communicating neural pathways.¹⁷ TMS also involves the use of NMDA and AMPA receptors in this process and may enhance BDNF production or activity. Other processes include changes in cerebral blood flow, dopamine production, and alterations in gene expression. There is also short term (30-60 minutes after stimulation) and longer term (days, weeks, or maybe even months following repetitive stimulations) that occurs with TMS.¹⁸

Unlike ketamine therapy or other medications, because TMS is non-invasive and localized, it comes with no systemic side effects. The typical local and temporary side effects from TMS are a prickling sensation or tenderness on the scalp at the treatment site or mild headache following treatment. These typically resolve after the first few treatments or remain mild in nature, but can occur in about half of treated patients. Adverse events are extremely rare with TMS, typical drop-out rates from treatment are 1% or less. 

Read more: TMS therapy reviews →

TMS Therapy is administered in a clinical office setting by a qualified medical professional and has demonstrated varying level of success in treating the following conditions (similar to ketamine/esketamine, however, not all conditions have been FDA approved - FDA approved indications are marked in bold):

There are two options for TMS based on an individual’s needs, a standard course, or an accelerated course. The standard course is FDA approved and covered by all major insurers outside Medicaid. It consists of 36 sessions, 1 per weekday, over the course of 6 weeks, followed by a taper of three treatments week 7, two week 8, and one week 9. This FDA approved and insurance covered treatment can consist of an older and longer treatment called 10 Hz, which takes 18.5 minutes, or a newer and shorter treatment called intermittent theta burst (iTBS), which takes just over 3 minutes. There is also a non-FDA approved and non-insurance covered treatment referred to as accelerated TMS. This is most commonly pursued by patients looking for faster relief of symptoms or that may have geographical or other logistical barriers to the longer treatment course. Response can occur in as little as 2-3 days with the accelerated course. The accelerated protocol consists of 50 treatments, 10 per day spaced apart every hour, over the course of just 5 days. Inspire TMS Denver utilizes a sliding scale based on gross household income for self-pay with this treatment option. See more specifics of pricing for standard vs accelerated TMS on our pricing guide page.

The largest patient data registry through one TMS device manufacturer, Neurostar, is achieving response and remission rates of 69% and 36%, respectively, based on patient reported rating scale. This is open-label data, however. Review of randomized controlled trials shows less robust response, but still strong effect sizes, and there is typically considerable variation in findings as protocols tend to vary quite a bit between studies.¹⁹ Studies employing more treatments (eg at least 4 weeks and ideally 6+ weeks) and those utilizing more pulses per session (minimum of 3000 pulses with 10 Hz or 600 pulses with theta burst) typically result in improved outcomes. Additionally, if patients receiving TMS continue other standard of care treatments such as therapy and medication changes when indicated, this also results in better treatment outcomes and more representative of real world treatment. Additional other factors also play a role in outcomes.²⁰ ²¹ Our current response and remission rates at Inspire TMS are similar to referenced open-label large patient registries.

A recent large study out of Canada with 415 participants reviewed effectiveness of the older and longer protocol (10 Hz frequency) with the newer and shorter protocol

(iTBS - intermittent theta burst) and found no statistically significant difference in response/ or remission rates between the two protocols.²² They achieved 49% response and 32% remission rate with iTBS compared to 47% response and 27% remission rate with the 10 Hz protocol after 4-6 weeks of daily weekday treatments. Post-treatment response and remission rates also did not differ between the two at weeks 1, 4, and 12 after end of treatment and response and remission rates were maintained as far out as the 12 week mark. The treatment was well tolerated with only 1% of patients stopping treatment due to intolerance or adverse events. Inspire TMS Denver offers both protocols, but patients typically prefer iTBS as the treatments only take 3 minutes to perform, compared to 18.5 minutes with the 10 Hz protocol. 

Looking further out at longer term results, a systematic review and meta-analysis from 2019 found that for patients who achieved initial response, this response was sustained at the following rates: 66.5% at 3 months, 52.9% at 6 months, and 46.3% at 12 months.²³ And another study that utilized reintroduction of TMS as needed for patients that initially responded well to treatment, found that 61-67% (depending on rating scale) of these patients maintained response 1 year out.²⁴

Side-by-Side Q&A

Is Ketamine Therapy best for me?

Ketamine can offer very swift relief from depression and suicidal thoughts, but requires continued maintenance treatments to maintain the effects and there is some evidence that it may lose response or that patients may develop tolerance to treatment over time. Individuals with a history of cardiovascular events should not pursue ketamine therapy and those with a history of substance abuse likely should proceed cautiously. The sessions are less frequent than TMS, but do take 2 hours for monitoring and mild perceptual and cognitive disturbance can persist the day of treatment. Spravato can be covered through insurance with a prior authorization for treatment to help alleviate costs, but IV treatment is not typically covered and can quickly become expensive as treatments need to be continued long term to maintain response.

Is TMS Therapy best for me?

TMS is both non-invasive and drug-free but the effects take a little longer to establish compared to ketamine. It was FDA approved in 2008 and the response and remission rates have been steadily improving as the technique is perfected and new technology and protocols for treatment have been developed. Spravato was only FDA approved in 2019 and there is less clear data about long term results with ketamine therapy. TMS is a time commitment requiring daily sessions of therapy over 6 weeks (plus a taper the last 3 weeks). The treatments are quite quick, however, as patients typically can get in and out of the office in 10-20 minutes. Insurance covers TMS treatment for the standard course, but not the accelerated course to date.

The following comparison table is based on study results for treating

treatment-resistant major depression. A consultation with a treatment provider is necessary, however, to consider your individual needs and symptoms.