New patient guide for ketamine, part 1

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⚡ Quick Summary

  • Ketamine is a psychoactive substance that, when used correctly, can be an effective, fast-acting, safe antidepressant.
  • However, these effects may be temporary and repeated treatments are often needed.
  • Studies are still in the works to determine the efficacy of ketamine treatment in cases beyond depression.
  • Ketamine treatment can be administered in the form of ketamine infusions, ketamine-assisted psychotherapy (KAP), and high-dose KAP.
  • There is currently no direct evidence to suggest that one model is better than another. Consider your own preferences and work with providers to determine which treatment is right for you.

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Ketamine intro

The use of ketamine for depression treatment has garnered quite a bit of attention in the popular press in recent years. This media coverage has generated substantial interest and optimism among patients, families, clinicians, researchers, and patient advocacy groups.

For example, here are some articles that have been published – they may provide some useful context and insight into ketamine treatment:

In this wiki, we provide information about ketamine treatment in an evidence-based, objective manner. We hope this helps patients in making informed decisions and having fruitful conversations with their clinicians.

vial of ketamine

What is ketamine?

Ketamine is a chemical that is made up of two different forms – S-ketamine (called esketamine) and R-ketamine (called arketamine). S-ketamine and R-ketamine are virtually identical, except for a minor difference that makes these two chemicals mirror images of each other. The term “ketamine” refers to an equal mixture of S-ketamine and R-ketamine. Esketamine by itself is discussed separately in another article in the Osmind Wiki.

diagram of the structure of ketamine free base enantiomers

Ketamine is a drug that was approved by the FDA for general anesthesia in 1970. Since then, it has become widely used by anesthesiologists in the operating room to sedate patients for surgery and reduce pain. Beginning in the 1990s, researchers found that ketamine (at a lower dose than is used in the operating room) could help alleviate depression. Since then, a large number of studies have been conducted by researchers and physicians to study these antidepressant effects.

It has become clear that ketamine has rapid and substantial antidepressant effects (please see below for more details). As a result, a large number of ketamine clinics have opened to provide ketamine treatment for treatment-resistant depression (TRD). Note that ketamine is prescribed off-label by these clinicians, meaning it is used for a medical condition (depression) other than what the FDA approved it for (anesthesia). Off-label use of medications is legal in the US: the burden is on the prescribing clinician to make the best judgment of what a drug can or should be used for.

However, ketamine is also used illegally as a recreational drug. In this context, it may be known as “Special K.” The medical use of ketamine is completely different and separate than the illegal recreational use, which may be associated with drug abuse.

Ketamine is often classified as a psychoactive substance because it can cause hallucinations and dissociations (making people feel out of touch from their surroundings, bodies, or reality). Some patients also report difficulty with speech and movement. At high doses, some experience significant sensory detachment. All of these effects depend on the dose of ketamine: during medical treatment, patients may feel these effects in moderate or mild form, or none at all, depending on the treatment modality and dosage. Ketamine is liable for abuse and addiction if not used appropriately, so it is important to use ketamine only in the medical setting under the supervision of a trained healthcare professional. Ketamine is classified by the US Drug Enforcement Administration as a schedule III drug, which is defined as a drug with a “moderate to low potential for physical and psychological dependence.”

picture of a sad figurine

Does ketamine work as a treatment for depression?

When used correctly, ketamine is effective as a treatment for depression [Naughton et al. 2014]. Ketamine has been shown to produce a rapid and robust antidepressant effect for patients whose depression was previously resistant to treatment [Sanacora et al. 2017]. Charles Nemeroff, MD, PhD, a distinguished researcher who is currently Chair of Psychiatry at the University of Texas’ Dell Medical School, wrote in the American Journal of Psychiatry that “There is little debate over the antidepressant effects of intravenously administered low-dose (0.5 mg/kg) ketamine in major depressive disorder and bipolar depression” [Nemeroff 2018]. Indeed, a large number of studies have demonstrated that ketamine induces a rapid and substantial improvement in depression symptoms [Kishimoto et al. 2016; Fond et al. 2014, McGirr et al. 2015, Caddy et al. 2015, Xu et al. 2016]. Evidence also shows that ketamine reduces acute suicidality – an effect that may actually be independent of the antidepressant effects [Newport et al. 2015; Nemeroff 2018; Loo et al. 2018]. The finding that ketamine produces fast and significant improvements in depression symptoms is generally not controversial among academic physicians and researchers. The commonly cited statistic is that ketamine has approximately a 70% response rate after two weeks of treatment, in patients who have TRD [Singh et al. 2016; Mathew et al. 2012].

image

However, many studies suggest the antidepressant effects of ketamine are temporary: in most studies, the antidepressant effects of a single ketamine treatment disappear by approximately two weeks [Newport et al. 2015; Su et al. 2017; Kishimoto et al. 2016; Fond et al. 2014; McGirr et al. 2015; Caddy et al. 2015; Xu et al. 2016]. This means that, for treating depression, ketamine needs to be given to patients more than once. Emerging studies suggest that repeated dosing can extend the duration of antidepressant and antisuicidal effects for at least several weeks (and remain safe during this period) [Murrough et al. 2013; Singh et al. 2016; Malhi et al. 2016; Andrade et al. 2017; Vande et al. 2016; Ghasemi et al. 2014; Thomas et al. 2018]. However, there is limited long-term data on repeated ketamine treatments. This means the long-term efficacy and safety of repeated ketamine treatments have not yet been clearly established. With the current data, however, many clinicians have deemed ketamine treatment safe and effective: an increasing number of clinicians, both within community clinics and prestigious academic centers, are providing ketamine treatment for depression.

Some clinicians may hesitate to recommend repeated ketamine treatments to patients. Because there is limited evidence for the long-term efficacy and safety of repeated treatments, these clinicians may prefer to see more evidence accumulate before recommending these treatments. For example, anecdotal evidence from recreational drug users suggest that long-term repeated use of ketamine could cause urinary or liver problems [Loo et al. 2018; Short et al. 2018]. However, it is not clear if recreational ketamine use is comparable to medical ketamine use, and if there were confounding factors (such as other illicit drug use) leading to the urinary or liver problems in these people. The mechanism of action of ketamine treatment for depression has yet to be fully understood, and some clinicians may prefer to wait until there is a better understanding of how ketamine works as a medication before prescribing it to patients. As a result of the uncertain long-term efficacy and safety and lack of clear clinical guidelines surrounding ketamine treatment, some clinicians are reluctant to recommend it.

Summary and outlook

  • Ketamine is known to produce a rapid, robust antidepressant, and antisuicidal effect. The evidence here is of good quality and includes enough study participants to make a confident conclusion that ketamine is safe and effective in the short term (when supervised by a healthcare professional).
  • However, these antidepressant effects may be temporary, making it necessary for many patients to obtain repeated ketamine treatments.
  • There is not as much data on long-term use of ketamine or repeated ketamine treatments. Though a handful of studies have suggested repeated dosing can extend the duration of antidepressant effects for at least several weeks (and remain safe during this period), there is still not enough long-term data to draw strong conclusions.
  • Patients should work together with their healthcare providers to decide whether ketamine may be a good idea.

colorful illustration of two people talking to each other

Is ketamine safe?

Ketamine treatment has been shown to be generally safe for short-term use [Malhi et al. 2016; Andrade 2017; Wan et al. 2015; Wilkinson et al. 2018]. Ketamine has been used for anesthesia for several decades and its safety profile in the acute care setting is well-established. Reassuringly, the dose of ketamine for the treatment of depression is smaller than the anesthetic dose. Analysis of ketamine TRD trials also show that patients remain medically stable without complications. Studies show that ketamine can also be used concurrently with most standard antidepressants without reducing efficacy or increasing side effects [Andrade 2017]. Evidence suggests that some patients may experience increases in blood pressure exceeding 180/100 mm Hg and heart rates exceeding 110 beats per minute [Wan et al. 2015]. Therefore, it is advised that clinics have the capability to monitor blood pressure and heart rate and do a medical assessment especially for patients who might have an underlying cardiovascular illness.

Because ketamine can cause hallucinogenic/intoxicant/trance-like episodes, it is sometimes used illegally for recreational purposes. It may be associated with risk for abuse or addiction. Ketamine is classified by the US Drug Enforcement Administration as a schedule III drug, which are defined as drugs with a “moderate to low potential for physical and psychological dependence.” Specifically in the medical context, however, evidence does not show that ketamine is significantly addictive (although there is also no evidence to show that ketamine cannot cause problems with addiction). It is thus prudent to be careful about the possible abuse potential, and to carefully weigh the risks with a physician especially if one has a substance use or addiction disorder.

Long term ketamine abuse can be associated with bladder toxicity, liver injury, or neurotoxicity, but these are for long-term abusive use that is very different from ketamine medical treatment [Loo et al. 2018; Short et al. 2018]. Short-term ketamine use is known to be safe (when used correctly), but at this time there is insufficient data to draw strong conclusions for repeated long-term medical use.

How is ketamine treatment administered?

There are two models of ketamine treatment for TRD: the ketamine infusion model and the ketamine-assisted psychotherapy (KAP) model. Both appear safe and effective [Andrade 2017] and clinics typically offer one or the other.

hospital infusion drip

Ketamine infusions

In the ketamine infusion model, patients receive intravenous (IV) ketamine. In this framework, patients do not receive any treatment besides the ketamine infusion. The ketamine itself is supposed to elicit an antidepressant effect. The standard dose is 0.5mg/kg over 40 minutes IV. Some clinics use a 2- or 3- week course of ketamine delivered 2-3 times per week, followed by continued treatments based on empirically determined duration of responses for each patient. This treatment modality makes outcomes tracking critical – it is very important to assess periodically how patients are doing (using validated depression scales), in order to track changes in mood over time and determine when it is appropriate to administer another infusion. In this framework, clinics often have an “induction phase” which is the first 1-2 weeks of ketamine treatment with 2-3 infusions each week. The “maintenance phase” is the period afterwards in which the patient returns as needed for more infusions. Depending how the patient responds, the interval between treatment sessions may be different. It is expected that with ketamine infusions, some sort of long-term maintenance will be required, or else the patient may need to be transitioned to another treatment. Clinicians attempt to optimize the dose and frequency of ketamine infusion to extend the duration of the antidepressant effect for as long as possible.

In the model of ketamine infusion therapy, the hallucinogenic or dissociative effects of ketamine may be considered to be side effects, since the premise of this model is that the ketamine itself has antidepressant effects. The dosing and delivery protocol attempt to avoid the psychoactive effects that can result from ketamine use. This model is sometimes referred to as the “medical model” of ketamine and is the model that has been better characterized within the medical literature – most of the studies characterizing the safety and efficacy of ketamine treatment use the infusion model.

With ketamine infusions, the patient arrives at the clinic and may be seen by an assistant or a clinician before the treatment. The patient may have their vital signs measured and may be asked to answer a few questions. Then they are seated, usually in a quiet room that may also be darkened, and the IV is placed into the arm. The patient may be given eye shades and headphones. The patient then sits back in the seat, which is often reclined, for roughly 40 minutes as the infusion is delivered. Afterwards, the patient may have a brief post-treatment discussion with a clinician or assistant. Vital signs may be measured during and after the infusion as well. The patient may be monitored for a short period of time. When the patient is finished, they should not drive and instead must arrange for alternative transportation to return home. Generally after a treatment, the patient will still feel slightly altered in their mental state or may feel tired. It is advisable for patients to not plan to return to work or attend other similar engagements that day. The entire appointment may last roughly two hours.

picture of a colorful heart


Ketamine-assisted psychotherapy

The other type of ketamine treatment is ketamine-assisted psychotherapy (KAP) [Dore et al. 2019]. The KAP model views the psychoactive effects and dissociative experiences associated with ketamine as part of the treatment and patients receive psychotherapy (“talk therapy”) as they are feeling the effects of the ketamine. Ketamine and psychotherapy are paired together as an integrated treatment, instead of an infusion as a standalone treatment. The antidepressant effect is caused by a combination of the biochemical, psychocative, and psychological effects.

The treatment protocol is quite different between KAP and infusions. In KAP, ketamine is given not in IV form, but instead in the intramuscular (needle injection into the muscle), sublingual (under the tongue, often as a lozenge), or intranasal (spray into the nostril) routes. After patients receive the intramuscular/sublingual/intranasal ketamine, they receive psychotherapy with the practitioner (psychiatrist, therapist, psychologist, etc.). In addition, patients undergoing KAP may be prescribed ketamine to take home and administer at home as part of a structured treatment regimen. KAP is therefore a treatment process that may include both in-office sessions with the provider and at-home sessions on the patient’s own.

In the first KAP session, the provider usually attempts to determine the patient’s optimal ketamine dose in order to allow them to reliably enter a trance state. The trance state is ideal for psychotherapy and for the at-home sessions. The onset of this state after the ketamine is administered may take 10-20 minutes. During this state the patient remains conscious and aware, and is actively communicating with the provider while experiencing relief from depressive thoughts and a flexibility of thought. The trance state may have a high-intensity period lasting 30-60 minutes and a period of lesser intensity afterwards lasting less than 60 minutes. Each KAP session may last up to three hours and is an intensive period of thought, reflection, and psychotherapy. Some practices use shorter treatment protocols lasting 1.5 hours.

Providers will instruct patients how to use this trance state in their treatment: usually patients will be asked to do multiple sessions – in the office with the provider and possibly also at home on their own or with a relative. Depending how they respond, sessions may be implemented for a couple of weeks or many months. Over time, the frequency of sessions may be tapered as the patient improves, and upon remission could be stopped completely.

KAP uses ketamine as a facilitator of psychotherapy. Patients simultaneously work with their providers to create treatment goals as they would in traditional one-on-one psychotherapy sessions. At-home sessions may require the patient to work on certain issues and catalog thoughts and progress into a treatment journal.

High-dose KAP

There is another form of KAP that uses a higher dose of ketamine to induce a psychoactive effect. This type of KAP is not as common and patients must undergo special training for these treatments. The treatment is administered by intramuscular injection of ketamine at a high enough dose to cause sedation (while remaining conscious), attenuation of visual and tactile sensation, change in auditory sensation, and temporary partial paralysis. Patients undergo a dream-like and out-of-body experience that begins within a couple minutes and lasts a bit over an hour. This experience is used to help guide the patient to find meaning and liberation on a path towards wellness.

stack of stones perfectly balanced

Safety and efficacy

As mentioned above, most of the studies on ketamine treatment have used the infusion model of ketamine instead of KAP. Emerging studies suggest KAP is also safe and effective in the short term, and there is not expected to be a significant difference between the safety profiles of the two treatment models [Andrade 2017; Dore et al. 2019]. Like the infusion model of ketamine, there is no robust evidence to draw strong conclusions regarding long-term safety or efficacy.

Which type of ketamine treatment is best?

Ketamine infusions have been studied for longer than KAP, and as a result the infusion model has accumulated a larger number of clinical studies. However, there is no evidence to suggest that one model is the superior model. There are very few studies that have explored differences between the various routes of ketamine administration, and there have been no robust head-to-head comparison trials of infusions versus KAP. One study examined infusions versus intramuscular administration and found the results were comparable [Chilukuri et al. 2014]. Overall, there is insufficient evidence to suggest either model is more effective in decreasing TRD severity. In fact, one model might work better for some patients than for others. As a result, patients should consult with providers and work together to choose the type of ketamine treatment that most fits their personal preferences and condition. There are a few factors that may be helpful to consider:

  • Do you want to do psychotherapy? Some patients find it very helpful and invigorating, while others do not enjoy it.
  • Cost: the cost of each session is different (a 40 minute infusion over 2 hours versus 3 hour KAP session will incur different costs) and also the overall number of treatments that are needed may also be different.
  • Convenience: some patients may find that one of the two treatment models is more convenient for their own schedule.

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Related articles

New patient guide for ketamine, part 2
New patient guide for esketamine
Treatment options for treatment resistant depression

Additional resources

References

Andrade C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? J Clin Psychiatry 2017; 78:e852.

Andrade C. Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions. The Journal of clinical psychiatry. 2017 Jul;78(7):e858-61.

Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev 2015; :CD011612.

Chilukuri H, Reddy NP, Pathapati RM, Manu AN, Jollu S, Shaik AB. Acute antidepressant effects of intramuscular versus intravenous ketamine. Indian journal of psychological medicine. 2014 Jan;36(1):71.

Dore J, Turnipseed B, Dwyer S, Turnipseed A, Andries J, Ascani G, Monnette C, Huidekoper A, Strauss N, Wolfson P. Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. Journal of psychoactive drugs. 2019 Mar 15;51(2):189-98.

Fond G, Loundou A, Rabu C, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology (Berl) 2014; 231:3663.

Ghasemi M, Kazemi MH, Yoosefi A, et al. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Res 2014; 215:355.

Harvard Health Blog - Gene testing to guide antidepressant treatment: Has its time arrived?

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Malhi GS, Byrow Y, Cassidy F, et al. Ketamine: stimulating antidepressant treatment? BJPsych Open 2016; 2:e5.

Mathew SJ, Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, Murrough JW. Ketamine for treatment-resistant unipolar depression. CNS drugs. 2012 Mar 1;26(3):189-204.

McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 2015; 45:693.

Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins KA, Mathew SJ, Charney DS, Iosifescu DV. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological psychiatry. 2013 Aug 15;74(4):250-6.

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Nemeroff, Charles B. “Ketamine: quo vadis?.” Am J Psychiatry. (2018): 297-299.

Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. Am J Psychiatry 2015; 172:950.

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Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, Pinter C, Murrough JW, Sanacora G, Shelton RC, Kurian B. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. American Journal of Psychiatry. 2016 Aug 1;173(8):816-26.

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Thomas RK, Baker G, Lind J, Dursun S. Rapid effectiveness of intravenous ketamine for ultraresistant depression in a clinical setting and evidence for baseline anhedonia and bipolarity as clinical predictors of effectiveness. J Psychopharmacol 2018; 32:1110.

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Wilkinson ST, Katz RB, Toprak M, et al. Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital. J Clin Psychiatry 2018; 79.

Xu Y, Hackett M, Carter G, et al. Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis. Int J Neuropsychopharmacol 2016; 19.