A consensus statement on the use of ketamine in the treatment of mood disorders

This review (2017) investigates the potential and caution related to ketamine in the treatment of mood disorders.

Abstract

“Importance: Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.

Observations: This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.

Conclusions and Relevance: The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.”

Authors: Gerard Sanacora, Mark A. Frye, William McDonald, Sanjay J. Mathew, Mason S. Turner, Alan F. Schatzberg, Paul Summergrad & Charles B. Nemeroff

Summary

The T Task Force on Novel Biomarkers and Treatments found that 7 published placebo-controlled, double-blind, randomized clinical studies on ketamine hydrochloride infusion therapy in the treatment of depression comprised 147 treated patients provided compelling evidence that ketamine’s antidepressant effects are both rapid and robust, albeit transient.

The use of ketamine treatment in mood disorders is an urgent need for guidance. This review by the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments Subgroup on Treatment Recommendations for Clinical Use of Ketamine provides an overview and expert clinical opinion.

Ketamine hydrochloride has been shown to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment.

This review and consensus statement highlights the limitations of the existing knowledge on the use of ketamine for the treatment of mood disorders.

This article provides information on potentially important issues related to the off-label treatment approach to ketamine use in the treatment of psychiatric disorders.

Patient Selection

Ketamine has been used to treat major depressive episodes without psychotic features associated with major depressive disorder, but there are no clearly established indications for the use of ketamine in the treatment of other psychiatric disorders.

In addition to diagnostic considerations, a thorough pretreatment evaluation process should be conducted before initiating ketamine treatment. An informed consent process should also be completed during this evaluation.

Clinician Experience and Training

There are no published guidelines or recommendations for training clinicians to administer low doses of ketamine for the treatment of mood disorders.

Ketamine infusions of 0.5 mg/kg IV over 40 minutes produce peak plasma ketamine concentrations of 70 to 200 ng/mL, which are well below the peak plasma ketamine concentrations used for surgical anesthesia.

In a study of 84 patients with depression, 0.5 mg/kg per 40 minutes IV, Perry et al21 found no persistent medical complications or significant changes in oxygen saturation, but transient mean (SD) peak increases in systolic and diastolic blood pressure were reported in approximately 30% of the patients treated.

Ketamine hydrochloride, the drug used to treat mood disorders, does not appear to have significant effects on respiratory status in healthy individuals or patients with depression who are otherwise generally medically healthy. However, the drug may have meaningful effects on blood pressure and heart rate for some patients.

Patients may experience transient dissociative or psychotomimetic effects while being treated with ketamine. Clinicians should be prepared to treat any emergency behavioral situations and ensure rapid follow-up evaluations.

The minimal general training requirements and specific experience with ketamine administration should be based on local community standards of practice and clinical practice committees.

Treatment Setting

Although the acute effects of ketamine treatment with doses that are lower than those used in anesthesia are relatively low, the clinical setting should provide sufficient means of monitoring the patients and providing immediate care if necessary.

Dose

The most common dose of ketamine used in clinical trials is 0.5 mg/kg per 40 minutes IV. However, there is limited information regarding the use of different routes of delivery and doses of ketamine, and the total number of participants included is very few.

Although studies have shown that lower doses and reduced infusion rates are effective, studies showing higher doses and extended infusion rates have clinical benefit, but insufficient information was provided in those studies to allow meaningful analysis of any specific dose or route of treatment.

One rationale for dose adjustment is related to the dosing of ketamine for patients with a high body mass index. However, there is currently very limited information supporting this approach.

Delivery Procedure

To help ensure patient safety and minimize risks, it is strongly advised that site-specific standard operating procedures be developed and followed for the delivery of ketamine treatments for major depressive episodes.

Standard operating procedures should include ongoing assessments of patients’ physiological and mental status during the infusion process, including blood pressure and heart rate, and a clear plan for managing cardiovascular or behavioral events during treatment.

After treatment, the patient should be evaluated to ensure that they can return home safely. They should also be given recommendations regarding driving and heavy machinery, as well as use of concomitant medications, drugs, or alcohol.

Follow-up and Assessments

Although several case series and small studies have evaluated the efficacy of repeated ketamine administration for the treatment of major depressive episodes, there are still very few randomized clinical trials.

A recent randomized, placebo-controlled clinical trial of 68 patients with treatment-resistant major depressive disorder found both dosing regimens to be nearly equally efficacious. Patients who received ketamine 2 times weekly and continued to receive active medication for an additional 2 weeks had a mean 27-point decrease in the depression rating scale. Although this study was clearly not definitive, it suggests that twice-weekly dosing is as efficacious as more frequent dosing for a period of up to 4 weeks.

Limited data exist to suggest a clear point of determining the futility of treatment, but an increased dose of ketamine may lead to a response in patients who had previously not responded to treatment.

Efficacy of Longer-term Repeated Administration

There is very limited published data on the longer-term effectiveness and safety of ketamine treatment in mood disorders. It is strongly recommended that patients be informed about the potential risks of longer-term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration.

Safety Measures and Continuation of Treatment

A thorough assessment of cognitive function, urinary discomfort, and substance use should be considered before repeated administrations of ketamine.

Considering the potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder and limit the number and frequency of treatments to the minimum necessary to achieve clinical response.

We advise against the prescription of ketamine for at-home self-administration. Discontinue treatment if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment.

Future Directions

Ketamine infusions have generated much excitement and hope for patients with refractory mood disorders, but many questions remain unanswered. Future research is needed to address these unanswered questions and concerns, and a coordinated system of data collection on all patients receiving ketamine is needed.

Dr Summergrad has received grant funding from Janssen, Corcept, Merck, Gilead, Xhale, Amnestix, Synosia, Neuronetics, and Intersect ENT, and consulting fees and stock options from Mental Health Data Services Inc and Quartet Health Inc. Dr Nemeroff has received income or equity from American Psychiatric Publishing.

Supplementary Online Content

The number of trials and subjects studied for neurostimulation in recently developed mood disorders is very difficult to obtain, and the number of subjects studied with each modality varies. However, a review covering most of neurostimulation treatment modalities was recently provided by Milev et al.

A small proofofconcept placebo controlled trial and a case report have been published in posttraumatic stress disorder PTSD patients, but there are very few reports evaluating the use of ketamine in treating psychiatric disorders other than major depressive episodes associated with either major depressive disorder or bipolar disorder.

The study showed that ketamine produced a significant reduction in symptoms of PTSD compared to midazolam in subjects who had received at least one dose of the study medication. Although there was evidence of transient improvement in PTSD and associated depressive symptoms following the treatment with ketamine the evidence supporting the use of ketamine for the treatment of PTSD to date remains weak.

Data regarding the use of ketamine in obsessive compulsive disorder are inconclusive and inconsistent. A small controlled crossover trial found that ketamine reduced OCD symptoms in subjects within the first week of treatment. A small open label study of OCD patients found that none experienced a response reducing symptoms over the days following a single ketamine infusion however four of the seven subjects with comorbid depression experienced a transient antidepressant response to the treatment

There are insufficient data to allow a meaningful review of the evidence related to these disorders or to support the use of ketamine treatments outside of the research setting. Symptom severity and previous treatment resistance should be used as factors in calculating the risk benefit ratio. Ketamine should not be firstline treatment for any level of episode severity and more established therapies should be initiated as first line treatments.

A relatively small study found that ketamine was associated with transient clinical improvements in patients who had previously failed a course of electroconvulsive therapy ECT. However, further research is needed to determine its efficacy and safety. There is little information regarding potential drugdrug interactions with ketamine, however, it has been hypothesized that the use of benzodiazepines or other gamma agonists may increase the risk of side effects.

Ketamine may be attenuated by amino butyric acid and GABA potentiating agents This is important to consider in light of the fact that rapid acting benzodiazepines are frequently used to attenuate the potential emergence and anxiogenic effects of ketamine. Ketamine can have physiologically meaningful effects on cardiovascular function. Approximately of patients receiving intravenous ketamine infusions mgkg over minutes had transient increases in mean peak blood pressure measures.

The other published studies are generally in agreement with the recent findings, and it is important to screen for baseline hypertension and tachycardia prior to initiating treatment. Patients should be asked about any recent changes in exercise tolerance and should have a physical and laboratory screening procedure performed to evaluate potential risks of ketamine-induced cardiovascular changes and to understand the risk benefit ratio of the treatment.

Ketamine is contraindicated in those in whom a significant elevation of blood pressure would constitute a serious hazard. Patients with baseline blood pressure or heart rate greater than should be considered at higher risk and treatment of hypertension should be considered prior to initiating treatment.

Blood pressure should be kept below mm(g for SBP and mm(g for DBP at all times during the infusion process. If the blood pressure increases, the infusion should be stopped and the blood pressure should be monitored closely. A decrease in SBP from baseline blood pressure despite evidence of an increased cardiac demand should be considered a stop criteria.

Ketamine use can have adverse effects on cognitive function. However, there is no clear agreement on the type or frequency of cognitive assessments that should be performed. The available studies examining the effects of ketamine treatment of mood disorders on cognition have not demonstrated any evidence of cognitive decline. However, considering the preclinical literature suggesting that ketamine could produce cognitive dysfunction and potentially even excitotoxic degeneration, some assessment of cognition should be used to follow patients receiving ongoing ketamine treatment.

Health Quality Ontario reviewed the economics of repetitive transcranial magnetic stimulation for treatmentresistant depression. A systematic review of randomized trials of deep brain stimulation for treatment resistant depression was published in Biological psychiatry. A meta-analysis of ketamine and other glutamate receptor modulators for depression in bipolar disorder was published in The Cochrane database of systematic reviews. Ketamine has an effect on major depressive disorder and posttraumatic stress disorder in patients.

Ketamine is effective in treating obsessivecompulsive disorder and posttraumatic stress disorder, but can cause dysphoria and anxiety in patients with a history of major depressive disorder. Ketamine improves depression scores in patients with anxious bipolar depression, according to a study published in the Journal of clinical psychiatry. Ketamine has been shown to reduce suicidal ideation in a randomized controlled trial, and has been suggested to have potential anti-suicidal properties.

Ketamine, an NMDA receptor antagonist, is used to treat major depressive disorder. However, concomitant benzodiazepine use attenuates the effects of ketamine and should be avoided in large scale studies. Ketamine infusions for treatment resistant depression: a series of patients treated weekly or twice weekly in an ECT clinic Journal of psychopharmacology. Ketamine treatment leads to permanent changes in EEG cognition and the astrocytic glutamate transporter EAAT in mice. Psychometric validation of the Oleary-Sant interstitial cystitis symptom index in a clinical trial of pentosan polysulfate sodium Urology.