Clinical Review & Education JAMA Psychiatry Special Communication A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders Gerard Sanacora, MD, PhD; Mark A. Frye, MD; William McDonald, MD; Sanjay J. Mathew, MD; Mason S. Turner, MD; Alan F. Schatzberg, MD; Paul Summergrad, MD; Charles B. Nemeroff, MD, PhD; for the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments Invited Commentary 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. Supplemental content 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. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.0080 Published online March 1, 2017. T he American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments found that the data from 7 published placebo-controlled, double-blind, randomized clinical studies on ketamine hydrochloride infusion therapy in the treatment of depression comprising 147 treated patients provide “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient.”1(p958) Reports of ketamine’s unique antidepressant effects, combined with frequent media coverage promulgating the potential benefits of ketamine treatment, have generated substantial interest and optimism among patients, families, patient advocacy groups, and clinicians alike. This interest has led to a rapidly escalating demand for clinical access to ketamine treatment and an increasing number of clinicians willing to provide it. However, many in the field suggest that caution should be used with this approach, as the numbers of patients included in these published studies and case series remain relatively small (the eTable in the Supplement compares other recently developed treatments), and ketamine treatment for mood disorders has not been tested in larger-scale clinical trials to demonstrate its durability and safety over time.2,3 Moreover, the treatment approach has not been subject to the scrutiny of a US Food and Drug Administration review or approval for an on-label psychiatric indication, jamapsychiatry.com Author Affiliations: Author affiliations are listed at the end of this article. Group Information: The American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments members are listed at the end of this article. Corresponding Author: Gerard Sanacora, MD, PhD, Yale University School of Medicine, 100 York St, Ste 2J, New Haven, CT 06511 (gerard.sanacora@yale.edu). and, despite more than 45 years of clinical experience with ketamine as an anesthetic agent, there are no postmarketing surveillance data on the use of ketamine for any psychiatric indication to provide information on its safety and effectiveness. The relatively unique nature of this situation presents an urgent need for some guidance on the issues surrounding the use of ketamine treatment in mood disorders. 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 is intended to complement the recent American Psychiatric Association meta-analysis1 and other recent reviews4-10 and aims to provide an overview and expert clinical opinion of the critical issues and considerations associated with the off-label use of ketamine treatment for mood disorders. Because relatively limited high-quality, published information on this topic exists, to our knowledge, this report is not intended to serve as a standard, guideline, clinical policy, or absolute requirement. The main intent of the report is to highlight the current state of the field and the critical issues to be considered when contemplating the use of ketamine for treatment-resistant depression. Use of this report cannot guarantee any specific outcome and is not endorsed or promulgated as policy of the American Psychiatric Association. (Reprinted) JAMA Psychiatry Published online March 1, 2017 Copyright 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/0/ by a Texas Tech University - Hsc User on 03/01/2017 E1 Clinical Review & Education Special Communication Table. Recommended Components of Preprocedural Evaluation for Appropriateness of Ketamine Hydrochloride Treatment Patient Selection There are no clearly established indications for the use of ketamine in the treatment of psychiatric disorders. However, the selection of appropriate patients for ketamine treatment requires consideration of the risks and benefits of the treatment in the context of the patient’s severity of depression, duration of current episode, previous treatment history, and urgency for treatment. To date, the strongest data supporting ketamine’s clinical benefit in psychiatric disorders are in the treatment of major depressive episodes without psychotic features associated with major depressive disorder.1,11 Even these data are limited by the fact that most of those studies evaluated efficacy only during the first week following a single infusion of ketamine. However, emerging studies suggest that repeated dosing can extend the duration of effect for at least several weeks.12,13 Although some limited data on the use of ketamine in treating other psychiatric diagnoses exist (eBox 1 in the Supplement), we do not believe there are sufficient data to provide a meaningful review of the assessment of risks and benefits of ketamine use in these other disorders at present. In addition to diagnostic considerations, appropriate patient selection requires an assessment of other medical, psychological, or social factors that may alter the risk to benefit ratio of the treatment and affect the patient’s capacity to provide informed consent. For these reasons, we recommend that each patient undergo a thorough pretreatment evaluation process (Table)14-17 that assesses several relevant features of the patient’s past and current medical and psychiatric condition before initiating ketamine treatment. We also recommend that an informed consent process be completed during this evaluation. Rationale for the suggestions listed in the Table are provided in eBox 1 in the Supplement. Clinician Experience and Training There are considerable differences in the experience and clinical expertise of the clinicians currently administering ketamine to patients for the treatment of mood disorders. At present, there are no published guidelines or recommendations outlining the specific training requirements that clinicians should complete before administering doses of ketamine that are lower than those used in anesthesia. In attempting to balance the needs for treatment availability and patient safety, one must consider the information available regarding the use of ketamine at the relevant dose range in similar patient populations to formulate an advisory on clinical credentialing for ketamine administration for the treatment of mood disorders. The peak plasma ketamine hydrochloride concentrations of 70 to 200 ng/mL seen with the typical antidepressant dose of 0.5 mg/kg delivered intravenously (IV) during 40 minutes (0.5 mg/kg per 40 minutes IV) do not produce general anesthetic effects. The concentrations are well below the peak plasma ketamine hydrochloride concentrations generally used for surgical anesthesia (2000-3000 ng/mL) and below the concentrations associated with awakening from ketamine hydrochloride anesthesia (500-1000 ng/mL).18-20 Reporting on 833 ketamine infusions in healthy individuals resulting in peak plasma ketamine concentraE2 A Consensus Statement on Ketamine in the Treatment of Mood Disorders Component Recommendation 1 A comprehensive diagnostic assessment should be completed to establish current diagnosis and evaluate history of substance use and psychotic disorders 2 Assessment of baseline symptom severity should be completed to allow later assessments of clinical change with treatmenta 3 A thorough history of antidepressant treatment should be collected and documented to confirm previous adequate trials of antidepressant treatments 4 A thorough review of systems should be performed to evaluate potential risk factors associated with ketamine treatmentb 5 Decisions on the specific physical examination and laboratory screening assessments should be made according to established guidelines and advisories issued by the American College of Cardiology Foundation/American Heart Association and the American Society of Anesthesiologists and should be based on a patient’s individual clinical characteristicsc 6 A careful review of past medical and psychiatric records and/or corroboration of the past history by family members are strongly encouraged; all current medications and allergies should be reviewed, including histories of opiate and benzodiazepine use; the use of a baseline urine toxicology screen is strongly encouraged to ensure the accuracy of the reported substance use and medication record 7 An informed consent process, including discussion of the risks associated with the treatment,d the limits of the available information pertaining to the potential benefits of the treatment, the fact that this is an off-label use of ketamine, and a discussion of alternative treatment options should be completed; this discussion should be complemented with written materials, and the patient should provide written informed consent before initiating treatment a Self-report versions of the Inventory of Depressive Symptomatology and Quick Inventory of Depressive Symptomatology (http://counsellingresource .com/quizzes/depression-testing/qids-depression/) are examples of scales that are available at no cost to clinicians and researchers. b This review should also include questions pertaining to functional exercise capacity, which has been demonstrated to provide a good screening tool for patients that are at increased risk for adverse events associated with anesthesia exposure and surgical procedures.14,15 c American College of Cardiology Foundation and the American Heart Association guidelines for perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery16 and practice advisory from the American Society of Anesthesiologists.17 d The Ketalar package insert (http://www.accessdata.fda.gov/drugsatfda_docs /label/2012/016812s039lbl.pdf) provides essential information related to risk of ketamine administration. tions in the same general range as those achieved with a dose of 0.5 mg/kg per 40 minutes IV, Perry et al21 found 3 individuals who became nonresponsive to verbal stimuli, but all remained medically stable during the infusion and none required any form of respiratory assistance. A second, more recent study reported no persistent medical complications or significant changes in oxygen saturation among 84 otherwise healthy patients with depression who received a total of 205 infusions of ketamine hydrochloride, 0.5 mg/kg per 40 minutes IV.9 However, transient mean (SD) peak increases in systolic (19.6 [12.8] mm Hg) and diastolic (13.4 [9.8] mm Hg) blood pressure were reported during the infusions, with blood pressure levels exceeding 180/100 mm Hg or heart rates exceeding 110 beats per minute in approximately 30% of the patients treated. A single serious adverse cardiovascularrelated event was reported in this study (0.49% of infusions), but it was considered to be attributable to a vasovagal episode following venipuncture for a blood draw, and it resolved without complications. JAMA Psychiatry Published online March 1, 2017 (Reprinted) jamapsychiatry.com Copyright 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/0/ by a Texas Tech University - Hsc User on 03/01/2017 Special Communication Clinical Review & Education A Consensus Statement on Ketamine in the Treatment of Mood Disorders The data available from these studies and other case reports in the literature suggest that the dose of ketamine hydrochloride typically used in the treatment of mood disorders (0.5 mg/kg per 40 minutes IV) does not appear to have significant effects on the respiratory status of healthy individuals or patients with depression who are otherwise generally medically healthy. However, ketamine treatment could have meaningful effects on blood pressure and heart rate for some patients. Considering the potential risks associated with ketamine hydrochloride administration at the dose of 0.5 mg/kg per 40 minutes IV, it is recommended that clinicians delivering the treatment be prepared to manage potential cardiovascular events should they occur. Based on this information, we suggest that a licensed clinician who can administer a Drug Enforcement Administration Schedule III medication (in most states this is an MD or DO with appropriate licensing) with Advanced Cardiac Life Support certification should provide the treatments. Because it is also possible for patients to experience prominent transient dissociative or even psychotomimetic effects while being treated with ketamine,22 clinicians should also be familiar with behavioral management of patients with marked mental status changes and be prepared to treat any emergency behavioral situations. Furthermore, it is suggested that an on-site clinician be available and able to evaluate the patient for potential behavioral risks, including suicidal ideation, before discharge to home. Finally, treating clinicians should be able to ensure that rapid follow-up evaluations of patients’ psychiatric symptoms can be provided as needed. In addition to the minimal general training requirements, it is also recommended that clinicians develop some level of experience with the specific method of ketamine administration before performing the procedure independently. Precise delineation of required experience and documentation of this experience should be based on local community standards of practice and/or clinical practice committees. Reports such as the Statement on Granting Privileges for Administration of Moderate Sedation to Practitioners Who Are Not Anesthesia Professionals, published by the American Society of Anesthesiologists,23 can be used to inform the development of these standards. Treatment Setting Although the administration of ketamine at peak plasma concentrations similar to those produced by a dose of 0.5 mg/kg per 40 minutes IV has proven to be relatively safe to date, the potentially concerning acute effects on cardiovascular function and behavior suggest that the clinical setting should provide sufficient means of monitoring the patients and providing immediate care if necessary. Although there are relativelylowlevelsofevidencetosupporttheuseofanyspecificmonitoring methods in reducing the risks of ketamine treatment with doses thatarelowerthanthoseusedinanesthesia,itshouldbeexpectedthat such a facility have a means of monitoring basic cardiovascular (electrocardiogram, blood pressure) and respiratory (oxygen saturation or end-tidal CO2) function. It should also be expected that there would bemeasuresinplacetorapidlyaddressandstabilizeapatientifanevent should arise. These measures would include a means of delivering oxygen to patients with reduced respiratory function, medication, and, if indicated,restraintstomanagepotentiallydangerousbehavioralsymptoms. Moreover, there should be an established plan to rapidly address any sustained alterations in cardiovascular function, such as providing jamapsychiatry.com advanced cardiac life support or transfer to a hospital setting capable of caring for acute cardiovascular events. Patients deemed at higher risk for complications based on pretreatment evaluation should be treated at a facility that is appropriately equipped and staffed to manage any cardiovascular or respiratory events that may occur. Medication Delivery Dose Most clinical trials and case reports available in the literature have used the ketamine hydrochloride dose of 0.5 mg/kg per 40 minutes IV that was cited in the original report by Berman et al.24 Limited information is available regarding the use of different routes of delivery and doses of ketamine. A meta-analysis of 6 trials assessing the effects of the standard dose of 0.5 mg/kg per 40 minutes IV and 3 trials assessing very low doses of ketamine hydrochloride (50-mg intranasal spray, 0.1-0.4 mg/kg IV, and 0.1-0.5 mg/kg IV intramuscularly or subcutaneously) reported that the dose of 0.5 mg/kg per 40 minutes IV appears to be more effective than very low doses in reducing the severity of depression.4 However, there is substantial heterogeneity in the design of the clinical trials, and the total number of participants included in that analysis is very few, markedly limiting the ability to draw any firm conclusions from this report. Although there is now a growing number of reports examining the effects of various doses and rates of ketamine infusion, including studies showing lower doses and reduced infusion rates25-27 to be effective and studies showing higher doses and extended infusion rates28,29 to have clinical benefit, at present we believe that insufficient information was provided in those studies to allow any meaningful analysis of any specific dose or route of treatment compared with the standard dose of 0.5 mg/kg per 40 minutes IV. Considering the lower-level evidence for doses and routes of administration other than 0.5 mg/kg per 40 minutes IV, if alternative doses are being used, that information should be presented to the patient during the informed consent process, and appropriate precautions should be made in managing any increased risk associated with the changes in ketamine administration. However, the use of alternative doses and routes of administration could be appropriate for individual patients under specific conditions. One example of a rationale for dose adjustment is related to the dosing of ketamine for patients with a high body mass index (calculated as weight in kilograms divided by height in meters squared). The fact that greater hemodynamic changes were observed in patients with a body mass index of 30 or higher who were receiving a dose of 0.5 mg/kg per 40 minutes9 suggests that adjusting the ketamine dosing to ideal body weight (using the person’s calculated ideal body weight and not actual body weight to determine dosing) may be an appropriate step to help ensure safety for patients with a body mass index of 30 or higher. However, there is currently very limited information supporting this approach. Delivery Procedure To help best ensure patient safety and to 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. The standard operating procedure should contain predosing considerations covering the following: (1) confir(Reprinted) JAMA Psychiatry Published online March 1, 2017 Copyright 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/0/ by a Texas Tech University - Hsc User on 03/01/2017 E3 Clinical Review & Education Special Communication mation of preprocedural evaluation and informed consent; (2) assessment of baseline vital signs, including blood pressure, heart rate, and oxygen saturation or end-tidal CO2; (3) criteria for acceptable baseline vital signs before initiation of medication delivery (eBox 2 in the Supplement); and (4) incorporation of a “time-out” procedure in which the name of the patient and correct dosing parameters are confirmed. Standard operating procedures should also include specifically defined ongoing assessments of patients’ physiological and mental status during the infusion process, including the following: (1) assessment of respiratory status (ie, oxygen saturation or endtidal CO2); (2) assessment of cardiovascular function (blood pressure and heart rate, reported on a regular basis); (3) assessment of the level of consciousness (ie, Modified Observer’s Assessment of Alertness/Sedation Scale30) or other documented assessment of responsiveness; and (4) delineation of criteria for stopping the infusion (eBox 3 in the Supplement) and a clear plan for managing cardiovascular or behavioral events during treatment. Immediateposttreatmentevaluations,assessments,andmanagement should ensure that the patient has returned to a level of function that will allow for safe return to his or her current living environment. This assessment should include documentation of return to both baseline physiological measures and mental status. It is also critical to ensure that a responsible adult is available to transport the patient home if the treatment is being administered on an outpatient basis. Recommendations regarding driving and use of heavy machinery, as well as use of concomitant medications, drugs, or alcohol, should also be reviewed before discharge. It is also important to review follow-up procedures and ensure that the patient has a means of rapidly contacting an appropriately trained clinician if necessary. Follow-up and Assessments Efficacy Measures of Short-term Repeated Administration The existing data surrounding the benefits of repeated infusions of ketamine remain limited.1,11 Although an increasing number of small case series evaluate the efficacy of repeated ketamine administration for the treatment of major depressive episodes, there is a very small numberofrandomizedclinicaltrialsintheliterature.1 Thelackofclinicaltrials in this area makes it difficult to provide suggestions on the frequency and duration of treatment with even moderate levels of confidence. Most studies and case reports published to date on this topic have examined the effects of less than 1 month of treatment.12,26,31-34 A recent randomized, placebo-controlled clinical trial (using saline as the placebo) of 68 patients with treatment-resistant major depressivedisorderexaminedtheefficacyofketamine,0.5mg/kgper40minutesIV,both2and3timesweeklyforupto2weeksandfoundbothdosing regimens to be nearly equally efficacious (change in mean [SD] Montgomery-Åsberg Depression Rating Scale total score for ketamine 2timesweekly,–18.4[12.0]vsplacebo,–5.7[10.2];andketamine3times weekly, –17.7 [7.3] vs placebo, –3.1 [5.7]).13 After 2 weeks of treatment, patients treated with ketamine 2 times weekly showed a 69% rate of response and 37.5% rate of remission vs placebo, at 15% and 7.7%, respectively,andthosetreatedwithketamine3timesweeklyhada53.8% rate of response and 23.1% rate of remission vs placebo, at 6% and 0%, respectively.Intheensuingopen-labelphaseofthestudy,patientswere allowed to continue with active medication at the dose frequency they E4 A Consensus Statement on Ketamine in the Treatment of Mood Disorders were originally assigned for an additional 2-week period. At the end of 4 weeks of treatment, the 13 patients who received ketamine 2 times weekly and continued to receive the additional 2 weeks of treatment had a mean 27-point reduction in the Montgomery-Åsberg Depression RatingScalescorecomparedwitha23-pointdecreaseforthe13patients who received ketamine 3 times weekly. Although this was clearly not adefinitivestudy,itisthebestevidencecurrentlyavailable,toourknowledge, to suggest that twice-weekly dosing is as efficacious as more frequent dosing for a period of up to 4 weeks. In general, most of the available reports describing the effects of repeated treatments showed the largestbenefitsoccurringearlyinthecourseoftreatment,butsomereports did show some cumulative benefit of continued treatment.31 Very limited data exist to suggest a clear point of determining the futility of treatment, but there are a few reports of patients responding after more than 3 infusions. Based on the limited data available, patients should be monitored closely using a rating instrument to assess clinical change to better reevaluate the risk to benefit ratio of continued treatment. In addition, only 1 report suggests that an increased dose of ketamine (beyond 0.5 mg/kg per 40 minutes) may lead to a response to treatment in patients who had previously not responded.28 Equally few data are available to suggest a standard number of treatments that should be administered to optimize longer-term benefit of the treatment. Efficacy of Longer-term Repeated Administration To our knowledge, there are extremely limited published data on the longer-term effectiveness and safety of ketamine treatment in mood disorders. This literature is confined to a few case series that do not allow us to make a meaningful statement about the longer-term use of ketamine.35,36 Several clinics providing such treatments are currently using a 2- or 3-week course of ketamine delivered 2 or 3 times per week, followed by a taper period and/or continued treatments based on empirically determined duration of responses for each patient. However, there remain no published data that clearly support this practice, and it is strongly recommended that the relative benefit of each ketamine infusion be considered in light of the potential risks associated with longer-term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration. The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment. Safety Measures and Continuation of Treatment Based on the known or suspected risks of cognitive impairment37 and cystitis38 associated with chronic high-frequency use of ketamine and the known substance abuse liability of the drug, assessments of cognitive function, urinary discomfort, and substance use39 should be considered if repeated administrations are provided (eBox 4 in the Supplement). Considering the known potential for abuse of ketamine40 and recent reports of abuse of prescribed ketamine for the treatment of depression,41 clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder. Close clinical follow- JAMA Psychiatry Published online March 1, 2017 (Reprinted) jamapsychiatry.com Copyright 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/0/ by a Texas Tech University - Hsc User on 03/01/2017 Special Communication Clinical Review & Education A Consensus Statement on Ketamine in the Treatment of Mood Disorders up with intermittent urine toxicology screening for drugs of abuse and inquiries about attempts to receive additional ketamine treatments at other treatment centers should be implemented when clinical suspicionofketamineabuseispresent.Moreover,thenumberandfrequency of treatments should be limited to the minimum necessary to achieve clinicalresponse.Consideringtheevidencesuggestingthatthemechanism of action requires some delayed physiological effect to the treatment and does not appear to require sustained blood concentrations of the drug to be present, there is no evidence to support the practice offrequentketamineadministration.Thepreviouslymentionedreport showingtwice-weeklydosingtobeatleastaseffectiveasdosing3times a week13 for up to 4 weeks appears to support this idea instead of more frequent dosing schedules. At this point of early clinical development, we strongly advise against the prescription of at-home self-administration of ketamine; it remains prudent to have all doses administered with medical supervision until more safety information obtained under controlled situations can be collected. Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment. The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected. ARTICLE INFORMATION Accepted for Publication: January 11, 2017. Published Online: March 1, 2017. doi:10.1001/jamapsychiatry.2017.0080 Author Affiliations: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Sanacora); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Frye); Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia (McDonald); Department of Psychiatry, Baylor College of Medicine, Houston, Texas (Mathew); Department of Psychiatry, Michael E. Debakey Veterans Affairs Medical Center, Houston, Texas (Mathew); Department of Psychiatry, Kaiser Permanente Northern California, San Francisco (Turner); Department of Psychiatry, Stanford University School of Medicine, Stanford, California (Schatzberg); Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (Summergrad); Department of Psychiatry, University of Miami Miller School of Medicine, Miami, Florida (Nemeroff). Conflict of Interest Disclosures: Dr Sanacora reported receiving consulting fees from Allergan, Alkermes, AstraZeneca, BioHaven Pharmaceuticals, Hoffman La-Roche, Johnson & Johnson (Janssen), Merck, Naurex, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, and Vistagen Therapeutics in the past 24 months and receiving research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co, Johnson & Johnson (Janssen), Hoffman La-Roche, Merck & Co, Naurex, and Servier in the last 24 months. Free medication was provided to Dr Sanacora for a National Institutes of Health–sponsored study by Sanofi. Dr Sanacora reported holding shares in BioHaven Pharmaceuticals Holding Company and being a co-inventor on patent No. 8778979 (“Glutamate agents in the treatment of mental disorders”). Dr Frye reported receiving grant support in 2016 from jamapsychiatry.com Future Directions The rapid onset of robust, transient antidepressant effects associated with ketamine infusions has generated much excitement and hope for patients with refractory mood disorders and the clinicians who treat them. However, it is necessary to recognize the major gaps that remain inourknowledgeaboutthelonger-termefficacyandsafetyofketamine infusions.Futureresearchisneededtoaddresstheseunansweredquestions and concerns. Although economic factors make it unlikely that large-scale, pivotal phase 3 clinical trials of racemic ketamine will ever be completed, there are several studies with federal and private foundation funding aiming to address some of these issues. It is imperative that clinicians and patients continue to consider enrollment in these studies when contemplating ketamine treatment of a mood disorder. It is only through these standardized clinical trials that we will be able to collect the data necessary to answer some of the crucial questions pertaining to the efficacy and safety of the drug. A second means of adding to the knowledge base is to develop a coordinated system of data collection on all patients receiving ketamine for the treatment of mood disorders. After such a registry is created, all clinicians providing ketamine treatment should consider participation. AssureRx, Janssen Research & Development, Mayo Foundation, Myriad Genetics, and Pfizer; serving as a paid consultant for Mayo, Janssen Research & Development LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc, Sunovion, Supernus Pharmaceuticals, and Teva Pharmaceuticals; and receiving continuing medical education and travel support from the American Physician Institute and CME Outfitters. Dr McDonald reported receiving research support from the National Institute of Mental Health, National Institute of Neurological Disease and Stroke, Stanley Foundation, Soterix, Neuronetics, and Cervel Neurotherapeutics; receiving reimbursement for travel and an honorarium for serving as a consultant on the Neurological Devices Panel of the Medical Devices Advisory Committee, Center for Devices and Radiological Health, Food and Drug Administration, and serving as an ad hoc member of several National Institute of Mental Health and National Institute of Neurological Disease and Stroke study sections; and receiving royalties or a stipend for a contract with Oxford University Press to co-edit a book on the clinical guide to transcranial magnetic stimulation in the treatment of depression and for serving as a section editor for Current Psychiatry Reports. Dr Mathew reported receiving research funding from the Department of Veterans Affairs, National Institute of Mental Health, Janssen Research & Development, and Otsuka; receiving consulting fees from or serving on advisory boards for Acadia, Alkermes, Cerecor, Genentech, Naurex, Otsuka, Teva, Valeant, and Vistagen Therapeutics; and receiving support from the Johnson Family Chair for Research in Psychiatry at Baylor College of Medicine and resources and use of facilities at the Michael E Debakey Veterans Affairs Medical Center in Houston, Texas. Dr Schatzberg reported receiving consulting fees from Forum, Gilead, Takeda, Xhale, Clintara, Pfizer, Myriad Genetics, Alkermes, and Neuronetics in the past 3 years; holding equity in Seattle Genetics, Incyte Genetics, Corcept (co-founder), Merck, Gilead, Xhale, Amnestix, Synosia, Neuronetics, and Intersect ENT; receiving grant funding from Janssen; and receiving royalties from American Psychiatric Publishing and Stanford University for use patents. Dr Summergrad reported receiving honoraria from CME Outfitters, Pharmasquire, and universities and associations for nonpromotional speaking; royalties from Harvard University Press, Springer, and American Psychiatric Press; and consulting fees and stock options from Mental Health Data Services Inc and Quartet Health Inc, in which he also has stock. Dr Nemeroff reported receiving consulting fees from Xhale, Takeda, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc, Lundbeck, Prismic Pharmaceuticals, Bracket (Clintara), Total Pain Solutions (TPS), Gerson Lehrman Group (GLG) Healthcare & Biomedical Council, Fortress Biotech, Sunovion Pharmaceuticals Inc, and Sumitomo Dainippon Pharma; being a share holder in Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health Inc, and Bracket Intermediate Holding Corp; receiving income or equity from American Psychiatric Publishing, Xhale, Bracket (Clintara), CME Outfitters, and Takeda; and holding patent No. 6,375,990B1 related to the method of and devices for transdermal delivery of lithium and patent No. 7,148,027B2 related to the method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay. Group Information: The American Psychiatric Association (APA) Task Force on Novel Biomarkers and Treatments members include: Charles B. Nemeroff, MD, PhD (University of Miami Miller School of Medicine); William McDonald, MD (Emory University School of Medicine); Linda Carpenter, MD (Butler Hospital, Brown University); Ned Kalin, MD (University of Wisconsin School of Medicine and Public Health); Carolyn Rodriquez, MD, PhD (Stanford University); Maurico Tohen, MD, DrPh, MBA (University of New Mexico); and Alik Widge, MD, PhD (Massachusetts General Hospital, Harvard University). (Reprinted) JAMA Psychiatry Published online March 1, 2017 Copyright 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/0/ by a Texas Tech University - Hsc User on 03/01/2017 E5 Clinical Review & Education Special Communication Additional Contributions: Shaun Gruenbaum, MD, Department of Anesthesiology, Yale University School of Medicine, assisted with and reviewed this manuscript. He was not compensated for his contribution. REFERENCES 1. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB; APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015; 172(10):950-966. 2. Sisti D, Segal AG, Thase ME. Proceed with caution: off-label ketamine treatment for major depressive disorder. Curr Psychiatry Rep. 2014;16 (12):527. 3. Zhang MW, Harris KM, Ho RC. 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