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A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression

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A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression ORIGINAL ARTICLE A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Carlos A. Zarate, Jr, MD; Jaskaran B. Singh, MD; Paul J. Carlson, MD; Nancy E. Brutsche, MSN; Rezvan Ameli, PhD; David A. Luckenbaugh, MA; Dennis S. Charney, MD; Husseini K. Manji, MD, FRCPC Context: Existing therapies for major depression have at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days alagofonsetofactionofseveralweeks,resultingincon- postinfusion. siderable morbidity. Exploring pharmacological strate- gies that have rapid onset of antidepressant effects within Main Outcome Measure: Changes in scores on the a few days and that are sustained would have an enor- primary efficacy measure, the 21-item Hamilton Depres- mous impact on patient care. Converging lines of evi- sion Rating Scale. dence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Results: Subjects receiving ketamine showed significant improvement in depression compared with subjects re- Objective: To determine whether a rapid antidepres- ceiving placebo within 110 minutes after injection, which sant effect can be achieved with an antagonist at the remained significant throughout the following week. The N-methyl-D-aspartate receptor in subjects with major effect size for the drug difference was very large (d=1.46 depression. [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d=0.68 [95% confidence interval, 0.13- Design: Arandomized,placebo-controlled,double- 1.23]) after 1 week. Of the 17 subjects treated with ket- blind crossover study from November 2004 to Septem- amine, 71% met response and 29% met remission criteria ber 2005. the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Setting: Mood Disorders Research Unit at the National Institute of Mental Health. Conclusions: Robust and rapid antidepressant effects re- sulted from a single intravenous dose of an N-methyl-D- Patients: Eighteen subjects with DSM-IV major depres- aspartate antagonist; onset occurred within 2 hours postin- sion (treatment resistant). fusion and continued to remain significant for 1 week. Interventions: After a 2-week drug-free period, sub- Trial Registration: clinicaltrials.gov Identifier: jects were given an intravenous infusion of either ket- NCT00088699. amine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and Arch Gen Psychiatry. 2006;63:856-864 HE TREATMENT OF DEPRES- achieve their full effects and in the mean- sion was revolutionized time, patients continue to suffer from their about a half century ago by symptoms and risk self-harm as well as the serendipitous discov- harm to their personal and professional ery of monoamine oxidase lives. Indeed, the lag period in onset of ac- Tinhibitors and tricyclic antidepressants. tion of several weeks of traditional anti- Since then, the availability of a host of depressants is recognized as a major limi- newer medications with better adverse- tation, resulting in considerable morbidity effect profiles has greatly increased our and high risk of suicidal behavior espe- ability to safely treat a significant percent- cially in the first 9 days after starting an- Author Affiliations: Mood and age of patients. However, the newer medi- tidepressant treatment.1 Pharmacologi- Anxiety Disorders Program, National Institute of Mental cations are largely “me too” drugs in as cal strategies that have rapid onset of Health, National Institutes of much as they exert their primary bio- antidepressant effects within hours or even Health, and Department of chemical effects by increasing the intra- a few days and that are sustained would Health and Human Services, synaptic levels of monoamines. Unfortu- therefore have an enormous impact on Bethesda, Md. nately, these medications take weeks to public health. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, AUG 2006 WWW.ARCHGENPSYCHIATRY.COM 856 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by Cherie Rufiange on 09/30/2019 Averyuseful“initiationandadaptation”paradigmfor thermore, that directly targeting the NMDA receptor understanding the delayed therapeutic actions of anti- would bring about rapid antidepressant effects. Indeed, depressants has been an important line of research for in a preliminary study of 8 subjects with major depres- several years now2;morerecentversionsofthispara- sion, it was reported that a single dose of the noncom- digm have focused attention away from monoaminergic petitive NMDA receptor antagonist ketamine resulted in systems to adaptive changes in other systems.3 This para- arapidandshort-livedantidepressanteffect.26 There- digm posits that the effect of acute drug administration fore, the objective of the present double-blind trial was is mediated via an initial direct target protein perturba- to determine if ketamine exerts rapid antidepressant ef- tion (eg, binding to a monoamine transporter, thereby fects in a relatively refractory population and, further- inhibiting monoamine reuptake); with repeated admin- more, if the effects of a single dose of ketamine are sus- istration, the same initial event, over time, leads to en- tained. during adaptive changes in critical neuronal networks, thereby resulting in stable long-term antidepressant ef- METHODS fects. Thus, this paradigm posits that the delay in the thera- peutic actions of existing pharmacologic agents is due PATIENT SELECTION to the fact that they initially act on substrates that are con- siderably upstream of targets that are ultimately respon- Subjects were recruited from referrals from local inpatient psy- sible for the antidepressant effects. In this context, the chiatric units or through advertisements placed in the local news- major systems that have been postulated to mediate the papers of the Washington, DC, metropolitan area; the Inter- delayed adaptive effects of antidepressants are neuro- net; and local and national referrals from physicians. Men and trophic signaling cascades and the glutamatergic sys- women, aged 18 to 65 years, who were inpatients with a diag- tem.4,5 These systems should not necessarily be viewed nosis of major depressive disorder recurrent without psy- chotic features as diagnosed by means of the Structured Clini- as separate, and the interested reader is referred to sev- 27 eral excellent reviews on the link between neurotro- cal Interview for Axis I DSM-IV Disorders–Patient Version were 5-7 eligible to participate. Patients with a DSM-IV diagnosis of bi- phins and glutamate systems ;hereinwediscusstherole polar disorder or who had a history of antidepressant- or sub- of the glutamatergic system, most notably the N-methyl- stance-induced hypomania or mania were excluded. All sub- D-aspartate (NMDA) system, in the actions of anti- jects were studied at the National Institute of Mental Health depressants.8-11 Clinical Research Center in Bethesda, Md, between November N-methyl-D-aspartate receptor antagonists have anti- 2004 and September 2005. Subjects were required to have a depressant effects in many animal models of depres- score of 18 or higher on the 21-item Hamilton Depression Rat- sion, including the application of inescapable stressors, ing Scale (HDRS)28 at screening and at the start of ketamine/ forced-swim, and tail suspension–induced immobility placebo infusions and to have previously failed at least 2 ad- tests; in learned helplessness models of depression; and equate antidepressant trials (adequacy of antidepressant trials was determined with the Antidepressant Treatment History in animals exposed to a chronic mild stress proce- 29 12-17 Form). dure. AsingledoseoftheNMDAantagonistket- All subjects were in good physical health as determined by amine hydrochloride in male Wistar rats interferes with medical history, physical examination, blood laboratory re- the induction of behavioral despair for up to 10 days af- sults, electrocardiogram, chest radiography, and urinalysis and ter its administration.18 Additionally, repeated adminis- toxicology findings. Subjects were free of comorbid substance tration of different classes of antidepressants—in a time abuse or dependence for at least 3 months, had a negative urine frame consistent with the delayed therapeutic effects— toxicology screen, and were judged clinically not to be a seri- brings about alterations in the expression of NMDA sub- ous suicide risk. Comorbid Axis I anxiety disorder diagnoses unit messenger RNA19 and radioligand binding to these were permitted if they did not require current treatment. Final receptors in regions of the brain implicated in the patho- selection was made by consensus of the investigator team. physiology of depression.8 The study was approved by the National Institute of Men- tal Health institutional review board. All subjects provided writ- Although clearly not unequivocal, several lines of evi- ten informed consent before entry into the study. Informed con- dence from diverse studies also suggest that dysfunc- sents and ongoing study participation were monitored by the tion of the glutamatergic system may play an important Central Office for Recruitment and Evaluation at the National role in the pathophysiology of depression.20,21 Notably, Institute of Mental Health. a recent study by Sanacora et al22 showed glutamate lev- The study was initially planned to include 22 patients; how- els in the occipital cortex to be significantly elevated
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