A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression | Anesthesiology | JAMA Psychiatry | JAMA Network
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    2 Comments for this article
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    Might Ketamine Itself be the Answer?
    Scott A. Irwin, MD, PhD | The Institute for Palliative Medicine at San Diego Hospice
    I have been excited and inspired by the works of Dr. Zarate and others investigating ketamine as a rapid treatment for depression. This work highlights the need for better and more rapid depression treatments, as well as for further investigations into the role of glutamate in depressive syndromes. I would like to address two conclusions that are surfacing from this work. The first is that drug companies need to pursue new agents targeting this mechanism, and the second is the need for and feasibility of using the intravenous route. I wonder if either of those is necessary.
    Ketamine
    at this dosing level has evidence for the successful treatment of cancer and post-operative pain with few side effects,(1-5) even when given via the oral,(6,7) sublingual,(8) or intranasal routes.(9) In fact, I wonder if first pass metabolism to norketamine improves efficacy, as norketamine is believed to be equipotent to ketamine as an analgesic and has a longer half-life.
    Recently, we published two cases of depression rapidly treated with oral ketamine, with no adverse reactions and good effect for anxiety as well.(10)
    So, might ketamine already be our answer? It is cheap, available, can be administered by many routes, and has increasing evidence of effectiveness with few side effects.
    REFERENCES:
    1. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. Aug 2004;99(2):482-495, table of contents.
    2. Lossignol DA, Obiols-Portis M, Body JJ. Successful use of ketamine for intractable cancer pain. Support Care Cancer. Mar 2005;13(3):188-193.
    3. Fitzgibbon EJ, Hall P, Schroder C, Seely J, Viola R. Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral ketamine. J Pain Symptom Manage. Feb 2002;23(2):165-170.
    4. Fine PG. Low-dose ketamine in the management of opioid nonresponsive terminal cancer pain. J Pain Symptom Manage. Apr 1999;17(4):296-300.
    5. Clark JL, Kalan GE. Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient. J Pain Symptom Manage. May 1995;10(4):310-314.
    6. Kannan TR, Saxena A, Bhatnagar S, Barry A. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. J Pain Symptom Manage. Jan 2002;23(1):60-65.
    7. Lauretti GR, Lima IC, Reis MP, Prado WA, Pereira NL. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology. Jun 1999;90(6):1528-1533.
    8. Mercadante S, Arcuri E, Ferrera P, Villari P, Mangione S. Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain. J Pain Symptom Manage. Nov 2005;30(5):485-491.
    9. Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain. Mar 2004;108(1-2):17-27.
    10. Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. Jul;13(7):903-908.

    Conflict of Interest: Career Development Support provided by the National Palliative Care Research Center; no other potential conflicts or relevant financial interests.
    CONFLICT OF INTEREST: None Reported
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    Cost Effectiveness of IV Ketamine for Treatment-Resistant Bipolar Depression
    Jon E Berner, MD, PhD | Woodinville Psychiatric Assoc.
    Dear Sir, The NIMH Mood Disorders group recently reported in the August issue successful extension of their IV ketamine treatment protocol from initial work with unipolar depression to bipolar depression.1 They note in the discussion section limitations related to a small sample size, limited generalizability due to narrow inclusion criteria, and absent data regarding maintenance dosing protocols. Our experience with ketamine in a fee-for-service community setting directly addresses the concerns raised in the discussion section but also raises questions about reliance on an IV route of administration.
    Cost matters. The IV route is much more expensive than the
    self administered oral2 or intranasal route3 commonly used in chronic pain settings. Intranasal ketamine is inexpensive; a two week supply is currently $84.00 for 300# 10 mg. doses at the local compounding pharmacy. In contrast, the cost for the IV setup is $150-$250 in community clinics presumably dosed every 3-7 days. Given relative minimal economic barriers to self-administered use, it is possible to gather useful clinical experience in the community with the drug in short periods of time, in contrast to the 2.5 year recruitment period for 18 patients in the NIMH trials. A retrospective review of IN ketamine trials, largely in refractory pain patients in our clinic during a nine month period from 2007 to 2008, reveals the complementary data requested by the discussion section: a large sample size (59/110 patients with a bipolar diagnosis), extensive comorbity (average number of psychotropic medications 2.8), and an average maintenance intranasal dose (217 mg). Probability of refill of the initial prescription after a 30 day trial (64%), suggests potential equivalent efficacy to the IV route (54%).
    Dose matters. IV dosing, with the locus of control fixed with the physician, inherently degrades the patient incentives to maximize efficacy. The variance in self-administered maintenance IN dosing (118 mg.) relative to mean (217 mg.) confirms a clinical experience, that optimal maintenance dosing requires titration. Some patients, given control of their dosing, can learn to tolerate mild perceptual distortions or dizziness.
    Cost-effectiveness of clinical treatment has important implications for understanding the link between addiction and NMDA activity. Clinical concern has typically focused on possible addiction to self-administered ketamine despite a very low prevalence relative to worldwide access4 and prominent elements of pseudo-addiction rather than euphoria in self-reports of dependent individuals.5,6 This focus tends to overshadow the observed strong link between a family history of alcohol dependence and ketamine responsiveness as observed in the structured trials at NIMH.7 Given the highly polygenetic nature of alcohol dependence, a statistical argument could be made for a follow-up community research strategy based on large numbers of patients and a broad variance in the scientific paradigms of interested investigators. The nasal and oral forms of ketamine, cheaper and more finely titrated, may advance addiction research and treatment more quickly.
    Jon Berner, MD, PhD
    References
    1. Diazgranados N, Ibrahim L, Brutsche N, Newberg A, Kronstein P, Khalife S, Kammerer W, Quezado Z, Luckkenbaugh D, Salvadore G, Machado-Vieira R, Manji H, Zarate C. A randomized add-on trial on an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010; 67(8):793-802.
    2. Cvrèek P. Side effects of ketamine in the long-term treatment of neuropathic pain. Pain Med. 2008 Mar; 9(2):253-7.
    3. Huge V, Lauchart M, Magerl W, Schelling G, Beyer A, Thieme D, Azad S. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain. 2010 Apr;14(4):387-94. Epub 2009 Sep 3.
    4. Degenhardt L, Dunn M. The epidemiology of GHB and ketamine use in an Australian household survey. Int J Drug Policy. 2008 Aug;19(4):311-6. Epub 2007 Oct 24.
    5. Reynaud-Maurupt C, Bello P, Akoka S, Toufik A. Characteristics and behaviors of ketamine users in France in 2003. J Psychoactive Drugs. 2007 Mar;39(1):1-11.
    6. Brunk D. Communication difficulties cited by users of ketamine. Clinical Psychiatry News. 2008; 3:42.
    7. Phelps L, Butsche N, Moral J, Luckenbaugh D, Manj H, Zarate Jr C. Family history of alcohol dependence and initial antidepressant response to a N-methyl-D-aspartate. Biol Psychiatry. 2009 Jan 15;65(2):181-4. Epub 2008 Nov 8.

    Conflict of Interest: None declared
    CONFLICT OF INTEREST: None Reported
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    Original Article
    August 2010

    A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression

    Author Affiliations

    Author Affiliations: Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Dr Newberg is now at the University of North Carolina at Chapel Hill; Dr Kronstein is now with the US Food and Drug Administration, Silver Spring, Maryland; Dr Khalife is now at the Manhattan Psychiatric Center, New York, New York; and Dr Manji is now with Johnson & Johnson Pharmaceuticals, New Brunswick, New Jersey.

    Arch Gen Psychiatry. 2010;67(8):793-802. doi:10.1001/archgenpsychiatry.2010.90
    Abstract

    Context  Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects—for instance, within a few hours or days—would have an enormous impact on patient care and public health.

    Objective  To determine whether an N-methyl-D-aspartate–receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression.

    Design  A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009.

    Setting  Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland.

    Patients  Eighteen subjects with DSM-IV bipolar depression (treatment-resistant).

    Interventions  Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion.

    Main Outcome Measures  Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores.

    Results  Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point.

    Conclusion  In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.

    Trial Registration  clinicaltrials.gov Identifier: NCT00088699

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