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The Promise of Ketamine for Treatment-Resistant Depression: Current Evidence and Future Directions

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The Promise of Ketamine for Treatment-Resistant Depression: Current Evidence and Future Directions Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Qatar Clinical Neuroscience Conference The promise of ketamine for treatment-resistant depression: current evidence and future directions Kaitlin E. DeWilde,1 Cara F. Levitch,1 James W. Murrough,1 Sanjay J. Mathew,2 and Dan V. Iosifescu1 1Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai, New York, New York. 2Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas Address for correspondence: Dan V. Iosifescu, M.D., Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai,1 Gustave L. Levy Place, Box 1230, New York, NY 10029. [email protected] Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments for MDD primarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with the NIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. Keywords: major depressive disorder; bipolar disorder; ketamine; antidepressant; treatment resistant Introduction showing that subanesthetic doses of ketamine (0.5 mg/kg) administered over a 40-min infusion Major depressive disorder (MDD) is a signifi- period can have a fast-acting antidepressant effects cant public health threat, accounting for 65.5 mil- on both treatment-naive and TRD patients.4–6 In lion disability-adjusted life years and ranking third the following section, we discuss the effects of ke- among the leading causes of global disease burden.1 tamine in single- and multiple-infusion studies. Current state-of-the-art antidepressant treatments Less attention has been dedicated so far to the primarily work on the monoamine system, pro- ability of ketamine to ameliorate specific NIMH viding relief for 54% of patients, according to Research Domain Criteria (RDoC)3,7 symptom a meta-analysis of controlled trials.2 Novel treat- clusters, including anhedonia, cognition, and sui- ments for depression have the potential to ame- cidality; we summarize these data in our review. liorate both individual suffering and public health We also review the existing limitations of ketamine cost burden. Recent research has highlighted the use, including safety concerns and the risks of ke- glutamate system as a potential novel antidepres- tamine misuse. The limitations of ketamine have sant target, particularly for those suffering from led to an active search for improved, ketamine- treatment-resistant depression (TRD) and who are like glutamatergic agents; we briefly review several less likely to benefit from additional monoamine such agents currently being tested as novel anti- treatments. depressants. Ketamine is a high-affinity, noncompetitive N- methyl-d-aspartate (NMDA) receptor antagonist. The efficacy of ketamine in mood disorders It is currently approved by the U.S. Food and Drug Administration (FDA) as an anesthetic agent and is Single infusion additionally used off-label to help manage chronic The rapid antidepressant effect and safety of a sin- pain.3 In the past 10 years, evidence has emerged gle intravenous (IV) infusion of ketamine has been doi: 10.1111/nyas.12646 Ann. N.Y. Acad. Sci. 1345 (2015) 47–58 C 2015 New York Academy of Sciences. 47 Ketamine for treatment-resistant depression DeWilde et al. Table 1. Studies of single-dose ketamine administration in patients with MDD Study Route of No. of patients Design No. of patients Treatment Duration of administration (n) receiving ketamine responsea (%) response or placebo Berman et al.9 Intravenous 7 Crossover Ket: n = 7 50% 72 h Placebo: n = 7 Zarate et al.10 Intravenous 17 Crossover Ket: n = 17 71% 72 h Placebo: n = 17 Lapidus et al.13 Intranasal 20 Crossover Ket: n = 20 44% 48 h Placebo: n = 20 Mathew et al.8 Intravenous 26 Openlabel Ket: n = 26 66% 72 h Placebo: n = 0 Ibrahim et al.48 Intravenous 42 Openlabel Ket: n = 26 62% 13 days Placebo: n = 0 Murrough Intravenous 73 Double blind Ket: n = 47 64% 72 h et al.16 Placebo: n = 25 aResponse is defined as ࣙ 50% reduction in depressive symptoms (e.g., HAM-D or MADRS score) 24 h following IV ketamine. examined in at least five randomized controlled tri- at least the next 3 days.9 Seventy-one percent of als(RCTs)inunipolarMDD(Table1).AsingleIV patients responded to ketamine. This finding was infusion of ketamine resulted in a 50–70% response replicated in another study that found a 79% re- rate in patients with MDD, with a response duration sponse rate.10 The results of these studies support of 72 h postinfusion.8–10 Response was defined as a the hypothesis that ketamine could be an effective 50% or greater reduction from baseline in depres- and safe treatment for bipolar as well as unipolar sion severity (e.g., Montgomery–Asberg Depression depression.11 Rating Scale (MADRS), Hamilton Depression Rat- ing Scale (HAM-D)). Ketamine effects were seen Repeated infusion as soon as 40 min after IV infusion and typically Relapse of depressive symptoms after a single IV lasted 3–7 days, with some patients experiencing dose of ketamine often occurs within 1 week, al- more prolonged mood improvement.10 In an RCT though this time period is highly variable be- of the effects of ketamine versus an anesthetic con- tween subjects. Our group has recently examined trol condition, midazolam, in TRD patients (n = a method to extend the period of response to ke- 72), response rates were 64.8% and 28% in the ke- tamine through repeated infusions (Table2). The ef- tamine and control conditions, respectively, after a fects of repeated infusions of ketamine (up to six IV single IV infusion over 40 min.6 infusions over 2 weeks) were examined in an open- Diazgrandos tested the effects of a single ke- label study by Murrough et al., and the response tamine infusion on patients with bipolar depression rate at the end of the study was 70.8%. Among re- in a crossover, placebo-controlled trial and found sponders, the average time to relapse after the last rapid (24 h) decreases in depressive symptoms, as infusion was 18 days.6 An additional trial by Dia- measured by MADRS, including suicidal ideation, mond et al. involved three or six repeated infusions starting at 40 min postinfusion and continuing for of ketamine over a 3-week period and found a lower 48 Ann. N.Y. Acad. Sci. 1345 (2015) 47–58 C 2015 New York Academy of Sciences. DeWilde et al. Ketamine for treatment-resistant depression Table 2. Studies of repeated dose IV ketamine administration in patients with MDD Study Method No. of patients (n) Design Treatment responsea (%) aan het Rot et al.49 IV 10 Open label 65% Murrough et al.16 IV 24 Open label 70.8% Diamond et al.12 IV 28 Open label 29% Rasmussen et al.50 IV 10 Open label 80% Segmiller et al.51 IV 6 Open label (esketamine) 50% aResponse is defined as ࣙ 50% reduction in depressive symptoms (e.g., HAM-D or MADRS score) 24 h following IV ketamine. response rate of 29%.12 In contrast to Murrough was well tolerated by participants. The lower re- et al., Diamond et al. enrolled both unipolar and sponse rate for IN compared to IV ketamine ad- bipolar subjects, which were split into two groups: ministration may be consistent with the lower blood treatment with three or six infusions over 3 weeks. ketamine levels achieved in the IN study compared These differences in study design may account for with levels previously reported after IV administra- the different results. tion. In the IN sample, the mean ketamine blood A large RCT comparing the efficacy of ketamine level was 72 ng/mL at 20 min and 84 ng/ML at given either twice or three times per week over 40 min. In contrast, mean ketamine levels reported a 4-week period was recently completed and re- after IV infusion are approximately 150 ng/mL at sults are pending (NCT01627782). An RCT inves- 30 min and 200 ng/mL at 40 min.14,15 Further stud- tigating the efficacy of repeated self-administered ies will be necessary to determine if and how equiv- intranasal S-ketamine administrations over a 2- alent bioavailability and efficacy can be obtained week double-blind period is also currently ongoing with IN administration. No RCTs as of yet have (NCT01998958). compared response rates between different admin- istration methods. Intranasal ketamine administration Although IV ketamine has potential as an effec- The efficacy of ketamine on symptom tive treatment for depression, it may not be the clusters most feasible standardized administration for use as a widespread treatment, for patients and clin- A recent trend in NIMH-funded studies has strongly icians alike. To come up with a less invasive ap- encouraged clinical trials to focus on RDoC (specific proach, other administrative methods have been symptom clusters, defined on the basis of underlying considered; however, these efforts have had to neurobiology)7 instead of discrete Diagnostic and take into account lower bioavailability compared Statistical Manual of Mental Disorders (DSM) diag- to IV administration.
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