Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study

Ibrahim, Lobna; Diazgranados, Nancy; Franco-Chaves, José A.; Brutsché, Nancy E.; Henter, Ioline D.; Kronstein, Phillip D.; Moaddel, Ruin; Wainer, Irving W.; Luckenbaugh, David A.; Manji, Husseini K.; Zarate, Carlos A.

doi:10.1038/npp.2011.338

Cited by 266 publications

(257 citation statements)

References 31 publications

(39 reference statements)

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“…The findings of one meta-analysis added to the existing evidence that support ketamine as a novel treatment option for depression, stating that ketamine has been shown to have a high response rate and rapid effect [87] . Several independent pilot studies demonstrate that after a single intravenous infusion of sub-anesthetic dosages of ketamine, its anti-depressant effects have an onset within hours and are sustained for an average of 4-7 d [88,89] . A systematic review also showed ketamine to be a rapid and effective treatment option for depression, as well as reducing suicidal ideation, with minimal short-term side effects [90] .…”

Section: Chronic Pain Managementmentioning

confidence: 99%

Ketamine use in current clinical practice

2016

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After nearly half a century on the market, ketamine still occupies a unique corner in the medical armamentarium of anesthesiologists or clinicians treating pain. Over the last two decades, much research has been conducted highlighting the drug's mechanisms of action, specifically those of its enantiomers. Nowadays, ketamine is also being utilized for pediatric pain control in emergency department, with its anti-hyperalgesic and anti-inflammatory effects being revealed in acute and chronic pain management. Recently, new insights have been gained on ketamine's potential anti-depressive and antisuicidal effects. This article provides an overview of the drug's pharmacokinetics and pharmacodynamics while also discussing the potential benefits and risks of ketamine administration in various clinical settings.

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Section: Chronic Pain Managementmentioning

confidence: 99%

Ketamine use in current clinical practice

2016

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“…[18][19][20][21][22][23][24][25][26][27][28][29][30][31] Other than two case reports, [32][33][34] no studies to date have examined ketamine's role in treating depression or anxiety in the hospice population. To our knowledge, no investigations of depression treatment for any population have been carried out with oral ketamine, and only a couple investigations of ketamine have assessed symptoms of anxiety.…”

Section: Introductionmentioning

confidence: 99%

“…To our knowledge, no investigations of depression treatment for any population have been carried out with oral ketamine, and only a couple investigations of ketamine have assessed symptoms of anxiety. 30,31 Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist and is commonly used as an anesthetic agent. In subanesthetic doses it can also be given as an adjuvant to opiates for the treatment of cancer pain, particularly when opiates alone are ineffective.…”

Section: Introductionmentioning

confidence: 99%

Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

Irwin

Iglewicz

Nelesen

et al. 2013

Journal of Palliative Medicine

130

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Background: Depression and anxiety are prevalent and undertreated in patients receiving hospice care. Standard antidepressants do not work rapidly or often enough to benefit most of these patients. Ketamine has many properties that make it an interesting candidate for rapidly treating depression and anxiety in patients receiving hospice care. To test this hypothesis, a 28-day, open-label, proof-of-concept trial of daily oral ketamine administration was conducted in order to evaluate the tolerability, potential efficacy, and time to potential efficacy in treating depression and anxiety in patients receiving hospice care. Methods:In this open-label study, 14 subjects with symptoms of depression or depression mixed with anxiety warranting psychopharmacological intervention received daily oral doses of ketamine hydrochloride (0.5 mg/ kg) over a 28-day period. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS), which was used to rate overall depression and anxiety symptoms at baseline, and on days 3, 7, 14, 21, and 28. Results: Over the 28-day trial there was significant improvement in both depressive symptoms (F 5,35 = 8.03, p = 0.002, g 2 = 0.534) and symptoms of anxiety (F 5,35 = 14.275, p < 0.001, g 2 = 0.67) for the eight subjects that completed the trial. One hundred percent of subjects completing the trial responded to ketamine for both anxiety and depression. A significant response in depressive symptoms occurred by day 14 for depression (mean D = 3.5, d = 1.14, 95% CI = 1.09-5.9, p = 0.01) and day 3 for anxiety (mean D = 2.4, d = 0.67, 95% CI = 1.0-3.7, p = 0.004). These improvements remained significant through day 28 for both depression (mean D = 4.0, d = 1.34, 95% CI = 2.3-5.9, p = 0.001) and anxiety (mean D = 6.09, d = 1.34, 95% CI = 3.6-8.6, p < 0.001). Side effects were rare, the most common being diarrhea, trouble sleeping, and trouble sitting still. Conclusions: Patients who received daily oral ketamine experienced a robust antidepressant and anxiolytic response with few adverse events. The response rate for depression is similar to those found with IV ketamine; however, the time to response is more protracted. The findings of the potential efficacy of oral ketamine for depression and the response of anxiety symptoms are novel. Further investigation with randomized, controlled clinical trials is necessary to firmly establish the efficacy and safety of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care or other subject populations.

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“…Preclinical and clinical studies have reported that low doses of the noncompetitive NMDAR antagonist and psychotomimetic ketamine have a rapid antidepressant action: a rapid (within hours) and sustained (up to 1 week) antidepressant effect on core symptoms can be induced by a single subanesthetic dose of intravenously-infused ketamine in patients with treatment-resistant depression [7,8,14,111] .…”

Section: Ketamine Has Rapid-onset Antidepressant Effi Cacymentioning

confidence: 99%

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study

Cited by 266 publications

References 31 publications

Ketamine use in current clinical practice

Ketamine use in current clinical practice

Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

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