Ketamine as a potential new and effective antidepressant

Author: Gabriele Nibbio
Date: 12/09/2014


Ketamine as a potential new and effective antidepressant

The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established.
There has been growing interest in the observation that ketamine has a rapid positive effect on depressive symptoms. Ketamine is used in medicine for inducing and maintaining anaesthesia, and illicitly for its hallucinogenic and dissociative effects. The fact that ketamine does not work through the ‘conventional’ antidepressant monoaminergic targets of serotonin and noradrenaline has provoked excitement: understanding its effects could provide novel insights into the pathophysiology of depression and open up a new class of medications.

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Preclinical studies: biological and molecular pathways

N-methyl-D-aspartate receptor (NMDA-R) antagonists in particular have long been linked to the pathophysiology of MDD ( Major Depressive Disorder) and the mechanism of action of AD (Anti Depressant) drugs1. The first pre-clinical work testing the hypothesis that various NMDA-R antagonists have AD-like effects was carried out in mice, where the authors showed that such agents caused a significant reduction of immobility in the FST (Forced Swimming Test) and the tail suspension test2, two tests with high predictive validity for AD treatments3.

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Pre-clinical studies have focused on the mechanisms of action of ketamine. The AD-like effects of ketamine are blocked by pretreatment with 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzol[f]quinoxaline-2,3-dione (NBQX), an a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist4.
An early study revealed decreased spontaneous activity of GABAergic interneurons and an increased firing rate of glutamatergic pyramidal neurons in the PFC (Pre Frontal Cortex) of rats given ketamine, suggesting that NMDA-R antagonism by ketamine blocked spontaneous GABAergic activity resulting in enhanced glutamatergic transmission. Stimulation of AMPA receptors leads to activity-dependent BDNF release5.
The use of conditional knockout mice has suggested that BDNF is required for the AD-like effect of ketamine6. Ketamine also shows an activation of neurotrophin signaling. In particular studies have shown a rather transient increase in the phosphorylation of the BDNF/NT-4 receptor, namely TrkB, following a single sub-anesthetic injection of ketamine in rodents7. In a randomized control trial with ketamine, plasma BDNF levels were found to be significantly higher in responders compared to that in non-responders8.

Some studies have shown a positive correlation between plasma levels of mTor and its downstream effectors, glycogen synthase kinase-3beta (GSK-3β) and dephosphorylation of eukaryotic elongation factor 2 (e-EF2) in patients who responded to ketamine9. Since phosphorylated e-EF2 is associated with inhibition of translation, its dephosphorylation, via mTor signaling activation, leads to increased protein synthesis, including BDNF synthesis10.

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Clinical evidence

The first randomized controlled trial investigating the AD properties of a single intravenous low dose of ketamine (0.5 mg/kg) in patients diagnosed with MDD showed a significant improvement in depressive symptoms within 72 hours after ketamine administration, and not with placebo11. Since this first trial, others have corroborated the rapid AD effects of ketamine administration12'13'14. When given to TRD (Treatment Resistant Depression) patients, single subanesthetic dose of ketamine typically improves mood within hours following ketamine administration and can persist, for the most part, for about two weeks15'16'17'18'19'20'21.
It also produces a rapid decrease in suicidal ideation in both bipolar depression and MDD22. Rapid-acting pharmacotherapy could readily reduce hospitalization time and allow disabled people to resume their daily routine including being able to work.

Safety and collateral effects

It is important to note that aside from the promising and consistent results gained in the clinic, ketamine poses some serious problems with regard to its acute psychotomimetic and physiological (increased blood pressure and heart rate) side effects. In addition, chronic use of ketamine has been associated with dependence23'24'25.


The longer-term role of ketamine in the management of depression is unclear. Optimal dosing and longer-term data on relapse prevention and tolerability are lacking. Although most studies administered ketamine at a dose of 0.5 mg/kg in a saline drip over about 40 minutes, this was not the only schedule, with for example a bolus administration of 0.2 mg/kg over 1–2 minutes. Most studies utilized participants with treatment-resistant MDDs: on the one hand this adds to the clinical appeal of a therapy that works on those who have failed to respond to standard treatment; on the other hand it leaves open the question of the effects of ketamine on mild, moderate or treatment-naïve depressive disorders. There is no current consensus whether those who are treatment refractory and fail to respond to traditional antidepressants have a neurobiologically distinct form of the illness.

It currently seems that the primary role of ketamine in depression may turn out to be as a prototype for the development of future glutamatergic antidepressants, and in furthering our understanding of the neuropathology of depression.

1 Pilc A, Wierońska JM, Skolnick P. Glutamate-based antidepressants: preclinical psychopharmacology. Biol Psychiatry. 2013;73:1125–1132. [PubMed]
2 Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions.Eur J Pharmacol. 1990;185:1–10. [PubMed]
3 Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985;85:367–370. [PubMed]
4 Maeng S, Zarate CA, Jr, Du J, Schloesser RJ, McCammon J, Chen G, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–352. [PubMed]
5 Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M. Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J Neurosci. 2009;29:8688–8697. [PMC free article][PubMed]
6 Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–95. [PMC free article] [PubMed]
7 Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012;62:35–41. [PMC free article] [PubMed]
8 Haile CN, Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Foulkes A, et al. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int J Neuropsychopharmacol. 2014;17:331–336. [PMC free article] [PubMed]
9 Yang C, Zhou ZQ, Gao ZQ, Shi JY, Yang JJ. Acute increases in plasma mammalian target of rapamycin, glycogen synthase kinase-3β, and eukaryotic elongation factor 2 phosphorylation after ketamine treatment in three depressed patients. Biol Psychiatry. 2013;73:e35–e36. [PubMed]
10 Dwyer JM, Duman RS. Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants. Biol Psychiatry. 2013;73:1189–1198. [PMC free article] [PubMed]
11 Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–354. [PubMed]
12 Zarate C, Jr, Machado-Vieira R, Henter I, Ibrahim L, Diazgranados N, Salvadore G. Glutamatergic modulators: the future of treating mood disorders? Harv Rev Psychiatry. 2010;18:293–303. [PMC free article][PubMed]
13 Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG, et al. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression.Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1155–1159. [PMC free article] [PubMed]
14 Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry.2010;67:793–802. [PMC free article] [PubMed]
15 Zarate CA, Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–864. [PubMed]
16 Zarate CA, Jr, Brutsche N, Laje G, Luckenbaugh DA, Venkata SL, Ramamoorthy A, et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry.2012;72:331–338. [PMC free article] [PubMed]
17 Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522–526. [PMC free article][PubMed]
18 Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry.2013;74:250–256. [PMC free article] [PubMed]
19 Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther.2012;91:303–309. [PMC free article] [PubMed]
20 Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011;14:1127–1131. [PubMed]
21 Aan Het Rot M, Zarate CA, Jr, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012;72:537–547. [PMC free article] [PubMed]
22 DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71:1605–1611. [PMC free article] [PubMed]
23 Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88:82–88. [PubMed]
24 Ghoneim MM, Hinrichs JV, Mewaldt SP, Petersen RC. Ketamine: behavioral effects of subanesthetic doses.J Clin Psychopharmacol. 1985;5:70–77. [PubMed]
25 Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214. [PubMed]

2014-09-12T12:03:20 - Gabriele Nibbio
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