New Role of Ketamine for Reversing the Unrelenting Treatment-Resistant Major Depression
Received Date: Nov 30, 2017 / Accepted Date: Dec 08, 2017 / Published Date: Dec 15, 2017
Major depressive disorder (MDD) is a debilitating mental state that affects more than 300 million people at a global level according to recent World Health Organization report [1,2] and also anticipate to be a second leading cause of disease burden by the year 2020 . Although a range of first class antidepressant medications primarily acted through a modulation of monoaminergic neurotransmitters are increasingly available, these drugs take at least three to eight weeks to actually produce a therapeutic effect [4,5]. Moreover, response and remission rates exhibited by these therapeutic interventions are inconsistent and significant amount of depressed patients found to be treatment-refractory to these conventional drugs . That being said, there is a huge unmet medical need for people who are suffering from the treatment-resistant major depressive disorder (TRD). Serendipitously, infusion of ketamine at a lower dose displayed a robust and rapid antidepressant response in patients with TRD ; however, its widespread application has been highly regulated due to the serious untoward effects and addiction liability. Herein, the author has briefly described the successful journey of this miraculous club drug from its anaesthetic agent to more recent rapidly acting antidepressant drug and the underlying mechanisms for antidepressant effects displayed by ketamine and its major metabolite hydroxynorketamine (HNK).
Broadly, ketamine acts as a non-competitive voltage dependent antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, which only blocks the receptor when the channel is open after activation . It is used widely as an anaesthetic agent during surgery and in the management of pain in both animals and humans. In the past few years, a single intravenous infusion of racemic ketamine (0.5 mg/kg) reported to elicit a remarkable anti-depressant response within 100 min of injection and effects persisted up to 7 days [6,8-10]. Coyle and Laws  demonstrated a discrepancy in peak response time depending upon primary diagnosis including 24 h for the MDD and 7 days for bipolar depression. In this way, intravenous infusion of ketamine at a lower dose seems to be promising therapeutic options in the populations with TRD, bipolar depression and suicidal ideation [12,13]. Moreover, discovery of several other NMDA receptor antagonists are underway for the therapeutic indication of TRD .
The antidepressant-like effects of ketamine and associated underlying molecular mechanisms have been well studied in the preclinical animal models . Acute injection of ketamine produced an antidepressant-like phenotype in the forced swim test (FST)  and therapeutic response reported to mediate via following crucial intracellular signaling pathways, i) the mammalian target of rapamycin, ii) the eukaryotic elongation factor 2 and iii) the glycogen synthase kinase-3 [17,18]. Additionally, the enhancement of GluA1 α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activity and intracellular brain-derived neurotrophic factor signaling appears critical for the antidepressant effect of ketamine [16,19,20]. Collectively, it has been posited these post-synaptic intracellular signaling mechanisms triggered by ketamine induces synaptogenesis and glutamate transmission . Interestingly, time taken for synaptic mechanisms have also been coincided with the behavioral outcomes i.e. acts within hours after a single ketamine administration and last longer up to 1 week [22,23].
Predominantly, ketamine is injected in the form of racemic mixture of equal parts of R (–) ketamine and S (+) ketamine, however, several publications precisely elucidated the therapeutic property of each of these enantiomers and associated underlying mechanisms . S-ketamine has about a 4-fold better affinity for the NMDA receptor and greater anesthetic potency . However, compared to S-ketamine, R-ketamine has been several times more efficient at reducing depression like behaviours and yielded longer-lasting antidepressant-like effects in the FST . These authors also extended their findings employing a major metabolite of ketamine called HNK and they observed promising antidepressant-like activity with acute HNK treatment. The antidepressant activity of HNK was associated with enhancement of neural activity by increasing synaptic levels of another neuronal receptor protein, AMPAR . In addition to this, HNK showed fewer propensities towards the untoward effects and does not elicit several of the cognitive and motor side effects that have been linked to ketamine . These findings revealed that production of a distinct metabolite of ketamine is necessary and sufficient to produce the ketamine antidepressant actions and open a new avenue for future ketamine research.
It has always been anticipated that ketamine generates the rapid and robust anti-depressant effect through other than NMDA receptor inhibition mechanisms, because even more potent NMDA receptor inhibitor, which binds to the same site as ketamine, fails to produce sustained antidepressant-like effects . Thus, several lines of research is ongoing to differentiate the strong dissociative effects of ketamine from that of rapid, potent and long lasting antidepressant response at low dose even after acute administration [28,14]. Taken together, ketamine has demonstrated rapid and robust efficacy as an antidepressant by improving core depressive symptoms including depressed mood, anhedonia and suicidal thoughts in patients with treatment-refractory unipolar and bipolar depression when administered at sub-anaesthetic doses. The discovery of antidepressant activity of ketamine has been designated as “discovery of the decades” and it serving as a choice of antidepressant drug due to unbelievable effects in patients with unrelenting TRD. However, few burning questions are yet to be answered. Do men and women experience differences in the antidepressant effect of ketamine? Does ketamine produce an immediate or sustained antidepressant effect via NMDA receptor inhibition? Will the antidepressant effects of ketamine sustained over time without a fear of addiction? Will repeat dosing become more successful in reducing depressive symptoms?
- Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, et al. (2005) Lifetime prevalence and age-of-onset distributions of dsm-iv disorders in the national comorbidity survey replication. Arch Gen Psychiatry 62: 593-602.
- Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, et al. (2013) Burden of depressive disorders by country, sex, age and year: Findings from the global burden of disease study 2010.
- Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, et al. (2007) Depression, chronic diseases and decrements in health: Results from the World Health Surveys. Lancet 370: 851-858.
- Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, et al. (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 163: 1905-1917.
- Wang SM, Han C, Lee SJ, Jun TY, Patkar AA, et al. (2016) Second generation antipsychotics in the treatment of major depressive disorder: an update. Chonnam Med J 52: 159-172.
- Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, et al. (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63: 856-864.
- Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA (2009) Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 15: 1595-1611.
- Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, et al. (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47: 351-354.
- Abdallah CG, Averill LA, Krystal JH (2015) Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Ann N Y Acad Sci 1344: 66-77.
- Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, et al. (2015) Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. Am J Psychiatry 172: 950-966.
- Coyle CM, Laws KR (2015) The use of ketamine as an antidepressant: A systematic review and meta-analysis. Hum Psychopharmacol 30: 152-163.
- Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, et al. (2017) The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis. Am J Psychiatry.
- Vande Voort JL, Ballard ED, Luckenbaugh DA, Bernert RA, Richards EM, et al. (2017) Antisuicidal response following ketamine infusion is associated with decreased night-time wakefulness in major depressive disorder and bipolar disorder. J Clin Psychiatry 78: 1068-1074.
- Machado-Vieira R, Henter ID, Zarate CA (2017) New targets for rapid antidepressant action. Prog Neurobiol 152: 21-37.
- Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4: 161.
- Garcia LS, Comim CM, Valvassori SS, Réus GZ, Andreazza AC, et al. (2008) Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels. Basic Clin Pharmacol Toxicol 103: 502-506.
- Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, et al. (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329: 959-964.
- Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS (2014) Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: Ketamine and other compounds. Annu Rev Pharmacol Toxicol 54: 119-139.
- Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, et al. (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63: 349-352.
- Malinow R (2016) Depression: Ketamine steps out of the darkness. Nature 533: 477-478.
- Abelaira HM, Réus GZ, Neotti MV, Quevedo J (2014) The role of mTOR in depression and antidepressant responses. Life Sci 101: 10-14.
- Kavalali ET, Monteggia LM (2012) Synaptic mechanisms underlying rapid antidepressant action of ketamine. Am J Psychiatry 169: 1150-1156.
- Wohleb ES, Gerhard D, Thomas A, Duman RS (2017) Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol 15: 11-20.
- Muller J, Pentyala S, Dilger J, Pentyala S (2016) Ketamine enantiomers in the rapid and sustained antidepressant effects. Ther Adv Psychopharmacol 6: 185-192.
- Domino E (2010) Taming the ketamine tiger. Anesthesiology 113: 678-686.
- Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, et al. (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533: 481-486.
- Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, et al. (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475: 91-95.
- Kokkinou M, Ashok AH, Howes OD (2017) The effects of ketamine on dopaminergic function: Meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry.
Citation: Dandekar MP (2017) New Role of Ketamine for Reversing the Unrelenting Treatment-Resistant Major Depression. J Pharma Reports 2: 132.
Copyright: ©2017 Dandekar MP. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
- Total views: 303
- [From(publication date): 0-2017 - Apr 20, 2018]
- Breakdown by view type
- HTML page views: 274
- PDF downloads: 29