Rapid Anti-Depressant Relief by Ketamine: Exploring A Complex Mechanism of Action

Author(s): Kenneth Blum*, Todd C. Pappas, Bryan Clifton, David Baron, Margaret A. Madigan, Lisa Lott, Mark Moran, Cannon Clifton, Scott Worrich, Ervey Clarke, Brent Boyett, Abdalla Bowirrat, Mark S. Gold

Journal Name: Current Psychopharmacology

Volume 8 , Issue 2 , 2019


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Abstract:

Background: Suicide rates and narcotic overdose have doubled since 2000. At least 30 percent of people with major depression are Treatment-Resistant (TR) and require novel therapeutics. ketamine at low doses has been shown in clinical trials to induce a rapid, short-lived anti-suicide and anti-depressant effect.

Objective: To review the potential mechanism of action of ketamines’ alleviation of depressive symptoms from both animal and available human literature.

Methods: This is a synthesis of information from papers listed in PUBMED Central. Although not exhaustive, this review highlights the most compelling work in the field related to this remarkable clinical rapid anti-depressant effect.

Results: While there have been several theories and with some scientific evidence to date, the conclusion here is that currently, an exact and acceptable mechanism of action (MOA) for ketamines’ rapid anti-depressant effect is not apparent. The MOA of this compound with psychoactive abuse potential at a higher dosage and acute antidepressive effect in the most resistant patients is unknown.

Discussion: Possible MOAs reviewed, include dopamine receptor modulation through epigenetic neuroadaptation via specific D1/D2 antagonism, D1 activation using optogenetic stimulation, and the role of D2/D3 availability in the ketamine therapeutic action.

Conclusion: Unraveling MOA could guide the development of other unique Psychoplastogens capable of rapidly promoting structural and functional neural plasticity in cases of TR Major Depressive Episodes (MDE) and unipolar Major Depression Disorder (MDD).

Keywords: Dopamine, ketamine, Mechanism of Action (MOA), rapid antidepressant effect, Treatment Resistant Depression (TRD), Major Depression Disorder (MDD).

[2]
Bohnert ASB, Ilgen MA. Understanding links among opioid use, overdose, and suicide. N Engl J Med 2019; 380(1): 71-9.
[3]
Smith RJ, Laiks LS. Behavioral and neural mechanisms underlying habitual and compulsive drug seeking. Prog Neuropsychopharmacol Biol Psychiatry 2018; 87(Pt A): 11-21.
[4]
Olson DE. Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics. J Exp Neurosci 2018; 121179069518800508
[5]
Zhang M, Radford KD, Driscoll M, Purnomo S, Kim J, Choi KH. Effects of subanesthetic intravenous ketamine infusion on neuroplasticity-related proteins in the prefrontal cortex, amygdala, and hippocampus of Sprague-Dawley rats. IBRO Rep 2019; 6: 87-94.
[6]
Moaddel R, Shardell M, Khadeer M, et al. Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects. Psychopharmacology 2018; 235(10): 3017-30.
[7]
Reed JL, Nugent AC, Furey ML, et al. Ketamine normalizes brain activity during emotionally valenced attentional processing in depression. Neuroimage Clin 2018; 20: 92-101.
[8]
Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev 2015; (9): CD011612
[9]
Grady SE, Marsh TA, Tenhouse A, Klein K. Ketamine for the treatment of major depressive disorder and bipolar depression: a review of the literature. Mental Health Clin 2017; 7(1): 16-23.
[10]
Ballard ED, Yarrington JS, Farmer CA, et al. Characterizing the course of suicidal ideation response to ketamine. J Affect Disord 2018; 241: 86-93.
[11]
Ren L, Deng J, Min S, Peng L, Chen Q. Ketamine in electroconvulsive therapy for depressive disorder: A systematic review and meta-analysis. J Psychiatr Res 2018; 104: 144-56.
[12]
Sinyor M, Williams M, Belo S, et al. Ketamine augmentation for major depressive disorder and suicidal ideation: Preliminary experience in an inpatient psychiatry setting. J Affect Disord 2018; 241: 103-9.
[13]
Ionescu DF, Bentley KH, Eikermann M, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. J Affect Disord 2019; 243: 516-24.
[14]
Kemp DE, Ganocy SJ, Brecher M, et al. Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression. J Affect Disord 2011; 130(1-2): 171-9.
[15]
Li Y, Jackson KA, Slon B, et al. CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects. Br J Clin Pharmacol 2015; 80(2): 276-84.
[16]
Naidoo V, Mdanda S, Ntshangase S, et al. Brain penetration of ketamine: intranasal delivery vs parenteral routes of administraion. J Psychiatr Res 2019; 112: 7-11.
[17]
Le Nedelec M, Glue P, Winter H, Goulton C, Medlicott NJ. The effect of route of administration on the enantioselective pharmacokinetics of ketamine and norketamine in rats. J Psychopharmacol 2018; 32(10): 1127-32.
[18]
Moreton JE, Meisch RA, Stark L, Thompson T. Ketamine self-administration by the Rhesus monkey. J Pharmacol Exp Ther 1977; 203(2): 303-9.
[19]
Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A review of ketamine abuse and diversion. Depress Anxiety 2016; 33(8): 718-27.
[20]
Witkin JM, Knutson DE, Rodriguez GJ, Shi S. Rapid-acting antidepressants. Curr Pharm Des 2018; 24(22): 2556-63.
[21]
Lur G, Fariborzi M, Higley MJ. Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission. PLoS One 2019; 14(3)e0213721
[22]
Boczek T, Lisek M, Ferenc B, Wiktorska M, Ivchevska I, Zylinska L. Region-specific effects of repeated ketamine administration on the presynaptic GABAergic neurochemistry in rat brain. Neurochem Int 2015; 91: 13-25.
[23]
Fuchs T, Jefferson SJ, Hooper A, Yee PH, Maguire J, Luscher B. Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. Mol Psychiatry 2017; 22(6): 920-30.
[24]
Pehrson AL, Sanchez C. Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants. Drug Des Devel Ther 2015; 9: 603-24.
[25]
Belujon P, Grace AA. Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol 2017; 20(12): 1036-46.
[26]
Gold MS, Blum K, Febo M, et al. Molecular role of dopamine in anhedonia linked to reward deficiency syndrome (RDS) and anti- reward systems. Front Biosci 2018; 10: 309-25.
[27]
Pecina M, Sikora M, Avery ET, et al. Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response. Eur Neuropsychopharmacol 2017; 27(10): 977-86.
[28]
Miguel-Hidalgo JJ, Waltzer R, et al. Glial and glutamatergic markers in depression, alcoholism, and their comorbidity. J Affect Disord 2010; 127(1-3): 230-40.
[29]
Choudary PV, Molnar M, Evans SJ, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 2005; 102(43): 15653-8.
[30]
Hashimoto K, Malchow B, Falkai P, Schmitt A. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 2013; 263(5): 367-77.
[31]
Sanacora G, Mason GF, Rothman DL, et al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999; 56(11): 1043-7.
[32]
Price RB, Shungu DC, Mao X, et al. Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol Psychiatry 2009; 65(9): 792-800.
[33]
Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2007; 64(2): 193-200.
[34]
Gabbay V, Mao X, Klein RG, et al. Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: relationship to anhedonia. Arch Gen Psychiatry 2012; 69(2): 139-49.
[35]
Croarkin PE, Levinson AJ, Daskalakis ZJ. Evidence for GABAergic inhibitory deficits in major depressive disorder. Neurosci Biobehav Rev 2011; 35(3): 818-25.
[36]
Bhagwagar Z, Wylezinska M, Jezzard P, et al. Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 2007; 61(6): 806-12.
[37]
Klumpers UM, Veltman DJ, Drent ML, et al. Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results. Eur J Nucl Med Mol Imaging 2010; 37(3): 565-74.
[38]
Karolewicz B, Maciag D, O’Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G. Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 2010; 13(4): 411-20.
[39]
Guilloux JP, Douillard-Guilloux G, Kota R, et al. Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol Psychiatry 2012; 17(11): 1130-42.
[40]
Sibille E, Morris HM, Kota RS, Lewis DA. GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders. Int J Neuropsychopharmacol 2011; 14(6): 721-34.
[41]
Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 2007; 32(2): 471-82.
[42]
Maciag D, Hughes J, O’Dwyer G, et al. Reduced density of calbindin immunoreactive GABAergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies. Biol Psychiatry 2010; 67(5): 465-70.
[43]
MacKenzie G, Maguire J. Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility. Epilepsy Res 2015; 109: 13-27.
[44]
Liu ZP, Song C, Wang M, et al. Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents. Mol Brain 2014; 7: 32.
[45]
Hewitt SA, Wamsteeker JI, Kurz EU, Bains JS. Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis. Nat Neurosci 2009; 12(4): 438-43.
[46]
Lin LC, Sibille E. Somatostatin, neuronal vulnerability and behavioral emotionality. Mol Psychiatry 2015; 20(3): 377-87.
[47]
Moda-Sava RN, Murdock MH, Parekh PK, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 2019; 364(6436)eaat8078
[48]
Hamilton JP, Sacchet MD, Hjørnevik T, et al. Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent 11C-raclopride positron emission tomography and functional magnetic resonance imaging investigation. Transl Psychiatry 2018; 8(1): 264.
[49]
Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, Luscher B. Gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry 2010; 68(6): 512-20.
[50]
Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 2002; 159(4): 663-5.
[51]
Sanacora G, Mason GF, Rothman DL, et al. Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 2003; 160(3): 577-9.
[52]
Hasler G, Neumeister A, van der Veen JW, et al. Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol Psychiatry 2005; 58(12): 969-73.
[53]
Ren Z, Pribiag H, Jefferson SJ, et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry 2016; 80(6): 457-68.
[54]
Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329(5994): 959-64.
[55]
Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012; 62(1): 35-41.
[56]
Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475(7354): 91-5.
[57]
Sutton MA, Taylor AM, Ito HT, Pham A, Schuman EM. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron 2007; 55(4): 648-61.
[58]
Verpelli C, Piccoli G, Zibetti C, et al. Synaptic activity controls dendritic spine morphology by modulating eEF2-dependent BDNF synthesis. J Neurosci 2010; 30(17): 5830-42.
[59]
Monteggia LM, Gideons E, Kavalali ET. The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine. Biol Psychiatry 2013; 73(12): 1199-203.
[60]
Tripp A, Kota RS, Lewis DA, Sibille E. Reduced somatostatin in subgenual anterior cingulate cortex in major depression. Neurobiol Dis 2011; 42(1): 116-24.
[61]
Rudy B, Fishell G, Lee S, Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol 2011; 71(1): 45-61.
[62]
Müller C, Remy S. Dendritic inhibition mediated by O-LM and bistratified interneurons in the hippocampus. Front Synaptic Neurosci 2014; 6: 23.
[63]
Klausberger T, Magill PJ, Márton LF, et al. Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 2003; 421(6925): 844-8.
[64]
Buzsaki G, Csicsvari J, Dragoi G, Harris K, Henze D, Hirase H. Homeostatic maintenance of neuronal excitability by burst discharges in vivo. Cerebral Cortex 2002; 12(9): 2640.
[65]
Fanselow EE, Richardson KA, Connors BW. Selective, state-dependent activation of somatostatin-expressing inhibitory interneurons in mouse neocortex. J Neurophysiol 2008; 100(5): 2640-52.
[66]
Thompson SM, Kallarackal AJ, Kvarta MD, et al. An excitatory synapse hypothesis of depression. Trends Neurosci 2015; 38(5): 279-94.
[67]
Leão RN, Mikulovic S, Leão KE, et al. OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons. Nat Neurosci 2012; 15(11): 1524-30.
[68]
Maccaferri G, McBain CJ. Passive propagation of LTD to stratum oriens-alveus inhibitory neurons modulates the temporoammonic input to the hippocampal CA1 region. Neuron 1995; 15(1): 137-45.
[69]
Higley MJ. Localized GABAergic inhibition of dendritic Ca(2+) signalling. Nat Rev Neurosci 2014; 15(9): 567-72.
[70]
Chiu CQ, Lur G, Morse TM, Carnevale NT, Ellis-Davies GC, Higley MJ. Compartmentalization of GABAergic inhibition by dendritic spines. Science 2013; 340(6133): 759-62.
[71]
Viollet C, Lepousez G, Loudes C, Videau C, Simon A, Epelbaum J. Somatostatinergic systems in brain: networks and functions. Mol Cell Endocrinol 2008; 286(1-2): 75-87.
[72]
Silberberg G, Markram H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron 2007; 53(5): 735-46.
[73]
Opal MD, Klenotich SC, Morais M, et al. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Mol Psychiatry 2014; 19(10): 1106-14.
[74]
Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016; 533(7604): 481-6.
[75]
Romeo B, Choucha W, Fossati P, Rotge JY. Meta-analysis of central and peripheral γ-aminobutyric acid levels in patients with unipolar and bipolar depression. J Psychiatry Neurosci 2017; 42(6)160228
[76]
Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and other nmda antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 2015; 172(10): 950-66.
[77]
Yoon G, Petrakis IL, Krystal JH. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder. JAMA Psych 2019; 76(3): 337-8.
[78]
Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry 2018; 23(1): 59-69.
[79]
Xu K, Krystal JH, Ning Y, et al. Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia. J Psychiatr Res 2015; 61: 64-72.
[80]
Stone JM, Pepper F, Fam J, et al. Glutamate, N-acetyl aspartate and psychotic symptoms in chronic ketamine users. Psychopharmacology 2014; 231(10): 2107-16.
[81]
Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 1995; 13(1): 9-19.
[82]
Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun 2019; 10(1): 223.
[83]
Nestler EJ, Gould E, Manji H, et al. Preclinical models: status of basic research in depression. Biol Psychiatry 2002; 52(6): 503-28.
[84]
Redpath NT, Proud CG. Cyclic AMP-dependent protein kinase phosphorylates rabbit reticulocyte elongation factor-2 kinase and induces calcium-independent activity. Biochem J 1993; 293(Pt 1): 31-4.
[85]
Diggle TA, Subkhankulova T, Lilley KS, Shikotra N, Willis AE, Redpath NT. Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity. Biochem J 2001; 353(Pt 3): 621-6.
[86]
Engin E, Stellbrink J, Treit D, Dickson CT. Anxiolytic and antidepressant effects of intracerebroventricularly administered somatostatin: behavioral and neurophysiological evidence. Neuroscience 2008; 157(3): 666-76.
[87]
Hou ZH, Yu X. Activity-regulated somatostatin expression reduces dendritic spine density and lowers excitatory synaptic transmission via postsynaptic somatostatin receptor 4. J Biol Chem 2013; 288(4): 2501-9.
[88]
Soumier A, Sibille E. Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice. Neuropsychopharmacology 2014; 39(9): 2252-62.
[89]
Pfeffer CK, Xue M, He M, Huang ZJ, Scanziani M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat Neurosci 2013; 16(8): 1068-76.
[90]
Somogyi P, Klausberger T. Defined types of cortical interneurone structure space and spike timing in the hippocampus. J Physiol 2005; 562(Pt 1): 9-26.
[91]
Gouzer G, Specht CG, Allain L, Shinoe T, Triller A. Benzodiazepine-dependent stabilization of GABA(A) receptors at synapses. Mol Cell Neurosci 2014; 63: 101-13.
[92]
Harraz MM, Tyagi R, Cortés P, Snyder SH. Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry 2016; 21(3): 313-9.
[93]
Tang J, Xue W, Xia B, et al. Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice. Sci Rep 2015; 5: 13573.
[94]
Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. European Psych 2014; 29(7): 419-23.
[95]
Heise C, Gardoni F, Culotta L, di Luca M, Verpelli C, Sala C. Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons. Front Cell Neurosci 2014; 8: 35.
[96]
Zorumski CF, Conway CR. Use of ketamine in clinical practice: a time for optimism and caution. JAMA Psych 2017; 74(4): 405-6.
[97]
Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 2017; 74(4): 399-405.
[98]
Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu Rev Pharmacol Toxicol 2014; 54: 119-39.
[99]
Fava M, Freeman MP, Flynn M, et al. Correction: double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 2019. [Epub ahead of print].
[100]
Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry 2018; 175(12): 1205-15.
[101]
Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG. Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in chinese hamster ovary cells. Anesthesiology 1999; 90(1): 174-82.
[102]
George MS. Is there really nothing new under the sun? is low-dose ketamine a fast-acting antidepressant simply because it is an opioid? Am J Psychiatry 2018; 175(12): 1157-8.
[103]
Krystal JH, Madonick S, Perry E, et al. Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism. Neuropsychopharmacology 2006; 31(8): 1793-800.
[104]
Pearson-Fuhrhop KM, Dunn EC, Mortero S, et al. Dopamine genetic risk score predicts depressive symptoms in healthy adults and adults with depression. PLoS One 2014; 9(5)e93772
[105]
Kadriu B, Musazzi L, Henter ID, Graves M, Popoli M, Zarate CA Jr. Glutamatergic neurotransmission: pathway to developing novel rapid-acting antidepressant treatments. Int J Neuropsychopharmacol 2019; 22(2): 119-35.


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Article Details

VOLUME: 8
ISSUE: 2
Year: 2019
Published on: 18 October, 2019
Page: [99 - 112]
Pages: 14
DOI: 10.2174/2211556008666190827150018

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