Therapeutic Effect of Novel Antidepressant Drugs Acting at Specific Receptors of Neurotransmitters and Neuropeptides

Author(s): Felix-Martin Werner*, Rafael Coveñas*.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 4 , 2019

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Abstract:

Background: Major depression is a frequent psychiatric disease. One- third of the depressive patients remain treatment-resistant; thus, it is urgent to find novel antidepressant drugs.

Objective: In major depression, in several brain areas the neural networks involved and the alterations of neurotransmitters and neuropeptides are updated. According to these networks, new pharmacological agents and effective combinations of antidepressant drugs achieving a more efficacious antidepressant treatment are suggested.

Results: In the neural networks, the prefrontal cortex has been included. In this brain area, glutamatergic neurons, which receive an activating potential from D2 dopaminergic neurons, presynaptically inhibit M1 muscarinic cholinergic neurons via NMDA receptors. Medium spiny GABAergic/somatostatin neurons, which receive projections from M1 muscarinic cholinergic neurons, presynaptically inhibit D2 dopaminergic neurons via GABAA/somatostatin1 receptors. The combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist can achive a rapid, long-lasting antidepressant effect.

Conclusion: In preclinical studies, the antidepressant effect of orvepitant, an NK1 receptor antagonist, has been demonstrated: this antagonist reaches a complete blockade of NK1 receptors. In clinical studies, the combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist should be investigated indepth as well as the therapeutic effect of orvepitant. In clinical studies, the antidepressant effect of a triple reuptake inhibitor should be examined and compared to current antidepressant drugs.

Keywords: M1 acetylcholine antagonist, NMDA receptor antagonist, orvepitant, selective serotonin reuptake inhibitor, neural network, acetylcholine, dopamine, GABA.

[1]
Werner FM, Coveñas R. Classical neurotransmitters and neuropeptides involved in major depression: A review. Int J Neurosci 2010; 120(7): 455-70.
[2]
Werner FM, Coveñas R. Classical neurotransmitters and neuropeptides involved in major depression in a multi-neurotransmitter system: A focus on antidepressant drugs. Curr Med Chem 2013; 20(38): 4853-8.
[3]
DeLucia V, Kelsberg G, Safranek S. Which SSRIs most effectively treat depression in adolescents? J Fam Pract 2016; 65(9): 632-4.
[4]
Soini E, Hallinen T, Brignone M, et al. Cost-utility analysis of vortioxetine versus agomelatine, bupropion SR, sertraline and venlafaxine XR after treatment switch in major depressive disorder in Finland. Expert Rev Pharmacoecon Outcomes Res 2017; 17(3): 293-302.
[5]
Wohleb ES, Wu M, Gerhard DM, et al. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Invest 2016; 126(7): 2482-94.
[6]
Jacobsen JPR, Krystal AD, Krishnan KRR, Caron MG. Adjunctive 5-hydroxytryptophan slow-release for treatment-resistant depression: clinical and preclinical rationale. Trends Pharmacol Sci 2016; 37(11): 933-44.
[7]
De Berardis D, Marini S, Serroni N, et al. S-Adenosyl-L-Methionine augmentation in patients with stage II treatment-resistant major depressive disorder: An open label, fixed dose, single-blind study. Sci World J 2013; 2013: 204649.
[8]
Pérez-Olmos I, Bustamante D, Ibáñez-Pinilla M. Serotonin transporter gene (5-HTT) polymorphism and major depressive disorder in patients in Bogotá, Colombia. Biomedica 2016; 36(2): 285-94.
[9]
Hatherall L, Sánchez C, Morilak DA. Chronic vortioxetine treatment reduces exaggerated expression of conditioned fear memory and restores active coping behavior in chronically stressed rats. Int J Neuropsychopharmacol 2017; 20(4): 316-23.
[10]
Orsolini L, Tomasetti C, Valchera A, et al. Current and future perspectives on the major depressive disorder: focus on the new multimodal antidepressant vortioxetine. CNS Neurol Disord Drug Targets 2017; 16(1): 65-92.
[11]
Orsolini L, Tomasetti C, Valchera A, et al. New advances in the treatment of generalized anxiety disorder: the multimodal antidepressant vortioxetine. Expert Rev Neurother 2016; 16(5): 483-95.
[12]
Chumboatong W, Thummayot S, Govitrapong P, Tocharus C, Jittiwat J, Tocharus J. Neuroprotection of agomelatine against cerebral ischemia/reperfusion injury through an antiapoptotic pathway in rat. Neurochem Int 2017; 102: 114-22.
[13]
De Berardis D, Fornaro M, Orsolini L, et al. Effect of agomelatine treatment on C-reactive protein levels in patients with major depressive disorder: An exploratory study in “real-world,” everyday clinical practice. CNS Spectr 2017; 22(4): 342-7.
[14]
De Berardis D, Fornaro M, Serroni N, et al. Agomelatine beyond borders: current evidences of its efficacy in disorders other than major depression. Int J Mol Sci 2015; 16(1): 1111-30.
[15]
Werner FM, Coveñas R. Novel antidepressant drugs in comparison to coventional antidepressant drugs. J Clin Case Rep 2014; 4: 11.
[16]
Castellano S, Ventimiglia A, Salomone S, et al. Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors improve cognitive function in partial responders depressed patients: results from a prospective observational cohort study. CNS Neurol Disord Drug Targets 2016; 15(10): 1290-8.
[17]
Atzori M, Cuevas-Olguin R, Esquivel-Rendon E, et al. Locus coeruleus norepinephrine release: A central regulator of CNS spatio-temporal activation. Front Synaptic Neurosci 2016; 8: 25.
[18]
Li QS, Tian C, Seabrook GR, Drevets WC, Narayan VA. Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response. Transl Psychiatry 2016; 6(9): e889.
[19]
Stauffer VL, Liu P, Goldberger C, et al. Is the noradrenergic symptom cluster a valid construct in adjunctive treatment of major depressive disorder? J Clin Psychiatry 2017; 78(3): 317-23.
[20]
Werner FM, Coveñas R. Additional antidepressant pharmacotherapies according to a neural network. Brain Disord Ther 2016; 5: 1.
[21]
Mischoulon D, Hylek L, Yeung AS, et al. Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. J Affect Disord 2017; 208: 6-14.
[22]
Cornelissen JC, Obeng S, Rice KC, Zhang Y, Negus SS, Banks ML. Application of receptor theory to the design and use of fixed-proportion of mu-opioid agonist and antagonist mixtures in Rhesus monkeys. J Pharmacol Exp Ther 2018; 365(1): 37-47.
[23]
Demontis F, Serra F, Serra G. Antidepressant-induced dopamine receptor dysregulation: A valid animal model of manic-depressive illness. Curr Neuropharmacol 2017; 15(3): 417-23.
[24]
McIntyre RS, Weiller E, Zhang P, Weiss C. Brexpiprazole as adjunctive treatment of major depressive disorder with anxious distress: Results from a post-hoc analysis of two randomised controlled trials. J Affect Disord 2016; 201: 116-23.
[25]
Sugama S, Kakinuma Y. Loss of dopaminergic neurons occurs in the ventral tegmental area and hypothalamus of rats following chronic stress: Possible pathogenetic loci for depression involved in Parkinson’s disease. Neurosci Res 2016; 111: 48-55.
[26]
Wohleb ES, Gerhard D, Thomas A, Duman RS. Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol 2017; 15(1): 11-20.
[27]
Petryshen TL, Lewis MC, Dennehy KA, Garza JC, Fava M. Antidepressant-like effect of low dose ketamine and scopolamine co-treatment in mice. Neurosci Lett 2016; 620: 70-3.
[28]
Han J, Wang DS, Liu SB, Zhao MG. Cytisine, a partial agonist of alpha4beta2 nicotinic acetylcholine receptors reduced unpredictable chronic mild stress-induced depression-like behaviors. Biomol Ther (Seoul) 2016; 24(3): 291-7.
[29]
Wang HR, Woo YS, Bahk WM. Ineffectiveness of nicotinic acetylcholine receptor antagonists for treatment-resistant depression: A meta-analysis. Int Clin Psychopharmacol 2016; 31(5): 241-8.
[30]
Ma K, Xu A, Cui S, Sun MR, Xue YC, Wang JH. Impaired GABA synthesis, uptake and release are associated with depression-like behaviors induced by chronic mild stress. Transl Psychiatry 2016; 6(10): e910.
[31]
Douillard-Guilloux G, Lewis D, Seney ML, Sibille E. Decrease in somatostatin-positive cell density in the amygdala of females with major depression. Depress Anxiety 2017; 34(1): 68-78.
[32]
Nowak G, Partyka A, Pałucha A, et al. Antidepressant-like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents. Br J Pharmacol 2006; 149(5): 581-90.
[33]
Ghose S, Winter MK, McCarson KE, Tamminga CA, Enna SJ. The GABAB; receptor as a target for antidepressant drug action. Br J Pharmacol 2011; 162(1): 1-17.
[34]
Kavalali ET, Monteggia LM. Synaptic mechanisms underlying rapid antidepressant action of ketamine. Am J Psychiatry 2012; 169(11): 1150-6.
[35]
Du Jardin KG, Müller HK, Sanchez C, Wegener G, Elfving B. Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine. Synapse 2017; 71(1): 37-45.
[36]
Can A, Zanos P, Moaddel R, et al. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monamine transporters. J Pharmacol Exp Ther 2016; 359(1): 159-70.
[37]
Pomierny-Chamioło L, Poleszak E, Pilc A, Nowak G. NMDA but not AMPA glutamatergic receptors are involved in the antidepressant-like activity of MTEP during the forced swim test in mice. Pharmacol Rep 2010; 62(6): 1186-90.
[38]
Lu X, Barr AM, Kinney JW, et al. A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus. Proc Natl Acad Sci USA 2005; 102(3): 874-9.
[39]
Flores-Burgess A, Millón C, Gago B, et al. Galanin (1-15) enhancement of the behavioral effects of Fluoxetine in the forced swimming test gives a new therapeutic strategy against depression. Neuropharmacology 2017; 118: 233-41.
[40]
Millón C, Flores-Burgess A, Narváez M, et al. The neuropeptides Galanin and Galanin(1-15) in depression-like behaviours. Neuropeptides 2017; 64: 39-45.
[41]
Wang YJ, Li H, Yang YT, et al. Association of galanin and major depressive disorder in the Chinese Han population. PLoS One 2013; 8(5): e64617.
[42]
Nikisch G, Agren H, Eap CB, Czernik A, Baumann P, Mathé AA. Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram. Int J Neuropsychopharmacol 2005; 8(3): 403-10.
[43]
Chen C, Wilcoxen KM, Huang CQ, et al. Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo [1,5-a]pyrimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists. J Med Chem 2004; 47(19): 4787-98.
[44]
Holsboer F, Ising M. Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. Eur J Pharmacol 2008; 583(2-3): 350-7.
[45]
Treutlein J, Strohmaier J, Frank J, et al. Association between neuropeptide Y receptor Y2 promoter variant rs6857715 and major depressive disorder. Psychiatr Genet 2017; 27(1): 34-7.
[46]
Nakhate KT, Yedke SU, Bharne AP, Subhedar NK, Kokare DM. Evidence for the involvement of neuropeptide Y in the antidepressant effect of imipramine in type 2 diabetes. Brain Res 2016; 1646: 1-11.
[47]
Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 2006; 59(3): 216-23.
[48]
Di Fabio R, Alvaro G, Braggio S, et al. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Bioorg Med Chem 2013; 21(21): 6264-73.
[49]
Ratti E, Bettica P, Alexander R, et al. Full central neurokinin-1 receptor blockade is required for efficacy in depression: Evidence from orvepitant clinical studies. J Psychopharmacol 2013; 27(5): 424-34.
[50]
Isogawa K, Nagayama H, Tsutsumi T, Kiyota A, Akiyoshi J, Hieda K. Simultaneous use of thyrotropin-releasing hormone test and combined dexamethasone/corticotropine-releasing hormone test for severity evaluation and outcome prediction in patients with major depressive disorder. J Psychiatr Res 2005; 39(5): 467-73.
[51]
Kose S, Cetin M. Triple reuptake inhibitors (TRIs): do they promise us a rose garden? Psych Clin Psychopharmacol 2018; 28: 119-22.
[52]
Sharma H, Santra S, Dutta A. Triple reuptake inhibitors as potential next-generation antidepressants: A new hope? Future Med Chem 2015; 7(17): 2385-406.
[53]
Grady SE, Marsh TA, Tenhouse A, Klein K. Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature. Ment Health Clin 2018; 7(1): 16-23.
[54]
Palucha-Poniewiera A, Podkowa K, Lenda T, Pilc A. The involvement of monoaminergic neurotransmission in the antidepressant-like action of scopolamine in the tail suspension test. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79: 155-61.


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Article Details

VOLUME: 25
ISSUE: 4
Year: 2019
Page: [388 - 395]
Pages: 8
DOI: 10.2174/1381612825666190410165243
Price: $65

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