Details of the Drug Combination

General Information of Drug Combination (ID: DCHPYDT)

• Drug Combination Name: Paroxetine + Mirtazapine
• Indication: Major Depression; Status: Phase 1 [1]
• Component Drugs:
  Paroxetine (DM5PVQE): Small molecular drug
  Mirtazapine (DML53ZJ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Paroxetine

Disease Entry	ICD 11	Status	REF
Anxiety disorder	6B00-6B0Z	Approved	[2]
Depression	6A70-6A7Z	Approved	[3]
Hot flushes	GA30	Approved	[2]
Major depressive disorder	6A70.3	Approved	[2]
Obsessive compulsive disorder	6B20	Approved	[2]
Panic disorder	6B01	Approved	[2]
Post-traumatic stress disorder	6B40	Approved	[2]

Paroxetine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Modulator	[5]

Paroxetine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Paroxetine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]

Paroxetine Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response	[11]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Decreases Expression	[12]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[13]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Expression	[13]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[14]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[15]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Increases Expression	[16]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[16]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Affects Expression	[16]
Platelet basic protein (PPBP)	OT1FHGQS	CXCL7_HUMAN	Decreases Expression	[17]
Platelet factor 4 (PF4)	OTEMJU68	PLF4_HUMAN	Decreases Expression	[17]
Transcription factor AP-2-alpha (TFAP2A)	OTMYT3NK	AP2A_HUMAN	Increases Expression	[18]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[16]
Interleukin-17A (IL17A)	OTY72FT2	IL17_HUMAN	Decreases Expression	[16]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Expression	[19]
Neural cell adhesion molecule L1-like protein (CHL1)	OT6E6E8P	NCHL1_HUMAN	Affects Response To Substance	[20]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Affects Response To Substance	[21]

Indication(s) of Mirtazapine

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[4]

Mirtazapine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 2C receptor (HTR2C)	TTWJBZ5	5HT2C_HUMAN	Antagonist	[22]

Mirtazapine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[23]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[24]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[23]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[25]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[25]

Mirtazapine Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[26]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[27]
Solute carrier family 2, facilitated glucose transporter member 4 (SLC2A4)	OTJZG0LD	GLUT4_HUMAN	Increases Expression	[28]
Solute carrier family 2, facilitated glucose transporter member 5 (SLC2A5)	OTZNYEKF	GTR5_HUMAN	Increases Expression	[28]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[26]

References

• [1] ClinicalTrials.gov (NCT01458626) Effectiveness Study of Mirtazapine Combined With Paroxetine in Major Depressive Patients Without Early Improvement
• [2] Paroxetine FDA Label
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4790).
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7241).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [7] New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther Clin Risk Manag. 2014 Jun 13;10:423-36.
• [8] CYP1A2 genetic polymorphisms are associated with treatment response to the antidepressant paroxetine. Pharmacogenomics. 2010 Nov;11(11):1535-43.
• [9] Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015 Aug;98(2):127-34.
• [10] Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator. Drug Metab Dispos. 2010 Mar;38(3):376-85.
• [11] ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):398-404. doi: 10.1016/j.pnpbp.2007.09.003. Epub 2007 Sep 15.
• [12] Serotonin transporter mRNA expression in peripheral leukocytes of patients with major depression before and after treatment with paroxetine. Neurosci Lett. 2005 Nov 25;389(1):12-6. doi: 10.1016/j.neulet.2005.06.048.
• [13] Immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) on human T lymphocyte function and gene expression. Eur Neuropsychopharmacol. 2007 Dec;17(12):774-80.
• [14] Direct and metabolism-dependent cytochrome P450 inhibition assays for evaluating drug-drug interactions. J Appl Toxicol. 2013 Feb;33(2):100-8.
• [15] Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay. Toxicol In Vitro. 2015 Oct;29(7):1729-35.
• [16] Paroxetine modulates immune responses by activating a JAK2/STAT3 signaling pathway. J Biochem Mol Toxicol. 2020 May;34(5):e22464. doi: 10.1002/jbt.22464. Epub 2020 Feb 5.
• [17] Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol. 2000 Apr;20(2):137-40. doi: 10.1097/00004714-200004000-00004.
• [18] Impact of selective serotonin reuptake inhibitors on neural crest stem cell formation. Toxicol Lett. 2017 Nov 5;281:20-25. doi: 10.1016/j.toxlet.2017.08.012. Epub 2017 Aug 24.
• [19] Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2). Gut. 2003 Feb;52(2):300-3. doi: 10.1136/gut.52.2.300.
• [20] Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics. 2011 Feb;12(2):171-84. doi: 10.2217/pgs.10.185.
• [21] Prediction of response to paroxetine and venlafaxine by serotonin-related genes in obsessive-compulsive disorder in a randomized, double-blind trial. J Clin Psychiatry. 2007 May;68(5):747-53. doi: 10.4088/jcp.v68n0512.
• [22] Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulatio... Mol Pharmacol. 2008 Mar;73(3):748-57.
• [23] A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001 Fall;7(3):249-64.
• [24] Impact of the CYP2D6 ultrarapid metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volunteers. J Clin Psychopharmacol. 2004 Dec;24(6):647-52.
• [25] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [26] Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells. Neurosci Lett. 2006 Mar 13;395(3):185-90. doi: 10.1016/j.neulet.2005.10.096. Epub 2005 Dec 1.
• [27] [Gynecomastia-galactorrhea during treatment with mirtazapine]. Presse Med. 2004 Apr 10;33(7):458. doi: 10.1016/s0755-4982(04)98631-9.
• [28] Effects of different antipsychotics and the antidepressant mirtazapine on glucose transporter mRNA levels in human blood cells. J Psychiatr Res. 2006 Jun;40(4):374-9. doi: 10.1016/j.jpsychires.2005.04.016. Epub 2005 Jul 5.