Details of the Drug Combination

General Information of Drug Combination (ID: DCCGTQH)

• Drug Combination Name: Quetiapine + Risperidone
• Indication: Schizophrenia; Status: Phase 4 [1]
• Component Drugs:
  Quetiapine (DM1N62C): Small molecular drug
  Risperidone (DMN6DXL): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Quetiapine

Disease Entry	ICD 11	Status	REF
Anorexia nervosa cachexia	6B80	Approved	[2]
Bipolar depression	N.A.	Approved	[2]
Bipolar disorder	6A60	Approved	[2]
Bipolar I disorder	N.A.	Approved	[2]
Delirium	N.A.	Approved	[2]
Major depressive disorder	6A70.3	Approved	[2]
Methamphetamine dependence	6C46.2	Approved	[2]
Schizoaffective disorder	6A21	Approved	[2]
Schizophrenia	6A20	Approved	[3]
Alcohol dependence	6C40.2	Phase 3	[4]

Quetiapine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[7]

Quetiapine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Solute carrier family 22 member 23 (SLC22A23)	DTMJK12	S22AN_HUMAN	Substrate	[9]

Quetiapine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[11]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Indication(s) of Risperidone

Disease Entry	ICD 11	Status	REF
Bipolar I disorder	N.A.	Approved	[5]
Schizoaffective disorder	6A21	Approved	[5]
Schizophrenia	6A20	Approved	[6]
Autism	N.A.	Investigative	[5]

Risperidone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Antagonist	[13]

Risperidone Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]

Risperidone Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[16]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[17]

Risperidone Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Hydroxylation	[18]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Response To Substance	[19]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response To Substance	[20]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response To Substance	[21]
D(3) dopamine receptor (DRD3)	OT0OFFKB	DRD3_HUMAN	Increases Response To Substance	[22]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases Expression	[23]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Affects Expression	[24]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[25]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[26]
Corticoliberin (CRH)	OT2MOC4T	CRF_HUMAN	Decreases Expression	[27]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[28]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[28]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Increases Response To Substance	[20]
Amine oxidase A (MAOA)	OT8NIWMQ	AOFA_HUMAN	Increases Response To Substance	[29]
D(4) dopamine receptor (DRD4)	OTAJTO7N	DRD4_HUMAN	Increases ADR	[30]
Synaptosomal-associated protein 25 (SNAP25)	OTUIQ81Q	SNP25_HUMAN	Affects Response To Substance	[31]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Increases Response To Substance	[32]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Bipolar Disorder	DCC5U45	N. A.	Phase 4	[33]

References

• [1] ClinicalTrials.gov (NCT00423878) Comparison of Antipsychotics for Metabolic Problems in Schizophrenia or Schizoaffective Disorder
• [2] Quetiapine FDA Label
• [3] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [4] ClinicalTrials.gov (NCT02362412) Study to Evaluate the Effects of Switching Different Strength Forms of FK949E in Bipolar Disorder Patients With Major Depressive Episodes. U.S. National Institutes ofHealth.
• [5] Risperidone FDA Label
• [6] 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: 96).
• [7] Receptor reserve-dependent properties of antipsychotics at human dopamine D2 receptors. Eur J Pharmacol. 2009 Apr 1;607(1-3):35-40.
• [8] Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates. J Pharm Pharmacol. 2004 Aug;56(8):967-75.
• [9] Genome-wide association study of antipsychotic-induced QTc interval prolongation. Pharmacogenomics J. 2012 Apr;12(2):165-72.
• [10] Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro. Drug Metab Dispos. 2012 Sep;40(9):1778-84.
• [11] A liquid chromatographic-electrospray-tandem mass spectrometric method for quantitation of quetiapine in human plasma and liver microsomes: application to study in vitro metabolism. J Anal Toxicol. 2004 Sep;28(6):443-8.
• [12] Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. Pharmacogenet Genomics. 2014 Jan;24(1):35-42.
• [13] Randomized clinical comparison of perospirone and risperidone in patients with schizophrenia: Kansai Psychiatric Multicenter Study. Psychiatry Clin Neurosci. 2009 Jun;63(3):322-8.
• [14] Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: in vivo evidence of involvement of P-glycoprotein in risperidone disposition. Clin Pharmacol Ther. 2005 Jul;78(1):43-51.
• [15] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [16] Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients. Clin Pharmacol Ther. 2005 Nov;78(5):520-8.
• [17] Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos. 2001 Oct;29(10):1263-8.
• [18] Risperidone plasma levels, clinical response and side-effects. Eur Arch Psychiatry Clin Neurosci. 2005 Aug;255(4):261-8. doi: 10.1007/s00406-004-0556-4. Epub 2004 Nov 29.
• [19] Relationship between response to risperidone, plasma concentrations of risperidone and CYP3A4 polymorphisms in schizophrenia patients. J Psychopharmacol. 2010 Jul;24(7):1115-20. doi: 10.1177/0269881109104932. Epub 2009 Apr 24.
• [20] Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J. 2010 Oct;10(5):418-30.
• [21] Variants of the dopamine D2 receptor gene and risperidone-induced hyperprolactinemia in children and adolescents. Pharmacogenet Genomics. 2009 May;19(5):373-82. doi: 10.1097/FPC.0b013e328329a60f.
• [22] A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 2009 Dec;9(6):404-10. doi: 10.1038/tpj.2009.26. Epub 2009 Jun 9.
• [23] Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs. BMC Neurosci. 2006 Oct 20;7:69.
• [24] Effect of risperidone and olanzapine on reproductive hormones, psychopathology and sexual functioning in male patients with schizophrenia. Psychoneuroendocrinology. 2009 Jan;34(1):129-39. doi: 10.1016/j.psyneuen.2008.08.015. Epub 2008 Oct 5.
• [25] The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther. 2000 Sep;22(9):1085-96. doi: 10.1016/S0149-2918(00)80086-7.
• [26] Recovery from new-onset diabetes in a schizophrenic man after withdrawal of olanzapine. Psychosomatics. 2002 Jan-Feb;43(1):67-70. doi: 10.1176/appi.psy.43.1.67.
• [27] Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. Neuropsychopharmacology. 2006 Apr;31(4):853-65. doi: 10.1038/sj.npp.1300911.
• [28] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [29] Different impacts of aquaporin 4 and MAOA allele variation among olanzapine, risperidone, and paliperidone in schizophrenia. J Clin Psychopharmacol. 2012 Jun;32(3):394-7. doi: 10.1097/JCP.0b013e31825370f4.
• [30] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [31] The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia. Neurosci Lett. 2005 May 6;379(2):81-9. doi: 10.1016/j.neulet.2004.12.037. Epub 2005 Jan 26.
• [32] Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J. 2006 Jan-Feb;6(1):42-51. doi: 10.1038/sj.tpj.6500342.
• [33] ClinicalTrials.gov (NCT02562287) Clozapine Versus Other Atypical Antipsychotics for Bipolar Disorder