Details of the Drug Combination

General Information of Drug Combination (ID: DC23QN8)

• Drug Combination Name: Dextroamphetamine + Risperidone
• Indication: Attention Deficit Disorder With Hyperactivity; Status: Phase 4 [1]
• Component Drugs:
  Dextroamphetamine (DMMIHVP): Small molecular drug
  Risperidone (DMN6DXL): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dextroamphetamine

Disease Entry	ICD 11	Status	REF
Attention deficit hyperactivity disorder	6A05.Z	Approved	[2]
Depression	6A70-6A7Z	Approved	[3]
Narcolepsy	7A20	Approved	[2]

Dextroamphetamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Trace amine-associated receptor-1 (TAAR1)	TTIU98M	TAAR1_HUMAN	Modulator	[6]

Dextroamphetamine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[7]

Dextroamphetamine Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[8]
Sodium-dependent noradrenaline transporter (SLC6A2)	OTMHQJMP	SC6A2_HUMAN	Decreases Activity	[9]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Expression	[8]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Decreases Activity	[9]
Synaptic vesicular amine transporter (SLC18A2)	OTUOMMM6	VMAT2_HUMAN	Affects Binding	[10]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[8]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[8]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[8]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[8]
Disrupted in schizophrenia 1 protein (DISC1)	OT43AW4H	DISC1_HUMAN	Increases Response To Substance	[11]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Response To Substance	[12]
Glial cell line-derived neurotrophic factor (GDNF)	OT8ICC4Z	GDNF_HUMAN	Affects Response To Substance	[13]
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Affects Response To Substance	[14]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Affects Response To Substance	[15]

Indication(s) of Risperidone

Disease Entry	ICD 11	Status	REF
Bipolar I disorder	N.A.	Approved	[4]
Schizoaffective disorder	6A21	Approved	[4]
Schizophrenia	6A20	Approved	[5]
Autism	N.A.	Investigative	[4]

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	[16]

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	[17]

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	[18]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[20]

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	[21]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Response To Substance	[22]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response To Substance	[23]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response To Substance	[24]
D(3) dopamine receptor (DRD3)	OT0OFFKB	DRD3_HUMAN	Increases Response To Substance	[25]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases Expression	[26]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Affects Expression	[27]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[28]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[29]
Corticoliberin (CRH)	OT2MOC4T	CRF_HUMAN	Decreases Expression	[30]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[31]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[31]
5-hydroxytryptamine receptor 2C (HTR2C)	OT6H8DE0	5HT2C_HUMAN	Increases Response To Substance	[23]
Amine oxidase A (MAOA)	OT8NIWMQ	AOFA_HUMAN	Increases Response To Substance	[32]
D(4) dopamine receptor (DRD4)	OTAJTO7N	DRD4_HUMAN	Increases ADR	[33]
Synaptosomal-associated protein 25 (SNAP25)	OTUIQ81Q	SNP25_HUMAN	Affects Response To Substance	[34]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Increases Response To Substance	[35]

References

• [1] ClinicalTrials.gov (NCT00794625) Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Dextroamphetamine FDA Label
• [4] Risperidone FDA Label
• [5] 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).
• [6] Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology. 2014 Oct;85:499-507.
• [7] Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica. 1999 Jul;29(7):719-32.
• [8] An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis. Arch Toxicol. 2013 Dec;87(12):2165-85. doi: 10.1007/s00204-013-1082-9. Epub 2013 Jul 3.
• [9] Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR. Neurotoxicology. 2019 May;72:95-100. doi: 10.1016/j.neuro.2019.02.011. Epub 2019 Feb 15.
• [10] Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res. 1994 Mar;22(1-4):219-26. doi: 10.1016/0169-328x(94)90050-7.
• [11] Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. Mol Psychiatry. 2016 Nov;21(11):1561-1572. doi: 10.1038/mp.2015.194. Epub 2016 Jan 12.
• [12] Serotonin transporter genotype and acute subjective response to amphetamine. Am J Addict. 2006 Sep-Oct;15(5):327-35. doi: 10.1080/10550490600859868.
• [13] Behavioral improvement and dopamine release in a Parkinsonian rat model. Neurosci Lett. 2002 Sep 13;330(1):5-8. doi: 10.1016/s0304-3940(02)00672-9.
• [14] An association study of the brain-derived neurotrophic factor Val66Met polymorphism and amphetamine response. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141B(6):576-83. doi: 10.1002/ajmg.b.30327.
• [15] Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. doi: 10.1073/pnas.0931309100. Epub 2003 Apr 25.
• [16] Randomized clinical comparison of perospirone and risperidone in patients with schizophrenia: Kansai Psychiatric Multicenter Study. Psychiatry Clin Neurosci. 2009 Jun;63(3):322-8.
• [17] 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.
• [18] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [19] 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.
• [20] Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos. 2001 Oct;29(10):1263-8.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] 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.