English Polski
Vol 19, No 2 (2022)
Review paper
Published online: 2021-12-30
Page views 3976
Article views/downloads 13
Get Citation

Connect on Social Media

Connect on Social Media

Use of verapamil as a P-glycoprotein inhibitor in patients with drug-resistant depression

Jarosław Sobiś1
Psychiatria 2022;19(2):144-153.


Drug-resistant depression is a common occurrence in clinical practice. Current antidepressant therapies have a high

failure rate. A P-glycoprotein as a blood-brain barrier component could limit the distribution of these drugs into the

brain. Verapamil is the most extensively characterized P-gp inhibitor and probably verapamil prevents up-regulation

of P-gp expression. Co-administration of P-gp inhibitors with P-gp-substarate drugs (antidepressants) represents

a potential strategy to overcome drug resistance.

Article available in PDF format

Add to basket: 49.00 PLN

Aready have access?


  1. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996; 19(2): 179–200.
  2. Warden D, Rush AJ, Trivedi MH, et al. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007; 9(6): 449–459.
  3. Black JL, O'Kane DJ, Mrazek DA. The impact of CYP allelic variation on antidepressant metabolism: a review. Expert Opin Drug Metab Toxicol. 2007; 3(1): 21–31.
  4. Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev. 2006; 58(3): 521–590.
  5. Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004; 9(5): 442–473.
  6. Caprifico A, Foot P, Polycarpou E, Calabrese G: Overcoming the blood-brain barrier: functionalized chitosan nanocarries. Pharmaceutics, 2020,12,2013; doi: 10.3390/pharmacetics12111013.
  7. Demeule M, Régina A, Jodoin J, et al. Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood–brain barrier. Vascular Pharmacology. 2002; 38(6): 339–348.
  8. Golden PL, Pollack GM. Blood-brain barrier efflux transport. J Pharm Sci. 2003; 92(9): 1739–1753.
  9. Schinkel AH, Wagenaar E, Mol CA, et al. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996; 97(11): 2517–2524.
  10. Zhou SF, Wang LL, Di YM, et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem. 2008; 15(20): 1981–2039.
  11. Dean M: ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia, 2009, 14, 3-9.
  12. Yu XQ, Xue CC, Wang G, et al. Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs. Curr Drug Metab. 2007; 8(8): 787–802.
  13. Leslie EM, Deeley RG, Cole SPC. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 2005; 204(3): 216–237.
  14. Vogelgesang S, Cascorbi I, Schroeder E, et al. Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics. 2002; 12(7): 535–541.
  15. Vogelgesang S, Glatzel M, Walker LC, et al. Cerebrovascular P-glycoprotein expression is decreased in Creutzfeldt-Jakob disease. Acta Neuropathol. 2006; 111(5): 436–443.
  16. Vautier S, Fernandez C. ABCB1: the role in Parkinson's disease and pharmacokinetics of antiparkinsonian drugs. Expert Opin Drug Metab Toxicol. 2009; 5(11): 1349–1358.
  17. Langford D, Grigorian A, Hurford R, et al. Altered P-glycoprotein expression in AIDS patients with HIV encephalitis. J Neuropathol Exp Neurol. 2004; 63(10): 1038–1047.
  18. Bauer M, Karch R, Neumann F, et al. Age dependency of cerebral P-gp function measured with (R)-[11C]verapamil and PET. Eur J Clin Pharmacol. 2009; 65(9): 941–946.
  19. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005; 6(8): 591–602.
  20. Doran A, Obach RS, Smith BJ, et al. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos. 2005; 33(1): 165–174.
  21. Ejsing TB, Hasselstrøm J, Linnet K. The influence of P-glycoprotein on cerebral and hepatic concentrations of nortriptyline and its metabolites. Drug Metabol Drug Interact. 2006; 21(3-4): 139–162.
  22. Uhr M, Steckler T, Yassouridis A, et al. Penetration of Amitriptyline, but Not of Fluoxetine, into Brain is Enhanced in Mice with Blood-Brain Barrier Deficiency Due to Mdr1a P-Glycoprotein Gene Disruption. Neuropsychopharmacology. 2000; 22(4): 380–387.
  23. Uhr M, Grauer MT, Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry. 2003; 54(8): 840–846.
  24. Weiss J, Dormann SMG, Martin-Facklam M, et al. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther. 2003; 305(1): 197–204.
  25. Grauer MT, Uhr M. P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline. J Psychopharmacol. 2004; 18(1): 66–74.
  26. Uhr M, Grauer MT. abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res. 2003; 37(3): 179–185.
  27. Peer D, Dekel Y, Melikhov D, et al. Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models. Cancer Res. 2004; 64(20): 7562–7569.
  28. Wang JS, Zhu HJ, Gibson BB, et al. Sertraline and its metabolite desmethylsertraline, but not bupropion or its three major metabolites, have high affinity for P-glycoprotein. Biol Pharm Bull. 2008; 31(2): 231–234.
  29. Uhr M, Tontsch A, Namendorf C, et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron. 2008; 57(2): 203–209.
  30. Roberts RL, Joyce PR, Mulder RT, et al. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J. 2002; 2(3): 191–196.
  31. Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol. 2008; 18(3): 157–169.
  32. de Klerk OL, Willemsen ATM, Roosink M, et al. Locally increased P-glycoprotein function in major depression: a PET study with [11C]verapamil as a probe for P-glycoprotein function in the blood-brain barrier. Int J Neuropsychopharmacol. 2009; 12(7): 895–904.
  33. de Klerk OL, Willemsen ATM, Bosker FJ, et al. Regional increase in P-glycoprotein function in the blood-brain barrier of patients with chronic schizophrenia: a PET study with [(11)C]verapamil as a probe for P-glycoprotein function. Psychiatry Res. 2010; 183(2): 151–156.
  34. O'Brien FE, Dinan TG, Griffin BT, et al. Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol. 2012; 165(2): 289–312.
  35. Narang VS, Fraga C, Kumar N, et al. Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier. Am J Physiol Cell Physiol. 2008; 295(2): C440–C450.
  36. Bauer B, Hartz A, Fricker G, et al. Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier. Experimental Biology and Medicine. 2016; 230(2): 118–127.
  37. Ehret MJ, Levin GM, Narasimhan M, et al. Venlafaxine induces P-glycoprotein in human Caco-2 cells. Hum Psychopharmacol. 2007; 22(1): 49–53.
  38. de Klerk OL, Bosker FJ, Willemsen ATM, et al. Chronic stress and antidepressant treatment have opposite effects on P-glycoprotein at the blood-brain barrier: an experimental PET study in rats. J Psychopharmacol. 2010; 24(8): 1237–1242.
  39. Miller DS, Bauer B, Hartz AMS, et al. Modulation of p-glycoprotein transport function at the blood-brain barrier. Exp Biol Med (Maywood). 2005; 230(2): 118–127.
  40. Ott M, Fricker G, Bauer B. Pregnane X receptor (PXR) regulates P-glycoprotein at the blood-brain barrier: functional similarities between pig and human PXR. J Pharmacol Exp Ther. 2009; 329(1): 141–149.
  41. Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005; 2(1): 86–98.
  42. Zhu HJ, Liu GQ. Glutamate up-regulates P-glycoprotein expression in rat brain microvessel endothelial cells by an NMDA receptor-mediated mechanism. Life Sci. 2004; 75(11): 1313–1322.
  43. Bauer B, Hartz AMS, Pekcec A, et al. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol Pharmacol. 2008; 73(5): 1444–1453.
  44. Bauer B, Hartz A, Fricker G, et al. Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier. Experimental Biology and Medicine. 2016; 230(2): 118–127.
  45. András IE, Deli MA, Veszelka S, et al. The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells. J Cereb Blood Flow Metab. 2007; 27(8): 1431–1443.
  46. Magariños AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience. 1995; 69(1): 89–98.
  47. Vyas A, Mitra R, Shankaranarayana Rao BS, et al. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002; 22(15): 6810–6818.
  48. Kelmendi B, Saricicek A, Sanacora G: The role of glutamatergic system in the pathophysiology and treatment of mood disorders. Primary Psychiatry, 2006, 13, 80-85.
  49. Tsuruo T, Iida H, Tsukagoshi S, et al. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res. 1981; 41(5): 1967–1972.
  50. Tsuruo T, Iida H, Nojiri M, et al. Circumvention of vincristine and Adriamycin resistance in vitro and in vivo by calcium influx blockers. Cancer Res. 1983; 43(6): 2905–2910.
  51. Summers MA, Moore JL, McAuley JW. Use of verapamil as a potential P-glycoprotein inhibitor in a patient with refractory epilepsy. Ann Pharmacother. 2004; 38(10): 1631–1634.
  52. Iannetti P, Spalice A, Parisi P. Calcium-channel blocker verapamil administration in prolonged and refractory status epilepticus. Epilepsia. 2005; 46(6): 967–969.
  53. Iannetti P, Parisi P, Spalice A, et al. Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. Epilepsy Res. 2009; 85(1): 89–95.
  54. Wurpel JN, Iyer SN. Calcium channel blockers verapamil and nimodipine inhibit kindling in adult and immature rats. Epilepsia. 1994; 35(2): 443–449.
  55. George B, Kulkarni SK, Mathur R. Motor and electrographic response of refractory experimental status epilepticus in rats and effect of calcium channel blockers. Indian J Exp Biol. 2000; 38(2): 105–112.
  56. Straub H, Köhling R, Speckmann EJ. Strychnine-induced epileptiform activity in hippocampal and neocortical slice preparations: suppression by the organic calcium antagonists verapamil and flunarizine. Brain Res. 1997; 773(1-2): 173–180.
  57. Tfelt-Hansen P, Tfelt-Hansen J. Verapamil for cluster headache. Clinical pharmacology and possible mode of action. Headache. 2009; 49(1): 117–125.
  58. Leone M, Rapoport A. Preventive and surgical management of cluster headache. In: Olsen J, Goadsby PJ, Romadan NM, Tfelt-Hansen P, Welch KMA, eds. The Headaches, 3rd edn, Philadelphia, PA: Lippincott Williams & Wilkins. ; 2006: 809–814.
  59. Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007; 69(7): 668–675.
  60. Hollister LE, Trevino ES. Calcium channel blockers in psychiatric disorders: a review of the literature. Can J Psychiatry. 1999; 44(7): 658–664.
  61. Goodnick PJ. The use of nimodipine in the treatment of mood disorders. Bipolar Disord. 2000; 2(3 Pt 1): 165–173.
  62. Magee L, Schick B, Donnenfeld A, et al. The safety of calcium channel blockers in human pregnancy: A prospective, multicenter cohort study. American Journal of Obstetrics and Gynecology. 1996; 174(3): 823–828.
  63. Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology. 1992; 42(4 Suppl 5): 149–160.
  64. Cohen LS, Friedman JM, Jefferson JW, et al. A reevaluation of risk of in utero exposure to lithium. JAMA. 1994; 271(2): 146–150.
  65. Wisner KL, Peindl KS, Perel JM, et al. Verapamil treatment for women with bipolar disorder. Biol Psychiatry. 2002; 51(9): 745–752.
  66. Kunsman GW, Kunsman CM, Presses CL, et al. A mixed-drug intoxication involving venlafaxine and verapamil. J Forensic Sci. 2000; 45(4): 926–928.
  67. Mikus G, Eichelbaum M, Fischer C, et al. Interaction of verapamil and cimetidine: stereochemical aspects of drug metabolism, drug disposition and drug action. J Pharmacol Exp Ther. 1990; 253(3): 1042–1048.
  68. Kroemer HK, Gautier JC, Beaune P, et al. Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993; 348(3): 332–337.
  69. Busse D, Cosme J, Beaune P, et al. Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995; 353(1): 116–121.
  70. Tracy T, Korzekwa K, Gonzalez F, et al. Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. British Journal of Clinical Pharmacology. 2001; 47(5): 545–552.
  71. Busse D, Templin S, Mikus G, et al. Cardiovascular effects of (R)- and (S)-verapamil and racemic verapamil in humans: a placebo-controlled study. Eur J Clin Pharmacol. 2006; 62(8): 613–619.
  72. Echizen H, Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem. Clin Pharmacokinet. 1986; 11(6): 425–449.
  73. Wang YH, Jones DR, Hall SD. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos. 2004; 32(2): 259–266.
  74. Ludden TM. Nonlinear pharmacokinetics: clinical Implications. Clin Pharmacokinet. 1991; 20(6): 429–446.
  75. Gupta SK, Hwang S, Atkinson L, et al. Simultaneous first-order and capacity-limited elimination kinetics after oral administration of verapamil. J Clin Pharmacol. 1996; 36(1): 25–34.
  76. Maeda K, Takano J, Ikeda Y, et al. Nonlinear pharmacokinetics of oral quinidine and verapamil in healthy subjects: a clinical microdosing study. Clin Pharmacol Ther. 2011; 90(2): 263–270.
  77. Kivistö KT, Neuvonen PJ, Tarssanen L. Pharmacokinetics of verapamil in overdose. Hum Exp Toxicol. 1997; 16(1): 35–37.
  78. Harder S, Rietbrock S, Thürmann P. Concentration/effect analysis of verapamil: evaluation of different approaches. Int J Clin Pharmacol Ther Toxicol. 1993; 31(10): 469–475.
  79. Morel N, Burgi V, Feron O, et al.: The action of calcium channel blockers in recombinant L-type calcium channel alpha-1-subunits. Br J Pharmacol, 1998, 125, 1005-1012.
  80. Zhou SF, Xue CC, Yu XQ, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007; 29(6): 687–710.
  81. Tröger U, Lins H, Scherrmann JM, et al. Tetraparesis associated with colchicine is probably due to inhibition by verapamil of the P-glycoprotein efflux pump in the blood-brain barrier. BMJ. 2005; 331(7517): 613.
  82. Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol. 2011; 2011: 187103.
  83. Popović M, Caballero-Bleda M, Popović N, et al. Neuroprotective effect of chronic verapamil treatment on cognitive and noncognitive deficits in an experimental Alzheimer's disease in rats. Int J Neurosci. 1997; 92(1-2): 79–93.
  84. Mustafa SB, Olson MS. Effects of calcium channel antagonists on LPS-induced hepatic iNOS expression. Am J Physiol. 1999; 277(2): G351–G360.
  85. Irita K, Fujita I, Takeshige K, et al. Calcium channel antagonist induced inhibition of superoxide production in human neutrophils. Mechanisms independent of antagonizing calcium influx. Biochem Pharmacol. 1986; 35(20): 3465–3471.
  86. Hotchkiss RS, Bowling WM, Karl IE, et al. Calcium antagonists inhibit oxidative burst and nitrite formation in lipopolysaccharide-stimulated rat peritoneal macrophages. Shock. 1997; 8(3): 170–178.
  87. Liu Y, Lo YC, Qian Li, et al. Verapamil protects dopaminergic neuron damage through a novel anti-inflammatory mechanism by inhibition of microglial activation. Neuropharmacology. 2011; 60(2-3): 373–380.
  88. Maes M, Yirmyia R, Noraberg J, et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009; 24(1): 27–53.
  89. Sarandol A, Sarandol E, Eker SS, et al. Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Hum Psychopharmacol. 2007; 22(2): 67–73.
  90. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 2006; 97(6): 1634–1658.
  91. Pérez-Tomás R. Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr Med Chem. 2006; 13(16): 1859–1876.
  92. Seelig A. A general pattern for substrate recognition by P-glycoprotein. Eur J Biochem. 1998; 251(1-2): 252–261.
  93. Pauli-Magnus C, von Richter O, Burk O, et al. Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein. J Pharmacol Exp Ther. 2000; 293(2): 376–382.
  94. Komoto Ch, Nakamura T, Yamamori M, et al. Reversal effects of Ca⁺⁺ antagonists on multidrug resistance via down-regulation of MDR1 mRNA. Kobe J Med Sci. 2007; 53: 355–363.
  95. Sulová Z, Seres M, Barancík M, et al. Does any relationship exist between P-glycoprotein-mediated multidrug resistance and intracellular calcium homeostasis. Gen Physiol Biophys. 2009; 28 Spec No Focus: F89–F95.
  96. Sulová Z, Macejová D, Seres M, et al. Combined treatment of P-gp-positive L1210/VCR cells by verapamil and all-trans retinoic acid induces down-regulation of P-glycoprotein expression and transport activity. Toxicol In Vitro. 2008; 22(1): 96–105.
  97. Kawakami M, Nakamura T, Okamura N, et al. Knock-down of sorcin induces up-regulation of MDR1 in HeLa cells. Biol Pharm Bull. 2007; 30(6): 1065–1073.
  98. Jiang W, Krishnan RRK, O'Connor CM. Depression and heart disease: evidence of a link, and its therapeutic implications. CNS Drugs. 2002; 16(2): 111–127.
  99. Pratt LA, Ford DE, Crum RM, et al. Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up. Circulation. 1996; 94(12): 3123–3129.
  100. Lespérance F, Frasure-Smith N, Juneau M, et al. Depression and 1-year prognosis in unstable angina. Arch Intern Med. 2000; 160(9): 1354–1360.
  101. Jiang W, Glassman A, Krishnan R, et al. Depression and ischemic heart disease: what have we learned so far and what must we do in the future? Am Heart J. 2005; 150(1): 54–78.
  102. Murray CJ, Lopez AD: Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet, 1997, 349, 1436-1442.
  103. Lahmeyer HW, Bellur SN. Cardiac regulation and depression. J Psychiatr Res. 1987; 21(1): 1–6.
  104. Wyatt RJ, Portnoy B, Kupfer DJ, et al. Resting plasma catecholamine concentrations in patients with depression and anxiety. Arch Gen Psychiatry. 1971; 24(1): 65–70.
  105. Kleiger R, Miller J, Bigger J, et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. The American Journal of Cardiology. 1987; 59(4): 256–262.
  106. van Zyl LT, Hasegawa T, Nagata K. Effects of antidepressant treatment on heart rate variability in major depression: a quantitative review. Biopsychosoc Med. 2008; 2: 12.
  107. Schwatrz PJ, La Rovere MT, Vanoli E: Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation, 1992, 85, 77-91.
  108. Billman GE. Effect of calcium channel antagonists on susceptibility to sudden cardiac death: protection from ventricular fibrillation. J Pharmacol Exp Ther. 1989; 248(3): 1334–1342.
  109. Hansen J. Treatment with Verapamil During and After an Acute Myocardial Infarction. Journal of Cardiovascular Pharmacology. 1991; 18: 20–25.
  110. Kailasam MT, Parmer RJ, Cervenka JH, et al. Divergent effects of dihydropyridine and phenylalkylamine calcium channel antagonist classes on autonomic function in human hypertension. Hypertension. 1995; 26(1): 143–149.
  111. Pinar E, García-Alberola A, Llamas C, et al. Effects of verapamil on indexes of heart rate variability after acute myocardial infarction. Am J Cardiol. 1998; 81(9): 1085–1089.
  112. Pardridge WM. Blood-brain barrier delivery. Drug Discov Today. 2007; 12(1-2): 54–61.
  113. Bauer B, Hartz A, Fricker G, et al. Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier. Experimental Biology and Medicine. 2016; 230(2): 118–127.
  114. Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression? J Clin Psychiatry. 2003; 64(2): 123–133.
  115. Nakagami T, Yasui-Furukori N, Saito M, et al. Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone: in vivo evidence of involvement of P-glycoprotein in risperidone disposition. Clin Pharmacol Ther. 2005; 78(1): 43–51.
  116. Clarke G, O'Mahony SM, Cryan JF, et al. Verapamil in treatment resistant depression: a role for the P-glycoprotein transporter? Hum Psychopharmacol. 2009; 24(3): 217–223.
  117. O'Brien FE, Clarke G, Fitzgerald P, et al. Inhibition of P-glycoprotein enhances transport of imipramine across the blood-brain barrier: microdialysis studies in conscious freely moving rats. Br J Pharmacol. 2012; 166(4): 1333–1343.
  118. Robey RW, Lazarowski A, Bates SE. P-glycoprotein--a clinical target in drug-refractory epilepsy? Mol Pharmacol. 2008; 73(5): 1343–1346.
  119. Yamamoto-Furusho JK. Genetic factors associated with the development of inflammatory bowel disease. World J Gastroenterol. 2007; 13(42): 5594–5597.
  120. Dudarewicz M, Barańska M, Rychlik-Sych M, et al. C3435T Polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with inflammatory bowel disease in a Polish population. Pharmacological Reports. 2012; 64(2): 343–350.
  121. Lemma GL, Wang Z, Hamman MA, et al. The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates. Clin Pharmacol Ther. 2006; 79(3): 218–230.