Skip to main content
SpringerLink
Log in

Targeting Serotonin 5-HT2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Schizophrenia is a major mental illness associated with profound disability. Current treatments for schizophrenia (antipsychotics) all have a similar mechanism of action and are primarily dopamine type 2 receptor (D2R) antagonists. Antipsychotics are not fully effective for the majority of schizophrenia patients, suggesting the need for alternative approaches. The primary focus of this review is to assess the evidence for the role of the serotonin type 2A receptor (5-HT2AR) in schizophrenia. Topics include an overview of 5-HT2AR physiology and pathophysiology in schizophrenia, 5-HT2AR interaction with other neurotransmitter systems, including the glutamatergic system, a review of the 5-HT2AR/d-lysergic acid diethylamide (LSD) model of schizophrenia, a contrast of the 5-HT2AR and glutamatergic models of schizophrenia, and finally, a review of Food and Drug Administration (FDA)-approved and investigational 5-HT2AR-modulating compounds. Recent studies with lumeteperone, pimavanserin, and roluperidone are highlighted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kantrowitz JT. Managing negative symptoms of schizophrenia: how far have we come? CNS Drugs. 2017;31(5):373–88.

    PubMed  Google Scholar 

  2. Kurtz MM, Moberg JP, Ragland JD, Gur RC, Gur RE. Symptoms versus neurocognitive test performance as predictors of psychosocial status in schizophrenia: a 1- and 4-year prospective study. Schizophr Bull. 2005;31:167–74.

    PubMed  Google Scholar 

  3. Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr. A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry. 2001;58(2):165–71.

    CAS  PubMed  Google Scholar 

  4. Keefe RS, Haig GM, Marder SR, Harvey PD, Dunayevich E, Medalia A, et al. Report on ISCTM consensus meeting on clinical assessment of response to treatment of cognitive impairment in schizophrenia. Schizophr Bull. 2016;42(1):19–33.

    PubMed  Google Scholar 

  5. Green MF, Hellemann G, Horan WP, Lee J, Wynn JK. From perception to functional outcome in schizophrenia: modeling the role of ability and motivation. Arch Gen Psychiatry. 2012;69(12):1216–24.

    PubMed  PubMed Central  Google Scholar 

  6. Yang LH, Ruiz B, Mandavia AD, Grivel MM, Wong LY, Phillips MR, et al. Advancing study of cognitive impairments for antipsychotic-naive psychosis comparing high-income versus low- and middle-income countries with a focus on urban China: systematic review of cognition and study methodology. Schizophr Res. 2020. https://doi.org/10.1016/j.schres.2020.01.026.

    Article  PubMed  Google Scholar 

  7. Gold R, Butler PD, Revheim N, Leitman DI, Hansen JA, Gur RC, et al. Auditory emotion recognition impairments in Schizophrenia: relationship to acoustic features and cognition. Am J Psychiatry. 2012;169(4):424–32.

    PubMed  Google Scholar 

  8. Thomas ML, Green MF, Hellemann G, Sugar CA, Tarasenko M, Calkins ME, et al. Modeling deficits from early auditory information processing to psychosocial functioning in schizophrenia. JAMA Psychiatry. 2017;74(1):37–46.

    PubMed  PubMed Central  Google Scholar 

  9. Kantrowitz JT, Hoptman MJ, Leitman DI, Moreno-Ortega M, Lehrfeld JM, Dias E, et al. Neural substrates of auditory emotion recognition deficits in schizophrenia. J Neurosci. 2015;35(44):14909–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kantrowitz JT, Leitman DI, Lehrfeld JM, Laukka P, Juslin PN, Butler PD, et al. Reduction in tonal discriminations predicts receptive emotion processing deficits in schizophrenia and schizoaffective disorder. Schizophr Bull. 2013;39(1):86–93.

    PubMed  Google Scholar 

  11. Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188(4194):1217–9.

    CAS  PubMed  Google Scholar 

  12. Wong DF, Wagner HN, Tune LE, Dannals RF, Pearlson GD, Links JM, et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science. 1986;234(4783):1558–63.

    CAS  PubMed  Google Scholar 

  13. Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry. 2001;50(11):873–83.

    CAS  PubMed  Google Scholar 

  14. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kishimoto T, Hagi K, Nitta M, Kane JM, Correll CU. Long-term effectiveness of oral second-generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta-analysis of direct head-to-head comparisons. World Psychiatry. 2019;18(2):208–24.

    PubMed  PubMed Central  Google Scholar 

  16. Meftah AM, Deckler E, Citrome L, Kantrowitz JT. New discoveries for an old drug: a review of recent olanzapine research. Postgrad Med. 2020;3:1–11.

    Google Scholar 

  17. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23.

    CAS  PubMed  Google Scholar 

  18. Girgis RR, Zoghbi AW, Javitt DC, Lieberman JA. The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: a critical and comprehensive review. J Psychiatr Res. 2019;108:57–83.

    PubMed  Google Scholar 

  19. Kantrowitz JT. N-methyl-d-aspartate-type glutamate receptor modulators and related medications for the enhancement of auditory system plasticity in schizophrenia. Schizophr Res. 2019;207:70–9.

    PubMed  Google Scholar 

  20. Correll CU, Davis RE, Weingart M, Saillard J, O’Gorman C, Kane JM, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2020;77:349–58.

    PubMed Central  Google Scholar 

  21. Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(7):1159–72.

    CAS  PubMed  Google Scholar 

  22. Lieberman JA, Stroup TS. The NIMH-CATIE Schizophrenia Study: what did we learn? Am J Psychiatry. 2011;168(8):770–5.

    PubMed  Google Scholar 

  23. Garay RP, Bourin M, de Paillette E, Samalin L, Hameg A, Llorca PM. Potential serotonergic agents for the treatment of schizophrenia. Expert Opin Investig Drugs. 2016;25(2):159–70.

    CAS  PubMed  Google Scholar 

  24. Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, et al. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol, 2 mg/day: comparison with reference dose risperidone, 6 mg/day. Schizophr Res. 2012;141(2–3):144–52.

    PubMed  Google Scholar 

  25. Davidson M, Saoud J, Staner C, Noel N, Luthringer E, Werner S, et al. Efficacy and safety of MIN-101: a 12-week randomized, double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia. Am J Psychiatry. 2017;174(12):1195–202.

    PubMed  Google Scholar 

  26. Meltzer HY, Massey BW, Horiguchi M. Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia. Curr Pharm Biotechnol. 2012;13(8):1572–86.

    CAS  PubMed  Google Scholar 

  27. Friedman JH. Pimavanserin for the treatment of Parkinson’s disease psychosis. Expert Opin Pharmacother. 2013;14(14):1969–75.

    CAS  PubMed  Google Scholar 

  28. Pazos A, Probst A, Palacios JM. Serotonin receptors in the human brain-IV. Autoradiographic mapping of serotonin-2 receptors. Neuroscience. 1987;21(1):123–39.

    CAS  PubMed  Google Scholar 

  29. de Lecea L. Hypocretins and the neurobiology of sleep-wake mechanisms. Prog Brain Res. 2012;198:15–24.

    PubMed  PubMed Central  Google Scholar 

  30. Doherty MD, Pickel VM. Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area. Brain Res. 2000;864(2):176–85.

    CAS  PubMed  Google Scholar 

  31. Hoyer D, Pazos A, Probst A, Palacios JM. Serotonin receptors in the human brain. II. Characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites. Brain Res. 1986;376(1):97–107.

    CAS  PubMed  Google Scholar 

  32. Ikemoto K, Nishimura A, Okado N, Mikuni M, Nishi K, Nagatsu I. Human midbrain dopamine neurons express serotonin 2A receptor: an immunohistochemical demonstration. Brain Res. 2000;853(2):377–80.

    CAS  PubMed  Google Scholar 

  33. Nocjar C, Roth BL, Pehek EA. Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. Neuroscience. 2002;111(1):163–76.

    CAS  PubMed  Google Scholar 

  34. Bortolozzi A, Diaz-Mataix L, Scorza MC, Celada P, Artigas F. The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem. 2005;95(6):1597–607.

    CAS  PubMed  Google Scholar 

  35. Vazquez-Borsetti P, Celada P, Cortes R, Artigas F. Simultaneous projections from prefrontal cortex to dopaminergic and serotonergic nuclei. Int J Neuropsychopharmacol. 2011;14(3):289–302.

    CAS  PubMed  Google Scholar 

  36. Mocci G, Jimenez-Sanchez L, Adell A, Cortes R, Artigas F. Expression of 5-HT2A receptors in prefrontal cortex pyramidal neurons projecting to nucleus accumbens. Potential relevance for atypical antipsychotic action. Neuropharmacology. 2014;79:49–58.

    CAS  PubMed  Google Scholar 

  37. Kantrowitz JT, Javitt DC. Glutamatergic approaches to the conceptualization and treatment of schizophrenia. In: Javitt DC, Kantrowitz JT, editors. Handbook of neurochemistry and molecular neurobiology. 3rd ed. New York: Springer; 2009.

    Google Scholar 

  38. Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. 2010;83(3–4):108–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Aghajanian GK, Marek GJ. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology. 1997;36(4–5):589–99.

    CAS  PubMed  Google Scholar 

  40. Vaidya VA, Marek GJ, Aghajanian GK, Duman RS. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci. 1997;17(8):2785–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Rodriguez JJ, Doherty MD, Pickel VM. N-methyl-d-aspartate (NMDA) receptors in the ventral tegmental area: subcellular distribution and colocalization with 5-hydroxytryptamine(2A) receptors. J Neurosci Res. 2000;60(2):202–11.

    CAS  PubMed  Google Scholar 

  42. Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008;452(7183):93–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Shah UH, Gonzalez-Maeso J. Serotonin and glutamate interactions in preclinical schizophrenia models. ACS Chem Neurosci. 2019;10(7):3068–77.

    CAS  PubMed  Google Scholar 

  44. Hideshima KS, Hojati A, Saunders JM, On DM, de la Fuente Revenga M, Shin JM, et al. Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice. Psychopharmacology (Berl). 2018;235(11):3149–65.

    CAS  Google Scholar 

  45. Woolley DW, Shaw E. A Biochemical and pharmacological suggestion about certain mental disorders. Proc Natl Acad Sci USA. 1954;40(4):228–31.

    CAS  PubMed  Google Scholar 

  46. Feldstein A, Hoagland H, Freeman H. On the relationship of serotonin to schizophrenia. Science. 1958;128(3320):358.

    CAS  PubMed  Google Scholar 

  47. Bowers MB Jr. Serotonin (5HT) systems in psychotic states. Psychopharmacol Commun. 1975;1(6):655–62.

    PubMed  Google Scholar 

  48. Bleich A, Brown SL, Kahn R, van Praag HM. The role of serotonin in schizophrenia. Schizophr Bull. 1988;14(2):297–315.

    CAS  PubMed  Google Scholar 

  49. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther. 2008;14(4):295–314.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Busch AK, Johnson WC. L.S.D. 25 as an aid in psychotherapy; preliminary report of a new drug. Dis Nerv Syst. 1950;11(8):241–3.

    CAS  PubMed  Google Scholar 

  51. Halberstadt AL, Chatha M, Klein AK, McCorvy JD, Meyer MR, Wagmann L, et al. Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of d-lysergic acid diethylamide (LSD). Neuropharmacology. 2019;19:107856.

    Google Scholar 

  52. De Gregorio D, Posa L, Ochoa-Sanchez R, McLaughlin R, Maione S, Comai S, et al. The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors. Pharmacol Res. 2016;113(Pt A):81–91.

    PubMed  Google Scholar 

  53. Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001;60(6):1181–8.

    CAS  PubMed  Google Scholar 

  54. Lopez-Gimenez JF, Gonzalez-Maeso J. Hallucinogens and serotonin 5-HT2A receptor-mediated signaling pathways. Curr Top Behav Neurosci. 2018;36:45–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Titeler M, Lyon RA, Glennon RA. Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology (Berl). 1988;94(2):213–6.

    CAS  Google Scholar 

  56. Glennon RA, Titeler M, McKenney JD. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 1984;35(25):2505–11.

    CAS  PubMed  Google Scholar 

  57. Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res. 2015;15(277):99–120.

    Google Scholar 

  58. De Gregorio D, Comai S, Posa L, Gobbi G. d-Lysergic acid diethylamide (LSD) as a model of psychosis: mechanism of action and pharmacology. Int J Mol Sci. 2016;17(11):1953.

    PubMed Central  Google Scholar 

  59. Anastasopoulos G, Photiades H. Effects of LSD-25 on relatives of schizophrenic patients. J Ment Sci. 1962;108:95–8.

    CAS  PubMed  Google Scholar 

  60. Langs RJ, Barr HL. Lysergic acid diethylamide (LSD-25) and schizophrenic reactions. A comparative study. J Nerv Ment Dis. 1968;147(2):163–72.

    CAS  PubMed  Google Scholar 

  61. Hoch PH, Cattell JP, Pennes HH. Effects of mescaline and lysergic acid (d-LSD-25). Am J Psychiatry. 1952;108(8):579–84.

    CAS  PubMed  Google Scholar 

  62. Gouzoulis-Mayfrank E, Habermeyer E, Hermle L, Steinmeyer A, Kunert H, Sass H. Hallucinogenic drug induced states resemble acute endogenous psychoses: results of an empirical study. Eur Psychiatry. 1998;13(8):399–406.

    CAS  PubMed  Google Scholar 

  63. Selvaraj S, Arnone D, Cappai A, Howes O. Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci Biobehav Rev. 2014;45:233–45.

    CAS  PubMed  Google Scholar 

  64. Radhakrishnan R, Matuskey D, Nabulsi N, Gaiser E, Gallezot JD, Henry S, et al. In vivo 5-HT6 and 5-HT2A receptor availability in antipsychotic treated schizophrenia patients vs. unmedicated healthy humans measured with [(11)C]GSK215083 PET. Psychiatry Res Neuroimaging. 2020;295:111007.

    PubMed  Google Scholar 

  65. Mann JJ, Metts AV, Ogden RT, Mathis CA, Rubin-Falcone H, Gong Z, et al. Quantification of 5-HT1A and 5-HT2A receptor binding in depressed suicide attempters and non-attempters. Arch Suicide Res. 2019;23(1):122–33.

    PubMed  Google Scholar 

  66. Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res. 1995;688(1–2):121–33.

    CAS  PubMed  Google Scholar 

  67. Hurlemann R, Matusch A, Kuhn KU, Berning J, Elmenhorst D, Winz O, et al. 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacology (Berl). 2008;195(4):579–90.

    CAS  Google Scholar 

  68. Rasmussen H, Frokjaer VG, Hilker RW, Madsen J, Anhoj S, Oranje B, et al. Low frontal serotonin 2A receptor binding is a state marker for schizophrenia? Eur Neuropsychopharmacol. 2016;26(7):1248–50.

    CAS  PubMed  Google Scholar 

  69. Cheah SY, Lawford BR, Young RM, Morris CP, Voisey J. mRNA expression and DNA methylation analysis of serotonin receptor 2A (HTR2A) in the human schizophrenic brain. Genes (Basel). 2017;8(1):E14.

    Google Scholar 

  70. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148(10):1301–8.

    CAS  PubMed  Google Scholar 

  71. Kantrowitz JT, Javitt DC. Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models. Clin Schizophr Relat Psychoses. 2010;4(3):189–200.

    PubMed  PubMed Central  Google Scholar 

  72. Rosenbaum G, Cohen BD, Luby ED, Gottlieb JS, Yelen D. Comparison of sernyl with other drugs: simulation of schizophrenic performance with sernyl, LSD-25, and amobarbital (Amytal) sodium, I: attention, motor function and proprioception. Arch Gen Psychiatry. 1959;1:651–6.

    CAS  Google Scholar 

  73. Luby ED, Gottlieb JS, Cohen BD, Rosenbaum G, Domino EF. Model psychoses and schizophrenia. Am J Psychiatry. 1962;119:61–7.

    CAS  PubMed  Google Scholar 

  74. Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Obradovic M, et al. Psychological effects of (S)-ketamine and N, N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry. 2005;38(6):301–11.

    CAS  PubMed  Google Scholar 

  75. Kantrowitz JT, Tampi RR. Risk of psychosis exacerbation by tricyclic antidepressants in unipolar Major Depressive Disorder with psychotic features. J Affect Disord. 2008;106(3):279–84.

    CAS  PubMed  Google Scholar 

  76. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25(4):455–67.

    CAS  PubMed  Google Scholar 

  77. Heekeren K, Daumann J, Neukirch A, Stock C, Kawohl W, Norra C, et al. Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis. Psychopharmacology (Berl). 2008;199(1):77–88.

    CAS  Google Scholar 

  78. Umbricht D, Vollenweider FX, Schmid L, Grubel C, Skrabo A, Huber T, et al. Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology. 2003;28(1):170–81.

    CAS  PubMed  Google Scholar 

  79. McKenna DJ, Repke DB, Lo L, Peroutka SJ. Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes. Neuropharmacology. 1990;29(3):193–8.

    CAS  PubMed  Google Scholar 

  80. Naatanen R, Sussman ES, Salisbury D, Shafer VL. Mismatch negativity (MMN) as an index of cognitive dysfunction. Brain Topogr. 2014;27(4):451–66.

    PubMed  PubMed Central  Google Scholar 

  81. Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res. 2005;76(1):1–23.

    PubMed  Google Scholar 

  82. Javitt DC, Spencer KM, Thaker GK, Winterer G, Hajos M. Neurophysiological biomarkers for drug development in schizophrenia. Nat Rev Drug Discov. 2008;7(1):68–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Light GA, Swerdlow NR, Thomas ML, Calkins ME, Green MF, Greenwood TA, et al. Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2. Schizophr Res. 2015;163(1–3):63–72.

    PubMed  Google Scholar 

  84. Erickson MA, Ruffle A, Gold JM. A meta-analysis of mismatch negativity in schizophrenia: from clinical risk to disease specificity and progression. Biol Psychiatry. 2016;79(12):980–7.

    PubMed  Google Scholar 

  85. Kantrowitz JT, Epstein ML, Lee M, Lehrfeld N, Nolan KA, Shope C, et al. Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: correlation with symptoms. Schizophr Res. 2018;191:70–9.

    PubMed  Google Scholar 

  86. Kantrowitz JT, Epstein ML, Beggel O, Rohrig S, Lehrfeld JM, Revheim N, et al. Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist d-serine. Brain. 2016;139(Pt 12):3281–95.

    PubMed  PubMed Central  Google Scholar 

  87. Greenwood LM, Leung S, Michie PT, Green A, Nathan PJ, Fitzgerald P, et al. The effects of glycine on auditory mismatch negativity in schizophrenia. Schizophr Res. 2018;191:61–9.

    PubMed  Google Scholar 

  88. Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O, et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology. 2008;33(9):2187–99.

    CAS  PubMed  Google Scholar 

  89. Kantrowitz JT, Swerdlow NR, Dunn W, Vinogradov S. Auditory system target engagement during plasticity-based interventions in schizophrenia: a focus on modulation of N-methyl-d-aspartate-type glutamate receptor function. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3(7):581–90.

    PubMed  PubMed Central  Google Scholar 

  90. Umbricht D, Javitt D, Novak G, Bates J, Pollack S, Lieberman J, et al. Effects of risperidone on auditory event-related potentials in schizophrenia. Int J Neuropsychopharmacol. 1999;2(4):299–304.

    CAS  PubMed  Google Scholar 

  91. Umbricht D, Javitt D, Novak G, Bates J, Pollack S, Lieberman J, et al. Effects of clozapine on auditory event-related potentials in schizophrenia. Biol Psychiatry. 1998;44(8):716–25.

    CAS  PubMed  Google Scholar 

  92. Friedman T, Sehatpour P, Dias E, Perrin M, Javitt DC. Differential relationships of mismatch negativity and visual p1 deficits to premorbid characteristics and functional outcome in schizophrenia. Biol Psychiatry. 2012;71(6):521–9.

    PubMed  Google Scholar 

  93. Kahkonen S, Makinen V, Jaaskelainen IP, Pennanen S, Liesivuori J, Ahveninen J. Serotonergic modulation of mismatch negativity. Psychiatry Res. 2005;138(1):61–74.

    PubMed  Google Scholar 

  94. Leung S, Croft RJ, Guille V, Scholes K, O’Neill BV, Phan KL, et al. Acute dopamine and/or serotonin depletion does not modulate mismatch negativity (MMN) in healthy human participants. Psychopharmacology (Berl). 2010;208(2):233–44.

    CAS  Google Scholar 

  95. Shiga T, Horikoshi S, Kanno K, Kanno-Nozaki K, Hikita M, Itagaki S, et al. Plasma levels of dopamine metabolite correlate with mismatch negativity in patients with schizophrenia. Psychiatry Clin Neurosci. 2020.

  96. Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17(8):2921–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998;281(5381):1349–52.

    CAS  PubMed  Google Scholar 

  98. Moghaddam B, Krystal JH. Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull. 2012;38(5):942–9.

    PubMed  PubMed Central  Google Scholar 

  99. Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maeso J. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett. 2011;493(3):76–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Moreno JL, Holloway T, Rayannavar V, Sealfon SC, Gonzalez-Maeso J. Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice. Neurosci Lett. 2013;1(536):69–73.

    Google Scholar 

  101. Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, et al. Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci. 2003;23(26):8836–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Santini MA, Balu DT, Puhl MD, Hill-Smith TE, Berg AR, Lucki I, et al. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI. Behav Brain Res. 2014;1(259):242–6.

    Google Scholar 

  103. Meltzer HY, Matsubara S, Lee JC. The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol Bull. 1989;25(3):390–2.

    CAS  PubMed  Google Scholar 

  104. Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther. 1989;251(1):238–46.

    CAS  PubMed  Google Scholar 

  105. Olten B, Bloch MH. Meta regression: Relationship between antipsychotic receptor binding profiles and side-effects. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):272–81.

    CAS  PubMed  Google Scholar 

  106. Blasi G, Selvaggi P, Fazio L, Antonucci LA, Taurisano P, Masellis R, et al. Variation in dopamine D2 and serotonin 5-HT2A receptor genes is associated with working memory processing and response to treatment with antipsychotics. Neuropsychopharmacology. 2015;40(7):1600–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Tollens F, Gass N, Becker R, Schwarz AJ, Risterucci C, Kunnecke B, et al. The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity. Eur Neuropsychopharmacol. 2018;28(9):1035–46.

    CAS  PubMed  Google Scholar 

  108. Kantrowitz JT. The potential role of lumateperone-something borrowed? something new? JAMA Psychiatry. 2020.

  109. Lieberman JA, Davis RE, Correll CU, Goff DC, Kane JM, Tamminga CA, et al. ITI-007 for the treatment of schizophrenia: a 4-week randomized, double-blind, controlled trial. Biol Psychiatry. 2016;79(12):952–61.

    CAS  PubMed  Google Scholar 

  110. Shahid M, Walker GB, Zorn SH, Wong EH. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol. 2009;23(1):65–73.

    CAS  PubMed  Google Scholar 

  111. Snyder GL, Vanover KE, Zhu H, Miller DB, O’Callaghan JP, Tomesch J, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 2015;232(3):605–21.

    CAS  Google Scholar 

  112. Kusumi I, Boku S, Takahashi Y. Psychopharmacology of atypical antipsychotic drugs: from the receptor binding profile to neuroprotection and neurogenesis. Psychiatry Clin Neurosci. 2015;69(5):243–58.

    CAS  PubMed  Google Scholar 

  113. Anon. Nuplazid prescribing information; 2018. https://www.nuplazid.com/pdf/NUPLAZID-Prescribing-Information-PI-v8-Sep-2018.pdf.

  114. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76.

    CAS  PubMed  Google Scholar 

  115. Leucht S, Crippa A, Siafis S, Patel MX, Orsini N, Davis JM. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry. 2020;177(4):342–53.

    PubMed  Google Scholar 

  116. Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin C, Farde L, et al. PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Int J Neuropsychopharmacol. 2008;11(2):163–71.

    CAS  PubMed  Google Scholar 

  117. Nasrallah HA, Fedora R, Morton R. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res. 2019;208:217–20.

    PubMed  Google Scholar 

  118. Bugarski-Kirola D, Arango C, Fava M, Nasrallah H, Liu IY, Abbs B, et al. ADVANCE: phase 2, randomized, double-blind, placebo- controlled study of adjunctive pimavanserin in patients with negative symptoms of schizophrenia. American Society of Clinical Psychopharmacology Annual Meeting (virtual meeting); 2020.

  119. Axelrod BN, Goldman RS, Alphs LD. Validation of the 16-item Negative Symptom Assessment. J Psychiatr Res. 1993;27(3):253–8.

    CAS  PubMed  Google Scholar 

  120. Various Posters. J Prev Alzheimer’s Dis. 2019;6(1):45–154.

  121. Keefe RSE, Harvey PD, Khan A, Saoud JB, Staner C, Davidson M, et al. Cognitive effects of MIN-101 in patients with schizophrenia and negative symptoms: results from a randomized controlled trial. J Clin Psychiatry. 2018;79(3).

  122. White L, Harvey PD, Opler L, Lindenmayer JP. Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. The PANSS Study Group. Psychopathology. 1997;30(5):263–74.

    CAS  PubMed  Google Scholar 

  123. Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68(2–3):283–97.

    PubMed  Google Scholar 

  124. Rinaldi-Carmona M, Congy C, Santucci V, Simiand J, Gautret B, Neliat G, et al. Biochemical and pharmacological properties of SR 46349B, a new potent and selective 5-hydroxytryptamine2 receptor antagonist. J Pharmacol Exp Ther. 1992;262(2):759–68.

    CAS  PubMed  Google Scholar 

  125. Meltzer HY, Arvanitis L, Bauer D, Rein W. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry. 2004;161(6):975–84.

    PubMed  Google Scholar 

  126. Truffinet P, Tamminga CA, Fabre LF, Meltzer HY, Riviere ME, Papillon-Downey C. Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia. Am J Psychiatry. 1999;156(3):419–25.

    CAS  PubMed  Google Scholar 

  127. Sramek JJ, Kirkesseli S, Paccaly-Moulin A, Davidson J, Jhee SS, Hourani J, et al. A bridging study of fananserin in schizophrenic patients. Psychopharmacol Bull. 1998;34(4):811–8.

    CAS  PubMed  Google Scholar 

  128. Den Boer JA, Vahlne JO, Post P, Heck AH, Daubenton F, Olbrich R. Ritanserin as add-on medication to neuroleptic therapy for patients with chronic or subchronic schizophrenia. Hum Psychopharmacol. 2000;15(3):179–89.

    Google Scholar 

  129. Nishio H, Inoue A, Nakata Y. Binding affinity of sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes. Arch Int Pharmacodyn Ther. 1996;331(2):189–202.

    CAS  PubMed  Google Scholar 

  130. Duinkerke SJ, Botter PA, Jansen AA, van Dongen PA, van Haaften AJ, Boom AJ, et al. Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial. Br J Psychiatry. 1993;163:451–5.

    CAS  PubMed  Google Scholar 

  131. Akhondzadeh S, Malek-Hosseini M, Ghoreishi A, Raznahan M, Rezazadeh SA. Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1879–83.

    CAS  PubMed  Google Scholar 

  132. Kinon BJ, Millen BA, Zhang L, McKinzie DL. Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia. Biol Psychiatry. 2015;78(11):754–62.

    CAS  PubMed  Google Scholar 

  133. Kantrowitz JT, Grinband J, Goff DC, Lahti AC, Marder SR, Kegeles LS, et al. Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers. Neuropsychopharmacology. 2020.

  134. Mehta MA, Schmechtig A, Kotoula V, McColm J, Jackson K, Brittain C, et al. Group II metabotropic glutamate receptor agonist prodrugs LY2979165 and LY2140023 attenuate the functional imaging response to ketamine in healthy subjects. Psychopharmacology (Berl). 2018;235(7):1875–86.

    CAS  Google Scholar 

  135. Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, et al. A non-D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med. 2020;382(16):1497–506.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY, USA

    Joshua T. Kantrowitz

  2. Department of Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032, USA

    Joshua T. Kantrowitz

  3. Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY, 10914, USA

    Joshua T. Kantrowitz

Authors
  1. Joshua T. Kantrowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joshua T. Kantrowitz.

Ethics declarations

Funding

No funding was received specifically for the preparation of this article.

Conflict of interest

Dr. Kantrowitz reports having received consulting payments within the last 24 months from Krog & Partners Incorporated, Alphasights, Charles River Associates, Putnam Associates, Third Bridge, Piper Jaffray, MEDACorp, Simon Kucher, LifeSci Capital, ECRI Institute, ExpertConnect, Cellohealth, Acsel Health, Strafluence, Guidepoint, L.E.K. and System Analytic. He has served on the Aristada Schizophrenia Advisory Board for Alkermes and the MedinCell Psychiatry Advisory Board. He has conducted clinical research supported by the NIMH, Roche, Sunovion, the Stanley Foundation, Takeda, Taisho, Lundbeck, Boehringer Ingelheim, NeuroRX, Teva and Lilly within the last 24 months. Dr. Kantrowitz is a co-investigator on a study that receives lumeteperone and reimbursement for safety testing for investigator-initiated research from Intra-Cellular Therapies Inc. He owns a small number of shares of common stock from GSK.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author contributions

Not applicable.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kantrowitz, J.T. Targeting Serotonin 5-HT2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches. CNS Drugs 34, 947–959 (2020). https://doi.org/10.1007/s40263-020-00752-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-020-00752-2

Search

Navigation