Skip to main content

Pharmacotherapy and Emerging Treatment Strategies for Schizophrenia

  • Chapter
  • First Online:
Cognizance of Schizophrenia:: A Profound Insight into the Psyche

Abstract

Schizophrenia (ScZ) is a mental condition in which individuals’ views of reality are distorted. Hallucinations, delusions, altered cognition, and behavior are some of the symptoms of ScZ, making it a challenging condition to deal with daily life. Recognizing the clinical manifestations of ScZ early is essential. It is caused by genetic factors, alterations in the neurotransmitter system, mitochondrial dysfunction, immunological variables, and psychological issues. Apart from these causes, traumatic events in childhood or particularly cannabis consumption during adolescence (a critical phase in the development of the brain) may influence the disease’s origin, progression, and relapse risk. Initiating early treatment immediately after the initial episode of psychosis is important for recovery. The patients usually require long-term treatment. There are multiple medications available for treating and managing symptoms associated with ScZ. These medicines have been shown to ameliorate the symptoms related to ScZ. However, several drugs show adverse side effects. This chapter discusses the well-known drugs and the mechanism of action, and some of the emerging compounds that can be used to treat ScZ effectively. Curcumin, emodin, stigmasterol, spinach, vitamins, exogenous melatonin, and cannabidiol, among other developing medicines, have all been proven to ameliorate symptoms linked with schizophrenia.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abbas A, Roth BL (2008) Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opin Pharmacother 9(18):3251–3259

    Article  CAS  Google Scholar 

  • Akhondzadeh S, Mohammadi N, Noroozian M, Karamghadiri N, Ghoreishi A, Jamshidi AH, Forghani S (2009) Added ondansetron for stable schizophrenia: a double blind, placebo controlled trial. Schizophr Res 107(2–3):206–212

    Article  Google Scholar 

  • Amiri S, Dizaji R, Momeny M, Gauvin E, Hosseini MJ (2021) Clozapine attenuates mitochondrial dysfunction, inflammatory gene expression, and behavioral abnormalities in an animal model of schizophrenia. Neuropharmacology 187:108503

    Article  CAS  Google Scholar 

  • Andrabi SS, Vishnoi S, Kaushik M, Parveen K, Tabassum H, Akram M, Parvez S (2019) Reversal of schizophrenia-like symptoms and cholinergic alterations by melatonin. Arch Med Res 50(5):295–303

    Article  CAS  Google Scholar 

  • Arnt J, Bang-Andersen B, Grayson B, Bymaster FP, Cohen MP, DeLapp NW, Giethlen B, Kreilgaard M, McKinzie DL, Neill JC, Nelson DL, Nielsen SM, Poulsen MN, Schaus JM, Witten LM (2010) Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol 13(8):1021–1033

    Article  CAS  Google Scholar 

  • Asmal L, Flegar SJ, Wang J, Rummel-Kluge C, Komossa K, Leucht S (2013) Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev (11):CD006625

    Google Scholar 

  • Au AF, Luthra V, Stern R (2004) Clozapine-induced acute interstitial nephritis. Am J Psychiatry 161(8):1501

    Article  Google Scholar 

  • Baandrup L (2020) Polypharmacy in schizophrenia. Basic Clin Pharmacol Toxicol 126(3):183–192

    Article  CAS  Google Scholar 

  • Ballon J, Stroup TS (2013) Polypharmacy for schizophrenia. Curr Opin Psychiatry 26(2):208–213

    Article  Google Scholar 

  • Bansal V, Chatterjee I (2022) Association of vitamins and neurotransmitters: understanding the effect on schizophrenia. Neurochem J 16(1):39–45

    Article  CAS  Google Scholar 

  • Barbui C, Bighelli I, Carrà G, Castellazzi M, Lucii C, Martinotti G, Nosè M, Ostuzzi G, Star Network Investigators (2016) Antipsychotic dose mediates the association between polypharmacy and corrected QT interval. PLoS One 11(2):e0148212

    Article  Google Scholar 

  • Barnes TR, Paton C (2011) Antipsychotic polypharmacy in schizophrenia: benefits and risks. CNS Drugs 25(5):383–399

    Article  Google Scholar 

  • Barnes TR, Schizophrenia Consensus Group of British Association for Psychopharmacology (2011) Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 25(5):567–620

    Article  CAS  Google Scholar 

  • Barnes NM, Hales TG, Lummis SC, Peters JA (2009a) The 5-HT3 receptor--the relationship between structure and function. Neuropharmacology 56(1):273–284

    Article  CAS  Google Scholar 

  • Barnes TR, Shingleton-Smith A, Paton C (2009b) Antipsychotic long-acting injections: prescribing practice in the UK. Br J Psychiatry 52(Suppl):S37–S42

    Article  Google Scholar 

  • Brown HE, Roffman JL (2014) Vitamin supplementation in the treatment of schizophrenia. CNS Drugs 28(7):611–622

    Article  CAS  Google Scholar 

  • Brunton L, Chabner B, Knollman B (2010) Goodman and Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-Hill Professional, New York, NY. ISBN 978-0-07-162442-8

    Google Scholar 

  • Buckley PF (1997) New dimensions in the pharmacologic treatment of schizophrenia and related psychoses. J Clin Pharmacol 37(5):363–378

    Article  CAS  Google Scholar 

  • Bymaster FP, Hemrick-Luecke SK, Perry KW, Fuller RW (1996) Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, alpha 1-adrenergic and muscarinic receptors in vivo in rats. Psychopharmacology 124(1–2):87–94

    Article  CAS  Google Scholar 

  • Caruso F, Rossi M, Kaur S, Garcia-Villar E, Molasky N, Belli S, Sitek JD, Gionfra F, Pedersen JZ, Incerpi S (2020) Antioxidant properties of embelin in cell culture. Electrochemistry and theoretical mechanism of scavenging. potential scavenging of superoxide radical through the cell membrane. Antioxidants 9(5):382

    Article  CAS  Google Scholar 

  • Casey DE, Zorn SH (2001) The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 62(7):4–10

    CAS  Google Scholar 

  • Citrome L, McEvoy JP, Todtenkopf MS, McDonnell D, Weiden PJ (2019) A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future. Neuropsychiatr Dis Treat 15:2559–2569

    Article  CAS  Google Scholar 

  • Constantine RJ, Andel R, McPherson M, Tandon R (2015) The risks and benefits of switching patients with schizophrenia or schizoaffective disorder from two to one antipsychotic medication: a randomized controlled trial. Schizophr Res 166(1–3):194–200

    Article  Google Scholar 

  • Correll CU, Frederickson AM, Kane JM, Manu P (2007) Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res 89(1–3):91–100

    Article  Google Scholar 

  • Correll CU, Shaikh L, Gallego JA, Nachbar J, Olshanskiy V, Kishimoto T, Kane JM (2011) Antipsychotic polypharmacy: a survey study of prescriber attitudes, knowledge and behavior. Schizophr Res 131(1–3):58–62

    Article  Google Scholar 

  • Cui Y, Chen LJ, Huang T, Ying JQ, Li J (2020) The pharmacology, toxicology and therapeutic potential of anthraquinone derivative emodin. Chin J Nat Med 18(6):425–435

    CAS  Google Scholar 

  • Cui X, McGrath JJ, Burne T, Eyles DW (2021) Vitamin D and schizophrenia: 20 years on. Mol Psychiatry 26(7):2708–2720

    Article  Google Scholar 

  • Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C (2014) Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383(9916):533–540

    Article  CAS  Google Scholar 

  • Dassa D, Kaladjian A, Azorin JM, Giudicelli S (1993) Clozapine in the treatment of psychotic refractory depression. Br J Psychiatry 163:822–824

    Article  CAS  Google Scholar 

  • Davies C, Bhattacharyya S (2019) Cannabidiol as a potential treatment for psychosis. Ther Adv Psychopharmacol 9:2045125319881916

    Article  CAS  Google Scholar 

  • Davis RE, Correll CU (2016) ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother 16(6):601–614

    Article  CAS  Google Scholar 

  • Divac N, Prostran M, Jakovcevski I, Cerovac N (2014) Second-generation antipsychotics and extrapyramidal adverse effects. Biomed Res Int 2014:656370

    Article  Google Scholar 

  • Dome P, Teleki Z, Kotanyi R (2007) Paralytic ileus associated with combined atypical antipsychotic therapy. Prog Neuro-Psychopharmacol Biol Psychiatry 31(2):557–560

    Article  CAS  Google Scholar 

  • Duan C, Jenkins ZM, Castle D (2021) Therapeutic use of melatonin in schizophrenia: a systematic review. World J Psychiatry 11(8):463–476

    Article  Google Scholar 

  • Dunlop J, Watts SW, Barrett JE, Coupet J, Harrison B, Mazandarani H, Nawoschik S, Pangalos MN, Ramamoorthy S, Schechter L, Smith D, Stack G, Zhang J, Zhang G, Rosenzweig-Lipson S (2011) Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist. J Pharmacol Exp Ther 337(3):673–680

    Article  CAS  Google Scholar 

  • Durg S, Naveen Kumar B, Vandal R, Dhadde SB, Thippeswamy BS, Veerapur VP, Badami S (2017) Antipsychotic activity of embelin isolated from Embelia ribes: a preliminary study. Biomed Pharmacother 90:328–331

    Article  CAS  Google Scholar 

  • Elbe D (2010) Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. J Can Acad Child Adolesc Psychiatry 19(3):230

    Google Scholar 

  • Emsley R, Oosthuizen P, van Rensburg SJ (2003) Clinical potential of omega-3 fatty acids in the treatment of schizophrenia. CNS Drugs 17(15):1081–1091

    Article  CAS  Google Scholar 

  • van Epen JH (1970) Experience with fluspirilene (R 6218), a long-acting neuroleptic. Psychiatr Neurol Neurochir 73(4):277–284

    Google Scholar 

  • Feng B, Mills JB, Davidson RE, Mireles RJ, Janiszewski JS, Troutman MD, de Morais SM (2008) In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos 36(2):268–275

    Article  CAS  Google Scholar 

  • Freedman R (2003) Schizophrenia. N Engl J Med 349(18):1738–1749

    Article  CAS  Google Scholar 

  • Freudenreich O, Goff DC (2002) Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 106(5):323–330

    Article  CAS  Google Scholar 

  • Friedman JH (2013) Pimavanserin for the treatment of Parkinson’s disease psychosis. Expert Opin Pharmacother 14(14):1969–1975

    Article  CAS  Google Scholar 

  • Friend DG (1959) Polypharmacy; multiple-ingredient and shotgun prescriptions. N Engl J Med 260(20):1015–1018

    Article  CAS  Google Scholar 

  • Froemming JS, Lam YW, Jann MW, Davis CM (1989) Pharmacokinetics of haloperidol. Clin Pharmacokinet 17(6):396–423

    Article  CAS  Google Scholar 

  • Funahashi M, Mitoh Y, Matsuo R (2004) Activation of presynaptic 5-HT3 receptors facilitates glutamatergic synaptic inputs to area postrema neurons in rat brain slices. Methods Find Exp Clin Pharmacol 26(8):615–622

    Article  CAS  Google Scholar 

  • Galimberti D, Scarpini E (2015) Idalopirdine as a treatment for Alzheimer’s disease. Expert Opin Investig Drugs 24(7):981–987

    Article  CAS  Google Scholar 

  • Gammone MA, Riccioni G, Parrinello G, D’Orazio N (2018) Omega-3 polyunsaturated fatty acids: benefits and endpoints in sport. Nutrients 11(1):46

    Article  Google Scholar 

  • Gao J, Li M (2014) Differential effects of intermittent versus continuous haloperidol treatment throughout adolescence on haloperidol sensitization and social behavior in adulthood. Prog Neuro-Psychopharmacol Biol Psychiatry 54:67–75

    Article  CAS  Google Scholar 

  • Garay RP, Bourin M, de Paillette E, Samalin L, Hameg A, Llorca PM (2016) Potential serotonergic agents for the treatment of schizophrenia. Expert Opin Investig Drugs 25(2):159–170

    Article  CAS  Google Scholar 

  • García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J (2020) Cannabidiol: a potential new alternative for the treatment of anxiety, depression, and psychotic disorders. Biomolecules 10(11):1575

    Article  Google Scholar 

  • Garnock-Jones KP (2016) Brexpiprazole: a review in schizophrenia. CNS Drugs 30(4):335–342

    Article  CAS  Google Scholar 

  • Garnock-Jones KP (2017) Cariprazine: a review in schizophrenia. CNS Drugs 31(6):513–525

    Article  CAS  Google Scholar 

  • Gerson SL, Meltzer H (1992) Mechanisms of clozapine-induced agranulocytosis. Drug Saf 7(1):17–25

    Article  Google Scholar 

  • Goh KK, Chen CY, Chen CH, Lu ML (2021) Effects of omega-3 polyunsaturated fatty acids supplements on psychopathology and metabolic parameters in schizophrenia: a meta-analysis of randomized controlled trials. J Psychopharmacol 35(3):221–235

    Article  CAS  Google Scholar 

  • Goodnick PJ (2001) Ziprasidone: profile on safety. Expert Opin Pharmacother 2(10):1655–1662

    Article  CAS  Google Scholar 

  • Gorelick J, Iraqi RH, Bernstein N (2020) Ecdysteroid content and therapeutic activity in elicited spinach accessions. Plants 9(6):727

    Article  CAS  Google Scholar 

  • Grech P, Taylor D (2012) Long-term antipsychotic polypharmacy: how does it start, why does it continue? Ther Adv Psychopharmacol 2(1):5–11

    Article  Google Scholar 

  • Greenberg WM, Citrome L (2007) Ziprasidone for schizophrenia and bipolar disorder: a review of the clinical trials. CNS Drug Rev 13(2):137–177

    Article  CAS  Google Scholar 

  • Gründer G, Hippius H, Carlsson A (2009) The ‘atypicality’ of antipsychotics: a concept re-examined and re-defined. Nat Rev Drug Discov 8(3):197–202

    Article  Google Scholar 

  • Gupta G, Kazmi I, Afzal M, Upadhyay G, Singh RK, Habtemariam S (2013) Antidepressant-like activity of Embelin isolated from Embelia ribes. Phytopharmacology 4:87

    CAS  Google Scholar 

  • Hamelin BA, Allard S, Laplante L, Miceli J, Wilner KD, Tremblay J, LeBel M (1998) The effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic agent ziprasidone. Pharmacotherapy 18(1):9–15

    CAS  Google Scholar 

  • Hartung B, Sampson S, Leucht S (2015) Perphenazine for schizophrenia. Cochrane Database Syst Rev 2015(3):CD003443

    Google Scholar 

  • Hashimoto Y, Uno J, Miwa T, Kurihara M, Tanifuji H, Tensho M (2012) Effects of antipsychotic polypharmacy on side-effects and concurrent use of medications in schizophrenic outpatients. Psychiatry Clin Neurosci 66(5):405–410

    Article  Google Scholar 

  • Hippius H (1989) The history of clozapine. Psychopharmacology 99:S3–S5

    Article  Google Scholar 

  • Hjorth S (2021) The more, the merrier…? Antipsychotic polypharmacy treatment strategies in schizophrenia from a pharmacology perspective. Front Psychiatry 12:760181

    Article  Google Scholar 

  • Homayoun H, Moghaddam B (2007) Fine-tuning of awake prefrontal cortex neurons by clozapine: comparison with haloperidol and N-desmethylclozapine. Biol Psychiatry 61(5):679–687

    Article  CAS  Google Scholar 

  • Ijaz S, Bolea B, Davies S, Savović J, Richards A, Sullivan S, Moran P (2020) Antipsychotic polypharmacy and metabolic syndrome in schizophrenia: a review of systematic reviews. Focus 18(4):482–492

    Article  Google Scholar 

  • Ito H, Koyama A, Higuchi T (2005) Polypharmacy and excessive dosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry 187:243–247

    Article  Google Scholar 

  • Jacob S, Ibrahim MM, Mohammed F (2013) Polypharmacy in the management of patients with schizophrenia on risperidone in a tertiary-care hospital in Malaysia. Ment Health Fam Med 10(1):37–43

    Google Scholar 

  • Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, Marsboom RH, Hérin VV, Schaper WK (1970) The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug. Arzneim Forsch 20(11):1689–1698

    CAS  Google Scholar 

  • Janssen-Cilag. Janssen-Cilag. Risperdal. Janssen-Cilag product information; 2005.

    Google Scholar 

  • Jaszczyszyn A, Gąsiorowski K, Świątek P, Malinka W, Cieślik-Boczula K, Petrus J, Czarnik-Matusewicz B (2012) Chemical structure of phenothiazines and their biological activity. Pharmacol Rep 64(1):16–23

    Article  CAS  Google Scholar 

  • Johnson M, Kozielska M, Pilla Reddy V, Vermeulen A, Li C, Grimwood S, de Greef R, Groothuis GM, Danhof M, Proost JH (2011) Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D2 receptor occupancy of olanzapine in rats. Pharm Res 28(10):2490–2504

    Article  CAS  Google Scholar 

  • Kahn RS, Sommer IE (2015) The neurobiology and treatment of first-episode schizophrenia. Mol Psychiatry 20(1):84–97

    Article  CAS  Google Scholar 

  • Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45(9):789–796

    Article  CAS  Google Scholar 

  • Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW (2002) Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 63(9):763–771

    Article  CAS  Google Scholar 

  • Khan H, Chaudhary A, Ali Khan R, Ali W (2020) Curcumin Reverses the Scopolamine-induced Cognitive Impairment by iNOS and Acetylcholinesterase Inhibition in Rodent Model of Schizophrenia. Int J Pharmaceu Sci Drug Res 12(2):122–128

    Article  CAS  Google Scholar 

  • Khilnani G, Khilnani AK (2011) Inverse agonism and its therapeutic significance. Indian J Pharm 43(5):492–501

    Article  CAS  Google Scholar 

  • Khodaie-Ardakani MR, Seddighi S, Modabbernia A, Rezaei F, Salehi B, Ashrafi M, Shams-Alizadeh N, Mohammad-Karimi M, Esfandiari GR, Hajiaghaee R, Akhondzadeh S (2013) Granisetron as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res 47(4):472–478

    Article  Google Scholar 

  • Knöchel C, Voss M, Grüter F, Alves GS, Matura S, Sepanski B, Stäblein M, Wenzler S, Prvulovic D, Carvalho AF, Oertel-Knöchel V (2015) Omega 3 fatty acids: novel neurotherapeutic targets for cognitive dysfunction in mood disorders and schizophrenia? Curr Neuropharmacol 13(5):663–680

    Article  Google Scholar 

  • Knudson JF, Kortepeter C, Dubitsky GM, Ahmad SR, Chen M (2000) Antipsychotic drugs and venous thromboembolism. Lancet 356(9225):252–253

    Article  CAS  Google Scholar 

  • Koller EA, Cross JT, Doraiswamy PM, Malozowski SN (2003) Pancreatitis associated with atypical antipsychotics: from the Food and Drug Administration’s MedWatch surveillance system and published reports. Pharmacotherapy 23(9):1123–1130

    Article  CAS  Google Scholar 

  • Komiya H, Umegaki H, Asai A, Kanda S, Maeda K, Shimojima T, Nomura H, Kuzuya M (2018) Factors associated with polypharmacy in elderly home-care patients. Geriatr Gerontol Int 18(1):33–41

    Article  Google Scholar 

  • Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, Kissling W, Leucht S (2010) Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev (3):CD006654

    Google Scholar 

  • Kondo M, Koyama Y, Nakamura Y, Shimada S (2018) A novel 5HT3 receptor-IGF1 mechanism distinct from SSRI-induced antidepressant effects. Mol Psychiatry 23(4):833–842

    Article  CAS  Google Scholar 

  • Kong DS, Yeo SH (1989) An open clinical trial with the long-acting neuroleptics flupenthixol decanoate and fluphenazine decanoate in the maintenance treatment of schizophrenia. Pharmatherapeutica 5(6):371–379

    CAS  Google Scholar 

  • Kreyenbuhl J, Marcus SC, West JC, Wilk J, Olfson M (2007a) Adding or switching antipsychotic medications in treatment-refractory schizophrenia. Psychiatr Serv 58(7):983–990

    Article  Google Scholar 

  • Kreyenbuhl JA, Valenstein M, McCarthy JF, Ganoczy D, Blow FC (2007b) Long-term antipsychotic polypharmacy in the VA health system: patient characteristics and treatment patterns. Psychiatr Serv 58(4):489–495

    Article  Google Scholar 

  • Krogmann A, Peters L, von Hardenberg L, Bödeker K, Nöhles VB, Correll CU (2019) Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. CNS Spectr 24(S1):38–69

    Article  Google Scholar 

  • Lähteenvuo M, Tiihonen J (2021) Antipsychotic polypharmacy for the management of schizophrenia: evidence and recommendations. Drugs 81(11):1273–1284

    Article  Google Scholar 

  • Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J, American Psychiatric Association, & Steering Committee on Practice Guidelines (2004) Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 161(2):1–56

    Google Scholar 

  • Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382(9896):951–962

    Article  CAS  Google Scholar 

  • Li P, Snyder GL, Vanover KE (2016) Dopamine targeting drugs for the treatment of schizophrenia: past, present and future. Curr Top Med Chem 16(29):3385–3403

    Article  CAS  Google Scholar 

  • Liaury K, Miyaoka T, Tsumori T, Furuya M, Hashioka S, Wake R, Tsuchie K, Fukushima M, Limoa E, Tanra AJ, Horiguchi J (2014) Minocycline improves recognition memory and attenuates microglial activation in Gunn rat: a possible hyperbilirubinemia-induced animal model of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 50:184–190

    Article  CAS  Google Scholar 

  • Lin SK (2020) Antipsychotic polypharmacy: a dirty little secret or a fashion? Int J Neuropsychopharmacol 23(2):125–131

    Article  Google Scholar 

  • Lindenmayer JP, Czobor P, Volavka J, Lieberman JA, Citrome L, Sheitman B, Chakos M, McEvoy JP (2002) Olanzapine in refractory schizophrenia after failure of typical or atypical antipsychotic treatment: an open-label switch study. J Clin Psychiatry 63(10):931–935

    Article  CAS  Google Scholar 

  • Liu J, Ogden A, Comery TA, Spiros A, Roberts P, Geerts H (2014) Prediction of efficacy of vabicaserin, a 5-HT2C agonist, for the treatment of schizophrenia using a quantitative systems pharmacology model. CPT Pharmacometrics Syst Pharmacol 3(4):e111

    Article  CAS  Google Scholar 

  • Löhrs L, Hasan A (2019) Risikofaktoren für die Entstehung und den Verlauf der Schizophrenie [Risk factors for the development of schizophrenia]. Fortschr Neurol Psychiatr 87(2):133–143

    Google Scholar 

  • Maeda K, Lerdrup L, Sugino H, Akazawa H, Amada N, McQuade RD, Stensbøl TB, Bundgaard C, Arnt J, Kikuchi T (2014) Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther 350(3):605–614

    Article  Google Scholar 

  • Mann SK, Marwaha R (2022) Chlorpromazine. StatPearls. StatPearls Publishing, Treasure Island, FL

    Google Scholar 

  • Maric N, Myin-Germeys I, Delespaul P, de Graaf R, Vollebergh W, Van Os J (2004) Is our concept of schizophrenia influenced by Berkson’s bias? Soc Psychiatry Psychiatr Epidemiol 39(8):600–605

    Article  CAS  Google Scholar 

  • Maric NP, Jovicic MJ, Mihaljevic M, Miljevic C (2016) Improving current treatments for schizophrenia. Drug Dev Res 77(7):357–367

    Article  CAS  Google Scholar 

  • Markovic M, Gallipani A, Patel KH, Maroney M (2017) Brexpiprazole. Ann Pharmacother 51(4):315–322

    Article  CAS  Google Scholar 

  • Matar HE, Almerie MQ, Sampson SJ (2018) Fluphenazine (oral) versus placebo for schizophrenia. Cochrane Database Syst Rev 6(6):CD006352

    Google Scholar 

  • McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK, CATIE Investigators (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 163(4):600–610

    Article  Google Scholar 

  • McKim WA (2007) Drugs and behavior: an introduction to behavioral pharmacology, 6th edn. Prentice Hall, Upper Saddle River, NJ, p 416. ISBN 978-0-13-219788-5

    Google Scholar 

  • Melkersson KI, Hulting AL, Brismar KE (2000) Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry 61(10):742–749

    Article  CAS  Google Scholar 

  • Meltzer HY, Huang M (2008) In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog Brain Res 172:177–197

    Article  CAS  Google Scholar 

  • Meltzer HY, Massey BW (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 11(1):59–67

    Article  CAS  Google Scholar 

  • Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S, International Suicide Prevention Trial Study Group (2003) Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60(1):82–91

    Article  CAS  Google Scholar 

  • Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (2012) Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day. Schizophr Res 141(2–3):144–152

    Article  Google Scholar 

  • Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M (2013) Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr Bull 39(2):306–318

    Article  Google Scholar 

  • Mitra S, Anjum J, Muni M, Das R, Rauf A, Islam F, Bin Emran T, Semwal P, Hemeg HA, Alhumaydhi FA, Wilairatana P (2022) Exploring the journey of emodin as a potential neuroprotective agent: novel therapeutic insights with molecular mechanism of action. Biomed Pharmacother 149:112877

    Article  CAS  Google Scholar 

  • Modabbernia A, Heidari P, Soleimani R, Sobhani A, Roshan ZA, Taslimi S, Ashrafi M, Modabbernia MJ (2014) Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res 53:133–140

    Article  Google Scholar 

  • Moghaddam AH, Maboudi K, Bavaghar B, Sangdehi S, Zare M (2021) Neuroprotective effects of curcumin-loaded nanophytosome on ketamine-induced schizophrenia-like behaviors and oxidative damage in male mice. Neurosci Lett 765:136249

    Article  CAS  Google Scholar 

  • Monsma FJ Jr, Shen Y, Ward RP, Hamblin MW, Sibley DR (1993) Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol 43(3):320–327

    CAS  Google Scholar 

  • Morera-Fumero AL, Abreu-Gonzalez P (2013) Role of melatonin in schizophrenia. Int J Mol Sci 14(5):9037–9050

    Article  Google Scholar 

  • Morozova MA, Lepilkina TA, Rupchev GE, Beniashvily AG, Burminskiy DS, Potanin SS, Bondarenko EV, Kazey VI, Lavrovsky Y, Ivachtchenko AV (2014) Add-on clinical effects of selective antagonist of 5HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: pilot study. CNS Spectr 19(4):316–323

    Article  Google Scholar 

  • Mucci F, Della Vecchia A, Baroni S, Marazziti D (2021) Cariprazine as a therapeutic option for schizophrenia: a drug evaluation. Expert Opin Pharmacother 22(4):415–426

    Article  CAS  Google Scholar 

  • Noroozian M, Ghasemi S, Hosseini SM, Modabbernia A, Khodaie-Ardakani MR, Mirshafiee O, Farokhnia M, Tajdini M, Rezaei F, Salehi B, Ashrafi M, Yekehtaz H, Tabrizi M, Akhondzadeh S (2013) A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia. Psychopharmacology 228(4):595–602

    Article  CAS  Google Scholar 

  • Onaolapo AY, Aina OA, Onaolapo OJ (2017) Melatonin attenuates behavioural deficits and reduces brain oxidative stress in a rodent model of schizophrenia. Biomed Pharmacother 92:373–383

    Article  CAS  Google Scholar 

  • Pae CU (2020) Antipsychotic polypharmacy in treatment of schizophrenia; should or should not? Chonnam Med J 56(3):157–165

    Article  CAS  Google Scholar 

  • Palmer BA, Richardson EJ, Heesacker M, DePue MK (2018) Public stigma and the label of gambling disorder: does it make a difference? J Gambl Stud 34(4):1281–1291

    Article  Google Scholar 

  • Pandina G, Lane R, Gopal S, Gassmann-Mayer C, Hough D, Remmerie B, Simpson G (2011) A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 35(1):218–226

    Article  CAS  Google Scholar 

  • Patel KR, Cherian J, Gohil K, Atkinson D (2014) Schizophrenia: overview and treatment options. P T 39(9):638–645

    Google Scholar 

  • Peres FF, Diana MC, Levin R, Suiama MA, Almeida V, Vendramini AM, Santos CM, Zuardi AW, Hallak J, Crippa JA, Abílio VC (2018) Cannabidiol administered during peri-adolescence prevents behavioral abnormalities in an animal model of schizophrenia. Front Pharmacol 9:901

    Article  Google Scholar 

  • Pluta K, Morak-Młodawska B, Jeleń M (2011) Recent progress in biological activities of synthesized phenothiazines. Eur J Med Chem 46(8):3179–3189

    Article  CAS  Google Scholar 

  • Procyshyn RM, Honer WG, Wu TK, Ko RW, McIsaac SA, Young AH, Johnson JL, Barr AM (2010) Persistent antipsychotic polypharmacy and excessive dosing in the community psychiatric treatment setting: a review of medication profiles in 435 Canadian outpatients. J Clin Psychiatry 71(5):566–573

    Article  CAS  Google Scholar 

  • Purdon SE, Malla A, Labelle A, Lit W (2001) Neuropsychological change in patients with schizophrenia after treatment with quetiapine or haloperidol. J Psychiatry Neurosci 26(2):137–149

    CAS  Google Scholar 

  • Rice DP, Kelman S, Miller LS (1992) The economic burden of mental illness. Hosp Community Psychiatry 43(12):1227–1232

    CAS  Google Scholar 

  • Rijcken CA, Monster TB, Brouwers JR, de Jong-van den Berg LT (2003) Chlorpromazine equivalents versus defined daily doses: how to compare antipsychotic drug doses? J Clin Psychopharmacol 23(6):657–659

    Article  CAS  Google Scholar 

  • Sakurai H, Bies RR, Stroup ST, Keefe RS, Rajji TK, Suzuki T, Mamo DC, Pollock BG, Watanabe K, Mimura M, Uchida H (2013) Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data. Schizophr Bull 39(3):564–574

    Article  Google Scholar 

  • Salimi K, Jarskog LF, Lieberman JA (2009) Antipsychotic drugs for first-episode schizophrenia: a comparative review. CNS Drugs 23(10):837–855

    Article  CAS  Google Scholar 

  • Sarkhel S (2009) Kaplan and Sadock’s synopsis of psychiatry: behavioral sciences/clinical psychiatry. Indian J Psychiatry 51(4):331

    Article  Google Scholar 

  • Schoevers J, Leweke JE, Leweke FM (2020) Cannabidiol as a treatment option for schizophrenia: recent evidence and current studies. Curr Opin Psychiatry 33(3):185–191

    Article  Google Scholar 

  • Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124(1–2):57–73

    Article  CAS  Google Scholar 

  • Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, McLean S, Guanowsky V, Howard HR, Lowe JA III (1995) Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 275(1):101–113

    CAS  Google Scholar 

  • Seeman P (2006) Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Target 10(4):515–531

    Article  CAS  Google Scholar 

  • Seillier A, Martinez AA, Giuffrida A (2020) Differential effects of Δ9-tetrahydrocannabinol dosing on correlates of schizophrenia in the sub-chronic PCP rat model. PLoS One 15(3):e0230238

    Article  CAS  Google Scholar 

  • Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R (2002) Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 159(4):561–566

    Article  Google Scholar 

  • Shen WW (1994) Pharmacotherapy of schizophrenia: the American current status. Keio J Med 43(4):192–200

    Article  CAS  Google Scholar 

  • Shen JH, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams JB, Giller E, Detke MJ, Kane JM (2014) A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia. J Psychiatr Res 53:14–22

    Article  Google Scholar 

  • Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T, Haraguchi T, Kanahara N, Shiraishi T, Fujisaki M, Fukami G, Nakazato M, Iyo M, Hashimoto K (2010) A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann General Psychiatry 9:27

    Article  Google Scholar 

  • Snyder GL, Vanover KE, Zhu H, Miller DB, O’Callaghan JP, Tomesch J, Li P, Zhang Q, Krishnan V, Hendrick JP, Nestler EJ, Davis RE, Wennogle LP, Mates S (2015) Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology 232(3):605–621

    Article  CAS  Google Scholar 

  • Son H, Jung S, Shin JH, Kang MJ, Kim HJ (2018) Anti-stress and anti-depressive effects of spinach extracts on a chronic stress-induced depression mouse model through lowering blood corticosterone and increasing brain glutamate and glutamine levels. J Clin Med 7(11):406

    Article  CAS  Google Scholar 

  • Stahl SM (2016a) Mechanism of action of brexpiprazole: comparison with aripiprazole. CNS Spectr 21(1):1–6

    Article  Google Scholar 

  • Stahl SM (2016b) Mechanism of action of cariprazine. CNS Spectr 21(2):123–127

    Article  Google Scholar 

  • Stauch B, Johansson LC, Cherezov V (2020) Structural insights into melatonin receptors. FEBS J 287(8):1496–1510

    Article  CAS  Google Scholar 

  • Thompson AJ, Lummis SC (2006) 5-HT3 receptors. Curr Pharm Des 12(28):3615–3630

    Article  CAS  Google Scholar 

  • Tollefson GD, Beasley CM Jr, Tran PV, Street JS, Krueger JA, Tamura RN, Graffeo KA, Thieme ME (1997) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 154(4):457–465

    Article  CAS  Google Scholar 

  • Torre DL, Falorni A (2007) Pharmacological causes of hyperprolactinemia. Ther Clin Risk Manag 3(5):929–951

    Google Scholar 

  • Tsuchie K, Miyaoka T, Furuya M, Liaury K, Ieda M, Wake R, Horiguchi J, Takechi M (2013) The effects of antipsychotics on behavioral abnormalities of the Gunn rat (unconjugated hyperbilirubinemia rat), a rat model of schizophrenia. Asian J Psychiatr 6(2):119–123

    Article  Google Scholar 

  • Uzbay T, Parlakpinar H, Akdag E, Celik T, Yararbas G, Ulusoy G, Acet A, Kose A, Kayir H (2013) Chronic melatonin treatment reverses disruption of prepulse inhibition in pinealectomized and pinealectomized-plus-ovariectomized rats. Behav Brain Res 239:1–7

    Article  CAS  Google Scholar 

  • Velligan DI, Newcomer J, Pultz J, Csernansky J, Hoff AL, Mahurin R, Miller AL (2002) Does cognitive function improve with quetiapine in comparison to haloperidol? Schizophr Res 53(3):239–248

    Article  Google Scholar 

  • Volavka J, Czobor P, Nolan K, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Cooper TB, Lieberman JA (2004) Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychopharmacol 24(2):225–228

    Article  CAS  Google Scholar 

  • Vyas P, Hwang BJ, Brašić JR (2020) An evaluation of lumateperone tosylate for the treatment of schizophrenia. Expert Opin Pharmacother 21(2):139–145

    Article  CAS  Google Scholar 

  • Wang X, Ding S, Lu Y, Jiao Z, Zhang L, Zhang Y, Yang Y, Zhang Y, Li W, Lv L (2019) Effects of sodium nitroprusside in the acute dizocilpine (MK-801) animal model of schizophrenia. Brain Res Bull 147:140–147

    Article  CAS  Google Scholar 

  • Wisher D (2012) Martindale: the complete drug reference. J Med Lib Assoc 100(1):75–76

    Article  Google Scholar 

  • Wynn JK, Green MF, Hellemann G, Karunaratne K, Davis MC, Marder SR (2018) The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: a randomized controlled study. Schizophr Res 195:572–573

    Article  Google Scholar 

  • Xia L, Liu L, Hong X, Wang D, Wei G, Wang J, Zhou H, Xu H, Tian Y, Dai Q, Wu HE, Chang C, Wang L, Kosten TR, Zhang XY (2020) One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia. Neuropsychopharmacology 45(8):1362–1368

    Article  Google Scholar 

  • Yadav M, Parle M, Jindal DK, Dhingra S (2018) Protective effects of stigmasterol against ketamine-induced psychotic symptoms: possible behavioral, biochemical and histopathological changes in mice. Pharmacol Rep 70(3):591–599

    Article  CAS  Google Scholar 

  • Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ (2006) Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study. Schizophr Res 88(1–3):102–110

    Article  Google Scholar 

  • Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU (2013) Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 16(6):1205–1218

    Article  CAS  Google Scholar 

  • Zink M, Englisch S, Meyer-Lindenberg A (2010) Polypharmacy in schizophrenia. Curr Opin Psychiatry 23(2):103–111

    Article  Google Scholar 

  • Zugno AI, Chipindo H, Canever L, Budni J, Alves de Castro A, Bittencourt de Oliveira M, Heylmann AS, Gomes Wessler P, da Rosa Silveira F, Damázio LS, Mastella GA, Kist LW, Bogo MR, Quevedo J, Gama CS (2015) Omega-3 fatty acids prevent the ketamine-induced increase in acetylcholinesterase activity in an animal model of schizophrenia. Life Sci 121:65–69

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jitendra Kumar Sinha .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sinha, J.K. et al. (2023). Pharmacotherapy and Emerging Treatment Strategies for Schizophrenia. In: Chatterjee, I. (eds) Cognizance of Schizophrenia:: A Profound Insight into the Psyche. Springer, Singapore. https://doi.org/10.1007/978-981-19-7022-1_10

Download citation

Publish with us

Policies and ethics