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First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects

Michael D Jibson, MD, PhD
Section Editor
Stephen Marder, MD
Deputy Editor
Richard Hermann, MD


Antipsychotic medications have been used for more than 60 years to treat acute psychosis from any cause and to manage chronic psychotic disorders such as schizophrenia. As a class, antipsychotics are also effective in the treatment of acute agitation, bipolar mania, and other psychiatric conditions.  

First-generation antipsychotics (FGAs), also known as neuroleptics, conventional or typical antipsychotics, have significant potential to cause extrapyramidal side effects and tardive dyskinesia. This propensity to cause movement disorders is the primary difference between FGAs and second-generation antipsychotics (SGAs). In other respects, such as other side effects and their mechanism of action, the two classes have substantial overlap and comparable efficacy.

The pharmacology, administration, and side effects of FGAs are discussed here. The pharmacology, administration, and side effects of SGAs are discussed separately. The efficacy and administration of antipsychotic drugs for specific psychotic disorders are also described separately, as are antipsychotic poisoning, tardive dyskinesia, neuroleptic malignant syndrome, and other antipsychotic drug side effects. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania" and "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis" and "Delusional disorder" and "Brief psychotic disorder" and "Treatment of postpartum psychosis" and "First generation (Typical) antipsychotic medication poisoning" and "Second generation (atypical) antipsychotic medication poisoning" and "Tardive dyskinesia: Etiology and epidemiology" and "Neuroleptic malignant syndrome" and "Pharmacotherapy for schizophrenia: Side effect management".)


The mechanism of action of all first-generation antipsychotics (FGAs) appears to be postsynaptic blockade of brain dopamine D2 receptors. Evidence supporting this mechanism includes strong antagonism of D2 receptors in both cortical and striatal areas [1], a high correlation between D2 receptor binding and clinical potency [2], and a consistent requirement of 65 percent D2 receptor occupancy for antipsychotic efficacy in functional imaging studies [3]. The nonspecific localization of FGA dopamine binding throughout the central nervous system is consistent with their risk of movement disorders and prolactinemia. Aside from their common activity as D2 antagonists, each FGA has distinct effects on neuronal 5-HT2a, alpha-1, histaminic, and muscarinic receptors, which generally correspond to their individual side effect profiles, as shown in the table (table 1).

High and low potency FGAs — The pharmacologic differences described above are the basis for the classification of FGAs as either high- or low-potency drugs. The high-potency FGAs (fluphenazine, haloperidol, loxapine, perphenazine, pimozide, thiothixene, and trifluoperazine) are dosed in the range of 1 to 10s of milligrams and have low activity at histaminic and muscarinic receptors. They are associated with little sedation, weight gain, or anticholinergic activity, but a high risk for extrapyramidal side effects. The low-potency FGAs (chlorpromazine and thioridazine) are dosed in 100s of milligrams and have high histaminic and muscarinic activity with a corresponding increased prevalence of sedation and anticholinergic effects, but lower risk of extrapyramidal side effects.


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Literature review current through: Sep 2016. | This topic last updated: Feb 4, 2016.
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  1. Stone JM, Davis JM, Leucht S, Pilowsky LS. Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs--an original patient data meta-analysis of the SPECT and PET in vivo receptor imaging literature. Schizophr Bull 2009; 35:789.
  2. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002; 47:27.
  3. Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157:514.
  4. Odou P, Vaiva G, Luyckx M, et al. Neuroleptic monitoring: relation between antipsychotic efficiency and radioreceptor assay of serum haloperidol. Eur J Clin Pharmacol 1996; 50:357.
  5. Ulrich S, Neuhof S, Braun V, Meyer FP. Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder. Pharmacopsychiatry 1998; 31:163.
  6. Spyker DA, Munzar P, Cassella JV. Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers. J Clin Pharmacol 2010; 50:169.
  7. Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry 2011; 198:51.
  8. Kwentus J, Riesenberg RA, Marandi M, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord 2012; 14:31.
  9. Dahl ML. Cytochrome p450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet 2002; 41:453.
  10. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet 2009; 48:761.
  11. Midha KK, Hubbard JW, McKay G, et al. The role of metabolites in a bioequivalence study 1: loxapine, 7-hydroxyloxapine and 8-hydroxyloxapine. Int J Clin Pharmacol Ther Toxicol 1993; 31:177.
  12. Saddichha S, Manjunatha N, Ameen S, Akhtar S. Metabolic syndrome in first episode schizophrenia - a randomized double-blind controlled, short-term prospective study. Schizophr Res 2008; 101:266.
  13. Salih IS, Thanacoody RH, McKay GA, Thomas SH. Comparison of the effects of thioridazine and mesoridazine on the QT interval in healthy adults after single oral doses. Clin Pharmacol Ther 2007; 82:548.
  14. Gao K, Kemp DE, Ganocy SJ, et al. Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review. J Clin Psychopharmacol 2008; 28:203.
  15. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951.
  16. Coley KC, Carter CS, DaPos SV, et al. Effectiveness of antipsychotic therapy in a naturalistic setting: a comparison between risperidone, perphenazine, and haloperidol. J Clin Psychiatry 1999; 60:850.
  17. Morgenstern H, Glazer WM. Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications. Results of the Yale Tardive Dyskinesia Study. Arch Gen Psychiatry 1993; 50:723.
  18. Glazer WM, Morgenstern H, Doucette JT. Predicting the long-term risk of tardive dyskinesia in outpatients maintained on neuroleptic medications. J Clin Psychiatry 1993; 54:133.
  19. Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: is risk declining with modern antipsychotics? Mov Disord 2006; 21:589.
  20. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161:414.
  21. Roerig JL, Steffen KJ, Mitchell JE. Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 2011; 25:1035.
  22. Ferentinos P, Dikeos D. Genetic correlates of medical comorbidity associated with schizophrenia and treatment with antipsychotics. Curr Opin Psychiatry 2012; 25:381.
  23. Kane JM, Davis JM, Schooler N, et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. Am J Psychiatry 2002; 159:554.
  24. Serafetinides EA, Collins S, Clark ML. Haloperidol, clopenthixol, and chlorpromazine in chronic schizophrenia. Chemically unrelated antipsychotics as therapeutic alternatives. J Nerv Ment Dis 1972; 154:31.
  25. Dossenbach M, Treuer T, Kryzhanovskaya L, et al. Olanzapine versus chlorpromazine in the treatment of schizophrenia: a pooled analysis of four 6-week, randomized, open-label studies in the Middle East and North Africa. J Clin Psychopharmacol 2007; 27:329.
  26. Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res 2004; 70:1.
  27. Vidarsdottir S, de Leeuw van Weenen JE, Frölich M, et al. Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab 2010; 95:118.
  28. Cookson JC. Side effects during long-term treatment with depot antipsychotic medication. Clin Neuropharmacol 1991; 14 Suppl 2:S24.
  29. Brambilla F, Guastalla A, Guerrini A, et al. Glucose-insulin metabolism in chronic schizophrenia. Dis Nerv Syst 1976; 37:98.
  30. Doss FW. The effect of antipsychotic drugs on body weight: a retrospective review. J Clin Psychiatry 1979; 40:528.
  31. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27:596.
  32. Nielsen J, Graff C, Kanters JK, et al. Assessing QT interval prolongation and its associated risks with antipsychotics. CNS Drugs 2011; 25:473.
  33. Fenton M, Rathbone J, Reilly J, Sultana A. Thioridazine for schizophrenia. Cochrane Database Syst Rev 2007; :CD001944.
  34. Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004; 24:62.
  35. Reilly JG, Ayis SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355:1048.
  36. Salvo F, Pariente A, Shakir S, et al. Sudden cardiac and sudden unexpected death related to antipsychotics: A meta-analysis of observational studies. Clin Pharmacol Ther 2016; 99:306.
  37. Shah AA, Aftab A, Coverdale J. QTc prolongation with antipsychotics: is routine ECG monitoring recommended? J Psychiatr Pract 2014; 20:196.
  38. Moss AJ. Measurement of the QT interval and the risk associated with QTc interval prolongation: a review. Am J Cardiol 1993; 72:23B.
  39. Sharma ND, Rosman HS, Padhi ID, Tisdale JE. Torsades de Pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol 1998; 81:238.
  40. Lawrence KR, Nasraway SA. Conduction disturbances associated with administration of butyrophenone antipsychotics in the critically ill: a review of the literature. Pharmacotherapy 1997; 17:531.
  41. Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994; 22:433.
  42. U.S. Food and Drug Administration. Information for Healthcare Professionals: Haloperidol (marketed as Haldol, Haldol Decanoate and Haldol Lactate). FDA Alert. [9/2007]. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085203.htm.
  43. Marder SR, Essock SM, Miller AL, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:1334.
  44. Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry 1989; 46:722.
  45. Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol Ther 1999; 65:10.
  46. Fruensgaard K. Parenteral treatment of acute psychotic patients with agitation: a review. Curr Med Res Opin 1978; 5:593.
  47. Cassella JV, Spyker DA, Yeung PP. A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers. Int J Clin Pharmacol Ther 2015; 53:963.
  48. DiGiacomo J. Cardiovascular effects of psychotropic drugs. Cardiovasc Rev Rep 1989; 10:31.
  49. Tuason VB, Escobar JI, Garvey M, Schiele B. Loxapine versus chlorpromazine in paranoid schizophrenia: a double-blind study. J Clin Psychiatry 1984; 45:158.
  50. Jackson KC, Lipman AG. Drug therapy for delirium in terminally ill patients. Cochrane Database Syst Rev 2004; :CD004770.
  51. Atypical antipsychotics in the elderly. Med Lett Drugs Ther 2005; 47:61.
  52. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294:1934.
  53. Ballard C, Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009; 8:151.
  54. Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005; 353:2335.
  55. Schneeweiss S, Setoguchi S, Brookhart A, et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007; 176:627.
  56. US Food and Drug Administration. Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances. Available at http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm053171 (Accessed on November 11, 2015).
  57. Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med 2007; 146:775.
  58. Murray-Thomas T, Jones ME, Patel D, et al. Risk of mortality (including sudden cardiac death) and major cardiovascular events in atypical and typical antipsychotic users: a study with the general practice research database. Cardiovasc Psychiatry Neurol 2013; 2013:247486.
  59. Huybrechts KF, Gerhard T, Crystal S, et al. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study. BMJ 2012; 344:e977.
  60. Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23 Suppl 1:27.
  61. Regal RE, Billi JE, Glazer HM. Phenothiazine-induced cholestatic jaundice. Clin Pharm 1987; 6:787.
  62. Watson RG, Olomu A, Clements D, et al. A proposed mechanism for chlorpromazine jaundice--defective hepatic sulphoxidation combined with rapid hydroxylation. J Hepatol 1988; 7:72.
  63. Velamoor VR. Neuroleptic malignant syndrome. Recognition, prevention and management. Drug Saf 1998; 19:73.
  64. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185.
  65. Hagopian V, Stratton DB, Busiek RD. Five cases of pigmentary retinopathy associated with thioridazine administration. Am J Psychiatry 1966; 123:97.
  66. Tekell JL, Silva JA, Maas JA, et al. Thioridazine-induced retinopathy. Am J Psychiatry 1996; 153:1234.
  67. Rennie IG. Clinically important ocular reactions to systemic drug therapy. Drug Saf 1993; 9:196.
  68. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs 2010; 24:501.
  69. Peuskens J, Pani L, Detraux J, De Hert M. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 2014; 28:421.
  70. Froes Brandao D, Strasser-Weippl K, Goss PE. Prolactin and breast cancer: The need to avoid undertreatment of serious psychiatric illnesses in breast cancer patients: A review. Cancer 2016; 122:184.
  71. Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. Int Clin Psychopharmacol 2011; 26:130.
  72. La Torre A, Conca A, Duffy D, et al. Sexual dysfunction related to psychotropic drugs: a critical review part II: antipsychotics. Pharmacopsychiatry 2013; 46:201.
  73. Dean AJ, McDermott BM, Marshall RT. PRN sedation-patterns of prescribing and administration in a child and adolescent mental health inpatient service. Eur Child Adolesc Psychiatry 2006; 15:277.
  74. Green JF, McElholm A, King DJ. A comparison of the sedative and amnestic effects of chlorpromazine and lorazepam. Psychopharmacology (Berl) 1996; 128:67.
  75. Bloechliger M, Rüegg S, Jick SS, et al. Antipsychotic drug use and the risk of seizures: follow-up study with a nested case-control analysis. CNS Drugs 2015; 29:591.