- Author: Frances R Frankenburg, MD; Chief Editor: Glen L Xiong, MD more...
Antipsychotic medications diminish the positive symptoms of schizophrenia and prevent relapses.
Antipsychotics, 1st Generation
First-generation (conventional or typical) antipsychotics, are strong dopamine D2 antagonists. However, each drug in this class has various effects on other receptors, such as serotonin type 2 (5-HT2), alpha1, histaminic, and muscarinic receptors.
First-generation antipsychotics have a high rate of extrapyramidal side effects, including rigidity, bradykinesia, dystonias, tremor, and akathisia. Tardive dyskinesia (TD)—that is, involuntary movements in the face and extremities—is another adverse effect that can occur with first-generation antipsychotics. Neuroleptic malignant syndrome (NMS) can occur with these agents.
Chlorpromazine is a phenothiazine antipsychotic that is a dopamine D2 receptor antagonist. It was the first conventional antipsychotic developed and is still in wide use for treatment of schizophrenia. Chlorpromazine is available in oral tablets, syrup, and concentrate; as an injectable solution for intramuscular (IM) administration; and in suppository form.
Chlorpromazine is a low-potency medication and is associated with sedation and weight gain.
Fluphenazine is a high-potency typical antipsychotic that blocks postsynaptic dopaminergic D1 and D2 receptors. It has some alpha-adrenergic and anticholinergic effects. It is available orally and in a depot formulation (fluphenazine decanoate). A short-acting IM injection is also available for acute agitation. Fluphenazine is clinically comparable to haloperidol, a first-generation antipsychotic with similar potency, route of administration, side effects, and efficacy.
Haloperidol is a dopamine D2 antagonist noted for high potency and low potential for causing orthostasis. The drawback is the high potential for extrapyramidal symptoms or dystonia. Haloperidol can interact with CYP3A4 and CYP2D6 inhibitors and inducers. It also can interact with drugs that prolong QTc intervals. Haloperidol is available in tablets, as a liquid concentrate, in IM and intravenous (IV) forms, and in long-acting IM form for depot injection.
Perphenazine is a phenothiazine antipsychotic that blocks postsynaptic dopaminergic receptors and has alpha-adrenergic blocking effects. It has slightly lower potency than haloperidol and it sometimes classified as a midpotency drug. It is available in an oral formulation.
Thiothixene is a dopamine D2 antagonist with anticholinergic and alpha-blocking effects. It is rarely used in the United States now.
Trifluoperazine is a piperazine phenothiazine agent that is an antagonist at the postsynaptic mesolimbic dopaminergic D2 receptors.
Loxapine's mechanism of action is unknown but probably involves antagonism of central dopamine D2 and serotonin 5-HT2A receptors. The inhaled dosage form is indicated for acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.
Inhaled loxapine is a first-generation agent that may be similar to second-generation agents. In a new formulation, it can be inhaled, which may make it attractive for some patients.
Loxapine inhaled is the first noninjectable therapy to treat acute agitation associated with schizophrenia and bipolar I disorder. Approval by the US Food and Drug Administration (FDA) was based on 2 phase III studies of 658 individuals.
Antipsychotics, 2nd Generation
Second-generation (novel or atypical) antipsychotics, with the exception of aripiprazole, are dopamine D2 antagonists, but are associated with lower rates of extrapyramidal adverse effects and TD than the first-generation antipsychotics. However, they have higher rates of metabolic adverse effects and weight gain.
Asenapine is indicated for acute and maintenance treatment of schizophrenia. It is absorbed poorly in the gastrointestinal (GI) tract and thus is available in a sublingual form. The most common side effects include sedation, weight gain, dizziness, extrapyramidal symptoms, and oral hypoesthesia.
Asenapine's mechanism of action is unknown. Its efficacy is thought to be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2 receptors. Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors; dopamine D2, D3, D4, and D1 receptors; alpha1- and alpha2-adrenergic receptors; and histamine H1 receptors, with moderate affinity for H2 receptors. The addition of serotonin antagonism to dopamine antagonism may improve the negative symptoms of psychoses and may reduce the incidence of extrapyramidal adverse effects when compared with typical antipsychotics.
Clozapine is the oldest atypical antipsychotic agent and probably the most effective. Because it is associated with about a 1% risk of agranulocytosis, patients must undergo white blood cell (WBC) count monitoring every week for the first 6 months (the period of greatest risk), then every 2 weeks for 6 months, and finally every 4 weeks, as long as the absolute neutrophil count (ANC) is normal. If the ANC drops, a strict protocol of monitoring and possibly medication cessation must then be followed.
Clozapine is an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors. It has some dopamine D2 antagonism and high D4 affinity. It carries a high adverse effect burden, including sedation, drooling, constipation, and possible cardiac effects. Because it can cause agranulocytosis, patients must have regular blood tests. It is indicated for refractory schizophrenia and for reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.
The anticholinergic adverse effects, sedation, and drooling can be burdensome. Constipation and cardiac adverse effects (cardiomyopathy and myocarditis) can be life-threatening. However, approximately one third of patients who have not responded to conventional antipsychotic agents do better on clozapine. Violence, hostility, and suicidality may be diminished with the use of clozapine.
Iloperidone is indicated for acute treatment of schizophrenia. Its precise mechanism of action is unknown, but it is known to antagonize dopamine D2 and serotonin 5-HT2 receptors. However, it shows high affinity for 5-HT2A, D2, and D3 receptors and low-to-moderate affinity for D1, D4, H1, 5-HT1A, 5HT6, 5-HT7, and NE alpha1 receptors. Adverse effects include dizziness, orthostatic hypotension, tachycardia, weight gain, dry mouth, and sedation. Iloperidone causes fewer extrapyramidal symptoms than do other antipsychotics.
Lurasidone is an atypical antipsychotic whose precise mechanism of action is unknown. It is a dopamine D2 and serotonin 5-HT2A receptor antagonist. It is indicated for schizophrenia. This drug has not been tested in children or adolescents.
A major route of metabolism for lurasidone is via CYP3A4. Dose reduction is recommended in the presence of moderate CYP3A4 inhibitors. Coadministration with strong CYP3A4 inducers is not recommended.
Olanzapine is a selective monoaminergic antagonist at serotonin, dopamine D1-4, muscarinic, histamine H1, and alpha1-adrenergic receptors. It is available as a regular tablet, a rapidly disintegrating tablet, a short-acting injectable solution, and a long-acting injectable formulation. The most common side effects of olanzapine include weight gain, sedation, akathisia, hypotension, dry mouth, and constipation.
Paliperidone is the major active metabolite of risperidone and was the first oral agent to allow once-daily dosing. It is indicated for acute and maintenance treatment of schizophrenia. Its mechanism of action not completely understood but is thought to involve antagonism of dopamine D2 and serotonin 5HT-2A receptors. Paliperidone also elicits antagonist activity at adrenergic alpha1 and alpha2 receptors and histamine H1 receptors. Paliperidone is available in an osmotic delivery capsule and in long-term injectable IM forms (once monthly, q3mo).
Quetiapine may act by antagonizing dopamine and serotonin receptors. It is used for treatment of schizophrenia. Quetiapine is available in immediate-release and extended-release tablets. Major adverse effects include sedation, orthostatic hypotension, akathisia, dry mouth, and weight gain.
Risperidone has both dopamine D2 and serotonin 5-HT2 antagonism. It is available in tablets, oral disintegrating tablets, and an oral solution, as well as a long-acting form for IM injection that uses microspheres made of biodegradable polymers. It has few anticholinergic effects. Primary adverse effects of risperidone include mild sedation, hypotension, akathisia, increase in prolactin, and weight gain.
Ziprasidone antagonizes dopamine D2, serotonin 5-HT2, histamine H1, and alpha1-adrenergic receptors. It is available in capsule and short-acting IM injection forms. It is indicated for treatment of acute agitation in patients with schizophrenia. Ziprasidone appears to cause less weight gain, hyperglycemia, and hyperlipidemia than other drugs in its category do.
The precise mechanism by which cariprazine works for schizophrenia is unknown. Efficacy could be mediated through a combination of partial agonist activity at central dopamine (D2) and serotonin 5-HT1A receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which have in vitro receptor binding profiles similar to the parent drug.
Serotonin-Dopamine Activity Modulators
Serotonin-dopamine activity modulators (SDAMs) act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.
Serotonin-dopamine activity modulator (SDAM) indicated for schizophrenia. Dosage modifications are necessary with renal or hepatic impairment. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4.
Aripiprazole shows high affinity for D2, D3, 5-HT1A, and 5HT2A receptors and moderate affinity for D4, 5HT2C, 5-HT7, alpha1 adrenergic, and H2 receptors and possesses moderate affinity for the serotonin reuptake transporter. It is thought to be a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors, alpha1, and histamine H1 receptors. It is available in tablets, orally disintegrating tablets, and short- and long-term (once-monthly, q6wk) IM injections. The most common adverse effects include headache, nausea, vomiting, insomnia, tremor, and constipation.
Oral aripiprazole is indicated for acute and maintenance treatment of schizophrenia. It is also used for acute and maintenance treatment of bipolar I disorder, adjunctive therapy for major depressive disorder, and treatment of irritability associated with autistic disorder.
The once-monthly IM injection is indicated for treatment of schizophrenia and for treatment of acute exacerbation of psychotic symptoms in adults.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). 4th ed. Washington, DC: American Psychiatric Press; 2000.
Wright IC, Rabe-Hesketh S, Woodruff PW, et al. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. 2000 Jan. 157(1):16-25. [Medline].
Tamminga CA, Stan AD, Wagner AD. The hippocampal formation in schizophrenia. Am J Psychiatry. 2010 Oct. 167(10):1178-93. [Medline].
Mattai A, Hosanagar A, Weisinger B, Greenstein D, Stidd R, Clasen L. Hippocampal volume development in healthy siblings of childhood-onset schizophrenia patients. Am J Psychiatry. 2011 Apr. 168(4):427-35. [Medline].
Sigmundsson T, Suckling J, Maier M, et al. Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. Am J Psychiatry. 2001 Feb. 158(2):234-43. [Medline].
Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res. 2009 Mar. 108(1-3):3-10. [Medline].
McIntosh AM, Owens DC, Moorhead WJ, Whalley HC, Stanfield AC, Hall J, et al. Longitudinal volume reductions in people at high genetic risk of schizophrenia as they develop psychosis. Biol Psychiatry. 2011 May 15. 69(10):953-8. [Medline].
Olabi B, Ellison-Wright I, McIntosh AM, et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry. 2011 Jul 1. 70(1):88-96. [Medline].
Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry. 1996 Jan-Feb. 3(5):241-53. [Medline].
Cioffi CL. Modulation of NMDA receptor function as a treatment for schizophrenia. Bioorg Med Chem Lett. 2013 Jul 19. [Medline].
Drexhage RC, Weigelt K, van Beveren N, Cohen D, Versnel MA, Nolen WA, et al. Immune and neuroimmune alterations in mood disorders and schizophrenia. Int Rev Neurobiol. 2011. 101:169-201. [Medline].
Fan X, Goff DC, Henderson DC. Inflammation and schizophrenia. Expert Rev Neurother. 2007 Jul. 7(7):789-96. [Medline].
Selten JP, Cantor-Graae E, Kahn RS. Migration and schizophrenia. Curr Opin Psychiatry. 2007 Mar. 20(2):111-5. [Medline].
Bourque F, van der Ven E, Malla A. A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol Med. 2011 May. 41(5):897-910. [Medline].
Kirkbride J, Coid JW, Morgan C, et al. Translating the epidemiology of psychosis into public mental health: evidence, challenges and future prospects. J Public Ment Health. 2010 Jun. 9(2):4-14. [Medline].
Kety SS, Wender PH, Jacobsen B, et al. Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Replication of the Copenhagen Study in the rest of Denmark. Arch Gen Psychiatry. 1994 Jun. 51(6):442-55. [Medline].
Brooks M. New Schizophrenia Genes Identified. Medscape Medical News. Jul 22 2014. [Full Text].
Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014 Jul 24. 511(7510):421-7. [Medline].
Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005 May 15. 57(10):1117-27. [Medline].
Shifman S, Johannesson M, Bronstein M, et al. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 2008 Feb. 4(2):e28. [Medline].
Wratten NS, Memoli H, Huang Y, Dulencin AM, Matteson PG, Cornacchia MA, et al. Identification of a schizophrenia-associated functional noncoding variant in NOS1AP. Am J Psychiatry. April/2009. 166:434-41. [Medline].
O'Brien NL, Way MJ, Kandaswamy R, et al. The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder. Psychiatr Genet. 2014 Jul 18. [Medline].
Bassett AS, Costain G, Fung WL, Russell KJ, Pierce L, Kapadia R, et al. Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res. 2010 Nov. 44(15):1005-9. [Medline].
Bassett AS, Scherer SW, Brzustowicz LM. Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry. 2010 Aug. 167(8):899-914. [Medline]. [Full Text].
Owen MJ, O'Donovan MC, Thapar A, Craddock N. Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry. 2011 Mar. 198:173-5. [Medline].
Sahoo T, Theisen A, Rosenfeld JA, et al. Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genet Med. 2011 Oct. 13(10):868-80. [Medline].
Corvin AP, Morris DW, McGhee K, Schwaiger S, Scully P, Quinn J, et al. Confirmation and refinement of an 'at-risk' haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus. Mol Psychiatry. 2004 Feb. 9(2):208-13. [Medline].
Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lönnqvist J, et al. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry. 2004 Nov. 9(11):1037-41. [Medline].
Hennah W, Thomson P, McQuillin A, Bass N, Loukola A, Anjorin A, et al. DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry. 2009 Sep. 14(9):865-73. [Medline].
Huffaker SJ, Chen J, Nicodemus KK, Sambataro F, Yang F, Mattay V, et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med. 2009 May. 15(5):509-18. [Medline]. [Full Text].
Kirov G, Ivanov D, Williams NM, Preece A, Nikolov I, Milev R, et al. Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria. Biol Psychiatry. 2004 May 15. 55(10):971-5. [Medline].
Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P. Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry. 2001 May. 6(3):293-301. [Medline].
Morris DW, Rodgers A, McGhee KA, Schwaiger S, Scully P, Quinn J, et al. Confirming RGS4 as a susceptibility gene for schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004 Feb 15. 125B(1):50-3. [Medline].
Schindler KM, Pato MT, Dourado A, Macedo A, Azevedo MH, Kennedy JL, et al. Association and linkage disequilibrium between a functional polymorphism of the dopamine-2 receptor gene and schizophrenia in a genetically homogeneous Portuguese population. Mol Psychiatry. 2002. 7(9):1002-5. [Medline].
Shifman S, Bronstein M, Sternfeld M, Pisanté-Shalom A, Lev-Lehman E, Weizman A, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet. 2002 Dec. 71(6):1296-302. [Medline]. [Full Text].
Steinberg S, Mors O, Børglum AD, Gustafsson O, Werge T, Mortensen PB, et al. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry. 2011 Jan. 16(1):59-66. [Medline]. [Full Text].
Tang JX, Chen WY, He G, Zhou J, Gu NF, Feng GY, et al. Polymorphisms within 5' end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population. Mol Psychiatry. 2004 Jan. 9(1):11-2. [Medline].
Williams HJ, Norton N, Dwyer S, Moskvina V, Nikolov I, Carroll L, et al. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry. 2011 Apr. 16(4):429-41. [Medline].
Xu B, Roos JL, Dexheimer P, et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet. 2011 Aug 7. 43(9):864-8. [Medline].
Girard SL, Gauthier J, Noreau A, et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011 Jul 10. 43(9):860-3. [Medline].
Brooks M. De Novo Gene Mutations Linked to Schizophrenia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/819742.. Accessed: February 4, 2014.
Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014 Jan 22. [Medline].
Lencz T, Guha S, Liu C, Rosenfeld J, Mukherjee S, Derosse P. Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder. Nat Commun. 2013 Nov 19. 4:2739. [Medline].
Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003 Dec. 60(12):1187-92. [Medline].
Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010 Mar. 167(3):261-80. [Medline].
Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. 2004 Aug. 61 (8):774-80. [Medline].
Torrey EF, Bowler AE, Rawlings R, Terrazas A. Seasonality of schizophrenia and stillbirths. Schizophr Bull. 1993. 19(3):557-62. [Medline].
Clarke MC, Tanskanen A, Huttunen M, Whittaker JC, Cannon M. Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am J Psychiatry. 2009 Sep. 166(9):1025-30. [Medline].
Anderson P. Teen Marijuana Use Linked to Earlier Psychosis Onset. Medscape Medical News. May 14 2014. [Full Text].
Haro JM, Novick D, Bertsch J, et al. Cross-national clinical and functional remission rates: Worldwide Schizophrenia Outpatient Health Outcomes (W-SOHO) study. Br J Psychiatry. 2011 Sep. 199:194-201. [Medline].
Hoang U, Stewart R, Goldacre MJ. Mortality after hospital discharge for people with schizophrenia or bipolar disorder: retrospective study of linked English hospital episode statistics, 1999-2006. BMJ. 2011 Sep 13. 343:d5422. [Medline]. [Full Text].
Xia J, Merinder LB, Belgamwar MR. Psychoeducation for schizophrenia. Cochrane Database Syst Rev. 2011 Jun 15. CD002831. [Medline].
Jones P, Rodgers B, Murray R, Marmot M. Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet. 1994 Nov 19. 344(8934):1398-402. [Medline].
Ho BC, Andreasen NC. Long delays in seeking treatment for schizophrenia. Lancet. 2001 Mar 24. 357(9260):898-900. [Medline].
Green AI, Drake RE, Brunette MF, Noordsy DL. Schizophrenia and co-occurring substance use disorder. Am J Psychiatry. 2007 Mar. 164(3):402-8. [Medline].
Foti DJ, Kotov R, Guey LT, Bromet EJ. Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization. Am J Psychiatry. 2010 Aug. 167(8):987-93. [Medline].
Yücel M, Bora E, Lubman DI, et al. The impact of cannabis use on cognitive functioning in patients with schizophrenia: a meta-analysis of existing findings and new data in a first-episode sample. Schizophr Bull. 2012 Mar. 38(2):316-30. [Medline]. [Full Text].
Brauser D. Cannabis Not the Only Illicit Drug Linked to Schizophrenia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/807520. Accessed: July 17, 2013.
Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord. 1982 Sep. 4(3):173-93. [Medline].
Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry. 2010 Sep. 197(3):174-9. [Medline].
Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003 Jan. 60(1):82-91. [Medline].
Shioiri T, Shinada K, Kuwabara H, Someya T. Early prodromal symptoms and diagnoses before first psychotic episode in 219 inpatients with schizophrenia. Psychiatry Clin Neurosci. 2007 Aug. 61(4):348-54. [Medline].
Tiihonen J, Suokas JT, Suvisaari JM, Haukka J, Korhonen P. Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry. 2012 May. 69(5):476-83. [Medline].
Bennett DJ, Ogloff JR, Mullen PE, et al. Schizophrenia disorders, substance abuse and prior offending in a sequential series of 435 homicides. Acta Psychiatr Scand. 2011 Sep. 124(3):226-33. [Medline].
Fazel S, Långström N, Hjern A, Grann M, Lichtenstein P. Schizophrenia, substance abuse, and violent crime. JAMA. 2009 May 20. 301(19):2016-23. [Medline].
Cummings JL, Gosenfeld LF, Houlihan JP, McCaffrey T. Neuropsychiatric disturbances associated with idiopathic calcification of the basal ganglia. Biol Psychiatry. 1983 May. 18(5):591-601. [Medline].
Rosebush PI, MacQueen GM, Clarke JT, et al. Late-onset Tay-Sachs disease presenting as catatonic schizophrenia: diagnostic and treatment issues. J Clin Psychiatry. 1995 Aug. 56(8):347-53. [Medline].
Pope HG Jr, Katz DL. Psychiatric and medical effects of anabolic-androgenic steroid use. A controlled study of 160 athletes. Arch Gen Psychiatry. 1994 May. 51(5):375-82. [Medline].
Reuler JB, Girard DE, Cooney TG. Current concepts. Wernicke's encephalopathy. N Engl J Med. 1985 Apr 18. 312(16):1035-9. [Medline].
Salokangas RK. Medical problems in schizophrenia patients living in the community (alternative facilities). Curr Opin Psychiatry. 2007 Jul. 20(4):402-5. [Medline].
Brauser D. Long-term Injectable Drug Effective for Schizophrenia. Medscape Medical News. May 11 2012. [Full Text].
Cassels C. FDA Approves Once-Monthly Treatment for Schizophrenia. Medscape Medical News. Mar 1 2013. [Full Text].
Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012 May. 73(5):617-24. [Medline]. [Full Text].
Citrome L. New second-generation long-acting injectable antipsychotics for the treatment of schizophrenia. Expert Rev Neurother. 2013 Jul. 13(7):767-83. [Medline].
Lieberman JA, Stroup TS. The NIMH-CATIE Schizophrenia Study: what did we learn?. Am J Psychiatry. 2011 Aug. 168(8):770-5. [Medline].
Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006 Oct. 63(10):1079-87. [Medline].
Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D, et al. Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia : A Randomized Clinical Trial. JAMA Psychiatry. 2015 Jun 24. [Medline].
Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008 Mar 29. 371(9618):1085-97. [Medline].
McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. 2007 Jul. 164(7):1050-60. [Medline].
[Guideline] Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010 Jan. 36(1):71-93. [Medline]. [Full Text].
Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry. 2013 Sep. 70(9):913-20. [Medline].
Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L, et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology. 2003 May. 28(5):995-1003. [Medline].
Woerner MG, Robinson DG, Alvir JM, Sheitman BB, Lieberman JA, Kane JM. Clozapine as a first treatment for schizophrenia. Am J Psychiatry. 2003 Aug. 160(8):1514-6. [Medline].
Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007 Nov. 68(11):1751-62. [Medline].
Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry. 2011 Nov. 72(11):1439-44. [Medline].
Essock SM, Schooler NR, Stroup TS, McEvoy JP, Rojas I, Jackson C, et al. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry. 2011 Jul. 168(7):702-8. [Medline].
Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009 Mar. 35(2):443-57. [Medline]. [Full Text].
Honer WG, MacEwan GW, Gendron A, Stip E, Labelle A, Williams R, et al. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2012 Jan. 73(1):13-20. [Medline].
Asmal L, Flegar SJ, Wang J, Rummel-Kluge C, Komossa K, Leucht S. Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2013 Nov 18. 11:CD006625. [Medline].
Rosenheck RA, Krystal JH, Lew R, Barnett PG, Fiore L, Valley D, et al. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med. 2011 Mar 3. 364(9):842-51. [Medline].
Kishimoto T, Robenzadeh A, Leucht C, Leucht S, Watanabe K, Mimura M, et al. Long-Acting Injectable vs Oral Antipsychotics for Relapse Prevention in Schizophrenia: A Meta-Analysis of Randomized Trials. Schizophr Bull. 2013 Jan 2. [Medline].
Subotnik KL, Nuechterlein KH, Ventura J, et al. Risperidone nonadherence and return of positive symptoms in the early course of schizophrenia. Am J Psychiatry. 2011 Mar. 168(3):286-92. [Medline].
Takeuchi H, Suzuki T, Remington G, et al. Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study. Schizophr Bull. 2013 Sep. 39(5):993-8. [Medline]. [Full Text].
Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry. 2001 Nov. 158(11):1774-82. [Medline].
Strom BL, Eng SM, Faich G, Reynolds RF, D'Agostino RB, Ruskin J, et al. Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). Am J Psychiatry. 2011 Feb. 168(2):193-201. [Medline].
Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007. 68 Suppl 1:20-7. [Medline].
Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry. 2010 Oct. 197(4):266-71. [Medline].
Stroup TS, McEvoy JP, Ring KD, Hamer RH, LaVange LM, Swartz MS, et al. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry. 2011 Sep. 168(9):947-56. [Medline].
Wang M, Tong JH, Zhu G, Liang GM, Yan HF, Wang XZ. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res. 2012 Jun. 138(1):54-7. [Medline].
Hägg S, Spigset O, Söderström TG. Association of venous thromboembolism and clozapine. Lancet. 2000 Apr 1. 355(9210):1155-6. [Medline].
Thomassen R, Vandenbroucke JP, Rosendaal FR. Antipsychotic drugs and venous thromboembolism. Lancet. 2000 Jul 15. 356(9225):252. [Medline].
Lowry F. Psychotropic Drugs Can Reduce Bone Mass in Kids. Medscape Medical News. Jun 24 2014. [Full Text].
Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011 Feb. 68(2):128-37. [Medline].
[Guideline] Dixon LB, Dickerson F, Bellack AS, Bennett M, Dickinson D, Goldberg RW, et al. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. Schizophr Bull. 2010 Jan. 36(1):48-70. [Medline]. [Full Text].
Guo X, Zhai J, Liu Z, Fang M, Wang B, Wang C, et al. Effect of antipsychotic medication alone vs combined with psychosocial intervention on outcomes of early-stage schizophrenia: A randomized, 1-year study. Arch Gen Psychiatry. 2010 Sep. 67(9):895-904. [Medline].
Wexler BE, Bell MD. Cognitive remediation and vocational rehabilitation for schizophrenia. Schizophr Bull. 2005 Oct. 31(4):931-41. [Medline].
Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. 2011 May. 168(5):472-85. [Medline].
Grant PM, Huh GA, Perivoliotis D, Stolar NM, Beck AT. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia. Arch Gen Psychiatry. 2012 Feb. 69(2):121-7. [Medline].
Puig O, Penadés R, Baeza I, De la Serna E, Sánchez-Gistau V, Bernardo M, et al. Cognitive remediation therapy in adolescents with early-onset schizophrenia: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2014 Aug. 53(8):859-68. [Medline].
Brooks, M. Cognitive Therapy a Viable Monotherapy for Schizophrenia?. Medscape Medical News. Available at http://www.medscape.com/viewarticle/820258. Accessed: February 19, 2014.
Morrison, Anthony P., Turkington, D., Pyle, M., et al. Cognitive therapy for people with schizophrenia spectrum disorders not taking antipsychotic drugs: a single-blind randomised controlled trial. The Lancet. February 2014. [Full Text].
Bond GR, Drake RE. Making the Case for IPS Supported Employment. Adm Policy Ment Health. 2012 Nov 17. [Medline].
McHugo GJ, Drake RE, Xie H, Bond GR. A 10-year study of steady employment and non-vocational outcomes among people with serious mental illness and co-occurring substance use disorders. Schizophr Res. 2012 Jul. 138(2-3):233-9. [Medline].
Pharoah F, Mari J, Rathbone J, Wong W. Family intervention for schizophrenia. Cochrane Database Syst Rev. 2010 Dec 8. CD000088. [Medline].
Hegelstad WT, Larsen TK, Auestad B, Evensen J, Haahr U, Joa I, et al. Long-term follow-up of the TIPS early detection in psychosis study: effects on 10-year outcome. Am J Psychiatry. 2012 Apr. 169(4):374-80. [Medline].
Weiser M. Early intervention for schizophrenia: the risk-benefit ratio of antipsychotic treatment in the prodromal phase. Am J Psychiatry. 2011 Aug. 168(8):761-3. [Medline].
Bechdolf A, Wagner M, Ruhrmann S, Harrigan S, Putzfeld V, Pukrop R, et al. Preventing progression to first-episode psychosis in early initial prodromal states. Br J Psychiatry. 2012 Jan. 200(1):22-9. [Medline].
Rosenberg O, Gersner R, Klein LD, Kotler M, Zangen A, Dannon P. Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study. Ann Gen Psychiatry. 2012 May 6. 11:13. [Medline]. [Full Text].
Levkovitz Y, Rabany L, Harel EV, Zangen A. Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study. Int J Neuropsychopharmacol. 2011 Aug. 14(7):991-6. [Medline].
Cassels, C. Antipsychotic Linked to Potentially Fatal Skin Reaction. Medscape Medical News. Available at http://www.medscape.com/viewarticle/836427. Accessed: December 13, 2014.
Baldessarini RJ, Frankenburg FR. Clozapine. A novel antipsychotic agent. N Engl J Med. 1991 Mar 14. 324(11):746-54. [Medline].
Brauser D. Psychosocial Interventions May Help Nip Psychosis in the Bud. Medscape Medical News. Available at http://www.medscape.com/viewarticle/829526. Accessed: August 9, 2014.
Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic Risk in Patients With First-Episode Schizophrenia Spectrum Disorders: Baseline Results From the RAISE-ETP Study. JAMA Psychiatry. Oct 8 2014.
Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009 Jan 21. CD000059. [Medline].
Kane JM, Peters-Strickland T, Baker RA, Hertel P, Eramo A, Jin N, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014 Nov. 75(11):1254-60. [Medline]. [Full Text].
Kane JM, Peters-Strickland T, Baker RA, Hertel P, Eramo A, Jin N, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014 Nov. 75(11):1254-60. [Medline].
Keller DM. Parkinsonism a major mortality risk factor in schizophrenia. Medscape Medical News. March 5, 2014. [Full Text].
Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, 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 Feb. 14(1):31-40. [Medline].
Lesem MD, Tran-Johnson TK, Riesenberg RA, Feifel D, Allen MH, Fishman R, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011 Jan. 198(1):51-8. [Medline]. [Full Text].
Lowry F. Rapid Rise in Cardiometabolic Risk in Early Schizophrenia. Medscape Medical News. Oct 14 2014. [Full Text].
Miklowitz DJ, O'Brien MP, Schlosser DA, Addington J, Candan KA, Marshall C, et al. Family-focused treatment for adolescents and young adults at high risk for psychosis: results of a randomized trial. J Am Acad Child Adolesc Psychiatry. 2014 Aug. 53(8):848-58. [Medline]. [Full Text].
Schoepf D, Uppal H, Potluri R, Heun R. Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions. Presented at: The 22nd European Congress of Psychiatry (EPA); March 3, 2014; Munich, Germany. Abstract FC07. Eur Arch Psychiatry Clin Neurosci. 2014 Feb. 264(1):3-28. [Medline]. [Full Text].