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Despite pharmacologic advances, the treatment of schizophrenia remains a challenge, and suboptimal outcomes are still all too frequent. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good “effectiveness” measure mapping onto functional outcomes is still lacking. Moreover, the field has to advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate whether, and which, first- or second-generation antipsychotics should be used. However, an individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Moreover, acute and long-term goals and effects of medication treatment need to be balanced. While the acute response to appropriately dosed first-generation antipsychotics may not differ much from second-generation antipsychotics, advantages of lower rates of extrapyramidal side effects, tardive dyskinesia, and, possibly, relapse may favor second-generation antipsychotics. However, when considering individual adverse effect prof iles, the differentiation into first- and second-generation antipsychotics as unified classes can not be upheld, and a more differentiated view and treatment selection is required. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To improve the treatment outcomes in schizophrenia, research efforts are needed that elucidate biomarkers of the illness and of treatment response (both therapeutic and adverse effects). Moreover, new treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects.

[1]  Helena Chmura Kraemer,et al.  Clinical trials design lessons from the CATIE study. , 2009, The American journal of psychiatry.

[2]  S. Leucht,et al.  Comparative remission rates of schizophrenic patients using various remission criteria , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[3]  S. Kapur,et al.  Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders , 2008, Schizophrenia Research.

[4]  L. Hranov,et al.  Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial , 2008, The Lancet.

[5]  J. Lieberman,et al.  Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. , 2007, The American journal of psychiatry.

[6]  Yue-Cune Chang,et al.  Optimizing Early Prediction for Antipsychotic Response in Schizophrenia , 2006, Journal of clinical psychopharmacology.

[7]  Peter B. Jones,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). , 2006, Archives of general psychiatry.

[8]  J. Lieberman,et al.  Olanzapine and haloperidol in first episode psychosis: Two-year data , 2006, Schizophrenia Research.

[9]  J. Lieberman,et al.  Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. , 2006, The American journal of psychiatry.

[10]  Peter B. Jones,et al.  Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. , 2005, Schizophrenia bulletin.

[11]  J. Kane,et al.  Early-Onset Hypothesis of Antipsychotic Drug Action: A Hypothesis Tested, Confirmed and Extended , 2005, Biological Psychiatry.

[12]  Philip D. Harvey,et al.  Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. , 2005, The American journal of psychiatry.

[13]  D. Weinberger,et al.  Remission in schizophrenia: proposed criteria and rationale for consensus. , 2005, The American journal of psychiatry.

[14]  Robert M Bilder,et al.  Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. , 2004, The American journal of psychiatry.

[15]  Julie Kreyenbuhl,et al.  Practice guideline for the treatment of patients with schizophrenia , 1997 .

[16]  J. Lieberman,et al.  Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. , 2003, The American journal of psychiatry.

[17]  C. Correll,et al.  Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. , 2003, The American journal of psychiatry.

[18]  S. Kapur,et al.  Delayed onset hypothesis of antipsychotic action — a hypothesis tested and rejected , 2003, Schizophrenia Research.

[19]  R. Liberman,et al.  Teaching persons with severe mental disabilities to be their own case managers. , 2002, Psychiatric services.

[20]  N Freemantle,et al.  Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis , 2000, BMJ : British Medical Journal.

[21]  A Labelle,et al.  Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. , 2000, Archives of general psychiatry.

[22]  J. Lieberman,et al.  Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. , 1999, Archives of general psychiatry.

[23]  A. Breier,et al.  Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia∗ ∗ See accompanying Editorial, in this issue. , 1999, Biological Psychiatry.

[24]  R. Conley,et al.  Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. , 1998, The American journal of psychiatry.

[25]  N. Schooler 199. Comparing new anti-psychotic medications: What do the data say? , 1998, Biological Psychiatry.

[26]  C. Eap,et al.  Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. , 1998, The American journal of psychiatry.

[27]  A. Baldacchino,et al.  THE USE OF OLANZAPINE IN NON-COMPLIANT OR TREATMENT-RESISTANT CLOZAPINE POPULATIONS IN HOSPITAL , 1998 .

[28]  M. Tohen,et al.  Olanzapine vs. placebo in rapid-cycling bipolar disorder , 1998, Schizophrenia Research.

[29]  Michael F. Green,et al.  605 Risperidone's effects on verbal working memory , 1997, Schizophrenia Research.

[30]  M. Cuesta,et al.  Olanzapine in treatment-refractory schizophrenia: results of an open-label study. The Spanish Group for the Study of Olanzapine in Treatment-Refractory Schizophrenia. , 1997, The Journal of clinical psychiatry.

[31]  G. Tollefson,et al.  Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. , 1997 .

[32]  J. Peuskens,et al.  A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia , 1997, Acta psychiatrica Scandinavica.

[33]  R. Rosenheck,et al.  A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. , 1997, The New England journal of medicine.

[34]  R. Tamura,et al.  Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. , 1997 .

[35]  L. Arvanitis,et al.  Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo , 1997, Biological Psychiatry.

[36]  C. Tamminga,et al.  Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group. , 1997, The American journal of psychiatry.

[37]  J. Lieberman,et al.  Relapse and rehospitalization during maintenance treatment of schizophrenia. The effects of dose reduction and family treatment. , 1997, Archives of general psychiatry.

[38]  R. Tamura,et al.  Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. , 1997, The American journal of psychiatry.

[39]  Kane Jm Commentary on the clozapine conflict. , 1996 .

[40]  A. Malhotra,et al.  Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. , 1996, The American journal of psychiatry.

[41]  Michael F. Green,et al.  What are the functional consequences of neurocognitive deficits in schizophrenia? , 1996, The American journal of psychiatry.

[42]  R. Bilder,et al.  The effects of clozapine and haldol on memory functioning in treatment refractory schizophrenics , 1996, Schizophrenia Research.

[43]  Charles M Beasley,et al.  Olanzapine versus Placebo and Haloperidol , 1996, Neuropsychopharmacology.

[44]  M. J. Arranz,et al.  Association between clozapine response and allelic variation in 5-HT2A receptor gene , 1995, The Lancet.

[45]  H. Meltzer,et al.  Clozapine: is another view valid? , 1995, The American journal of psychiatry.

[46]  R. Conley,et al.  Patient response and resource management: another view of clozapine treatment of schizophrenia. , 1995, The American journal of psychiatry.

[47]  D. Jeste,et al.  Neuroleptic withdrawal in schizophrenic patients. A review of the literature. , 1995, Archives of general psychiatry.

[48]  R. Baldessarini,et al.  Neuroleptic withdrawal in schizophrenic patients. , 1995, Archives of general psychiatry.

[49]  C. Wurthmann,et al.  Randomized, Double‐Blind, Controlled Trial of Risperidone Versus Clozapine in Patients With Chronic Schizophrenia , 1995, Journal of clinical psychopharmacology.

[50]  M. Tohen,et al.  One hundred years of schizophrenia: a meta-analysis of the outcome literature. , 1994 .

[51]  S. Marder,et al.  Risperidone in the treatment of schizophrenia. , 1994, The American journal of psychiatry.

[52]  John M. Davis,et al.  Depot Antipsychotic Drugs , 1994, Drugs.

[53]  Green Ai,et al.  Decreased substance use in chronically psychotic patients treated with clozapine. , 1994 .

[54]  L. Friedman,et al.  Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine , 1993, Biological Psychiatry.

[55]  W. Gaebel,et al.  Intermittent versus maintenance neuroleptic long-term treatment in Schizophrenia—2-year results of a German multicenter study , 1993 .

[56]  S Pollack,et al.  Does clozapine cause tardive dyskinesia? , 1993, The Journal of clinical psychiatry.

[57]  E. Češková,et al.  Double-blind Comparison of Risperidone and Haloperidol in Schizophrenic and Schizoaffective Psychoses , 1993, Pharmacopsychiatry.

[58]  Philip D. Harvey,et al.  Cognitive deficits in schizophrenia. , 1993, The Psychiatric clinics of North America.

[59]  P. Janicak Principles and Practice of Psychopharmacotherapy , 1993 .

[60]  J. Wilkins,et al.  Unrecognized cocaine use among schizophrenic patients. , 1993, The American journal of psychiatry.

[61]  S. Marder,et al.  A one-year comparison of four dosages of haloperidol decanoate , 1993, Schizophrenia Research.

[62]  H. Hermesh,et al.  Poor neuroleptic response in acutely exacerbated schizophrenic patients , 1993, Acta psychiatrica Scandinavica.

[63]  G. Remington,et al.  Acutely psychotic patients receiving high-dose haloperidol therapy. , 1993, Journal of clinical psychopharmacology.

[64]  A Labelle,et al.  A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. , 1993, Journal of clinical psychopharmacology.

[65]  J. Kane,et al.  Depot neuroleptic therapy: an underutilized treatment option. , 1992, The Journal of clinical psychiatry.

[66]  A. Mallya,et al.  Restraint, seclusion, and clozapine. , 1992, The Journal of clinical psychiatry.

[67]  P. Czobor,et al.  Haloperidol blood levels and clinical effects. , 1992, Archives of general psychiatry.

[68]  R E Litman,et al.  Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine. , 1992, Archives of general psychiatry.

[69]  J. Peuskens,et al.  Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double‐blind comparative study , 1992, Acta psychiatrica Scandinavica.

[70]  M. Herz,et al.  Intermittent vs maintenance medication in schizophrenia. Two-year results. , 1991, Archives of general psychiatry.

[71]  A. Rifkin,et al.  Dosage of haloperidol for schizophrenia. , 1991, Archives of general psychiatry.

[72]  D S Rae,et al.  Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. , 1990, JAMA.

[73]  S. Hirsch,et al.  Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years. , 1990 .

[74]  R. Buchanan,et al.  Continuous versus targeted medication in schizophrenic outpatients: outcome results. , 1990, The American journal of psychiatry.

[75]  G. Simpson,et al.  Fluphenazine dose, clinical response, and extrapyramidal symptoms during acute treatment. , 1990, Archives of general psychiatry.

[76]  S. Marder,et al.  A controlled dose comparison of haloperidol in newly admitted schizophrenic patients. , 1990, Archives of general psychiatry.

[77]  N. Andreasen The Scale for the Assessment of Negative Symptoms (SANS): Conceptual and Theoretical Foundations , 1989, British Journal of Psychiatry.

[78]  S. Hirsch,et al.  Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical outcome at one year. , 1989, BMJ.

[79]  J. McEvoy,et al.  Dose of fluphenazine, familial expressed emotion, and outcome in schizophrenia. Results of a two-year controlled study. , 1988, Archives of general psychiatry.

[80]  G Honigfeld,et al.  Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. , 1988, Archives of general psychiatry.

[81]  D. A. Johnson,et al.  Double-Blind Comparison of Half-Dose and Standard-Dose Flupenthixol Decanoate in the Maintenance Treatment of Stabilised Out-Patients with Schizophrenia , 1987, British Journal of Psychiatry.

[82]  S. Marder,et al.  Low- and conventional-dose maintenance therapy with fluphenazine decanoate. Two-year outcome. , 1987, Archives of general psychiatry.

[83]  J. Kane,et al.  Depot neuroleptics: a comparative review of standard, intermediate, and low-dose regimens. , 1986, Journal of Clinical Psychiatry.

[84]  J. Kane Compliance Issues in Outpatient Treatment , 1985, Journal of clinical psychopharmacology.

[85]  S. Marder,et al.  Costs and benefits of two doses of fluphenazine. , 1984, Archives of general psychiatry.

[86]  A. Rifkin,et al.  Low-dose neuroleptic treatment of outpatient schizophrenics. I. Preliminary results for relapse rates. , 1983, Archives of general psychiatry.

[87]  J. Kane,et al.  Tardive dyskinesia: prevalence and risk factors, 1959 to 1979 , 1982, Archives of general psychiatry.

[88]  G. Hogarty,et al.  Fluphenazine and social therapy in the aftercare of schizophrenic patients. Relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride. , 1979, Archives of general psychiatry.

[89]  J. Curran PROGRESS IN PSYCHIATRIC DRUG TREATMENT , 1977 .

[90]  J. Davis,et al.  Overview: maintenance therapy in psychiatry: I. Schizophrenia. , 1975, The American journal of psychiatry.

[91]  F. Quitkin,et al.  Very High Dosage vs Standard Dosage Fluphenazine in Schizophrenia: Frederic Quitkin, MD; Arthur Rifkin, MD; Donald F. Klein, MD , 1975 .

[92]  D. Klein Diagnosis and Drug Treatment of Psychiatric Disorders , 1969, British Journal of Psychiatry.

[93]  Jonathan O. Cole,et al.  High Dose Chlorpromazine Therapy in Chronic Schizophrenia: Report of National Institute of Mental Health—Psychopharmacology Research Branch Collaborative Study Group , 1968 .

[94]  Daniel M. Hartung,et al.  Metabolic testing rates in 3 state Medicaid programs after FDA warnings and ADA/APA recommendations for second-generation antipsychotic drugs. , 2010, Archives of general psychiatry.

[95]  D. Casey Clozapine: neuroleptic-induced EPS and tardive dyskinesia , 2004, Psychopharmacology.

[96]  J. Gerlach,et al.  High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response, side effects, serum haloperidol, and serum prolactin , 2004, Psychopharmacology.

[97]  J. Kane,et al.  The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. , 2003, The Journal of clinical psychiatry.

[98]  W. Honer,et al.  An open comparison of clozapine and risperidone in treatment-resistant schizophrenia. , 1998, Pharmacopsychiatry.

[99]  R. Fireworker,et al.  Clozapine reduces rehospitalization among schizophrenia patients. , 1998, Psychopharmacology bulletin.

[100]  M. Tohen,et al.  Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. , 1997, Archives of general psychiatry.

[101]  J. Kane,et al.  Drug therapy : schizophrenia , 1996 .

[102]  W A Hargreaves,et al.  Clozapine eligibility among state hospital patients. , 1996, Schizophrenia bulletin.

[103]  Nancy H. Covell,et al.  Clozapine's effectiveness for patients in state hospitals: results from a randomized trial. , 1996, Psychopharmacology bulletin.

[104]  H. Meltzer,et al.  Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. , 1995, The American journal of psychiatry.

[105]  M. Olfson,et al.  The Cost of Relapse in Schizophrenia , 2017, PharmacoEconomics.

[106]  H. Meltzer,et al.  Substance abuse among patients with treatment-resistant schizophrenia: characteristics and implications for clozapine therapy. , 1994, The American journal of psychiatry.

[107]  R. Buchanan,et al.  Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. , 1994, The American journal of psychiatry.

[108]  P. Weiden,et al.  Treatment of neuroleptic-resistant schizophrenic relapse. , 1993, Psychopharmacology bulletin.

[109]  B. Cornblatt,et al.  The New York High-Risk Project: anhedonia, attentional deviance, and psychopathology. , 1993, Schizophrenia bulletin.

[110]  F. Müller-Spahn RISPERIDONE IN THE TREATMENT OF CHRONIC SCHIZOPHRENIC PATIENTS: AN INTERNATIONAL DOUBLE‐BLIND PARALLEL‐GROUP STUDY VERSUS HALOPERIDOL. , 1992, Clinical neuropharmacology.

[111]  B. Diamond,et al.  Risperidone: clinical safety and efficacy in schizophrenia. , 1992, Psychopharmacology bulletin.

[112]  Werner Kissling Guidelines for Neuroleptic Relapse Prevention in Schizophrenia , 1991, Springer Berlin Heidelberg.

[113]  R. Wyatt,et al.  When symptoms persist: choosing among alternative somatic treatments for schizophrenia. , 1991, Schizophrenia bulletin.

[114]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[115]  M. Borenstein,et al.  Compliance in the long-term treatment of schizophrenia. , 1985, Psychopharmacology bulletin.

[116]  Barbara A. Cornblatt,et al.  The New York High-Risk Project. , 1984 .