Fortschr Neurol Psychiatr 2013; 81(5): e1-e13
DOI: 10.1055/s-0033-1335405
Review
© Georg Thieme Verlag KG Stuttgart · New York

Pharmacological Treatment of Schizophrenia

Psychopharmakologische Schizophreniebehandlung
S. Leucht
1   Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, München, Germany
,
S. Heres
1   Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, München, Germany
,
W. Kissling
1   Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, München, Germany
,
J. M. Davis
2   Department of Psychiatry, University of Illinois at Chicago, IL, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
23 May 2013 (online)

Abstract

We present the pharmacological treatment of schizophrenia based on a simple algorithm that starts with the most important decisions starting from the choice of an antipsychotic drug for an acutely ill patient and ends with maintenance treatment. It represents experts opinions, a formal guideline development process was not followed. Concerning acute treatment we present recommendations for the choice of drug in acutely patients, the treatment of agitated patients, persistent depression, negative symptoms and treatment resistance. Concerning maintenance treatment with antipsychotics we discuss indication, choice of drug, continuous versus intermittent treatment, duration of relapse prevention and dose.

Zusammenfassung

In diesem Artikel stellen wir die pharmakologische Schizophreniebehandlung basierend auf einem einfachen Algorithmus dar, der mit den wichtigsten Entscheidungen in der Akutbehandlung beginnt und mit der Erhaltungstherapie endet. Die verwendete Methodik ist ein Expertenkonsensus, ein formaler Leitlinienentwicklungsprozess wurde nicht verwendet. In der Akutbehandlung geben wir Empfehlungen hinsichtlich der Auswahl des Medikaments die Behandlung agitierter Patienten, für persistierende bei Depression, Negativsymptomen und Therapieresistenz. In der Erhaltungstherapie diskutieren wir Indikation, Auswahl des Medikaments, kontinuierliche versus intermittierende Behandlung, Dauer einer Rezidivprophylaxe und Dosis.

 
  • References

  • 1 Adams CE, Coutinho E, Davis JM et al. Cochrane Schizophrenia Group. The Cochrane Library. Chichester, UK: John Wiley & Sons Ltd; 2008
  • 2 Adams CE, Fenton MKP, Quraishi S et al. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. British Journal of Psychiatry 2000; 179: 190-199
  • 3 Agid O, Kapur S, Arenovich T et al. Delayed-onset hypothesis of antipsychotic action – a hypothesis tested and rejected. Archives of General Psychiatry 2003; 60: 1228-1235
  • 4 Agid O, Kapur S, Warrington L et al. Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. Schizophrenia Research 2008; 102: 241-248
  • 5 Akhondzadeh S, Tabatbaee M, Amini H et al. Celecoxib as adjunctive therapy in schizophrenia: A double-blind, randomized and placebo-controlled trial. Schizophrenia Research 2007; 90: 179-185
  • 6 Aleman A, Sommer IE, Kahn RS. Efficacy of slow repetitive transcranial magnetic stimulation in the treatment of resistant auditory hallucinations in schizophrenia: a meta-analysis. Journal of Clinical Psychiatry 2007; 68: 416-421
  • 7 Alexander J, Tharyan P, Adams C et al. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting – pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. British Journal of Psychiatry 2004; 185: 63-69
  • 8 Allison DB, Mentore JL, Heo M et al. Antipsychotic-induced weight gain: A comprehensive research synthesis. American Journal of Psychiatry 1999; 156: 1686-1696 
  • 9 Altamura AC, Velona I, Curreli R et al. Is olanzapine better than haloperidol in resistant schizophrenia? A double-blind study in partial responders. International Journal of Psychiatry in Clinical Practice 2002; 6: 107-111
  • 10 Alvir JMJ. Agranulocytosis: incidence and risk factors. Journal of Clinical Psychiatry 1994; 55: 137-138
  • 11 Andreasen NC, Pressler M, Nopoulos P et al. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biological Psychiatry 2010; 67: 255-262
  • 12 Arato M, O'Connor R, Meltzer H. Zeus study group. Ziprasidone in the long-term treatment of negative symptoms and the prevention of exacerbation of schizophrenia. International Clinical Psychopharmacology 2002; 17: 207-215
  • 13 Ascher-Svanum H, Nyhuis AW, Faries DE et al. Clinical, functional, and economic ramifications of early nonresponse to antipsychotics in the naturalistic treatment of schizophrenia. Schizophrenia Bulletin 2008; 34: 1163-1171
  • 14 Baldessarini RJ, Cohen BM, Teicher MH. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Archives of General Psychiatry 1988; 45: 79-91
  • 15 Barbui C, Saraceno B, Liberati A et al. Low-dose neuroleptic therapy and relapse in schizophrenia: meta-analysis of randomized controlled trials. European Psychiatry 1996; 11: 306-311
  • 16 Barbui C, Signoretti A, Mule S et al. Does the addition of a second antipsychotic drug improve Clozapine treatment?. Schizophrenia Bulletin 2009; 35: 458-468
  • 17 Barnes TR, McPhillips MA. How to distinguish between the neuroleptic-induced deficit syndrome, depression and disease-related negative symptoms in schizophrenia. International Clinical Psychopharmacology 1995; 10 (Suppl. 03) 115-121
  • 18 Basan A, Kissling W, Leucht S. Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials. Schizophrenia Research 2004; 70: 33-37
  • 19 Battaglia J, Moss S, Rush J et al. Haloperidol, lorazepam, or both for psychotic agitation: a multicenter, prospective, double blind, emergency department study. American Journal of Emergency Medicine 1997; 15: 335-340
  • 20 Baumann P, Hiemke C, Ulrich S et al. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 2004; 37: 243-265
  • 21 Bollini P. Antipsychotic drugs: is more worse? A meta analysis of the published randomized controlled trials. Psychological Medicine 1994; 24: 307-316
  • 22 Breier A, Hamilton SH. Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia. Biological Psychiatry 1999; 45: 403-411
  • 23 Buchanan RW, Ball MP, Weiner E et al. Olanzapine treatment of residual positive and negative symptoms. American Journal of Psychiatry 2005; 162: 124-129
  • 24 Buchanan RW, Kreyenbuhl J, Kelly DL et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophrenia Bulletin 2010; 36: 71-93
  • 25 Bushe C, Shaw M, Peveler RC. A review of the association between antipsychotic use and hyperprolactinaemia. Journal of Psychopharmacology 2008; 22: 46-55
  • 26 Carpenter WT, Hanlon TE, Heinrichs DW et al. Continuous vs. targeted medication in schizophrenic outpatients: outcome results. American Journal of Psychiatry 1990; 147: 1138-1163
  • 27 Casey DE, Daniel DG, Tamminga C et al. Divalproex ER combined with olanzapine or risperidone for treatment of acute exacerbations of schizophrenia. Neuropsychopharmacology 2009; 34: 1330-1338
  • 28 Casey DE, Daniel DG, Wassef AA et al. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology 2003; 28: 182-192
  • 29 Chakos M, Lieberman J, Hoffman E et al. Effectiveness of second generation antipsychotics for treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. American Journal of Psychiatry 2001; 158: 518-526
  • 30 Chang JS, Ahn YM, Park HJ et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry 2008; 69: 720-731
  • 31 Chang YC, Lane HY, Yang KH et al. Optimizing early prediction for antipsychotic response in schizophrenia. Journal of Clinical Psychopharmacology 2006; 26: 554-559
  • 32 Cheine M, Ahonen J, Wahlbeck K. Beta-blocker supplementation of standard drug treatment for schizophrenia. Cochrane Database of Systematic Reviews 2001; Art No. CD000234
  • 33 Chen EYH, Hui CLM, Lam MML et al. Maintenance treatment with quetiapine vs. discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. British Medical Journal 2010; 341: c4024
  • 34 Cheung HK. Schizophrenics fully remitted on neuroleptics for 3–5 years–to stop or continue drugs?. British Journal of Psychiatry 1981; 138: 490-494 
  • 35 Chua WL, Santiago AD, Kulkarni J et al. Estrogen for schizophrenia. Cochrane Database of Systematic Reviews 2005; Art No. CD004719.
  • 36 Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. Journal of Clinical Psychiatry 2007; 68: 1876-1885 
  • 37 Conley RR, Kelly DL, Nelson MW et al. Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia. Clinical Neuropharmacology 2005; 28: 163-168
  • 38 Conley RR, Tamminga CA, Bartko JJ et al. Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. American Journal of Psychiatry 1998; 155: 914-920
  • 39 Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of one-year studies. American Journal of Psychiatry 2004; 161: 414-415
  • 40 Correll CU, Malhotra AK, Kaushik S et al. Early prediction of antipsychotic response in schizophrenia. American Journal of Psychiatry 2003; 160: 2063-2065 
  • 41 Correll CU, Rummel-Kluge C, Corves C et al. Antipsychotic combinations vs. monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophrenia Bulletin 2009; 35: 443-457
  • 42 Correll CU, Schenk EM. Tardive dyskinesia and new antipsychotics. Current Opinion in Psychiatry 2008; 21: 151-156
  • 43 Correll C, Agarwal V, Kane J. Gradual and Overlapping Antipsychotic Switch Strategies Are Associated with Less All-Cause Discontinuation in Schizophrenia: Results from a Meta-analysis of Different Switch Strategies. presented at the ACNP congress 2011
  • 44 Crow TJ, MacMillan JF, Johnson AL et al. A randomised controlled trial of prophylactic neuroleptic treatment. British Journal of Psychiatry 1986; 148: 120-127
  • 45 Davis JM, Chen N. Dose-response and dose equivalence of antipsychotics. Journal of Clinical Psychopharmacology 2004; 24: 192-208
  • 46 Davis JM. Dose equivalence of the antipsychotic drugs. Journal of Psychiatric Research 1974; 11: 65-69
  • 47 Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Archives of General Psychiatry 2003; 60: 553-564 
  • 48 De Hert M, Dekker JM, Wood D et al. Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). European Psychiatry 2009; 24: 412-424
  • 49 De Hert M, Detraux J, van Winkel R et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2011 ; 8: 114-26
  • 50 Dellva MA, Tran P, Tollefson GD et al. Standard olanzapine versus placebo and ineffective dose olanzapine in the maintenance treatment of schizophrenia. PsychiatrServ 1997; 48: 1571-1577
  • 51 Ehrenreich H, Hinze-Selch D, Stawicki S et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Molecular Psychiatry 2007; 12: 206-220
  • 52 Elias A, Kumar A. Testosterone for schizophrenia. Database of Systematic Reviews 2007; Art. No. CD006197.
  • 53 Emsley RA, Raniwalla J, Bailey PJ et al. A comparison of the effects of quetiapine (“Seroquel”) and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. International Clinical Psychopharmacology 2000; 15: 121-131
  • 54 Essali A, Al-Haj HN, Li C et al. Clozapine vs. typical neuroleptic medication for schizophrenia. Cochrane Database of Systematic Reviews 2009; Art. No. CD000059.
  • 55 Essock SM, Schooler NR, Stroup TS et al. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry 2011; 168: 702-708
  • 56 Falkai P, Wobrock T, Lieberman J et al. World Federation of Societies of Biological Psychiatry (WFSBP) – Guidelines for biological treatment of schizophrenia, part 1: Acute treatment of schizophrenia. World Journal of Biological Psychiatry 2005; 6: 132-191
  • 57 Fleischhacker WW, Heikkinen ME, Olie JP et al. Weight change on aripiprazole-clozapine combination in schizophrenic patients with weight gain and suboptimal response on clozapine: 16-week double-blind study. European Psychiatry 2008; 23: S114-S115
  • 58 Gaebel W, Awad AG. Prediction of Neuroleptic Treatment Outcome in Schizophrenia. Concepts and Methods. Wien: Springer Verlag; 1994
  • 59 Gaebel W, Falkai P, Weinmann S et al Behandlungsleitlinie Schizophrenie. Darmstadt: Steinkopff; 2006
  • 60 Gaebel W, Riesbeck M, Wölwer W et al. Relapse prevention in first episode schizophrenia. Maintenance vs. intermittent drug treatment with a prodrome based early intervention: Results of a randomised controlled trial within the German research network on schizophrenia. Journal of Clinical Psychiatry 2010; Published online: 29 June 2010 DOI: 10.4088/JCP.09m05459yel.
  • 61 Gaebel W, Weinmann S, Sartorius N et al. Schizophrenia practice guidelines: international survey and comparison. British Journal of Psychiatry 2005; 187: 248-255
  • 62 Gallego JA, Robinson DG, Sevy SM et al. Time to Treatment Response in First-Episode Schizophrenia: Should Acute Treatment Trials Last Several Months?. J Clin Psychiatry 2011; 72: 1691-1696
  • 63 Gallego JA, Nielsen J, De Hert M et al. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Saf 2012; 11: 527-542
  • 64 Gardner DM, Murphy AL, O'Donnell H et al. International consensus study of antipsychotic dosing. American Journal of Psychiatry 2010; 167: 686-693
  • 65 Geddes J, Freemantle N, Harrison P et al. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. British Medical Journal 2000; 321: 1371-1376
  • 66 Goodwin G, Fleischhacker W, Arango C et al. Advantages and disadvantages of combination treatment with antipsychotics ECNP Consensus Meeting, March 2008, Nice. European Neuropsychopharmacology 2009; 19: 520-532
  • 67 Hajak G, Marienhagen J, Langguth B et al. High-frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined treatment and neuroimaging study. Psychological Medicine 2004; 34: 1157-1163
  • 68 Hamann J, Leucht S, Kissling W. Shared decision making in psychiatry. Acta Psychiatrica Scandinavica 2003; 107: 403-409
  • 69 Hartung B, Wada M, Laux G et al. Perphenazine for schizophrenia. Cochrane Database of Systematic Reviews. 2005; Art. No. CD003443.
  • 70 Hatta K, Otachi T, Sudo Y et al. Difference in early prediction of antipsychotic non-response between risperidone and olanzapine in the treatment of acute-phase schizophrenia. Schizophr Res 2011; 128: 127-135
  • 71 Hatta K, Otachi T, Sudo Y et al. A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non-response to risperidone. Psychiatry Res 2012; 198: 194-201
  • 72 Herz MI, Glazer WM, Mostert MA et al. Intermittent vs. maintenance medication in schizophrenia. Two-year results. Archives of General Psychiatry 1991; 48: 333-339
  • 73 Hiemke C, Baumann P, Bergemann N et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011; 44: 195-235
  • 74 Hogarty GE, McEvoy JP. Dose of fluphenazine, familial expressed emotions and outcome in schizophrenia. Archives of General Psychiatry 1988; 45: 797-805
  • 75 Hogarty GE, Ulrich RF. The limitations of antipsychotic medication on schizophrenia relapse and adjustment and the contributions of psychosocial treatment. Journal of Psychiatric Research 1998; 32: 243-250
  • 76 Hogarty GE, Ulrich RF, Mussare F et al. Drug discontinuation among long term, successfully maintained schizophrenic outpatients. Diseases of the Nervous System 1976; 37: 494-500
  • 77 Honer WG, MacEwan GW, Gendron A 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; 73: 13-20
  • 78 Hoyberg OJ, Fensbo C. Risperidone vs. perphenazine in the treatment of chronic schizophrenic patients with acute exacerbation. Acta Psychiatrica Scandinavica 1993; 88: 396-402
  • 79 Huf G, Coutinho ES, Adams CE. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol vs. intramuscular haloperidol plus promethazine. British Medical Journal 2007; 335: 869
  • 80 Huf G, Coutinho ESF, Adams CE et al. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam vs. haloperidol plus promethazine. British Medical Journal 2003; 327: 708-711
  • 81 Jager M, Schmauss M, Laux G et al. Early improvement as a predictor of remission and response in schizophrenia: Results from a naturalistic study 3. European Psychiatry 2009; 24: 501-506
  • 82 Jeste DV, Lacro JP, Gilbert PL et al. Treatment of late-life schizophrenia with neuroleptics. Schizophrenia Bulletin 1993; 19: 817-830
  • 83 Johnson DA. The duration of maintenance therapy in chronic schizophrenia. Acta Psychiatrica Scandinavica 1976; 53: 298-301
  • 84 Johnson DA, Ludlow JM, Street K et al. Double-blind comparison of half-dose and standard-dose flupenthixol decanoate in the maintenance treatment of stabilised out-patients with schizophrenia. British Journal of Psychiatry 1987; 151: 634-638
  • 85 Johnson DAW. Further observation on the duration of depot neuroleptic maintenance therapy in schizophrenia. British Journal of Psychiatry 1979; 135: 524-530
  • 86 Jolley AG, Hirsch SR. Trial brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years. 540 British Medical Journal 1990; 301: 837-842
  • 87 Jones PB, Barnes TRE, Davies L 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). Archives of General Psychiatry 2006; 63: 1079-1086
  • 88 Joy CB, Mumby-Croft R, Joy LA. Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database of Systematic Reviews 2006; Art No. CD001257
  • 89 Kahn RS, Fleischhacker WW, Boter H et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371: 1085-1097
  • 90 Kane JM. Fluphenazine vs. placebo in patients with remitted, acute first-episode schizophrenia. Archives of General Psychiatry 1982; 39: 70-73
  • 91 Kane JM, Correll CU, Goff DC et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. Journal of Clinical Psychiatry 2009; 70: 1348-1357
  • 92 Kane JM, Davis JM, Schooler N et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. American Journal of Psychiatry 2002; 159: 554-560
  • 93 Kane JM, Honigfeld G, Singer J et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry 1988; 45: 789-796
  • 94 Kane JM, Khanna S, Rajadhyaksha S et al. Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia. International Clinical Psychopharmacology 2006; 21: 21-28
  • 95 Kane JM, Leucht S, Carpenter D et al. Optimising pharmacologic treatment of psychotic disorders. Journal of Clinical Psychiatry 2003; 64: 1-100
  • 96 Kane JM, Marder SR, Schooler NR et al. Clozapine and haloperidol in moderately refractory schizophrenia – a 6-month randomized and double-blind comparison. Archives of General Psychiatry 2001; 58: 965-972
  • 97 Kane JM, Meltzer HY, Carson WH et al. Aripiprazole for treatment-resistant schizophrenia: Results of a multicenter, randomized, double-blind, comparison study vs. perphenazine. Journal of Clinical Psychiatry 2007; 68: 213-223
  • 98 Kane JM, Rifkin A, Woerner M et al. Low-dose neuroleptic treatment of outpatient schizophrenics. I. Preliminary results for relapse rates. Archives of General Psychiatry 1983; 40: 893-896
  • 99 Kapur S, Arenovich T, Agid O et al. Evidence for onset of antipsychotic effects within the first 24h of treatment. American Journal of Psychiatry 2005; 162: 939-946
  • 100 Kinon BJ, Chen L, Ascher-Svanum H et al. Predicting response to atypical antipsychotics based on early response in the treatment of schizophrenia. Schizophrenia Research 2008; a 102: 230-240
  • 101 Davis JM, Mentalon L, Watanabe MD. Depot antipsychotic drugs. Place in therapy. Drugs 1994; 47: 741-773
  • 102 Kinon BJ, Kane JM, Johns C et al. Treatment of neuroleptic-resistant schizophrenic relapse. Psychopharmacology Bulletin 1993; 29: 309-314
  • 103 Kinon BJ, Volavka J, Stauffer V et al. Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study. Journal of Clinical Psychopharmacology 2008; b 28: 392-400
  • 104 Kinon BJ, Chen L, Ascher-Svanum H et al. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology 2010; 35: 581-590
  • 105 Kishimoto T. New results alter balance of evidence of meta-analysis on long-acting injectable vs. oral antipsychotics in schizophrenia. Schizophr Bull 2012; epub ahead of print.
  • 106 Kishimoto T, Agarwal V, Kishi T et al. Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol Psychiatry 2011;
  • 107 Kissling W, Kane JM, Barnes TR et al. Guidelines for neuroleptic relapse prevention in schizophrenia: towards consensus view. In: Kissling W, (Ed.), Guidelines for Neuroleptic Relapse Prevention in Schizophrenia. Heidelberg, Berlin: Springer; 1991: 155-163
  • 108 Klein DF, Davis JM. Diagnosis and Drug Treatment of Psychiatric Disorders. Baltimore: Williams and Wilkins; 1969
  • 109 Klein E, Kolsky Y, Puyerovsky M et al. Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study. Biological Psychiatry 4 1999; 6: 1451-1454
  • 110 Kleinberg DL, Davis JM, de Coster R et al. Prolactin levels and adverse events in patients treated with risperidone. Journal of Clinical Psychopharmacology 1999; 19: 57-61
  • 111 Krakowski MI, Czobor P, Citrome L et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Archives of General Psychiatry 2006; 63: 622-629
  • 112 Lambert M, Schimmelmann BG, Naber D et al. Early- and delayed antipsychotic response and prediction of outcome in 528 severely impaired patients with schizophrenia treated with amisulpride. Pharmacopsychiatry 2009; 42: 277-283
  • 113 Lecrubier Y, Quintin P, Bouhassira M et al. The treatment of negative symptoms and deficit states of chronic schizophrenia: olanzapine compared to amisulpride and placebo in a 6-month double-blind controlled clinical trial. Acta Psychiatr Scand 2006; 114: 319-27
  • 114 Lehman AF, Lieberman JA, Dixon LB et al. Practice guideline for the treatment of patients with schizophrenia, second edition. American Journal of Psychiatry 2004; 161: 1-56
  • 115 Leucht C, Heres S, Kane JM et al. (in press). Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of randomised long-term trials. Schizophrenia Research
  • 116 Leucht S, Heres S, Kissling W et al. Evidence-based pharmacotherapy of schizophrenia. Int J Neuropsychopharmacol 2011 ; 14: 269-284
  • 117 Leucht S, Tardy M, Komossa K et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379: 2063-2071
  • 118 Leucht S, Cipriani A, Spineli L et al. Multiple treatments meta-analysis on the efficacy and tolerability of 15 antipsychotic drugs in schizophrenia. Lancet 2013; accepted for publication.
  • 119 Leucht C, Kitzmantel M, Chua L et al. Haloperidol vs. chlorpromazine for schizophrenia. Cochrane Database of Systematic Reviews. 2008; Art. No. CD004278.
  • 120 Leucht S, Arbter D, Engel RR et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry Published online: 8 January 2008; DOI: 10.1038/sj.mp.4002136.
  • 121 Leucht S, Barnes TRE, Kissling W et al. Relapse prevention in schizophrenia with new-generation antipsychotics: A systematic review and exploratory meta-analysis of randomized, controlled trials. American Journal of Psychiatry 2003; 160: 1209-1222
  • 122 Leucht S, Busch R, Hamann J et al. Early onset of antipsychotic drug action: a hypothesis tested, confirmed and extended. Biological Psychiatry 2005; 57: 1543-1549
  • 123 Leucht S, Busch R, Kissling W et al. Early prediction of antipsychotic non-response. Journal of Clinical Psychiatry 2007; 68: 352-360
  • 124 Leucht S, Corves C, Arbter D et al. Second-generation vs. first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373: 31-41
  • 125 Leucht S, Heres S. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. Journal of Clinical Psychiatry 2006; 67: 3-8
  • 126 Leucht S, Kane JM, Etschel E et al. Linking the PANSS, BPRS, and CGI: Clinical implications. Neuropsychopharmacology 2006; 31: 2318-2325
  • 127 Leucht S, Kane JM, Kissling W et al. Clinical implications of BPRS scores. British Journal of Psychiatry 2005; 187: 363-371
  • 128 Leucht S, Kane JM, Kissling W et al. What does the PANSS mean?. Schizophrenia Research 2005; 79: 231-238
  • 129 Leucht S, Kissling W, McGrath J. Lithium for schizophrenia. Cochrane Database of Systematic Reviews. 2007; Art. No. CD003834.
  • 130 Leucht S, Komossa K, Rummel-Kluge C et al. A meta-analysis of head to head comparisons of second generation antipsychotics in the treatment of schizophrenia. American Journal of Psychiatry 2009; 166: 152-163
  • 131 Leucht S, McGrath J, White P et al. Carbamazepine augmentation for schizophrenia: how good is the evidence?. Journal of Clinical Psychiatry 2002; 63: 218-224
  • 132 Leucht S, Pitschel-Walz G, Engel R et al. Amisulpride – an unusual atypical antipsychotic. A meta-analysis of randomized controlled trials. American Journal of Psychiatry 2002; 159: 180-190
  • 133 Leucht S, Shamsi AS, Busch R et al. Early prediction of antipsychotic response – replication and six weeks extension. Schizophrenia Research 2008; 101: 312-319
  • 134 Leucht S, Wahlbeck K, Hamann J et al. New generation antipsychotics vs. low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003; 361: 1581-1589
  • 135 Levine SZ, Rabinowitz J. Trajectories and antecedents of treatment response over time in early-episode psychosis. Schizophrenia Bulletin Advance Access 2008;
  • 136 Levine SZ, Leucht S. Elaboration on the early-onset hypothesis of antipsychotic drug action: treatment response trajectories. Biological Psychiatry 2010; 68: 86-92
  • 137 Lewis SW, Barnes TR, Davies L et al. Randomized controlled trial of effect of prescription of clozapine vs. other second-generation antipsychotic drugs in resistant schizophrenia. Schizophrenia Bulletin 2006; 32: 715-723
  • 138 Lieberman JA, Stroup TS, McEvoy JP et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 2005; 353: 1209-1223
  • 139 Lieberman JA. Maximizing clozapine therapy: managing side effects. Journal of Clinical Psychiatry 1998; 59: 38-43
  • 140 Lin CH, Chou LS, Lin CH et al. Early prediction of clinical response in schizophrenia patients receiving the atypical antipsychotic zotepine. Journal of Clinical Psychiatry 2007; 68: 1522-1527
  • 141 Lindenmayer JP, Citrome L, Khan A et al. A randomized, double-blind, parallel-group, fixed-dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-resistant schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 2011; 31: 160-8
  • 142 Lindenmayer JP, Khan A, Iskander A et al. A randomized controlled trial of olanzapine vs. haloperidol in the treatment of primary negative symptoms and neurocognitive deficits in schizophrenia. Journal of Clinical Psychiatry 2007; 68: 368-379
  • 143 Marder SR, Vanputten T, Mintz J et al. Costs and benefits of 2 doses of fluphenazine. Archives of General Psychiatry 1984; 41: 1025-1029
  • 144 McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptic in acute schizophrenia. Optimal dose of neuroleptic in acute schizophrenia 1991; 48: 740-745
  • 145 McEvoy JP, Lieberman JA, Stroup TS et al. Effectiveness of clozapine vs. olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. American Journal of Psychiatry 2006; 163: 600-610
  • 146 McGorry PD. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders. Australian and New Zealand Journal of Psychiatry 2005; 39: 1-30
  • 147 Moller HJ, Kissling W, Lang C et al. Efficacy and side effects of haloperidol in psychotic patients: oral vs. intravenous administration. American Journal of Psychiatry 1982; 139: 1571-1575
  • 148 Muller N, Riedel M, Scheppach C et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. American Journal of Psychiatry 2002; 159: 1029-1034
  • 149 Naber D, Hippius H. The European experience with use of clozapine. Hospital and Community Psychiatry 1990; 41: 886-890
  • 150 NICE. Schizophrenia: full national guideline on core interventions in primary and secondary care. National Institute for Clinical: Excellence Royal College of Psychiatrists. 2003
  • 151 Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects – a comprehensive literature review. CNS Drugs 2005; 19: 1-93
  • 152 Nolte S, Wong D, Latchford G. Amphetamines for schizophrenia. Cochrane Database of Systematic Reviews. 2004; Art No. CD004964.
  • 153 Odejide OA, Aderounmu AF. Double-blind placebo substitution: withdrawal of fluphenazine decanoate in schizophrenic patients. Journal of Clinical Psychiatry 1982; 43: 195-196
  • 154 Omori IM, Wang J. Sulpiride vs. placebo for schizophrenia. Cochrane Database of Systematic Reviews 2009; Art. No. CD007811.
  • 155 Patel MX, Taylor M, David AS. Antipsychotic long-acting injections: mind the gap. British Journal of Psychiatry (Suppl.) 2009; 52: S1-S4
  • 156 Paton C, Whittington C, Barnes TR. Augmentation with a second antipsychotic in patients with schizophrenia who partially respond to clozapine – a meta-analysis. Journal of Clinical Psychopharmacology 2007; 27: 198-204
  • 157 Pietzcker A, Gaebel W, Koepcke W et al. Intermittent vs. maintenance neuroleptic long-term treatment in schizophrenia – 2 years results of a german multicenter study. Journal of Psychiatric Research 1993; 27: 321-339
  • 158 Premkumar TS, Pick J. Lamotrigine for schizophrenia. Cochrane Database of Systematic Reviews 2006; Art No. CD005962.
  • 159 Rappard F, Müller N. Celecoxib Add-on Therapy Does Not Have Beneficial Antipsychotic Effects Over Risperidone Alone in Schizophrenia. Neuropsychopharmacology 2004; 29 (Suppl. 01) S222
  • 160 Raveendran NS, Tharyan P, Alexander J et al. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine vs. intramuscular haloperidol plus promethazine. British Medical Journal 2007; 335: 865
  • 161 Robinson D, Woerner MG, Alvir JM et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Archives of General Psychiatry 1999; 56: 241-247
  • 162 Rosenheck R, Cramer J, Xu WC et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. New England Journal of Medicine 1997; 337: 809-815
  • 163 Rosenheck R, Perlick D, Bingham S et al. Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia – a randomized controlled trial. Journal of the American Medical Association 2003; 290: 2693-2702
  • 164 Rummel C, Kissling W, Leucht S. Antidepressants for the negative symptoms of schizophrenia. Cochrane Database of Systematic Reviews. 2006; Art No. CD005581.
  • 165 Rummel-Kluge C, Komossa K, Schwarz S et al. Second generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull. 2012; 38: 167-177
  • 166 Sampath G, Shah A, Krska J et al. Neuroleptic discontinuation in the very stable schizophrenic patient – relapse rates and serum neuroleptic levels. Human Psychopharmacology: Clinical and Experimental 1992; 7: 255-264
  • 167 Schennach-Wolff R, Seemüller FH, Mayr A et al. An early improvement threshold to predict response and remission in first-episode schizophrenia. Br J Psychiatry 2010; 196: 460-466
  • 168 Schooler NR, Keith SJ, Severe JB et al. Relapse and rehospitalization during maintenance treatment of schizophrenia. Archives of General Psychiatry 1997; 54: 453-463
  • 169 See RE, Fido AA, Maurice M et al. Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia. Biological Psychiatry 1999; 45: 1653-1656
  • 170 Sepehry AA, Potvin S, Elie R et al. Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis. Journal of Clinical Psychiatry 2007; 68: 604-610
  • 171 Shalev A, Hermesh H, Rothberg J et al. Poor neuroleptic response in acutely exacerbated schizophrenic patients. Acta Psychiatrica Scandinavica 1993; 87: 86-91
  • 172 Shepherd M, Watt D, Falloon I et al. The natural history of schizophrenia: a five-year follow-up study of outcome and prediction in a representative sample of schizophrenics. Psychological Medicine (Suppl.) 1989; 15: 1-46
  • 173 Simpson GM, Mahmoud RA, Lasser RA et al. A 1-year double-blind study of 2 doses of long-acting risperidone in stable patients with schizophrenia or schizoaffective disorder. Journal of Clinical Psychiatry 2006; 67: 1194-1203
  • 174 Singh SP, Singh V, Kar N et al. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. British Journal of Psychiatry 2010; 197: 174-179
  • 175 Siris SG. Diagnosis of secondary depression in schizophrenia: Implications for DSM-IV. Schizophrenia Bulletin 1991; 17: 75-98
  • 176 Smith RC, Infante M, Singh A et al. The effects of olanzapine on neurocognitive functioning in medication-refractory schizophrenia. 2001; 4: 239-250
  • 177 Sommer IE, de Witte L, Begemann M et al. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry 2012; 73: 414-419
  • 178 Sommer IE, Begemann MJ, Temmerman A et al. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull 2012; 38: 1003-1011
  • 179 Stip E, Sepehry AA, Chouinard S. Add-on therapy with acetylcholinesterase inhibitors for memory dysfunction in schizophrenia: a systematic quantitative review, part 2. Clinical Neuropharmacology 2007; 30: 218-229
  • 180 Stone JM, Raffin M, Morrison P et al. The biological basis of antipsychotic response in schizophrenia. Journal of Psychopharmacology 2010; 24: 953-964
  • 181 Stroup TS, Lieberman JA, McEvoy JP et al. Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: A CATIE study. American Journal of Psychiatry 2007; 164: 415-427
  • 182 Suzuki T, Uchida H, Watanabe K et al. How effective is it to sequentially switch among Olanzapine, Quetiapine and Risperidone? – a randomized, open-label study of algorithm-based antipsychotic treatment to patients with symptomatic schizophrenia in the real-world clinical setting. Psychopharmacology (Berlin) 2007; 195: 285-295
  • 183 Taylor DM, Smith L. Augmentation of clozapine with a second antipsychotic – a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatrica Scandinavica 2009; 119: 419-425
  • 184 Tharyan P, Adams CE. Electroconvulsive therapy for schizophrenia. Cochrane Database of Systematic Reviews 2005; Art No. CD000076.
  • 185 Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophrenia Research 2009; 109: 10-14
  • 186 Tiihonen J, Haukka J, Taylor M et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011; 168: 603-9
  • 187 Tollefson GD, Beasley CM, Tran PV et al. Olanzapine vs. haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. American Journal of Psychiatry 1997; 154: 457-465
  • 188 Tranulis C, Sepehry AA, Galinowski A et al. Should we treat auditory hallucinations with repetitive transcranial magnetic stimulation? A metaanalysis. Canadian Journal of Psychiatry 2008; 53: 577-586
  • 189 Trikalinos TA, Churchill R, Ferri M et al. Effect sizes in cumulative meta-analyses of mental health randomized trials evolved over time. Journal of Clinical Epidemiology 2004; 57: 1124-1130
  • 190 Tuominen HJ, Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2006; Art No. CD003730.
  • 191 Uchida H, Suzuki T, Takeuchi H et al. Low dose vs. standard dose of antipsychotics for relapse prevention in schizophrenia: meta-analysis. Schizophr Bull. 2011; 37: 788-799
  • 192 Volavka J, Czobor P, Sheitman B et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. American Journal of Psychiatry 2002; 159: 255-262
  • 193 Volz A, Khorsand V, Gillies D et al. Benzodiazepines for schizophrenia. Cochrane Library, Wiley & Sons 2007;
  • 194 Wahlbeck K, Cheine M, Essali A et al. Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. American Journal of Psychiatry 1999; 156: 990-999
  • 195 Wang CY, Xiang YT, Cai ZJ et al. Risperidone maintenance treatment in schizophrenia. A randomised, controlled trial. American Journal of Psychiatry 2010; 167: 676-685
  • 196 Waraich P, Adams C, Hammill K et al. Haloperidol dose for the acutely ill phase of schizophrenia. Cochrane Database of Systematic Reviews 2002; Art. No. CD001951
  • 197 Whitehead C, Moss S, Cardno A et al. Antidepressants for the treatment of depression in people with schizophrenia: a systematic review. Psychological Medicine 2003; 33: 589-599
  • 198 Wirshing DA, Marshall BD, Green MF et al. Risperidone in treatment-refractory schizophrenia. American Journal of Psychiatry 1999; 156: 1374-1379
  • 199 Wunderink L, Nienhuis FJ, Sytema S et al. Guided discontinuation vs. maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. Journal of Clinical Psychiatry 2007; 68: 654-661
  • 200 Zimbroff DL, Kane JM, Tamminga CA et al. Controlled, dose response study of sertindole and haloperidol in the treatment of schizophrenia. American Journal of Psychiatry 1997; 154: 782-791