Current Status of Clinical Practice Guidelines in Schizophrenia

Differential Treatment Decisions

Consistent with this treatment philosophy, findings from a large meta-analysis of comparative efficacy and tolerability of 15 antipsychotic drugs in patients with schizophrenia challenged the stringent grouping of antipsychotics into “first-generation” and “second-generation” classes.17

In this analysis, all antipsychotic drugs were significantly more effective in improving symptoms compared with placebo. However, the differences in efficacy between drugs were small (standardized mean differences 0.11–0.55, median 0.24), and smaller overall than those for side effects. All drugs, except zotepine, were significantly better than placebo for all-cause discontinuation (a measure of drug acceptability); the most effective drugs also had the lowest discontinuation rates.

Antipsychotics differed in side-effects in this analysis.17 However, the stringent dichotomy between “first-generation” and “second-generation” antipsychotics based on weight gain or extrapyramidal side effects was an oversimplification. Apart from haloperidol, ziprasidone, and lurasidone, all drugs produced more weight gain than placebo. Haloperidol caused the most extrapyramidal side effects, followed by zotepine and chlorpromazine. However, chlorpromazine did not produce significantly more extrapyramidal side-effects than most “second-generation” antipsychotics. Five “second-generation” drugs were associated with significantly more extrapyramidal side effects than placebo. Differences among antipsychotics in QTc prolongation and prolactin concentration were large, but strictly dichotomous classifications into “first-generation” and “second-generation” antipsychotics were simplistic based on the analysis.

Overall, the authors concluded that antipsychotic drugs differed in many properties, but could not be “categorized into first- and second-generation groupings.” Rather, they argued that hierarchies in different domains (efficacy, discontinuation, and side effect, etc.) should guide clinicians in selection of antipsychotic drugs to meet the needs of individual patients. They further advised that their findings should be considered in the revision of clinical practice guidelines.

In line with the concept differential treatment selection, the current NICE guidelines for schizophrenia, updated in 2014, recommend that choice of antipsychotic medication in first-episode patients should be made by the patient and healthcare professional together, taking the benefits and possible side effects of each drug (ie, metabolic, extrapyramidal, cardiovascular, hormonal, etc.) into account.9 The selection of a drug for subsequent acute episodes and maintenance care should be influenced by the same criteria recommended for starting treatment.

In the United States, the NICE schizophrenia guidelines9 and PORT treatment recommendations10 are among the major guidelines used and/or influencing the treatment of schizophrenia18 along with the APA Practice Guidelines,7 the Expert Consensus Guidelines,19 the International Psychopharmacology Algorithm Project (IPAP),20 and the Texas medication algorithm project (T-MAP) antipsychotic algorithm21 for schizophrenia. The most recently updated guidelines from NICE integrate results from CATIE, CUtLASS, and EUFEST in its analysis. The 2006 T-MAP algorithm and the 2010 PORT recommendations incorporate CATIE and CUtLASS findings into their recommendations, but at the time of T-MAP’s publication, EUFEST results were not available.

In addition to timeliness, each guideline differs slightly in content, scope, focus, and goals. In brief, the PORT and T-MAP guidelines concisely present recommendations, and T-MAP and IPAP both feature easy-to-use algorithms.10, 21, 20 The NICE guidelines provide a relatively thorough examination of interventions.9 The APA Practice Guidelines and Expert Consensus Guidelines are more dated, but a number of their recommendations remain relevant today.7, 19

Unfortunately, clinician adherence to clinical practice guidelines in schizophrenia remains suboptimal,22, 23, 24-27 and uncertainty exists regarding how best to implement guidelines for maximum benefits.28 Nevertheless, clinical care systems should proceed with the elements of guideline implementation that are clinically warranted and reach consensus29, 30 in an effort to both achieve more effective. efficient care and close the gap between clinical practice and evidence-based medicine.


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8. Gaebe W, Falkai P, Weinmann S, Wobrock T. Behandlungsleitlinie Schizophrenie. In: Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN) (Eds). S3 Praxisleitlinien in Psychiatrie und Psychotherapie. Darmstadt: Steinkopf Verlag, 2005. 

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10. Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB; Schizophrenia Patient Outcomes Research Team (PORT). The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 2010;36:94-103. 

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12. AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: The AGREE project. Qual Saf Health Care. 2003;12:18-23.

13. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-23.

14. Jones PB1, 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;63:1079-87.

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16. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al; EUFEST study group. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371:1085-97.

17. Leucht S1, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-62.

18. Moore TA. Schizophrenia treatment guidelines in the United States. Clin Schizophr Relat Psychoses. 2011;5:40-9. 

19. Treatment of schizophrenia 1999. The expert consensus guideline series. J Clin Psychiatry. 1999;60:3-80.

20. International Psychopharmacology Algorithm Project (IPAP) schizophrenia algorithm 2006. Available from Accessed April 5, 2016. 

21. 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;68:1751-62.

22. Fantini G, Tibaldi G, Rucci P, Gibertoni D, Vezzoli M, Cifarelli L, et al. Quality of care indicators for schizophrenia: determinants of observed variations among Italian Departments of Mental Health. Results from the ETAS DSM study. Epidemiol Psychiatr Sci. 2016:1-15 

23. Semisa D, Casacchia M, Di Munzio W, Neri G, Buscaglia G, Burti L, et al; Gruppo SIEP-DIRECT’S. [Promoting recovery of schizophrenic patients: discrepancy between routine practice and evidence. The SIEP-DIRECT’S Project]. Epidemiol Psychiatr Soc. 2008;17:331-48.

24. Ruggeri M, Lora A, Semisa D; SIEP-DIRECT’S Group. The SIEP-DIRECT’S Project on the discrepancy between routine practice and evidence. An outline of main findings and practical implications for the future of community based mental health services. Epidemiol Psichiatr Soc. 2008;17:358-68.

25. Sernyak MJ, Dausey D, Desai R, Rosenheck R. Prescribers’ nonadherence to treatment guidelines for schizophrenia when prescribing neuroleptics. Psychiatr Serv. 2003;54:246-8.

26. Dickey B, Normand SL, Eisen S, Hermann R, Cleary P, Cortés D, Ware N. Associations between adherence to guidelines for antipsychotic dose and health status, side effects, and patient care experiences. Med Care. 2006;44:827-34.

27. Falzer PR, Garman DM, Moore BA. Examining the influence of clinician decision making on adherence to a clinical guideline. Psychiatr Serv. 2009;60:698-701.

28. Barbui C, Girlanda F, Ay E, Cipriani A, Becker T, Koesters M. Implementation of treatment guidelines for specialist mental health care. Cochrane Database Syst Rev. 2014;1:CD009780.

29. Feder G, Eccles M, Grol R, Griffiths C, Grimshaw J. Clinical guidelines: using clinical guidelines. BMJ. 1999;318:728-30.

30. Miller AL. Implementing treatment guidelines. Clin Schizophr Relat Psychoses. 2011;5:15-6.