Lisa Hartling, PhD; Ahmed M. Abou-Setta, MD, PhD; Serdar Dursun, MD, PhD; Shima S. Mousavi, MD; Dion Pasichnyk, BSc; Amanda S. Newton, RN, PhD
Acknowledgment: The authors thank Mrs. Carol Spooner and Ms. Janine Schouten for help in article selection and data extraction; Dr. Susan Armijo-Olivo for help in data extraction; Ms. Amy Beaith and Ms. Andrea Milne for help in literature searching; Ms. Annabritt Chisholm and Ms. Teodora Radisic for help in article retrieval; Mr. Ben Vandermeer for help in data analysis; Ms. Jennifer Seida for help in critical review and copyediting; Ms. Christine Ha, Ms. Elizabeth Sumamo Schellenberg, and Mr. Kai Wong for help in screening the gray literature; and the members of the technical expert panel (listed in full technical report).
Grant Support: By the Agency for Healthcare Research and Quality (AHRQ) (contract 290-2007-10021), U.S. Department of Health and Human Services.
Potential Conflicts of Interest: Dr. Hartling: Contract (money to institution): AHRQ. Dr. Abou-Setta: Grant (money to institution): AHRQ. Dr. Dursun: Grants/grants pending (money to institution): CIHR-Canada, Norlien Foundation; Patents (planned, pending, or issued): sodium nitroprusside for the treatment of schizophrenia, in partnership with the University of Alberta, TEC Edmonton Office. Dr. Newton: Grant (money to institution): AHRQ; Other (money paid to author): University of Alberta Evidence-based Practice Center. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0362.
Requests for Single Reprints: Lisa Hartling, PhD, University of Alberta, ECHA 4-472, 11405 87 Avenue, Edmonton, Alberta T6G 1C9, Canada; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Hartling and Mr. Pasichnyk: University of Alberta, ECHA 4-472, 11405 87 Avenue, Edmonton, Alberta T6G 1C9, Canada.
Dr. Abou-Setta: George & Fay Yee Centre for Healthcare I, University of Manitoba/Winnipeg Regional Health Authority, GH-714, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada.
Dr. Dursun: University of Alberta, Department of Psychiatry, Neurochemical Research Unit, CSB, 12-127, 11350 83 Avenue, Edmonton, Alberta T6G 2G3, Canada.
Dr. Mousavi: University of Alberta, Room #9416, Aberhart Center, 11402 University Avenue, Edmonton, Alberta T6G 2J3, Canada.
Dr. Newton: University of Alberta, 3-526 Edmonton Clinic Health Academy, 11405 87 Avenue, Edmonton, Alberta T6G 1C9, Canada.
Author Contributions: Conception and design: L. Hartling, A.M. Abou-Setta, S. Dursun.
Analysis and interpretation of the data: L. Hartling, A.M. Abou-Setta, S. Dursun, A.S. Newton.
Drafting of the article: L. Hartling, A.M. Abou-Setta, S. Dursun, A.S. Newton.
Critical revision of the article for important intellectual content: L. Hartling, A.M. Abou-Setta, S. Dursun, A.S. Newton.
Final approval of the article: L. Hartling, A.M. Abou-Setta, S. Dursun, A.S. Newton.
Provision of study materials or patients: S. Dursun.
Statistical expertise: A.M. Abou-Setta.
Obtaining of funding: L. Hartling.
Administrative, technical, or logistic support: A.M. Abou-Setta, S. Dursun, D. Pasichnyk.
Collection and assembly of data: L. Hartling, A.M. Abou-Setta, S. Dursun, S.S. Mousavi, D. Pasichnyk.
Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS. Antipsychotics in Adults With Schizophrenia: Comparative Effectiveness of First-Generation Versus Second-Generation Medications: A Systematic Review and Meta-analysis. Ann Intern Med. 2012;157:498-511. doi: 10.7326/0003-4819-157-7-201210020-00525
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Published: Ann Intern Med. 2012;157(7):498-511.
Debate continues about the comparative benefits and harms of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) in treating schizophrenia.
To compare the effects of FGAs with those of SGAs in the treatment of adults aged 18 to 64 years with schizophrenia and related psychosis on illness symptoms, diabetes mellitus, mortality, tardive dyskinesia, and a major metabolic syndrome.
English-language studies from 10 electronic databases to March 2012, reference lists of relevant articles, and gray literature.
Randomized trials for efficacy and cohort studies at least 2 years in duration for adverse events.
Two independent reviewers extracted data from 114 studies involving 22 comparisons and graded the strength of evidence for primary outcomes as insufficient, low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation approach.
Few differences of clinical importance were found for core illness symptoms; lack of precision in effect estimates precluded firm conclusions for many comparisons. Moderate-strength evidence showed a clinically important benefit of haloperidol over olanzapine for improving positive symptoms, but the benefit was scale-dependent: It was seen when the Scale for the Assessment of Positive Symptoms was used but not when the Positive and Negative Syndrome Scale (PANSS) was used. Moderate-strength evidence showed a clinically important benefit of olanzapine over haloperidol in improving negative symptoms when the PANSS and the Scale for the Assessment of Negative Symptoms were used. Low-strength evidence showed no difference in mortality for chlorpromazine verus clozapine or haloperidol versus aripiprazole, increased incidence of the metabolic syndrome for olanzapine versus haloperidol (risk differences, 2% and 22%), and higher incidence of tardive dyskinesia for chlorpromazine versus clozapine (risk differences, 5% and 9%). Evidence was insufficient to draw conclusions for diabetes mellitus.
All studies had high or unclear risk of bias. Length of study follow-up was often too brief to adequately measure adverse events. Medication comparisons, dosage, and outcome measurement were heterogenous for head-to-head comparisons. Selective patient populations limit generalizability.
Clear benefits of FGAs versus SGAs for treating schizophrenia remain inconclusive because of variation in assessing outcomes and lack of clinically important differences for most comparisons. The strength of evidence on safety for major medical events is low or insufficient.
Agency for Healthcare Research and Quality.
Appendix Table 1.
Antipsychotics Included in the Systematic Review
Appendix Table 2.
Ovid MEDLINE Search Strategy
Appendix Table 3.
Inclusion and Exclusion Criteria
Appendix Table 4.
Examples of Core Symptoms
Summary of evidence search and selection.
Summary of Results and Strength of Evidence for Core Illness Symptoms
Appendix Table 5.
Summary of Insufficient Strength of Evidence for Core Illness Symptoms When the PANSS Was Used
Positive symptoms (SAPS): haloperidol versus olanzapine.
IV = inverse variance; SAPS = Scale for the Assessment of Positive Symptoms.
Negative symptoms (PANSS and SANS): haloperidol versus olanzapine.
IV = inverse variance; PANSS = Positive and Negative Syndrome Scale; SANS = Scale for the Assessment of Negative Symptoms.
Global rating and total symptom score improvement (PANSS): haloperidol versus olanzapine.
IV = inverse variance; PANSS = Positive and Negative Syndrome Scale.
Global rating and total symptom score improvement (PANSS): haloperidol versus risperidone (with outlier).
Global rating and total symptom score improvement (PANSS): haloperidol versus risperidone (outlier removed).
Global rating and total symptom score improvement (BPRS): chlorpromazine versus clozapine.
BPRS = Brief Psychiatric Rating Scale; IV = inverse variance.
General psychopathology (MADRS): haloperidol versus olanzapine.
IV = inverse variance; MADRS = Montgomery–Asberg Depression Rating Scale.
Summary of Results for Other Outcomes
Appendix Table 6.
Summary of Results for 4 Key Adverse Events With Insufficient Strength of Evidence
Summary of Results and Strength of Evidence for Key Adverse Events
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Thomas E. Finucane, MD
Johns Hopkins Bayview Medical Center
October 4, 2012
Sponsorship of Research Articles Can Affect Findings
To the Editor:
In this (1) and in other contexts, the sponsorship of research articles has been shown to affect the findings. Can the authors say anything about the effects of Pharma sponsorship on the outcomes of the trials? This might be a particular problem with these vendors, as many have been paying billions of dollars in fines recently for a variety of behaviors related to promoting their products.
Thomas E. Finucane, MD
Johns Hopkins Bayview Medical Center
1. Lisa Hartling, PhD; Ahmed M. Abou-Setta, MD, PhD; Serdar Dursun, MD, PhD; Shima S. Mousavi, MD; Dion Pasichnyk, BSc; and Amanda S. Newton, RN, PhD Antipsychotics in Adults With Schizophrenia: Comparative Effectiveness of First-Generation Versus Second-Generation Medications: A Systematic Review and Meta-analysis . Ann Intern Med. 2 October 2012;157(7):498-511
Lisa Hartling, PhD Amanda S. Newton, RN, PhD Serdar Dursun, MD, PhD
University of Alberta
November 20, 2012
Conflict of Interest:
Dr. Hartling: Contract (money to institution): AHRQ. Dr. Abou-Setta: Grant (money to institution): AHRQ. Dr. Dursun: Grants/grants pending (money to institution): CIHR-Canada, Norlien Foundation; Patents (planned, pending, or issued): sodium nitroprusside for the treatment of schizophrenia, in partnership with the University of Alberta, TEC Edmonton Office. Dr. Newton: Grant (money to institution): AHRQ; Other (money paid to author): University of Alberta Evidence-based Practice Center.
Sponsorship of Research Articles Can Affect Findings: RESPONSE FROM AUTHORS
There is a strong body of evidence to support Dr. Finucane’s observation that sponsorship of research articles has been shown to affect reported results (e.g., 1). In particular, there is evidence showing that industry-sponsored studies may show results supporting the industry’s product. An important task for systematic reviewers is to explore variables that may affect the validity of the reported results, including the source of funding. In our systematic review comparing first-generation with second-generation antipsychotics (2,3), we found that 70% of the included studies were industry-funded. We also noted that funding source was not disclosed for 19% of studies.
In our review we discussed that the choice of medication comparisons, dosages and outcomes may be driven by the funder’s interests and priorities (3). We conducted extensive subgroup and sensitivity analyses to examine variables that could result in differential treatment effects. These analyses included source of funding, risk of bias, patient characteristics (e.g., race, treatment resistance), treatment characteristics (e.g., dose), and study methods (e.g., duration of followup).
We found some differences when studies were grouped according to whether or not they were supported by industry funding. The patterns were not consistent and in some cases few studies were available for the “no industry” subgroup; therefore, it was difficult to discern whether no differences within this subgroup were due to the funding source or simply inadequate statistical power to detect differences. These analyses are detailed in an appendix to our full technical report (3).
The results of our review should be interpreted within the context that most studies contributing to this body of evidence were industry-funded. Our inability to draw firm clinical conclusions stemmed from inconsistencies across studies in terms of treatment comparisons, the outcomes assessed, how outcomes were measured, and patient populations. Within this field, stakeholders need to reach consensus on the most important comparisons that will be most informative and provide the most valid and accurate information to inform clinical decisions. Further, decisions involving patients, their families and their physicians need to be made regarding the most important outcomes and these should be the focus of future research. As we have mentioned, longer-term studies are needed as well as examination of important patient subpopulations, such as those with medical and neurological comorbidities. As with all research, full disclosure of the source of funding and role of the funder in the design, analysis and reporting of results is essential to interpreting the evidence.
1. Sismondo S. Pharmaceutical company funding and its consequences: a qualitative systematic review. Contemp Clin Trials 2008;29(2):109-13. PMID:17919992.
2. Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Psichnyk D, Newton AS. Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis. Ann Intern Med 2012 Aug 14. doi: 10.7326/0003-4819-157-7-201210020-00525. [Epub ahead of print]
3. Abou-Setta AM, Mousavi SS, Spooner C, Schouten JR, Pasichnyk D, Armijo-Olivo S, Beaith A, Seida JC, Dursun S, Newton AS, Hartling L. First-Generation Versus Second-Generation Antipsychotics in Adults: Comparative Effectiveness [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Aug.
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