JBI Systematic Review Protocol The impact of antipsychotic side effects on attitudes toward medication in patients with schizophrenia: A systematic review Chiang Yan Ling 1, Piyanee Klainin 2, Jeanette Ignacio 3 1. Student, Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore National University Hospital (NUH) Centre for Evidence Based Nursing. Email: u0603747@nus.edu.sg. 2. Assistant Professor, Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore National University Hospital (NUH) Centre for Evidence Based Nursing. Email: nurpk@nus.edu.sg. 3. Lecturer, Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore National University Hospital (NUH) Centre for Evidence Based Nursing. Email: nurimjj@nus.edu.sg.
Background Schizophrenia is a serious, debilitating psychiatric disorder characterized by positive symptoms (namely hallucinations and delusions), negative symptoms (such as alogia, avolition, anhedonia, apathy and asociality), and disorganized symptoms (like disorganized speech and behaviour) 1. Antipsychotics have become the mainstay treatment 2,3 for symptomatic relief in both acute and chronic phases of schizophrenia, 4,5 and the maintenance of antipsychotic treatment has been shown to play a vital role in relapse prevention. 6,7 However, antipsychotics have long been associated with a wide range of side effects, 6,8 including anticholinergic, extrapyramidal, hormonal, cardiovascular and haematological reactions, and these potentially have an adverse effect on patients biological, psychological, sexual and social functioning. 3,8 Clinicians have frequently observed that some patients experience a changed subjective state barely after a few doses from the initiation of antipsychotic treatment. 9 This has been commonly described by patients as feeling apathetic, mummified, like zombies, and being incapable of thinking. 4 The development of undesirable side effects has shown to have many debilitating consequences, such as emotional distress, reduced quality of life, poorer interpersonal relationships, and reduced ability to undertake employment or fulfill work requirements. 3 Overall, many patients experience antipsychotics as unpleasant and something they would rather avoid. 2 As a result, medication noncompliance has become a major problem in antipsychotic treatment. 10,11 This has led to higher rates of relapse 5 and more frequent episodes of rehospitalisation. 12 The subsequent clinical course is usually poor, 13 with the exacerbations of symptoms eventually leading to the development of chronic psychosis. 14 Generally, it has become a challenge for patients to return to their pre-relapse level of social adjustment, fulfill social and familial roles, secure employment or reintegrate back into the society. 15 As such, medication compliance has become a focus of increasing concern for patients with schizophrenia, 2 However, there is a lack of an adequate methodology to directly assess medication compliance. Instead, some clinicians attempted to use other indirect but relatively more convenient methods of assessing medication compliance, and this has been done through examining a multitude of factors that appear to influence medication compliance. Among these, side effects and negative attitudes toward antipsychotics have emerged to be among the major predictors of medication noncompliance. 2,3,16,17 The importance of evaluating the patients perspective, especially their attitudes toward medication in the presence of side effects, has long been emphasised. 2,9,11,18 Hence, not only is it important to assess antipsychotic side effects independently, it is also essential to assess patients attitudes toward antipsychotics in relation to their experience of side effects. 4 However, no definite conclusion has been made thus far on the relationship between antipsychotic side effects and attitudes toward medication, as studies had conflicting results. There are studies that have found a positive relationship between antipsychotic side effects and negative attitudes toward medication, 4 with some of these relating negative attitudes toward medication to only specific individual side effects, such as sedation, 1 increased duration of sleep 19 and extrapyramidal symptoms. 5 However, there are a few studies that suggest a general weak relationship between antipsychotic side effects and negative attitudes toward medication. 3,19 2
This systematic review will therefore examine the impact of antipsychotic side effects on attitudes towards medication in patients with schizophrenia. The results from this review could provide insight on the relationship between antipsychotic side effects with patients attitudes toward medication. Unlike most of the other factors influencing medication noncompliance (such as demographic variables, psychopathology or insight), attitude is relatively modifiable, and its assessment allows for the potential implementation or intensification of more patient-centred, medication-directed interventions. This potentially increases patients acceptance of the necessity of pharmacological treatment 4, thereby promoting a more positive clinical course, better psychosocial functioning, formation of more stable and satisfactory social and family relationships, fewer symptoms and minimal episodes of rehospitalisation 3. Review Objective The objective of this systematic review is to systematically review the best available evidence to determine whether antipsychotic side effects have an impact on attitudes toward medication in patients with schizophrenia. More specifically, the review question is: What is the impact of antipsychotic side effects on attitudes toward medication in patients with schizophrenia? Criteria for Considering Studies for This Review Types of Studies This review will consider quantitative research papers that examine the magnitude of the effect of antipsychotic side effects on attitudes toward medication in patients with schizophrenia and report findings in quantifiable terms (such as effect sizes, correlation coefficients, or regression coefficient. The higest priority will be placed on studies with the highest level of evidence (such as randomised controlled trial and other experimental designs). Non-experimental studies, cohort studies, casecontrol studies, and cross-sectional studies will also be considered. Types of participants This review will consider studies that include adults who have a confirmed diagnosis of schizophrenia receiving medication treatment (typical or atypical antipsychotics) from any health care settings (inpatient or outpatient). Types of interventions This review will include studies that investigate the impact of antipsychotics side effects using standardised instruments (both self-rated and clinician-rated instruments), such as the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) or the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale. 3
Types of outcome measures / anticipated outcomes This review will include studies that quantitatively measure attitudes toward medication using standardised scales, such as the Drug Attitude Inventory (DAI). Attitudes toward medication refer to the patients perception towards different aspects of medication, including, but not limited to medication-taking, medication effects, and/or medication side effects. Exclusion criteria This review will exclude studies that involve: a. Qualitative data analyses as they do not represent the magnitude of the relationship between independent on dependent variables in measureable terms (e.g. correlation or regression coefficients); b. Patients aged less than 18 and more than 65 years old; c. Collecting data without using standardized instruments; and d. Collecting data using standardized instruments that focus on a single aspect of medication side effects (such as weight gain only). Search Strategy for Identification of Studies Prior to commencing this review, a preliminary search of the Joanna-Briggs Institute (JBI) Library of Systematic Reviews and the Cochrane Database of Systematic Reviews was conducted, and no activity of the review topic has been identified. The search strategy aims to find published studies and papers. A three-step search strategy will be utilised in each component of this review. An initial limited search of MEDLINE and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) was undertaken with the search terms antipsychotic, side effect, attitude and schizophrenia used singly or in combination, followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. The identified keywords and index terms are: Antipsychotic*, neuroleptic*; Side effect*, adverse effect*, adverse drug event*, adverse drug reaction*; Attitude*, subjective response*; Schizophren* A second search using all identified keywords and index terms will be undertaken, and it will extend to the following databases: MEDLINE CINAHL PsycINFO Scopus ScienceDirect Web of Science (Science Citation Index Expanded, Social Science Citation Index, Arts & Humanities Citation Index) 4
Search terms will be modified depending on the format used in each database, and the use of database-specific headings will be included where available (e.g. MeSH headings in MEDLINE). The search will be limited to studies in English language and those published between the years 1990 to 2009. The search strategy (Appendix I) will cover search fields limited to title, abstract and keywords. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. All studies identified during these searches will be assessed by two independent reviewers for relevance based on the title and abstract. For studies that meet the inclusion criteria or those with inconclusive titles and abstracts, the full text will be retrieved for further assessment against the inclusion criteria to determine their relevance to the review objective. The decision to consider the study for inclusion in the review will then be undertaken by the two reviewers. All references will be entered into the bibliographic software package Endnote. Methods of Review Assessment of Methodological Quality Studies selected for retrieval will be assessed by the two reviewers for methodological quality prior to inclusion in the review using the JBI Critical Appraisal Checklist for Cohort/Case Control appraisal (Appendix II) and the JBI Critical Appraisal Checklist for Descriptive/Case series studies (Appendix III). Any disagreements that arise between the reviewers will be resolved through discussion with a third reviewer. Data Extraction Data will be extracted from studies included in the review using the JBI Data Extraction Form for Comparative Cohort/Case Control studies (Appendix IV) and the JBI Data Extraction Form for Descriptive/Case series studies (Appendix V). Any disagreements that arise between the reviewers will be resolved through discussion with a third reviewer. Data Synthesis Where possible, quantitative research study results will be pooled in statistical meta-analysis using the JBI Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). All results will be double entered. Odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed using the standard Chi-square. Where statistical pooling is not possible, the findings will be presented in narrative form. Conflict of Interest There are no conflicts of interest regarding this systematic review. 5
References 1. Kua E. H., Tan C. H., Ko S. M., & Fones, C. (2004). Psychiatry for Doctors. (3 rd Ed.). Singapore: Armour Publishing. 2. Hofer A, Kemmler G, Eder U, Honeder M, Hummer M, Fleischhacker WW. Attitudes toward antipsychotics among outpatient clinic attendees with schizophrenia. J Clin Psychiatry. 2002;63(1):49-53. 3. Morrison P, Gaskill D, Meehan T, Lunney P, Lawrence G, Collings P. The use of the Liverpool University neuroleptic side effect rating scale (LUNSERS) in clinical practice. Aust N Z J Ment Health Nurs. 2000;9(4):166-76. 4. Cabeza IG, Amador MS, Lopez CA, de Chavez MG. Subjective response to antipsychotics in schizophrenic patients: clinical implications and related factors. Schizophr Res. 2000;41(2):349-55. 5. Lambert M, Conus P, Eide P et al. Impact of present and past antipsychotic side effects on attitude toward typical antipsychotic treatment and adherence. Eur Psychiatry. 2004;19(7):415-22. 6. Gervin M, Browne S, Garavan J, Roe M, Larkin C, O'Callaghan E. Dysphoric subjective response to neuroleptics in schizophrenia: relationship to extrapyramidal side effects and symptomatology. Eur Psychiatry. 1999;14(7):405-9. 7. Rossler W, Salize HJ, Riecher-Rossler A. Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol. 2005;15(4):399-409. 8. Day JC, Wood G, Dewey M, Bentall RP. A self-rating scale for measuring neuroleptic side effects: validation in a group of schizophrenic patients. Br J Psychiatry. 1995;166(5):650-3. 9. Awad AG. Subjective response to neuroleptics in schizophrenia. Schizophr Bull. 1993;19(3):609-18. 10. McCann TV, Clark E, Lu S. Subjective side effects of antipsychotics and medication adherence in people with schizophrenia. J Adv Nurs. 2009;65(3):534-43. 11. Fleischhacker WW, Oehl MA, Hummer M. Factors influencing compliance in schizophrenia patients. J Clin Psychiatry. 2003;64(Suppl 16):10-3. 12. Eaddy M, Grogg A, Locklear J. Assessment of compliance with antipsychotic treatment and resource utilization in a Medicaid population. Clin Ther. 2005;27(2):263-72. 13. Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull. 1991;17(2):325-51. 14. Lieberman JA, Sheitman B, Chakos M, et al. The development of treatment resistance in patients with schizophrenia: a clinical and pathophysiologic perspective. J Clin Psychopharmacol. 1998;18(2 suppl 1):20S-24S. 15. Sim E. Predicting outpatient's attitude of compliance on medication in a psychiatric setting. Singapore Nurs J. 2006;33(2):13-9. 16. Kemp R, David A. Psychological predictors of insight and compliance in psychotic patients. Br J Psychiatry. 1996;169:444-50. 17. Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV. Prevalence and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002;63(10):892-909. 18. Oehl M, Hummer M, Fleishhacker WW. Compliance with antipsychotic treatment. Acta Psychiatr Scand. 2000;102(suppl 407):83-6. 19. Hofer A, Rettenbacher MA, Edlinger M, Kemmler G, Widschwendter CG, Fleischhacker WW. Subjective response and attitudes toward antipsychotic drug therapy during the initial treatment period: a prospective follow-up study in patients with schizophrenia. Acta Psychiatr Scand. 2007;116(5):354-61. 6
Appendix I Search Strategy MEDLINE (with MeSH Headings) CINAHL (with CINAHL Headings) PsycINFO (with Subject Headings) Scopus ScienceDirect Web of Science 1. (antipsychotic* OR neuroleptic* OR "Antipsychotic Agents"[Mesh]) adverse drug reaction* OR "Drug Toxicity"[Mesh]) 3. (attitude* OR subjective response* ) 4. (schizophren* OR "Schizophrenia"[Mesh]) 1. (antipsychotic* OR neuroleptic* OR MH "Antipsychotic Agents+") adverse drug reaction* OR MH "Medication Side Effects (Saba CCC)" OR MH "Adverse Drug Event") 3. (attitude* OR subjective response* ) 4. (schizophren* OR MH "Schizophrenia") 1. (antipsychotic* OR neuroleptic* OR exp Neuroleptic Drugs /) adverse drug reaction* OR Side Effects (Drug)"/) 3. (attitude* OR Drug Usage Attitudes / OR subjective response* ) 4. (schizophren* OR exp Schizophrenia/) 1. (antipsychotic* OR neuroleptic*) adverse drug reaction* ) 3. (attitude* OR subjective response* ) 4. (schizophren*) 1. (antipsychotic* OR neuroleptic*) adverse drug reaction* ) 3. (attitude* OR subjective response* ) 4. (schizophren*) 1. (antipsychotic* OR neuroleptic*) adverse drug reaction* ) 3. (attitude* OR subjective response* ) 4. (schizophren*) 7
Appendix II JBI Critical Appraisal Checklist for Cohort/Case Control appraisal Appendix III JBI Critical Appraisal Checklist for Descriptive/Case series studies 8
Appendix IV JBI Data Extraction Form for Comparative Cohort/Case Control studies 9
Appendix V JBI Data Extraction Form for Descriptive/Case series studies 10