Advertisement

Association of First- vs. Second-Generation Antipsychotics with Lipid Abnormalities in Individuals with Severe Mental Illness: A Systematic Review and Meta-Analysis

  • Kurt BuhagiarEmail author
  • Farid Jabbar
Systematic Review
  • 54 Downloads

Abstract

Background and Objective

Individuals with severe mental illness experience increased morbidity and mortality as a result of metabolic problems that may partly be related to the adverse effects of antipsychotics. Compared with first-generation antipsychotics, second-generation antipsychotics collectively are considered to have stronger associations with lipid abnormalities, but evidence for this specific claim has not been systematically reviewed. The objective of this review was to evaluate the risk of dyslipidaemia with second-generation versus first-generation antipsychotics amongst individuals with severe mental illness.

Methods

Major electronic databases were searched until November 2018. Studies were eligible if they were cross-sectional, cohort, case–control or interventional, where any individual second-generation antipsychotic was directly compared with first-generation antipsychotics in individuals with severe mental illness, and where lipid metabolism was a primary or secondary outcome. The evidence was reviewed and appraised according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results

In total, 18 studies were eligible. The reported associations between second-generation antipsychotics vs. first-generation antipsychotics with dyslipidaemia were inconsistent, with high variability between studies and only a full qualitative synthesis was feasible. We had sufficient data, however, to undertake limited meta-analyses for clozapine, olanzapine and risperidone, all showing mildly elevated associations with dyslipidaemia “caseness” (clozapine, odds ratio 1.26, 95% confidence interval 1.16–1.38; olanzapine, odds ratio 1.29, 95% confidence interval 0.89–1.87; risperidone, odds ratio 1.05, 95% confidence interval 0.80–1.37) compared with first-generation antipsychotics, but heterogeneity was high (all I2 > 50%, p < 0.05). Clozapine was also associated with increased triglycerides (standardised mean difference = 0.51, 95% confidence interval 0.21–0.81, I2 = 5.74%), but not with cholesterol. Compared with haloperidol, neither olanzapine nor risperidone was associated with statistically significant increases in cholesterol or triglycerides.

Conclusions

There was considerable variation in study design and methodologies. Determining the comparative risk of second-generation vs. first-generation antipsychotics as a group of antipsychotics for lipid dysregulation may be of limited clinical utility, as drugs from either group have the potential to cause such adversity to varying degrees. It is therefore more valuable to consider the metabolic risks of specific antipsychotics rather than focusing on collective metabolic effects belonging to either antipsychotic group.

Notes

Acknowledgements

We thank Dr. Himanshu Mistry for his valuable contribution to determining the final eligibility of studies.

Compliance with Ethical Standards

Funding

No direct funding was received for this study. Kurt Buhagiar was partially funded by the National Institute for Health Research during the inception of the idea for this study.

Conflict of Interest

Kurt Buhagiar and Farid Jabbar have no conflicts of interest that are directly relevant to the content of this article.

Supplementary material

40261_2019_751_MOESM1_ESM.doc (3.9 mb)
Supplementary material 1 (DOC 4005 kb)

References

  1. 1.
    Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3:A42.Google Scholar
  2. 2.
    Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11–53.CrossRefGoogle Scholar
  3. 3.
    Osborn DPJ, Hardoon S, Omar RZ, et al. Cardiovascular risk prediction models for people with severe mental illness: results from the prediction and management of cardiovascular risk in people with severe mental illnesses (PRIMROSE) research program. JAMA Psychiatry. 2015;72:143–51.CrossRefGoogle Scholar
  4. 4.
    Osborn DPJ, Levy G, Nazareth I, et al. Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s General Practice Research Database. Arch Gen Psychiatry. 2007;64:242–9.CrossRefGoogle Scholar
  5. 5.
    Crump C, Winkleby MA, Sundquist K, Sundquist J. Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study. Am J Psychiatry. 2013;170:324–33.CrossRefGoogle Scholar
  6. 6.
    Brown S, Barraclough B, Inskip H. Causes of the excess mortality of schizophrenia. Br J Psychiatry. 2000;177:212–7.CrossRefGoogle Scholar
  7. 7.
    Breden EL, Liu MT, Dean SR. Metabolic and cardiac side effects of second-generation antipsychotics: what every clinician should know. J Pharm Prac. 2009;22:478–88.CrossRefGoogle Scholar
  8. 8.
    Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-Year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374:620–7.CrossRefGoogle Scholar
  9. 9.
    Hayes JF, Marston L, Walters K, et al. Mortality gap for people with bipolar disorder and schizophrenia: UK-based cohort study 2000–2014. Br J Psychiatry. 2017;211:175–81.CrossRefGoogle Scholar
  10. 10.
    De Hert M, Correll CU, Cohen D. Do antipsychotic medications reduce or increase mortality in schizophrenia? A critical appraisal of the FIN-11 study. Schizophr Res. 2010;117:68–74.CrossRefGoogle Scholar
  11. 11.
    Ingimarsson O, MacCabe JH, Haraldsson M, Jónsdóttir H, Sigurdsson E. Risk of diabetes and dyslipidemia during clozapine and other antipsychotic drug treatment of schizophrenia in Iceland. Nord J Psychiatry. 2017;71:496–502.CrossRefGoogle Scholar
  12. 12.
    Dan W. Differential metabolic effects of antipsychotic treatments. Eur Neuropsychopharmacol. 2006;16(S3):149–55.Google Scholar
  13. 13.
    Expert Panel on Detection and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;2001:2486–97.CrossRefGoogle Scholar
  14. 14.
    De Hert M, Schreurs V, Vancampfort D, Van Winkel R. Metabolic syndrome in people with schizophrenia: a review. World Psychiatry. 2009;8:15–22.CrossRefGoogle Scholar
  15. 15.
    Saari KM, Lindeman SM, Viilo KM, et al. A 4-fold risk of metabolic syndrome in patients with schizophrenia: the Northern Finland 1966 Birth Cohort Study. J Clin Psychiatry. 2005;66:559–63.CrossRefGoogle Scholar
  16. 16.
    Mauri MC, Paletta S, Maffini M, et al. Clinical pharmacology of atypical antipsychotics: an update. EXCLI J. 2014;13:1163–91.Google Scholar
  17. 17.
    Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res. 2004;70:1–17.CrossRefGoogle Scholar
  18. 18.
    De Hert M, van Eyck D, De Nayer A. Metabolic abnormalities associated with second generation antipsychotics: fact or fiction? Development of guidelines for screening and monitoring. Int Clin Psychopharmacol. 2006;21(Suppl. 2):S11–5.CrossRefGoogle Scholar
  19. 19.
    Falissard B, Mauri M, Shaw K, et al. The METEOR study: frequency of metabolic disorders in patients with schizophrenia. Focus on first and second generation and level of risk of antipsychotic drugs. Int Clin Psychopharmacol. 2011;26:291–302.CrossRefGoogle Scholar
  20. 20.
    Smith M, Hopkins D, Peveler RC, et al. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2008;192:406–11.CrossRefGoogle Scholar
  21. 21.
    American Diabetes Association. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596–601.CrossRefGoogle Scholar
  22. 22.
    Nasrallah HA, Newcomer JW. Atypical antipsychotics and metabolic dysregulation: evaluating the risk/benefit equation and improving the standard of care. J Clin Psychopharmacol. 2004;24(5 Suppl. 1):S7–14.CrossRefGoogle Scholar
  23. 23.
    Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–23.CrossRefGoogle Scholar
  24. 24.
    Olfson M, Marcus SC, Corey-Lisle P, et al. Hyperlipidemia following treatment with antipsychotic medications. Am J Psychiatry. 2006;163:1821–5.CrossRefGoogle Scholar
  25. 25.
    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). Eur Psychiatry. 2009;24:412–24.CrossRefGoogle Scholar
  26. 26.
    Saari K, Jokelainen J, Veijola J, et al. Serum lipids in schizophrenia and other functional psychoses: a general population northern Finland 1966 Birth Cohort Survey. Acta Psychiatr Scand. 2004;110:279–85.CrossRefGoogle Scholar
  27. 27.
    Saari K, Koponen H, Laitinen J, et al. Hyperlipidemia in persons using antipsychotic medication: a general population-based birth cohort study. J Clin Psychiatry. 2004;65:547–50.CrossRefGoogle Scholar
  28. 28.
    Rummel-Kluge C, Komossa K, Schwarz S, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010;123:225–33.CrossRefGoogle Scholar
  29. 29.
    Jeste DV, Gladsjo JA, Lindamer LA, et al. Medical comorbidity in schizophrenia. Schizophr Bull. 1996;22:413–30.CrossRefGoogle Scholar
  30. 30.
    Buhagiar K, Parsonage L, Osborn DP. Physical health behaviours and health locus of control in people with schizophrenia-spectrum disorder and bipolar disorder: a cross-sectional comparative study with people with non-psychotic mental illness. BMC Psychiatry. 2011;11:104.CrossRefGoogle Scholar
  31. 31.
    Zhang JP, Gallego JA, Robinson DG, et al. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2013;16:1205–18.CrossRefGoogle Scholar
  32. 32.
    British Medical Association and Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMJ Books & Pharmaceutical Press; 2017.Google Scholar
  33. 33.
    Moher D, Schulz KF, Altman D, et al. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001;285:1987–91.CrossRefGoogle Scholar
  34. 34.
    Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology. JAMA. 2000;283:2008–12.CrossRefGoogle Scholar
  35. 35.
    Whiting P, Harbord R, Kleijnen J. No role for quality scores in systematic reviews of diagnostic accuracy studies. BMC Med Res Methodol. 2005;5:19.CrossRefGoogle Scholar
  36. 36.
    Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation. 2005;112:2735–52.CrossRefGoogle Scholar
  37. 37.
    Alberti KG, Zimmet P, Shaw J. Metabolic syndrome: a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabetic Med. 2006;23:469–80.CrossRefGoogle Scholar
  38. 38.
    Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1–34.CrossRefGoogle Scholar
  39. 39.
    Gupta S, Steinmeyer C, Frank B, et al. Hyperglycemia and hypertriglyceridemia in real world patients on antipsychotic therapy. Am J Ther. 2003;10:348–55.CrossRefGoogle Scholar
  40. 40.
    Gaulin BD, Markowitz JS, Caley CF, et al. Clozapine-associated elevation in serum triglycerides. Am J Psychiatry. 1999;156:1270–2.Google Scholar
  41. 41.
    Wirshing DA, Boyd JA, Meng LR, et al. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002;63:856–65.CrossRefGoogle Scholar
  42. 42.
    Paton C, Esop R, Young C, et al. Obesity, dyslipidaemias and smoking in an inpatient population treated with antipsychotic drugs. Acta Psychiatr Scand. 2004;110:299–305.CrossRefGoogle Scholar
  43. 43.
    Smith RC, Lindenmayer JP, Bark N, et al. Clozapine, risperidone, olanzapine, and conventional antipsychotic drug effects on glucose, lipids, and leptin in schizophrenic patients. Int J Neuropsychopharmacol. 2005;8:183–94.CrossRefGoogle Scholar
  44. 44.
    Hardy TA, Marquez E, Kryzhanovskaya L, et al. Cross-sectional comparison of fasting lipids in normoglycemic patients with schizophrenia during chronic treatment with olanzapine, risperidone, or typical antipsychotics. J Clin Psychopharmacol. 2006;26:405–8.CrossRefGoogle Scholar
  45. 45.
    Lund BC, Perry PJ, Brooks JM, et al. Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry. 2001;58:1172–6.CrossRefGoogle Scholar
  46. 46.
    Lambert BL, Chang KY, Tafesse E, et al. Association between antipsychotic treatment and hyperlipidemia among California Medicaid patients with schizophrenia. J Clin Psychopharmacol. 2005;25:12–8.CrossRefGoogle Scholar
  47. 47.
    Koro CE, Fedder DO, L’Italien GJ, et al. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry. 2002;59:1021–6.CrossRefGoogle Scholar
  48. 48.
    Huang TL, Chen JF. Serum lipid profiles and schizophrenia: effects of conventional or atypical antipsychotic drugs in Taiwan. Schizophr Res. 2005;80:55–9.CrossRefGoogle Scholar
  49. 49.
    Meyer JM, Nasrallah HA, McEvoy JP, et al. The clinical antipsychotic trials of intervention effectiveness (CATIE) schizophrenia trial: clinical comparison of subgroups with and without the metabolic syndrome. Schizophr Res. 2005;80:9–18.CrossRefGoogle Scholar
  50. 50.
    Lieberman JA, Tollefson G, Tohen M, 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. Am J Psychiatry. 2003;160:1396–404.CrossRefGoogle Scholar
  51. 51.
    Lindenmayer JP, Czobor P, Volavka J, et al. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry. 2003;160:290–6.CrossRefGoogle Scholar
  52. 52.
    Krakowski M, Czobor P, Citrome L. Weight gain metabolic parameters, and the impact of race in aggressive inpatients randomized to double-blind clozapine, olanzapine or haloperidol. Schizophr Res. 2009;110:95–102.CrossRefGoogle Scholar
  53. 53.
    Wu RR, Zhao JP, Liu ZN, et al. Effects of typical and atypical antipsychotics on glucose-insulin homeostasis and lipid metabolism in first-episode schizophrenia. Psychopharmacology. 2006;186:572–8.CrossRefGoogle Scholar
  54. 54.
    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;371:1085–97.CrossRefGoogle Scholar
  55. 55.
    Perez-Iglesias R, Mata I, Pelayo-Teran JM, et al. Glucose and lipid disturbances after 1-year of antipsychotic treatment in a drug-naïve population. Schizophr Res. 2009;107:115–21.CrossRefGoogle Scholar
  56. 56.
    Davis SM, Koch GG, Davis CE, et al. Statistical approaches to effectiveness measurement and outcome-driven re-randomizations in the clinical antipsychotic trials of intervention effectiveness (CATIE) studies. Schizophr Bull. 2003;29:73–80.CrossRefGoogle Scholar
  57. 57.
    Bushe C, Paton C. The potential impact of antipsychotics on lipids in schizophrenia: is there enough evidence to confirm a link? J Psychopharmacol. 2005;19:76–83.CrossRefGoogle Scholar
  58. 58.
    de Leon J. Beyond the “hype” on the association between metabolic syndrome and atypical antipsychotics: the confounding effects of cohort, typical antipsychotics, severe mental illness, comedications, and comorbid substance use. J Clin Psychopharmacol. 2008;28:125–31.CrossRefGoogle Scholar
  59. 59.
    Leucht S, Kissling W, Davis JM. Second-generation antipsychotics for schizophrenia: can we resolve the conflict? Psychol Med. 2009;39:1591–602.CrossRefGoogle Scholar
  60. 60.
    Misiak B, Stańczykiewicz B, Łaczmański Ł, Frydecka D. Lipid profile disturbances in antipsychotic-naive patients with first-episode non-affective psychosis: a systematic review and meta-analysis. Schizophr Res. 2017;190:18–27.CrossRefGoogle Scholar
  61. 61.
    Atmaca M, Kuloglu M, Tezcan E, et al. Weight gain, serum leptin and triglyceride levels in patients with schizophrenia on antipsychotic treatment with quetiapine, olanzapine and haloperidol. Schizophr Res. 2003;60:99–100.CrossRefGoogle Scholar
  62. 62.
    Duncan EJ, Woolson SL, Hamer RM, et al. Risk of lipid abnormality with haloperidol, olanzapine, quatipaine, and risperidone in a Veterans Affairs population. J Clin Psychopharmacol. 2009;24:204–13.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Research DepartmentEast London NHS Foundation TrustLondonUK
  2. 2.East London NHS Foundation TrustNewham Centre for Mental HealthLondonUK

Personalised recommendations