Antipsychotic medication and long-term mortality risk in patients with schizophrenia; a systematic review and meta-analysis | Psychological Medicine | Cambridge Core

Patients with schizophrenia have a higher mortality risk than patients suffering from any other psychiatric disorder. Previous research is inconclusive regarding the association of antipsychotic treatment with long-term mortality risk. To this aim, we systematically reviewed the literature and performed a meta-analysis on the relationship between long-term mortality and exposure to antipsychotic medication in patients with schizophrenia. The objectives were to (i) determine long-term mortality rates in patients with schizophrenia using any antipsychotic medication; (ii) compare these with mortality rates of patients using no antipsychotics; (iii) explore the relationship between cumulative exposure and mortality; and (iv) assess causes of death. We systematically searched the EMBASE, MEDLINE and PsycINFO databases for studies that reported on mortality and antipsychotic medication and that included adults with schizophrenia using a follow-up design of more than 1 year. A total of 20 studies fulfilled our inclusion criteria. These studies reported 23,353 deaths during 821,347 patient years in 133,929 unique patients. Mortality rates varied widely per study. Meta-analysis on a subgroup of four studies showed a consistent trend of an increased long-term mortality risk in schizophrenia patients who did not use antipsychotic medication during follow-up. We found a pooled risk ratio of 0.57 (LL:0.46 UL:0.76 p value <0.001) favouring any exposure to antipsychotics. Statiscal heterogeneity was found to be high (Q = 39.31, I2 = 92.37%, p value < 0.001). Reasons for the increased risk of death for patients with schizophrenia without antipsychotic medication require further research. Prospective validation studies, uniform measures of antipsychotic exposure and classified causes of death are commendable.

Alphs, L, Benson, C, Cheshire-Kinney, K, Lindenmayer, J, Mao, L, Rodriguez, S, Starr, H (2015). Real-world outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a randomized, open-label, review board-blinded 15-month study. Journal of Clinical Psychiatry 76, 554–561.CrossRefGoogle ScholarPubMed

Borenstein, M, Hedges, L, Higgins, J, Rothstein, H (2009). Introduction to Meta-Analysis. John Wiley & Sons Ltd: Chichester, UK.CrossRefGoogle Scholar

Bushe, C, Taylor, M, Haukka, J (2010). Mortality in schizophrenia: a measurable clinical endpoint. Journal of Psychopharmacology 24, 17–25.CrossRefGoogle ScholarPubMed

Chen, V, Liao, Y, Lai, T, Lane, H, Shao, W, Dewey, M, Lee, C, Lu, M (2015). Survival analysis of the use of first and second generation antipsychotics among patients suffering schizophrenia: a nationwide population-based cohort study. Schizophrenia Research 169, 406–411.CrossRefGoogle ScholarPubMed

Copeland, L, Zeber, J, Wang, C, Parchman, M, Lawrence, V, Valenstein, M, Miller, A (2009). Patterns of primary care and mortality among patients with schizophrenia or diabetes: a cluster analysis approach to the retrospective study of healthcare utilization. BMC Health Services Research 9, 127.CrossRefGoogle ScholarPubMed

Correll, C, Detraux, J, De Lepeleire, J, De Hert, M (2015). Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World psychiatry 14, 119–136.CrossRefGoogle ScholarPubMed

Cullen, B, McGinty, E, Zhang, Y, Dosreis, S, Steinwachs, D, Guallar, E, Daumit, G (2013). Guideline-concordant antipsychotic use and mortality in schizophrenia. Schizophrenia Bulletin 39, 1159–1168.CrossRefGoogle ScholarPubMed

de Arce Cordon, R, Eding, E, Marques-Teixeira, J, Milanova, V, Rancans, E, Schreiner, A (2012). Descriptive analyses of the aripiprazole arm in the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). European Archives of Psychiatry and Clinical Neuroscience 262, 139–149.CrossRefGoogle ScholarPubMed

De Hert, M, Correll, C, Cohen, D (2010). Do antipsychotic medications reduce or increase mortality in schizophrenia? A critical appraisal of the FIN-11 study. Schizophrenia Research 117, 68–74.CrossRefGoogle ScholarPubMed

De Hert, M, Detraux, J, van Winkel, R, Yu, W, Correll, C (2012). Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nature Reviews Endocrinology 8, 114–126.CrossRefGoogle Scholar

Deslandes, P, Dwivedi, M, Sewell, R (2015). Five-year patient outcomes with risperidone long-acting injection or oral aripiprazole. Therapeutic Advances in Psychopharmacology 5, 151–157.CrossRefGoogle ScholarPubMed

Gaebel, W, Bergmans, P, De Arce, R, Rouillon, F, Cordes, J, Eriksson, L, Schreiner, A, Smeraldi, E (2010). Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology 35, 2367–2377.CrossRefGoogle ScholarPubMed

Girgis, R, Phillips, M, Li, X, Li, K, Jiang, H, Wu, C, Duan, N, Niu, Y, Lieberman, J (2011). Clozapine v. chlorpromazine in treatment-naive, first-episode schizophrenia: 9-year outcomes of a randomised clinical trial. British Journal of Psychiatry 199, 281–288.CrossRefGoogle ScholarPubMed

Haukka, J, Tiihonen, J, Harkanen, T, Lonnqvist, J (2008). Association between medication and risk of suicide, attempted suicide and death in nationwide cohort of suicidal patients with schizophrenia. Pharmacoepidemiology and Drug Safety 17, 686–696.CrossRefGoogle ScholarPubMed

Hayes, R, Downs, J, Chang, C, Jackson, R, Shetty, H, Broadbent, M, Hotopf, M, Stewart, R (2015). The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders. Schizophrenia Bulletin 41, 644–655.CrossRefGoogle ScholarPubMed

Higgins, J, Altman, D, Gotzsche, P, Juni, P, Moher, D, Oxman, A, Savovic, J, Schulz, K, Weeks, L, Sterne, J, Cochrane Bias Methods Group & Cochrane Statistical Methods Group (2011). The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. British Medical Journal 343, d5928.CrossRefGoogle ScholarPubMed

Higgins, J, Thompson, S, Deeks, J, Altman, D (2003). Measuring inconsistency in meta-analyses. British Medical Journal 327, 557–560.CrossRefGoogle ScholarPubMed

Horwitz, R, Viscoli, C, Clemens, J, Sadock, R (1990). Developing improved observational methods for evaluating therapeutic effectiveness. American Journal of Medicine 89, 630–638.CrossRefGoogle ScholarPubMed

Kasper, S, Moller, H, Hale, A (2010). The European post-marketing observational Sertindole study: an investigation of the safety of antipsychotic drug treatment. European Archives of Psychiatry and Clinical Neuroscience 260, 59–68.CrossRefGoogle ScholarPubMed

Kelly, D, McMahon, R, Liu, F, Love, R, Wehring, H, Shim, J, Warren, K, Conley, R (2010). Cardiovascular disease mortality in patients with chronics schizophrenia treated with clozapine: a retrospective cohort study. Journal of Clinical Psychiatry 71, 304–311.CrossRefGoogle ScholarPubMed

Khan, A, Faucett, J, Morrison, S, Brown, W (2013). Comparative mortality risk in adult patients with schizophrenia, depression, bipolar disorder, anxiety disorders, and attention-deficit/hyperactivity disorder participating in psychopharmacology clinical trials. JAMA Psychiatry 70, 1091–1099.CrossRefGoogle ScholarPubMed

Khan, A, Schwartz, K, Stern, C, Redding, N, Kolts, R, Brown, W, Robinson, D (2007). Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials. Journal of Clinical Psychiatry 68, 1828–1833.CrossRefGoogle ScholarPubMed

Leucht, S, Burkard, T, Henderson, J, Maj, M, Sartorius, N (2007). Physical illness and schizophrenia: a review of the literature. Acta Psychiatrica Scandinavica 116, 317–333.CrossRefGoogle ScholarPubMed

Levesque, L, Hanley, J, Kezouh, A, Suissa, S (2010). Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. British Medical Journal 340, b5087.CrossRefGoogle ScholarPubMed

Lieberman, J, Stroup, T, McEvoy, J, Swartz, M, Rosenheck, R, Perkins, D, Keefe, R, Davis, S, Davis, C, Lebowitz, B, Severe, J, Hsiao, J, Clinical Antipsychotic Trials of Intervention Effectiveness Investigators (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 353, 1209–1223.CrossRefGoogle ScholarPubMed

Meltzer, H, Alphs, L, Green, A, Altamura, A, Anand, R, Bertoldi, A, Bourgeois, M, Chouinard, G, Islam, M, Kane, J, Krishnan, R, Lindenmayer, J, Potkin, S, International Suicide Prevention Trial Study Group (2003). Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Archives of General Psychiatry 60, 82–91.CrossRefGoogle ScholarPubMed

Moher, D, Liberati, A, Tetzlaff, J, Altman, D, Prisma Group (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Medicine 6, e1000097.CrossRefGoogle ScholarPubMed

Montout, C, Casadebaig, F, Lagnaoui, R, Verdoux, H, Philippe, A, Begaud, B, Moore, N (2002). Neuroleptics and mortality in schizophrenia: prospective analysis of deaths in a French cohort of schizophrenic patients. Schizophrenia Research 57, 147–156.CrossRefGoogle Scholar

Olfson, M, Gerhard, T, Huang, C, Crystal, S, Stroup, T (2015). Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry 72, 1172–1181.CrossRefGoogle ScholarPubMed

Osborn, D, Levy, G, Nazareth, I, Petersen, I, Islam, A, King, M (2007). Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom's General Practice Rsearch Database. Archives of General Psychiatry 64, 242–249.CrossRefGoogle ScholarPubMed

Pocock, S, Elbourne, D (2000). Randomized trials or observational tribulations? New England Journal of Medicine 342, 1907–1909.CrossRefGoogle ScholarPubMed

Pridan, S, Baruch, Y, Swartz, M, Barak, Y (2014). Amisulpride for older patients with long-standing schizophrenia. Journal of Clinical Psychopharmacology 34, 736–737.CrossRefGoogle ScholarPubMed

Ran, M, Weng, X, Chan, C, Chen, E, Tang, C, Lin, F, Mao, W, Hu, S, Huang, Y, Xiang, M (2015). Different outcomes of never-treated and treated patients with schizophrenia: 14-year follow-up study in rural China. British Journal of Psychiatry 207, 495–500.CrossRefGoogle ScholarPubMed

Ritchie, C, Harrigan, S, Mastwyk, M, Macfarlane, S, Cheesman, N, Ames, D (2010). Predictors of adherence to atypical antipsychotics (risperidone or olanzapine) in older patients with schizophrenia: an open study of 3(1/2) years duration. International Journal of Geriatric Psychiatry 25, 411–418.CrossRefGoogle Scholar

Saha, S, Chant, D, McGrath, J (2007). A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Archives of General Psychiatry 64, 1123–1131.CrossRefGoogle ScholarPubMed

Sernyak, M, Desai, R, Stolar, M, Rosenheck, R (2001). Impact of clozapine on completed suicide. American Journal of Psychiatry 158, 931–937.CrossRefGoogle ScholarPubMed

Tandon, R, Nasrallah, H, Keshavan, M (2010). Schizophrenia, ‘Just the Facts’ 5. Treatment and prevention Past, present, and future. Schizophrenia Research 122, 1–23.CrossRefGoogle ScholarPubMed

Taylor, D, Douglas-Hall, P, Olofinjana, B, Whiskey, E, Thomas, A (2009). Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. British Journal of Psychiatry 194, 165–167.CrossRefGoogle ScholarPubMed

Tenback, D, Fiji, B, Smeets, H, van Os, J, van Harten, P (2012). All-cause mortality and medication risk factors in schizophrenia: a prospective cohort study. Journal of Clinical Psychopharmacology 32, 31–35.CrossRefGoogle ScholarPubMed

Thomas, S, Drici, M, Hall, G, Crocq, M, Everitt, B, Lader, M, Le Jeunne, C, Naber, D, Priori, S, Sturkenboom, M, Thibaut, F, Peuskens, J, Mittoux, A, Tanghoj, P, Toumi, M, Moore, N, Mann, R (2010). Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP). Acta Psychiatrica Scandinavica 122, 345–355.CrossRefGoogle ScholarPubMed

Tiihonen, J, Lonnqvist, J, Wahlbeck, K, Klaukka, T, Niskanen, L, Tanskanen, A, Haukka, J (2009). 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 374, 620–627.CrossRefGoogle ScholarPubMed

Tiihonen, J, Wahlbeck, K, Lonnqvist, J, Klaukka, T, Ioannidis, J, Volavka, J, Haukka, J (2006). Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. British Medical Journal 333, 224.CrossRefGoogle Scholar

Torniainen, M, Mittendorfer-Rutz, E, Tanskanen, A, Bjorkenstam, C, Suvisaari, J, Alexanderson, K, Tiihonen, J (2015). Antipsychotic treatment and mortality in schizophrenia. Schizophrenia Bulletin 41, 656–663.CrossRefGoogle ScholarPubMed

Walker, E, McGee, R, Druss, B (2015). Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry 72, 334–341.CrossRefGoogle ScholarPubMed

Weinmann, S, Read, J, Aderhold, V (2009). Influence of antipsychotics on mortality in schizophrenia: systematic review. Schizophrenia Research 113, 1–11.CrossRefGoogle ScholarPubMed

Wells, G, Shea, B, O'Connell, D, Peterson, J, Welch, V, Losos, M. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analyses http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.Google Scholar