ABSTRACT
Objective: Patients with early-phase schizophrenia or bipolar I disorder (BD-I) are at greater risk for antipsychotic-associated weight gain. This 12-week, randomized, double-blind study conducted between June 2017 and December 2021 evaluated weight effects of combination olanzapine and samidorphan (OLZ/SAM) versus olanzapine in early-phase illness.
Methods: Young adults (16–39 years) with DSM-5 schizophrenia, schizophreniform disorder, or BD-I, < 4 years since symptom onset, body mass index < 30 kg/m2, and < 24 weeks’ cumulative antipsychotic exposure were randomized to OLZ/SAM (5–20/10 mg/d) or olanzapine (5–20 mg/d). Primary endpoint was percent change from baseline body weight at week 12. Secondary endpoints, tested hierarchically, were proportions of patients with ≥ 10% or ≥ 7% weight gain, waist circumference change, and Clinical Global Impressions-Severity (CGI-S) change.
Results: Of 428 patients (OLZ/SAM, n = 213; olanzapine, n = 215), 408 had ≥ 1 postbaseline weight assessment and were analyzed. Percent weight change was significantly lower with OLZ/SAM versus olanzapine (4.91% vs 6.77%; least-squares mean [LSM] [SE] difference, −1.87% [0.75]; P = .012). Although fewer patients treated with OLZ/SAM had ≥ 10% weight gain, the difference was not statistically significant versus olanzapine (21.9% vs 30.4%, respectively; OR = 0.64; 95% CI = 0.39 to 1.05); hierarchical testing precluded further statistical evaluation of secondary endpoints. Proportions of patients with ≥ 7% weight gain (33.1% vs 44.8%; OR = 0.61, 95% CI = 0.39 to 0.94) and waist circumference change (2.99 vs 3.90 cm; LSM [SE] difference, −0.92 cm [0.58]; 95% CI = −2.06 to 0.22) favored OLZ/SAM. LSM (SE) CGI-S change with OLZ/SAM was −0.82 (0.06). OLZ/SAM and olanzapine had similar safety profiles, including small, similar metabolic parameter changes.
Conclusions: In patients with early-phase schizophrenia, schizophreniform disorder, or BD-I, OLZ/SAM treatment resulted in less weight gain versus olanzapine.
Trial Registration: ClinicalTrials.gov identifier: NCT03187769
Continue Reading...
Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.
References (43)
- Berk M, Malhi GS, Hallam K, et al. Early intervention in bipolar disorders: clinical, biochemical and neuroimaging imperatives. J Affect Disord. 2009;114(1-3):1–13. PubMed CrossRef
- Berk M, Brnabic A, Dodd S, et al. Does stage of illness impact treatment response in bipolar disorder? empirical treatment data and their implication for the staging model and early intervention. Bipolar Disord. 2011;13(1):87–98. PubMed CrossRef
- Lieberman JA, Jarskog LF, Malaspina D. Preventing clinical deterioration in the course of schizophrenia: the potential for neuroprotection. J Clin Psychiatry. 2006;67(6):983–990. PubMed CrossRef
- Tohen M, Vieta E, Gonzalez-Pinto A, et al; European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) Advisory Board. Baseline characteristics and outcomes in patients with first episode or multiple episodes of acute mania. J Clin Psychiatry. 2010;71(3):255–261. PubMed CrossRef
- Lieberman JA, Small SA, Girgis RR. Early detection and preventive intervention in schizophrenia: from fantasy to reality. Am J Psychiatry. 2019;176(10):794–810. PubMed CrossRef
- Correll CU, Martin A, Patel C, et al. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophrenia (Heidelb). 2022;8(1):5. PubMed CrossRef
- Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–951. PubMed CrossRef
- Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7(1):64–77. PubMed CrossRef
- Lieberman JA, Stroup TS, McEvoy JP, 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(12):1209–1223. PubMed CrossRef
- Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–962. PubMed CrossRef
- Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306–1315. PubMed CrossRef
- Yildiz A, Nikodem M, Vieta E, et al. A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania. Psychol Med. 2015;45(2):299–317. PubMed CrossRef
- Rummel-Kluge C, Komossa K, Schwarz S, et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull. 2012;38(1):167–177. PubMed CrossRef
- Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–1696. PubMed CrossRef
- Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry. 1999;60(6):358–363. PubMed CrossRef
- Meyer JM, Davis VG, Goff DC, et al. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res. 2008;101(1–3):273–286. PubMed CrossRef
- Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.
- Buchanan RW, Kreyenbuhl J, Kelly DL, et al; Schizophrenia Patient Outcomes Research Team (PORT). The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71–93. PubMed CrossRef
- Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA Psychiatry. 2014;71(12):1350–1363. PubMed CrossRef
- Robinson DG, Schooler NR, Correll CU, et al. Psychopharmacological treatment in the RAISE-ETP study: outcomes of a manual and computer decision support system based intervention. Am J Psychiatry. 2018;175(2):169–179. PubMed CrossRef
- Siskind D, Gallagher E, Winckel K, et al. Does switching antipsychotics ameliorate weight gain in patients with severe mental illness? a systematic review and meta-analysis. Schizophr Bull. 2021;47(4):948–958. PubMed CrossRef
- Ostuzzi G, Vita G, Bertolini F, et al. Continuing, reducing, switching, or stopping antipsychotics in individuals with schizophrenia-spectrum disorders who are clinically stable: a systematic review and network meta-analysis. Lancet Psychiatry. 2022;9(8):614–624. PubMed CrossRef
- Speyer H, Westergaard C, Albert N, et al. Reversibility of antipsychotic-induced weight gain: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;12:577919. PubMed CrossRef
- Correll CU, Vanover KE, Davis RE, et al. Safety and tolerability of lumateperone 42 mg: an open-label antipsychotic switch study in outpatients with stable schizophrenia. Schizophr Res. 2021;228:198–205. PubMed CrossRef
- Lee K, Abraham S, Cleaver R. A systematic review of licensed weight-loss medications in treating antipsychotic-induced weight gain and obesity in schizophrenia and psychosis. Gen Hosp Psychiatry. 2022;78:58–67. PubMed CrossRef
- Vancampfort D, Firth J, Correll CU, et al. The impact of pharmacological and non-pharmacological interventions to improve physical health outcomes in people with schizophrenia: a meta-review of meta-analyses of randomized controlled trials. Focus Am Psychiatr Publ. 2021;19(1):116–128. PubMed CrossRef
- Lybalvi [package insert]. Waltham, MA: Alkermes, Inc.; 2021.
- Silverman BL, Martin W, Memisoglu A, et al. A randomized, double-blind, placebo-controlled proof of concept study to evaluate samidorphan in the prevention of olanzapine-induced weight gain in healthy volunteers. Schizophr Res. 2018;195:245–251. PubMed CrossRef
- Martin WF, Correll CU, Weiden PJ, et al. Mitigation of olanzapine-induced weight gain with samidorphan, an opioid antagonist: a randomized double-blind phase 2 study in patients with schizophrenia. Am J Psychiatry. 2019;176(6):457–467. PubMed CrossRef
- Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020;177(12):1168–1178. PubMed CrossRef
- Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. J Clin Psychiatry. 2020;81(2):19m12769. PubMed CrossRef
- Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33, quiz 34–57. PubMed
- Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277. PubMed CrossRef
- Guy W. CGI Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare, National Institute of Mental Health; 1976:217–222.
- Huang M, Yu L, Pan F, et al. A randomized, 13-week study assessing the efficacy and metabolic effects of paliperidone palmitate injection and olanzapine in first-episode schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:122–130. PubMed CrossRef
- Ou JJ, Xu Y, Chen HH, et al. Comparison of metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia. Psychopharmacology (Berl). 2013;225(3):627–635. PubMed CrossRef
- Perez-Iglesias R, Crespo-Facorro B, Amado JA, et al. A 12-week randomized clinical trial to evaluate metabolic changes in drug-naive, first-episode psychosis patients treated with haloperidol, olanzapine, or risperidone. J Clin Psychiatry. 2007;68(11):1733–1740. PubMed CrossRef
- Teff KL, Rickels MR, Grudziak J, et al. Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease. Diabetes. 2013;62(9):3232–3240. PubMed CrossRef
- Rickels MR, Perez EM, Peleckis AJ, et al. Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia. Am J Physiol Endocrinol Metab. 2018;315(2):E250–E257. PubMed CrossRef
- Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19(suppl 1):1–93. PubMed CrossRef
- Citrome L, Holt RI, Walker DJ, et al. Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig. 2011;31(7):455–482. PubMed CrossRef
- Wu H, Siafis S, Hamza T, et al. Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials. Schizophr Bull. 2022;48(3):643–654. PubMed CrossRef
- Højlund M, Kemp AF, Haddad PM, et al. Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials. Lancet Psychiatry. 2021;8(6):471–486. PubMed CrossRef
Advertisement
GAM ID: sidebar-top