Effect of aripiprazole as an adjunct to atypical antipsychotics on weight and metabolic profile: a 12-week open-label trial

Bhanu Gupta, Kok-Seng Chee, Li-Qi Neo, Charmaine Tang, Jayaraman Hariram, Geoffrey Chern-Yee Tan, Swapna Verma, Sutapa Basu, Deva-Priya Appan, Chan-Chun Ting, Edimansyah Abdin, Jimmy Lee, Bhanu Gupta, Kok-Seng Chee, Li-Qi Neo, Charmaine Tang, Jayaraman Hariram, Geoffrey Chern-Yee Tan, Swapna Verma, Sutapa Basu, Deva-Priya Appan, Chan-Chun Ting, Edimansyah Abdin, Jimmy Lee

Abstract

Background: Atypical antipsychotics are widely prescribed, yet have been associated with weight gain and metabolic syndrome.

Aim: To study the effect of adjunct low-dose aripiprazole on weight and metabolic parameters of subjects on atypical antipsychotics (olanzapine, clozapine or risperidone).

Methods: The study was carried out as an open-label trial with a fixed dose of 5 mg aripiprazole added to the patient's current antipsychotic for 12 weeks. The primary outcome measure was mean change in weight, while secondary outcome measures included change in waist circumference; fasting blood glucose; HbA1c; triglycerides; total, HDL and LDL cholesterol levels; functioning; and neurocognition.

Results: For the overall study (n = 55), there was no significant effect of adjunct aripiprazole on the weight of the subjects. However, the clozapine group achieved significant weight loss (p = 0.002) and also had significant improvements in total cholesterol (p < 0.001), HDL (p = 0.016), LDL (p = 0.044) and triglyceride levels (p = 0.038). The olanzapine group had significant improvement in triglycerides (p = 0.001), and other metabolic parameters for this group showed improvement trends, but did not reach statistical significance. The risperidone group did not show any significant improvement in weight or metabolic parameters.

Conclusions: The study adds support to the adjunctive use of aripiprazole to clozapine for weight loss and improvement in metabolic profile, and for reduction in cardiometabolic risk for patients on olanzapine.

Trial registration: Clinicaltrials.gov identifier: NCT02949752.

Keywords: aripiprazole; atypical antipsychotics; metabolic syndrome; weight gain.

Conflict of interest statement

Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

© The Author(s), 2021.

Figures

Figure 1.
Figure 1.
Patient flow diagram through the trial as per CONSORT guidelines. aSubjects were withdrawn from the study for any of the following reasons: non-compliance (n = 1), abnormal baseline blood results/abnormalities in the results such that medication changes were required (n = 4), social issues (n = 2), patient/family’s request (n = 4) and mental state deterioration (n = 1). bSubjects dropped out from the study for any of the following reasons: loss to follow-up (n = 1) and side effects (n = 3).
Figure 2.
Figure 2.
Mean change in body weight (kg) from baseline for atypicals (olanzapine, risperidone and clozapine) and adjunct aripiprazole 5 mg.

References

    1. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American psychiatric association practice guideline for the treatment of patients with schizophrenia. Am J Psych 2020; 177: 868–872.
    1. Meltzer HY, Gadaleta E. Contrasting typical and atypical antipsychotic drugs. Focus 2021; 19: 3–13.
    1. Carli M, Kolachalam S, Longoni B, et al. Atypical antipsychotics and metabolic syndrome: from molecular mechanisms to clinical differences. Pharmaceuticals 2021; 14: 238.
    1. 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: 939–951.
    1. 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: 951–962.
    1. Grinchii D, Dremencov E. Mechanism of action of atypical antipsychotic drugs in mood disorders. Int J Mol Sci 2020; 21: 9532.
    1. Gaviria AM, Franco JG, Aguado V, et al. A non-interventional naturalistic study of the prescription patterns of antipsychotics in patients with schizophrenia from the Spanish province of Tarragona. PLoS ONE 2015; 10: e0139403.
    1. Marston L, Nazareth I, Petersen I, et al. Prescribing of antipsychotics in UK primary care: a cohort study. BMJ Open 2014; 4: e006135.
    1. Keating D, McWilliams S, Boland F, et al. Prescribing pattern of antipsychotic medication for first-episode psychosis: a retrospective cohort study. BMJ Open 2021; 11: e040387.
    1. Park S-C, Lee M-S, Kang S-G, et al. Patterns of antipsychotic prescription to patients with schizophrenia in Korea: results from the health insurance review & assessment service-national patient sample. J Korean Med Sci 2014; 29: 719–728.
    1. Seshadri M, Elsemary A, Thalitaya MD, et al. Study on the prescribing patterns of antipsychotic medication in a rural England Community Mental Health Team. Psychiatr Danub 2017; 29: 524–529.
    1. Aringhieri S, Carli M, Kolachalam S, et al. Molecular targets of atypical antipsychotics: from mechanism of action to clinical differences. Pharmacol Ther 2018; 192: 20–41.
    1. Lee J, Nurjono M, Wong A, et al. Prevalence of metabolic syndrome among patients with schizophrenia in Singapore. Ann Acad Med Singap 2012; 41: 457–462.
    1. Vancampfort D, Stubbs B, Mitchell AJ, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry 2015; 14: 339–347.
    1. McCracken E, Monaghan M, Sreenivasan S. Pathophysiology of the metabolic syndrome. Clin Dermatol 2018; 36: 14–20.
    1. Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113–1132.
    1. Regufe VM, Pinto CM, Perez PMVHC. Metabolic syndrome in type 2 diabetic patients: a review of current evidence. Porto Biomed J 2020; 5: e101.
    1. Association AD. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27: 596–601.
    1. De Hert M, Detraux J, Van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2012; 8: 114–126.
    1. Perez Rodriguez A, Tajima-Pozo K, Lewczuk A, et al. Atypical antipsychotics and metabolic syndrome. Cardiovasc Endocrinol 2015; 4: 132–137.
    1. Papanastasiou E. The prevalence and mechanisms of metabolic syndrome in schizophrenia: a review. Ther Adv Psychopharmacol 2013; 3: 33–51.
    1. Tumiel E, Wichniak A, Jarema M, et al. Nonpharmacological interventions for the treatment of cardiometabolic risk factors in people with schizophrenia – a systematic review. Front Psychiatry 2019; 10: 566.
    1. Cooper SJ, Reynolds GP, Barnes T, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016; 30: 717–748.
    1. Stroup TS, McEvoy JP, Ring KD, et al. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry 2011; 168: 947–956.
    1. Stroup TS, Byerly MJ, Nasrallah HA, et al. Effects of switching from olanzapine, quetiapine, and risperidone to aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: results from a randomized controlled trial. Schizophr Res 2013; 146: 190–195.
    1. Newcomer JW, Campos JA, Marcus RN, et al. A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine. J Clin Psychiatry 2008; 69: 1046–1056.
    1. Weiden PJ. Switching antipsychotics as a treatment strategy for antipsychotic-induced weight gain and dyslipidemia. J Clin Psychiatry 2007; 68: 34–39.
    1. Citrome L. A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia. Expert Opin Pharmacother 2012; 13: 1545–1573.
    1. 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: 273–286.
    1. 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: 225–233.
    1. Fleischhacker WW, Heikkinen ME, Olié JP, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010; 13: 1115–1125.
    1. Fan X, Borba CP, Copeland P, et al. Metabolic effects of adjunctive aripiprazole in clozapine-treated patients with schizophrenia. Acta Psychiatr Scand 2013; 127: 217–226.
    1. Chang JS, Ahn Y, Park HJ, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008; 69: 720–731.
    1. Henderson DC, Fan X, Copeland PM, et al. Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. J Clin Psychopharmacol 2009; 29: 165–169.
    1. Wang L-J, Ree S-C, Huang Y-S, et al. Adjunctive effects of aripiprazole on metabolic profiles: comparison of patients treated with olanzapine to patients treated with other atypical antipsychotic drugs. Prog Neuropsychopharmacol Biol Psychiatry 2013; 40: 260–266.
    1. Mizuno Y, Suzuki T, Nakagawa A, et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull 2014; 40: 1385–1403.
    1. Taylor DM, Barnes TR, Young AH. The Maudsley prescribing guidelines in psychiatry. Newark, NJ: John Wiley & Sons, 2021.
    1. Galling B, Roldan A, Hagi K, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 2017; 16: 77–89.
    1. Gupta B, LYS Chua, Ong J, Tan GCY, et al. Aripiprazole as an adjunct for weight loss in patient’s established on clozapine and olanzapine. In: Singapore health and biomedical congress, Singapore, 2& 3rd October 2015, p. S315. Singapore: Annals of the Academy of Medicine.
    1. Kay SR, Opler LA, Lindenmayer JP. The positive and negative syndrome scale (PANSS): rationale and standardisation. Br J Psychiatry Suppl 1989; 7: 59–67.
    1. Guy W, editor. Clinician global impression (CGI). In: ECDEU assessment manual for psychopharmacology. US Department of Health, Education, and Welfare Publication (ADM). Rockville, MD: National Institute of Mental Health, 1976, pp. 76–338.
    1. Association AP. Diagnostic criteria from DSM-IV-TR. Washington, DC: American Psychiatric Publishing, 2000.
    1. Üstün TB, Kostanjsek N, Chatterji S, et al. Measuring health and disability: manual for WHO disability assessment schedule WHODAS 2.0. Geneva: World Health Organization, 2010.
    1. Fervaha G, Agid O, Foussias G, et al. Toward a more parsimonious assessment of neurocognition in schizophrenia: a 10-minute assessment tool. J Psychiatr Res 2014; 52: 50–56.
    1. Pramyothin P, Khaodhiar L. Metabolic syndrome with the atypical antipsychotics. Curr Opin Endocrinol Diabetes Obes 2010; 17: 460–466.
    1. Fleischhacker WW, Uchida H. Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol 2014; 17: 1083–1093.
    1. Wang M, Tong J-H, Zhu G, et al. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res 2012; 138: 54–57.
    1. Boullart A, de Graaf J, Stalenhoef AF. Serum triglycerides and risk of cardiovascular disease. Biochim Biophys Acta 2012; 1821: 867–875.
    1. Mailman RB, Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Curr Pharm Des 2010; 16: 488–501.
    1. de Bartolomeis A, Tomasetti C, Iasevoli F. Update on the mechanism of action of aripiprazole: translational insights into antipsychotic strategies beyond dopamine receptor antagonism. CNS Drugs 2015; 29: 773–799.
    1. Tuplin EW, Holahan MR. Aripiprazole, a drug that displays partial agonism and functional selectivity. Cur Neuropharmacol 2017; 15: 1192–1207.
    1. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 2003; 28: 1400–1411.
    1. Deng C, Chen J, Hu C, et al. What is the mechanism for aripiprazole’s effect on reducing olanzapine-associated obesity? J Clin Psychopharmacol 2010; 30: 480–481.
    1. Bickerdike MJ. 5-HT2C receptor agonists as potential drugs for the treatment of obesity. Curr Top Med Chem 2003; 3: 885–897.
    1. Nonogaki K, Nozue K, Oka Y. Hyperphagia alters expression of hypothalamic 5-HT2C and 5-HT1B receptor genes and plasma des-acyl ghrelin levels in Ay mice. Endocrinology 2006; 147: 5893–5900.
    1. Wagner E, Kane JM, Correll CU, et al. Clozapine combination and augmentation strategies in patients with schizophrenia – recommendations from an international expert survey among the treatment response and resistance in psychosis (TRRIP) working group. Schizophr Bull 2020; 46: 1459–1470.
    1. Mitsonis CI, Dimopoulos NP, Mitropoulos PA, et al. Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: an open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 373–377.
    1. Riedel M, Spellmann I, Schennach-Wolff R, et al. Effect of aripiprazole on cognition in the treatment of patients with schizophrenia. Pharmacopsychiatry 2010; 43: 50–57.
    1. Muscatello MRA, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophr Res 2011; 127: 93–99.
    1. Englisch S, Esslinger C, Inta D, et al. Clozapine-induced obsessive-compulsive syndromes improve in combination with aripiprazole. Clin Neuropharmacol 2009; 32: 227–229.
    1. Schönfelder S, Schirmbeck F, Waltereit R, et al. Aripiprazole improves olanzapine-associated obsessive compulsive symptoms in schizophrenia. Clin Neuropharmacol 2011; 34: 256–257.
    1. Zheng W, Zheng Y-J, Li X-B, et al. Efficacy and safety of adjunctive aripiprazole in schizophrenia: meta-analysis of randomized controlled trials. J Clin Psychopharmacol 2016; 36: 628–636.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel