Availability of Data and Material
The datasets generated or analyzed during the study are available from the corresponding author upon reasonable request.
Conflicts of Interest
The authors have no potential conflicts of interest to disclose.
Author Contributions
Conceptualization: Hayun Choi. Data curation: Heewon Bae, Sungsuk Je. Formal analysis: Heewon Bae, Hayun Choi. Funding acquisition: Hayun Choi. Investigation: Heewon Bae, Ji Hyun Lee, Sungsuk Je. Methodology: Heewon Bae, Sungsuk Je, Hayun Choi. Project Administration: Sungsuk Je, Hayun Choi. Resources: Hayun Choi, Seung-Hoon Lee. Software: Sungsuk Je, Hayun Choi. Supervision: Ji Hyun Lee, Hayun Choi. Validation: Ji Hyun Lee, Sungsuk Je. Visualization: Heewon Bae. Writing—original draft: Heewon Bae. Writing—review and editing: Ji Hyun Lee, Hayun Choi.
Funding Statement
This study was supported by the VHS Medical Center Research Grant, Republic of Korea (grant number: VHSMC 22033).
Author | Year | Country | Aim | Methodology | Sample size | Subjects | Antipsychotics | Duration | Key findings |
---|---|---|---|---|---|---|---|---|---|
Grajales et al. [10] | 2019 | Spain | To discuss mechanisms of SGA and dysregulation of glucose metabolism | Narrative review | Clozapine, risperidone, olanzapine, ziprasidone, quetiapine, amisulpride, sertindole, lurasidone, paliperidone, iloperidone, asenapine and aripiprazole | Antipsychotics, particularly SGAs, contribute to weight gain and glucose dysregulation, both major factors in T2D development | |||
Vuk et al. [17] | 2017 | Croatia | To review antipsychotic-induced DKA | Narrative review | 83 | Olanzapine (N=32), clozapine (N=19), risperidone (N=9), 2SGAs (N=9), quetiapine (N=8), and aripiprazole (N=6) | 4 days to 4 years | Developed DKA following treatment with antipsychotics such as olanzapine, clozapine, or combination therapy within the first six months of treatment | |
Polcwiartek et al. [45] | 2017 | Denmark | To explore links between recent antipsychotic medication exposure and DKA, T1D and T2D | Case-control study | 165 | Amisulpride (N=1), aripiprazole (N=3), clozapine (N=11), olanzapine (N=34), paliperidone (N=2), quetiapine (N=12), risperidone (N=17), sertindole (N=1), and ziprasidone (N=1) | 32.4 years | Antipsychotic exposure was associated with DKA (OR 2.60; 95% CI 1.06–6.38) and T2D | |
T2D (OR 1.64; 95% CI 1.48–1.83) | |||||||||
Polcwiartek et al. [51] | 2016 | Denmark | To review antipsychotic-associated DKA with type1 etiology | Systematic review | 25 | Aripiprazole (N=6), clozapine (N=3), olanzapine (N=9), quetiapine (N=1), and risperidone (N=6) | 1.4–11 months | T1D risk and insulin treatment requirements in antipsychotic-related DKA | |
Stubbs et al. [9] | 2015 | UK | To investigate the prevalence of T2D in people with schizophrenia | Systematic review | 145,718 | 25.5 years to 54.4 years | Schizophrenia doubles the risk of developing T2D by recognized criteria | ||
Lipscombe et al. [15] | 2014 | Canada | To evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies | Retrospective cohort | 725,489 | Risperidone (N=234,231), olanzapine (N=100,050), other atypical (N=199,485), and typical (N=191,721) | Initiating antipsychotic medication carries a low risk of hyperglycemic emergencies, although individuals with pre-existing diabetes may have an increased vulnerability | ||
Guenette et al. [47] | 2013 | Canada | To review current case reports of DKA in the context of atypical antipsychotic treatment | Narrative review | 69 | Olanzapine (N=29), clozapine (N=18), risperidone (N=9), quetiapine (N=7), and aripiprazole (N=6) | 4 days to 4 years | Antipsychotic-induced DKA may occur early and without weight gain | |
Zhang et al. [1] | 2013 | USA | To compare SGAs vs. FGAs in first-episode schizophrenia patients | Systematic review | 2,236 | Olanzapine (N=584), risperidone (N=85), clozapine (N=219), amisulpride (N=207), quetiapine (N=207), ziprasidone (N=185), and pooled SGAs (N=749) | No SGA-FGA difference found in long-term glucose change | ||
Ely et al. [53] | 2013 | USA | To report 17 deaths due to DKA in psychiatric patients treated with SGAs | Case series | 17 | Quetiapine, olanzapine, and risperidone | SGA is considered to be the primary contributor to death in DKA patients | ||
Lipscombe et al. [6] | 2009 | Canada | To investigate the risk of hyperglycemia among persons with preexisting diabetes | Nested case-control study | 13,817 | Atypical and typical antipsychotics | In older DM patients, antipsychotic medication was linked to a notably higher risk of hyperglycemia-related hospitalization | ||
Cohen and Correll [49] | 2009 | Netherlands | To review case of antipsychotic-associated DM and DKA | Narrative review | 74 | Clozapine, olanzapine, risperidone, quetiapine, aripiprazole and 4 other atypical antipsychotics | 6 weeks | Possibility of glucose homeostasis deterioration with all antipsychotic drugs necessitates strict monitoring | |
Henderson et al. [50] | 2007 | USA | To assess the incidence of new-onset DM presenting as DKA in patients with schizophrenic disorders | Retrospective cohort | 819,308 | Olanzapine (N=776), risperidone (N=585), quetiapine (N=479), clozapine (N=226), and ziprasidone (N=57) | 7 years | High incidence of DM presenting as DKA in schizophrenia patients compared with general hospital population | |
Ramaswamy et al. [46] | 2007 | USA | To assess DKA risk in patients receiving risperidone or olanzapine | 102,632 | Risperidone and olanzapine | The risk of diabetic ketoacidosis was 1.62 times higher with olanzapine compared to risperidone (p=0.033) | |||
Reist et al. [5] | 2007 | USA | To study the prevalence of obesity, DM, and DKA over time in inpatients with schizophrenia compared to those without | Retrospective cohort | Risperidone, olanzapine, clozapine, quetiapine, ziprasidone, and aripiprazole | After SGAs were introduced, schizophrenia patients in the US saw a significant rise in obesity and DM prevalence | |||
Smith et al. [20] | 2005 | USA | To investigate fasting glucose levels in 210 patients, with schizophrenic or schizoaffective disorder, treated with a single antipsychotic medication | Cross-sectional study | 210 | Olanzapine (N=50–53), clozapine (N=48–49), risperidone (N=49–50), and conventional (N=51–52) | 6.1 months | Fasting blood sugar and lipid measurements didn’t differ significantly between drugs, but olanzapine raised triglycerides, and risperidone GTT led to higher 1-hour blood sugar levels | |
Leslie and Rosenheck [48] | 2004 | USA | To find the diabetes and ketoacidosis rates in stable antipsychotic monotherapy-treated schizophrenia patients | Retrospective cohort | 73,946 | Clozapine, risperidone, olanzapine, quetiapine, and all conventional antipsychotics | 25 months | Out of the 56,849 confirmed patients, 4,132 (7.3%) had diabetes, and 88 (0.2%) had ketoacidosis, with clozapine (hazard ratio=1.57) posing the highest risk for DM | |
Koller et al. [8] | 2004 | USA | To explore the clinical characteristics of quetiapine induced hyperglycemia | Narrative review | 55 | Quetiapine | 35.3 years | In quetiapine-related hyperglycemia reports, 34 patients developed new hyperglycemia, and 8 had worsened diabetes, mainly within 6 months of treatment initiation | |
Wilson et al. [19] | 2003 | USA | To evaluate the risk of new-onset diabetes and related glucose impairment in a cohort of patients treated with atypical antipsychotics | Narrative review | 126 | Clozapine, olanzapine, quetiapine, risperidone, and clozapine | 2 months | Out of 126 patients treated with atypical antipsychotics, 14 developed glucose intolerance, and 5 of them also developed DKA | |
Abidi and Bhaskara [23] | 2003 | Canada | To review the pharmacotherapy of schizophrenia | Narrative review | Clozapine, risperidone, and olanzapine | Atypical antipsychotics can compound a patient’s risk for developing metabolic complications | |||
Jin et al. [18] | 2002 | USA | To find association between atypical antipsychotic agents and new-onset T2D or DKA | Case reports and retrospective study | 45 | Clozapine (N=20), olanzapine (N=19), quetiapine (N=3), and risperidone (N=3) | Within 6 months | After starting atypical antipsychotic treatment, 50% of patients with new-onset DM or DKA manifested no weight gain | |
Koller et al. [7] | 2001 | USA | To investigate the risk and characteristics of clozapine-associated DM | Narrative review | 384 | Clozapine | Clozapine-induced DM suggests a temporal relation to initiation, young age, and immediate reversibility on withdrawal of the drug | ||
Mir and Taylor [22] | 2001 | UK | To review association between hyperglycemia and atypical antipsychotics | Narrative review | 34 | Clozapine (N=17), olanzapine (N=16), and quetiapine (N=1) | Hyperglycemia and ketoacidosis are truly induced by clozapine and olanzapine |
Author | Year | Country | Aim | Methodology | Sample size | Subjects | Antipsychotics | Duration | Key findings |
---|---|---|---|---|---|---|---|---|---|
Shamshoum et al. [30] | 2021 | Canada | To review the peripheral mechanisms of acute olanzapine-induced related metabolic disturbances | Narrative review | Clozapine and olanzapine | Preclinical in vivo studies in this review revealed gender-specific changes in glucose metabolism in response to Aps | |||
Ren et al. [28] | 2019 | China | To investigate olanzapine-induced insulin-desensitivity in the liver | Animal study | Rats | Olanzapine | IRS/PI3K/Akt signaling pathway mediates olanzapine-induced hepatic insulin resistance in male rats | ||
Nagata et al. [41] | 2018 | Japan | To clarify the mechanism of clozapine-induced acute hyperglycemia | Animal study | Wistar rat | Clozapine | Single clozapine administration raised rat serum glucose levels | ||
Liu et al. [31] | 2017 | Australia | To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use for 9 weeks in rats | Animal study | Rat | Clozapine and olanzapine | SGA-induced glucose-lipid metabolic disturbances may occur independently of weight gain, potentially via liver SREBP/ChREBP activation | ||
Castellani et al. [43] | 2017 | Canada | To investigate glucagon’s role in mediating olanzapine-induced blood glucose increase | Animal study | WT mice, Gcgr-/- mice | Olanzapine | Central role of the liver in mediating olanzapine-induced disturbances in glucose homeostasis | ||
Mondelli et al. [29] | 2013 | UK | To find the molecular pathways of haloperidol- and olanzapine-induced metabolic abnormalities | Animal study | Sprague-Dawley rat | Olanzapine and haloperidol | Different molecular pathways mediate glucose homeostasis disturbances induced by haloperidol and olanzapine, with olanzapine directly affecting the insulin pathway | ||
Panariello et al. [33] | 2012 | Italy | To investigate the effect of clozapine on insulin action by analyzing insulin signaling in vitro and in vivo | Laboratory and animal study | PCI2, L6 cells and C57/BL/KsJ mice | Clozapine | Clozapine impairs insulin signaling and glucose uptake by affecting Akt and PKC-z | ||
Smith et al. [42] | 2009 | New Zealand | To compare the effects of clozapine and quetiapine on the development of obesity and glucose metabolism. | Animal study | Sprague-Dawley rat | Clozapine and quetiapine | Clozapine and quetiapine impair glucose tolerance in rats independently of obesity-induced insulin resistance | ||
Smith et al. [40] | 2008 | New Zealand | To investigate the impact of SGAs on glucose metabolism | Animal study | Rat | Haloperidol, quetiapine, and clozapine | SGAs induce acute disruptions in glucose metabolism through increased glucagon secretion | ||
Engl et al. [32] | 2005 | Austria | To find pathogenesis of SGA-induced disturbance of glucose homeostasis | Laboratory study | L6 skeletal muscle cell | Olanzapine | Olanzapine reduces glycogen content in L6 cells by inhibiting insulin signaling |