Table 1.

Summary of the literature review results (human)

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

SGAs, second-generation antipsychotics; DKA, diabetic ketoacidosis; T1D, type 1 diabetes; T2D, type 2 diabetes; OR, odds ratio; CI, confidence interval; DM, diabetes mellitus; FGAs, firstgeneration antipsychotics; GTT, glucose tolerance tests