Psychiatry Investig Search

CLOSE


Psychiatry Investig > Volume 21(2); 2024 > Article
Bae, Lee, Je, Lee, and Choi: Diabetic Ketoacidosis Associated With Second Generation Antipsychotics: A Case Study and Review of Literature

Abstract

Objective

Second-generation antipsychotics (SGAs) have revolutionized the treatment of psychiatric disorders, but are associated with significant metabolic risks, including diabetes and hyperglycemic crises. This review explores the complex interplay between antipsychotics, diabetes, and hyperglycemic crises, highlighting the mechanisms underlying SGA-induced diabetes.

Methods

We present the case of a patient with schizophrenia who was taking antipsychotic medication and was admitted to the emergency room due to the sudden onset of diabetic ketoacidosis (DKA) without any history of diabetes. We extensively searched databases, including Elsevier, PubMed, IEEE, SpringerLink, and Google Scholar, for papers on the effects of antipsychotic drugs on DKA from 2002 to 2021. We focused on DKA, hyperglycemia, and atypical antipsychotics, and retrieved 117 papers. After full-text review, 32 papers were included in this comprehensive review.

Results

DKA was significantly more frequent in patients taking SGAs. Antipsychotics can induce insulin resistance either directly or through the onset of obesity. Antipsychotics can reduce insulin secretion from pancreatic β-cells, which is associated with absolute insulin deficiency.

Conclusion

As the use of antipsychotics continues to increase, understanding their risks and mechanisms is crucial for clinicians to enable informed treatment decisions and prevent potentially life-threatening complications.

INTRODUCTION

Antipsychotic drugs are commonly used to treat various psychiatric disorders, including schizophrenia, bipolar disorder, major depression, and the behavioral and psychological symptoms of dementia [1]. First-generation antipsychotics have been prescribed since the 1950s, and exert their therapeutic effects by blocking dopamine D2 receptors. The associated adverse effects include extrapyramidal symptoms, akathisia, and tardive dyskinesia [2]. To reduce these neurological adverse effects, second-generation antipsychotics (SGAs) were developed, and have been approved by the FDA since the 1990s [3]. SGAs target multiple neuroreceptors such as the serotoninergic 5-HT2A/5-HT2C, histaminergic H1, and muscarinic M3 receptors, apart from the D2 receptors. These drugs are now widely used as first-line antipsychotics due to the lower risk of side effects and are more successful in terms of long-term treatment and tolerability compared to first-generation antipsychotics [4]. However, SGAs cause metabolic disorders including obesity, hyperlipidemia, and diabetes [5,6]. Several studies have shown that the incidence of diabetes is higher in patients treated with SGAs [7,8]. According to a meta-analysis that evaluated 25 studies, schizophrenia patients treated with SGAs exhibited a 2.5 times higher risk of developing type 2 diabetes (T2D), compared to the control group [9]. SGA-induced diabetes can occur via various mechanisms involving SGA-induced insulin resistance and β-cell damage [10]. Patients with SGA-induced diabetes were 74% more susceptible to developing acute complications and showed higher mortality than the general population [11].
Diabetes is characterized by hyperglycemia (fasting plasma glucose level >126 mg/dL [7 mmol/L]) due to insufficient insulin production or insulin resistance [12]. Autoimmune damage to pancreatic cells results in type 1 diabetes (T1D) due to complete insulin deficiency. In contrast, T2D is caused by insulin resistance in cells that do not respond to insulin stimulation or cell dysfunction [12]. The association between diabetes and psychosis is complex and multifactorial. Risk factors for T2D, such as a sedentary lifestyle or poor diet, are more common in the population with psychotic disorders than in the general population. A sedentary lifestyle involves very little physical activity and primarily involves sitting or lying down for extended periods. Obesity is approximately 1.5 to 2.0 times more prevalent in patients with schizophrenia. Antipsychotic drugs contribute to diabetes by either inducing weight gain or promoting insulin resistance [13].
Hyperglycemic crisis is a metabolic emergency associated with uncontrolled diabetes, including the hyperosmotic hyperglycemic state (HHS) and diabetic ketoacidosis (DKA). Relative or absolute insulin deficiency and excessive regulation of hormones (glucagon, cortisol, catecholamine, and growth hormones) cause hyperglycemia and ketone body accumulation. Unlike in DKA, in HHS, higher insulin levels inhibit ketone production and limit metabolic acidosis. DKA is more common in young people with T1D, whereas HHS is more frequently reported in adult and elderly patients with T2D. However, many patients exhibit both HHS and DKA, and both DKA and HHS can occur in patients with T1D and T2D [14,15]. In a previous multicenter, retrospective cohort study, 59.4% of hyperglycemic emergency cases in patients aged 18-65 were attributed to DKA, compared to 9.6% of HHS hospitalizations. In contrast, these events were reported with a similar frequency of DKA and HHS hospitalizations in patients of age >66 years old. Therefore, clinicians should be careful about the possibility of DKA when prescribing antipsychotics to young and old patients, who are typically considered a risk group [15].
DKA is an acute complication of diabetes characterized by uncontrolled hyperglycemia, metabolic acidosis, and increased ketone bodies. Since it can be life-threatening, treatment should be started immediately and can reduce sequelae [16]. SGAs such as olanzapine, clozapine, risperidone, and quetiapine can cause DKA, and the average treatment period to onset may be about six months [17]. Although some mechanisms of DKA have been associated with SGAs, these associations remain uncertain. Several cases of antipsychotics-induced DKA have been reported, among which cases with the first sign of DKA characteristically presented in psychiatric patients without underlying diabetes [18]. Interestingly, the incidence of DKA in schizophrenia is 10-fold higher than that in the general population. One study reported that DKA occurred in 5 out of 11 individuals using antipsychotic medications [19]. The overall mortality rate in patients exposed to antipsychotics was 26.5% [20]. Despite the high risk of mortality, there has been little attention to DKA in the context of SGA use [21].
As psychiatric patients often use antipsychotic drugs chronically for extended periods, these side effects should be considered seriously [22,23]. It is noteworthy that the number of patients who have been prescribed antipsychotics has increased over the past decade [24]. Therefore, it is necessary to consider the occurrence of DKA with the use of SGAs. We present the case of a patient with schizophrenia who was taking antipsychotic medications but had no history of diabetes. This case report and review provides an overview of DKA and focuses on the molecular mechanisms through which antipsychotics can cause DKA.

CASE PRESENTATION

A 35-year-old male presented with dyspnea and a drug overdose that started 10 days before admission to the emergency room. He was diagnosed with schizophrenia 14 years ago and had been receiving long-acting injectable palmitate 234 mg once a month for 9 months, in addition to the oral administration of lithium 900 mg, quetiapine 400 mg, and lorazepam 0.5 mg daily. His auditory hallucinations, persecutory delusions, and depressive feelings had worsened 15 days back. There was no history of administration of any other medication or herbal supplement. His blood glucose and HbA1c levels 6 months back were 123 mg/mL and 5.9%, respectively. He was 174 cm tall and weighed 120 kg with a body mass index of 39.6 kg/m2. There was no prior diagnosis of diabetes, hypertension, or hyperlipidemia (Figure 1).
Physical examination revealed signs of acute illness and alert consciousness. At the time of admission, his blood pressure was 99/55 mm Hg, heart rate was 98 beats/min, respiratory rate was 32 breaths/min, and body temperature was 36.7°C. His weight was 116 kg, with a weight loss of 4 kg compared to that 6 months back.
Laboratory findings showed no abnormalities in the complete blood count. However, serum biochemical analysis revealed elevated blood glucose, blood urea nitrogen, and creatinine levels of 970 mg/dL, 34.2 mg/dL, and 2.78 mg/dL, respectively. The sodium level had decreased to 120 mEq/L, while the potassium level and serum osmolality had increased to 5.6 mEq/L and 342 mOsm/kg, respectively. The HbA1c level was 14.4%, while the ketone level had increased to 4.1 mmol/L. Arterial blood gas analysis showed metabolic acidosis with a 6.848 pH and 20.1 mm HgpCO2, 64.6 mm HgpO2, 3-3.5 mmol/L HCO, and 28 mmol/L lactate (reference range: 4.5-14.4) levels. The C-peptide level was 0.79 ng/mL, indicating diminished insulin secretion, and tests for both anti-insulin and anti-GAD antibodies were negative. The lithium level was 0.34 mmol/L.
After the diagnosis of DKA, all previously administered medications were discontinued, and the patient was admitted to the endocrinology department for aggressive fluid therapy, intravenous insulin administration, and electrolyte correction. After 1 week of hospitalization, his fasting blood glucose level was 417 mg/dL, and he began taking oral hypoglycemic agents in addition to insulin. The C-peptide level recovered to 2.04 ng/mL, indicating normal insulin secretion. After 2 weeks, the fasting blood glucose level was 167 mg/dL. After being transferred to the psychiatric department, he was administered aripiprazole. Insulin treatment was stopped one month after admission, and only oral hypoglycemic agents were continued. Two months after admission, the patient experienced shortness of breath and presyncope with cyanosis. On examination, his heart rate was regular but elevated at 128 beats/min, his blood pressure was 101/72 mm Hg, and his respiratory rate was 32 breaths/min; the oxygen saturation level of the room air was 85%. The D-dimer test results were positive, and further evaluation with computed tomography pulmonary angiography confirmed the presence of a pulmonary thromboembolism. Thrombi were detected in the main, superior, and inferior pulmonary arteries and the segmental branches. The patient received anticoagulant treatment with intravenous heparin and an oral anticoagulant, which resolved tachycardia and hypoxia within 10 days of treatment. After 3 months, the patient was able to discontinue the oral hypoglycemic agent, and their fasting blood sugar, postprandial blood sugar 2 hours after a meal, and HbA1c levels were 117 mg/dL, 146 mg/dL, and 5.7%, respectively. After 6 months, the patient’s fasting blood sugar level improved to 91 mg/dL, whereas the HbA1c level was 6.1% without the need for oral hypoglycemic agents. This case report was approved by the Clinical Trials Review Committee of the Veteran’s Health Service Medical Center (IRB No. 2023-06-012).

LITERATURE REVIEW METHODS

We analyzed the effects of antipsychotic drugs on DKA. Our eligibility criteria were as follows: english-language papers published from 2002 to 2021 in electronic databases, including Elsevier, PubMed, IEEE, SpringerLink, and Google Scholar. We included papers with keywords such as hyperglycemia, DKA, hyperosmolar hyperglycemic syndrome, SGA, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Exclusion criteria were limited to case reports.
A total of 117 papers examining the relationship between atypical antipsychotics and diabetes mellitus (DM) or DKA, as well as research papers identifying the underlying mechanisms, were included; of these, 38 duplicate papers and 47 single case reports were excluded. Each potentially relevant paper underwent a comprehensive review of its full text to ensure that it met the established eligibility criteria. Finally, we included 32 studies that were most relevant and closely aligned with our eligibility criteria in our analysis (Tables 1 and 2). This literature review was approved by the Clinical Trials Review Committee of the Veteran’s Health Service Medical Center (IRB No. 2022-03-015).

RESULTS

The patient was admitted to the emergency room after presenting with worsening psychosis, dyspnea, and polydipsia after taking excessive antipsychotics. He had no medical history of T1D or T2D. However, he was diagnosed with DKA after admission. The primary underlying causes of DKA and HHS include either a partial or complete lack of insulin, or an abundance of counter-regulatory hormones (Figure 2).

Mechanisms for SGA-induced DKA: focusing on molecular pathways

The pathophysiology of DKA requires insulin deficiency and an increase in counter-regulatory hormones (glucagon, catecholamines, and cortisol). In contrast, under hyperosmotic hyperglycemic state (HHS) conditions, insulin levels are relatively high, inhibiting ketone production and metabolic acidosis [15]. Insulin deficiency occurs under the complete loss of β-cell function over extended periods. However, this is not always the case because some patients present within a few years of diagnosis where complete β-cell dysfunction is impossible [25]. Studies have suggested that the mechanism could involve relative insulin deficiency and increased lipolysis caused by counter-regulatory hormones [26]. Insulin deficiency and counter-regulatory hormone increase leads to hyperglycemia and ketoacidosis. Hyperglycemia occurs due to increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose use in peripheral tissues. This is amplified by hormone imbalances and temporary insulin resistance. Ketoacidosis occurs when free fatty acids are liberated from adipose tissues into the blood, and uncontrolled fatty acid oxidation is induced in the liver.

Insulin deficiency: impairment of insulin signaling pathways

Alterations in the insulin signaling pathway associated with SGAs may occur in hepatocytes and skeletal muscles. SGAs affect the insulin signaling pathway in two ways: inhibition of insulin receptor substrate 1/2 (IRS-1/2) phosphorylation, and inhibition of Akt and glycogen synthase kinase-3 (GSK3) phosphorylation. A previous study found that olanzapine attenuated IRS-1 phosphorylation in insulin-stimulated human wild-type fibroblasts [27].
Male Sprague-Dawley rats treated with olanzapine (10 mg/d) for 8 weeks showed significantly reduced IRS-2 levels, reduced GSK3α-Ser21 phosphorylation, and increased GSK3β-Ser9 phosphorylation, which directly inhibit the hepatic insulin signaling pathway [28,29]. In contrast, another study reported that olanzapine (5 mg/kg/d) treatment for 8 weeks in the same mouse model increased IRS-1 Ser307 and IRS-2 Ser731 phosphorylation. This result demonstrated that the increase in baseline insulin triggers proteasomal degradation, finally resulting in the blockade of insulin signaling pathways [28]. SGAs also promote the decrease in Akt/GSK phosphorylation, a critical node of insulin signaling in the liver [30]. Oral olanzapine (3 mg/kg/d) or clozapine (20 mg/kg/d) treatment in female Sprague-Dawley rats for 9 weeks reduced hepatic Akt and GSK3β phosphorylation at the Ser9 and Ser473 levels, respectively [31].
Similar to hepatocytes, SGAs interfere with the insulin signaling pathway in skeletal muscle cellular models. The study showed that the Rat L6 skeletal muscle cells treated with olanzapine (10 and 100 µM) for 72 hours blocked IRS-1 phosphorylation and decreased Akt and GSK-3 phosphorylation [32]. In line with this finding, clozapine (1.5 µM) treatment using PC-12 cells and L6 skeletal muscle cells as a model of the brain and peripheral tissue, respectively, reduced the effect of insulin on insulin receptors by 40% and on insulin-induced IRS-1 tyrosine phosphorylation by 60% in 24 hours. Akt phosphorylation at Ser473 had decreased by approximately 40% [33].

Decrease in insulin secretion of pancreatic β-cells

Insulin secretion is tightly controlled by pancreatic β-cells. Pancreatic β-cells express various dopaminergic, serotonin, and cholinergic muscarinic receptors involved in insulin secretion.
There are five types of dopamine receptors, and the D2 and D3 receptors have been identified as those associated with insulin secretion. Dopamine is secreted along with insulin in a hyperglycemic state, released into the extracellular space, binds to D2 receptors, and partially suppresses insulin secretion by decreasing cell membrane depolarization and increasing cytosolic calcium influx [34]. Prolonged D2 blockade may lead to the depletion of insulin and an eventual defect in pancreatic compensation [35]. In addition, another study showed that dopaminergic negative feedback in mouse pancreatic islets was abolished by a specific antagonist of the dopamine receptor D3. D3 receptor activation results in changes in intracellular calcium dynamics, leading to reduced insulin secretion [36].
Serotonergic receptors are also expressed in response to glucose stimulation, and extracellular 5-HT may act as a stimulator or inhibitor of insulin secretion depending on the expression of different 5-HT receptor subtypes [37]. A study reported that selective serotonin reuptake inhibitors can reduce insulin secretion in isolated islets and β-cell lines, like direct 5HT2c agonists [35]. This study suggested that SGAs that exhibit partial agonist activity against 5HT2a/c receptors may adversely affect insulin secretion [38]. SGAs inhibit M3R action on glucose-dependent parasympathetic regulation of insulin secretion. Grajales et al. [10] reported that olanzapine and clozapine suppress M3R, which decreases cholinergic-stimulated insulin secretion by directly blocking these receptors in β-cells [10]. M3R is also located in the brain and can be affected by SGAs. Disruption of M3R density in the brain has also been observed in female Sprague-Dawley rats treated with olanzapine (0.25-2.0 mg/kg) which resulted in an up-regulation of M3R in the hypothalamic arcuate ventromedial nuclei and dorsal vagal complex of the brainstem. Elevated hypothalamic M3R levels negatively correlate with peripheral insulin levels [39].

Increase in counter-regulatory hormones

Several studies have reported that SGAs increase glucagon levels in pancreatic alpha cells. In male Sprague-Dawley rats injected with octreotide (250 mg/kg) for 5 min, clozapine increased glucagon levels despite an increase in both blood glucose and plasma insulin levels [40]. Similarly, male Wistar rats received intravenous injections of clozapine (2.5, 5, and 10 mg/kg). After clozapine administration, glucagon levels increased dosedependently at 2.5-10 mg/kg [41]. These results suggested that clozapine directly stimulates glucagon secretion.
Chronic treatment of male Sprague-Dawley rats with clozapine (10 mg/kg) or quetiapine (10 mg/kg) for 42 days increased insulin and glucagon levels [42]. Castellani et al. [43] previously reported that glucagon levels were higher in rats following clozapine (structurally similar to olanzapine) administration, and that this increase significantly contributed to elevated blood glucose levels [43]. Another possible mechanism through which SGAs could disturb insulin homeostasis is by suppressing the release of incretins, which amplify glucose-mediated insulin release from the gut [44].

DISCUSSION

Case reports of DKA induced by SGAs are infrequent [15,45,46]. DKA cases reported in other countries are 6, 18, 29, 7, and 9 for aripiprazole, clozapine, olanzapine, quetiapine, and risperidone, respectively [47]. In South Korea, DKA cases for clozapine, olanzapine, risperidone, and paliperidone were 1, 2, 3, and 2, respectively [48]. The average age of DKA onset among individuals taking antipsychotics was 37.5 years, with the majority falling within the 20-39 years age group, wherein 30-39 years accounted for 70% and 20-29 years for 20% [47]. In the present case, the patient was 35 years old, falling within this age range. Although the patient had not been previously diagnosed with DM, he had several risk factors that could lead to metabolic disease. He had been diagnosed with schizophrenia, was severely obese, and was taking two different SGAs; an overdose was suspected 10 days before admission. However, the exact cause of DKA, and not of HHS, was unclear. It is possible that severe psychological stress led to an excessive secretion of the stress hormone cortisol, and the concurrent use of lithium may have exacerbated dehydration, possibly contributing to DKA.
Patients treated with SGAs may exhibit dysfunctions in glucose metabolism [48,49]. Metabolic abnormalities include dry mouth, loss of appetite, and weight change. Hyperglycemia in DKA presented with polydipsia and polyuria that had occurred several days back. Metabolic acidosis is associated with acute symptoms of nausea, vomiting, and abdominal pain, as well as weight loss and general weakness. Aggravation of metabolic acidosis can progress to confusion or coma [42]. However, as these symptoms are similar to the side effects of SGAs, it is difficult to differentiate them clinically. Therefore, periodic observation and examination are important for patients taking SGAs [50]. In addition, DKA is caused by physical or mental stress, such as infection or surgery, in patients with insulin deficiency [43]. SGA-induced DKA, mediated by the abovementioned mechanisms, may occur even in the absence of previous conditions influencing its occurrence [51,52].
Sudden premature death has been reported in patients treated with SGAs [53]. A previous study reported that 391 patients with schizophrenia had 5 cases of DKA and 14 cases of pulmonary thromboembolism. One-third of the causes of death in DKA are thromboembolic, with septic embolisms. This is because hypercoagulation occurs owing to changes in the vascular endothelium and coagulation factors, and dehydration increases blood viscosity, leading to thrombosis. Similarly, the patient in the current case experienced fatal pulmonary thromboembolism as well. It is essential to be aware of these potential risks and closely monitor patients for adverse effects during treatment with antipsychotics.

Prevention

The guidelines of the American Diabetes Association and American Psychiatric Association published in 2004 and the Korean Medication Algorithm for Schizophrenia 2019 recommend checking the patient’s medical history, family history, height, weight, body mass index, waist circumference, blood pressure, fasting blood sugar, and lipid abnormalities before taking SGAs [15,54]. Weight should be monitored at regular outpatient visits at 4, 8, and 12 weeks after treatment with SGAs and thereafter. Blood pressure, fasting blood sugar, and lipid abnormalities were assessed at 12 weeks after the administration of SGAs. Subsequently, blood pressure and fasting blood sugar levels should be monitored annually, and lipid abnormalities should be monitored every five years. In addition to the above guidelines, recent reports recommend checking weight, fasting blood sugar, and lipid abnormalities quarterly for 1 year after 12 weeks of SGA treatment. It is hard to provide sufficient evidence to validate risk factors associated with the development of SGA-induced DKA. Individuals with risk factors for DM, such as obesity, immobility, and atypical antipsychotic intake, are at a higher risk of hyperglycemic crisis. However, the mechanism underlying the occurrence of DKA due to an absolute deficiency of insulin in these individuals has not been established. Nevertheless, we hope that this case report and review will lay the foundation for elucidating the mechanism of SGA-induced DKA in the future.

CONCLUSION

SGAs are associated with DKA, a hyperglycemic emergency. SGA-related DKA may be mediated by the mechanisms described earlier. It can be caused by insulin deficiency due to the impairment of insulin signaling pathways, inhibition of insulin secretion, and increase in counter-regulatory hormones. This mechanism causes DKA even in patients without underlying diabetes or obesity. Sudden premature death has been reported in patients exposed to antipsychotics. DKA is a fatal condition; therefore, prevention and prompt treatment are required. Therefore, clinicians should follow the guidelines for prevention and carefully examine patient symptoms during treatment with SGAs for extended periods. Clinicians should be aware that individuals with risk factors for DM, such as severe obesity, immobility, and irregular atypical antipsychotic intake, are at a higher risk of hyperglycemic crisis.

Notes

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).

ACKNOWLEDGEMENTS

We would like to express our deepest gratitude to the study coordinator, Aram Park (Veteran Health Service Medical Center) and the professor Joon Ho Moon (Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine), who made valuable contributions to this work.

Figure 1.
Flow chart illustrating the clinical progression of the case patient. ER, emergency room; NP, neuropsychiatry ward; BST, blood sugar test; DM, diabetes mellitus.
pi-2023-0301f1.jpg
Figure 2.
Pathophysiology of hyperglycemic emergencies and antipsychotics. Second-generation antipsychotics can induce insulin resistance either directly or through obesity. Increased food intake can lead to obesity and insulin resistance. Moreover, antipsychotics can reduce insulin secretion, which is associated with absolute insulin deficiency, from β-cells. FFAs, free fatty acid.
pi-2023-0301f2.jpg
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

Table 2.
Summary of the literature review results (animal models and cell lines)
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

DM, diabetes mellitus; DKA, diabetic ketoacidosis; FGAs, first-generation antipsychotics; SGAs, second-generation antipsychotics; APs, antipsychotics; WP, wild type

REFERENCES

1. Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2013;16:1205-1218.
crossref pmid pmc pdf
2. Arana GW. An overview of side effects caused by typical antipsychotics. J Clin Psychiatry 2000;61 Suppl 8:5-13. discussion 12-13.
pmid
3. Correll CU. From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry 2010;25 Suppl 2:S12-S21.
crossref pmid
4. El-Mallakh P, Findlay J. Strategies to improve medication adherence in patients with schizophrenia: the role of support services. Neuropsychiatric Dis Treat 2015;11:1077-1090.
crossref pmid pmc
5. Reist C, Mintz J, Albers LJ, Jamal MM, Szabo S, Ozdemir V. Second-generation antipsychotic exposure and metabolic-related disorders in patients with schizophrenia: an observational pharmacoepidemiology study from 1988 to 2002. J Clin Psychopharmacol 2007;27:46-51.
pmid
6. Lipscombe LL, Lévesque L, Gruneir A, Fischer HD, Juurlink DN, Gill SS, et al. Antipsychotic drugs and hyperglycemia in older patients with diabetes. Arch Intern Med 2009;169:1282-1289.
crossref pmid
7. Koller E, Schneider B, Bennett K, Dubitsky G. Clozapine-associated diabetes. Am J Med 2001;111:716-723.
crossref pmid
8. Koller EA, Weber J, Doraiswamy PM, Schneider BS. A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus. J Clin Psychiatry 2004;65:857-863.
crossref pmid
9. Stubbs B, Vancampfort D, De Hert M, Mitchell AJ. The prevalence and predictors of type two diabetes mellitus in people with schizophrenia: a systematic review and comparative meta‐analysis. Acta Psychiatr Scand 2015;132:144-157.
crossref pmid
10. Grajales D, Ferreira V, Valverde ÁM. Second-generation antipsychotics and dysregulation of glucose metabolism: beyond weight gain. Cells 2019;8:1336
crossref pmid pmc
11. Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a community cohort with schizophrenia. Br J Psychiatry 2010;196:116-121.
crossref pmid pmc
12. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 2014;383:1068-1083.
crossref pmid
13. Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB, 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.
crossref pmid pmc pdf
14. Fayfman M, Pasquel FJ, Umpierrez GE. Management of hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Med Clin North Am 2017;101:587-606.
pmid pmc
15. Lipscombe LL, Austin PC, Alessi-Severini S, Blackburn DF, Blais L, Bresee L, et al. Atypical antipsychotics and hyperglycemic emergencies: multicentre, retrospective cohort study of administrative data. Schizophr Res 2014;154:54-60.
crossref pmid
16. Umpierrez GE, Kitabchi AE. Diabetic ketoacidosis: risk factors and management strategies. Treat Endocrinol 2003;2:95-108.
pmid
17. Vuk A, Kuzman MR, Baretic M, Osvatic MM. Diabetic ketoacidosis associated with antipsychotic drugs: case reports and a review of literature. Psychiatr Danub 2017;29:121-135.
crossref pmid
18. Jin H, Meyer JM, Jeste DV. Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Ann Clin Psychiatry 2002;14:59-64.
crossref pmid
19. Wilson DR, D’Souza L, Sarkar N, Newton M, Hammond C. New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophr Res 2003;59:1-6.
crossref pmid
20. Smith RC, Lindenmayer JP, Bark N, Warner-Cohen J, Vaidhyanathaswamy S, Khandat A. Clozapine, risperidone, olanzapine, and conventional antipsychotic drug effects on glucose, lipids, and leptin in schizophrenic patients. Int J Neuropsychopharmacol 2005;8:183-194.
crossref pmid
21. English P, Williams G. Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgrad Med J 2004;80:253-261.
crossref pmid pmc pdf
22. Mir S, Taylor D. Atypical antipsychotics and hyperglycaemia. Int Clin Psychopharmacol 2001;16:63-73.
crossref pmid
23. Abidi S, Bhaskara SM. From chlorpromazine to clozapine—antipsychotic adverse effects and the clinician’s dilemma. Can J Psychiatry 2003;48:749-755.
crossref pmid pdf
24. Memarzia J, Tracy D, Giaroli G. The use of antipsychotics in preschoolers: a veto or a sensible last option? J Psychopharmacol 2014;28:303-319.
crossref pmid pdf
25. Barski L, Nevzorov R, Jotkowitz A, Rabaev E, Zektser M, Zeller L, et al. Comparison of diabetic ketoacidosis in patients with type-1 and type-2 diabetes mellitus. Am J Med Sci 2013;345:326-330.
crossref pmid
26. Poitout V, Amyot J, Semache M, Zarrouki B, Hagman D, Fontés G. Glucolipotoxicity of the pancreatic beta cell. Biochim Biophys Acta 2010;1801:289-298.
crossref pmid pmc
27. Alghamdi F, Guo M, Abdulkhalek S, Crawford N, Amith SR, Szewczuk MR. A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes. Cell Signal 2014;26:1355-1368.
crossref pmid
28. Ren L, Zhou X, Huang X, Wang C, Li Y. The IRS/PI3K/Akt signaling pathway mediates olanzapine-induced hepatic insulin resistance in male rats. Life Sci 2019;217:229-236.
crossref pmid
29. Mondelli V, Anacker C, Vernon AC, Cattaneo A, Natesan S, Modo M, et al. Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways. Transl Psychiatry 2013;3:e208
crossref pmid pmc pdf
30. Shamshoum H, Medak KD, Wright DC. Peripheral mechanisms of acute olanzapine induced metabolic dysfunction: a review of in vivo models and treatment approaches. Behav Brain Res 2021;400:113049
crossref pmid
31. Liu X, Wu Z, Lian J, Hu CH, Huang XF, Deng C. Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats. Sci Rep 2017;7:2762
crossref pmid pmc pdf
32. Engl J, Laimer M, Niederwanger A, Kranebitter M, Starzinger M, Pedrini MT, et al. Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 2005;10:1089-1096.
crossref pmid pdf
33. Panariello F, Perruolo G, Cassese A, Giacco F, Botta G, Barbagallo AP, et al. Clozapine impairs insulin action by up‐regulating Akt phosphorylation and Ped/Pea‐15 protein abundance. J Cell Physiol 2012;227:1485-1492.
crossref pmid pmc pdf
34. Rubí B, Ljubicic S, Pournourmohammadi S, Carobbio S, Armanet M, Bartley C, et al. Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion. J Biol Chem 2005;280:36824-36832.
crossref pmid
35. Simpson N, Maffei A, Freeby M, Burroughs S, Freyberg Z, Javitch J, et al. Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro. Mol Endocrinol 2012;26:1757-1772.
crossref pmid pmc pdf
36. Ustione A, Piston DW. Dopamine synthesis and D3 receptor activation in pancreatic β-cells regulates insulin secretion and intracellular [Ca 2+ ] oscillations. Mol Endocrinol 2012;26:1928-1940.
crossref pmid pmc
37. Cataldo Bascuñan LR, Lyons C, Bennet H, Artner I, Fex M. Serotonergic regulation of insulin secretion. Acta Physiol (Oxf) 2019;225:e13101
pmid
38. Bennet H, Mollet IG, Balhuizen A, Medina A, Nagorny C, Bagge A, et al. Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans. Diabetologia 2016;59:744-754.
crossref pmid pdf
39. Weston-Green K, Huang XF, Lian J, Deng C. Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. Eur Neuropsychopharmacol 2012;22:364-373.
crossref pmid
40. Smith GC, Chaussade C, Vickers M, Jensen J, Shepherd PR. Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat. Diabetologia 2008;51:2309-2317.
crossref pmid pdf
41. Nagata M, Kimura Y, Ishiwata Y, Takahashi H, Yasuhara M. Clozapine-induced acute hyperglycemia is accompanied with elevated serum concentrations of adrenaline and glucagon in rats. Biol Pharm Bull 2018;41:1286-1290.
crossref pmid
42. Smith GC, Vickers MH, Cognard E, Shepherd PR. Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: implications for glucose metabolism and food choice behaviour. Schizophr Res 2009;115:30-40.
crossref pmid
43. Castellani LN, Peppler WT, Sutton CD, Whitfield J, Charron MJ, Wright DC. Glucagon receptor knockout mice are protected against acute olanzapine-induced hyperglycemia. Psychoneuroendocrinology 2017;82:38-45.
crossref pmid
44. Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 2009;297:127-136.
crossref pmid
45. Polcwiartek C, Kragholm K, Rohde C, Hashemi N, Vang T, Nielsen J. Diabetic ketoacidosis and diabetes associated with antipsychotic exposure among a previously diabetes-naive population with schizophrenia: a nationwide nested case-control study. Diabetologia 2017;60:1678-1690.
crossref pmid pdf
46. Ramaswamy K, Kozma CM, Nasrallah H. Risk of diabetic ketoacidosis after exposure to risperidone or olanzapine. Drug Saf 2007;30:589-599.
crossref pmid
47. Guenette MD, Hahn M, Cohn TA, Teo C, Remington GJ. Atypical antipsychotics and diabetic ketoacidosis: a review. Psychopharmacology (Berl) 2013;226:1-12.
crossref pmid pdf
48. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004;161:1709-1711.
crossref pmid
49. Cohen D, Correll CU. Second-generation antipsychotic-associated diabetes mellitus and diabetic ketoacidosis: mechanisms, predictors, and screening need. J Clin Psychiatry 2009;70:765-766.
crossref pmid
50. Henderson DC, Cagliero E, Copeland PM, Louie PM, Borba CP, Fan X, et al. Elevated hemoglobin A1c as a possible indicator of diabetes mellitus and diabetic ketoacidosis in schizophrenia patients receiving atypical antipsychotics. J Clin Psychiatry 2007;68:533-541.
crossref pmid
51. Polcwiartek C, Vang T, Bruhn CH, Hashemi N, Rosenzweig M, Nielsen J. Diabetic ketoacidosis in patients exposed to antipsychotics: a systematic literature review and analysis of Danish adverse drug event reports. Psychopharmacology (Berl) 2016;233:3663-3672.
crossref pmid pdf
52. Kim HH, Yang HK, Ham H, Jeon HW, Lee JY, Hwang SW, et al. Two cases of diabetic ketoacidosis associated with paliperidone treatment in schizophrenia. J Korean Diabetes 2014;15:178-184.
crossref
53. Ely SF, Neitzel AR, Gill JR. Fatal diabetic ketoacidosis and antipsychotic medication. J Forensic Sci 2013;58:398-403.
crossref pmid
54. Lee JS, Yun JY, Kang SH, Lee SJ, Choi JH, Nam B, et al. Korean Medication Algorithm for Schizophrenia 2019, second revision: treatment of psychotic symptoms. Clin Psychopharmacol Neurosci 2020;18:386-394.
crossref pmid pmc
TOOLS
Share:
Facebook Twitter Linked In Google+
METRICS Graph View
  • 1 Crossref
  •   Scopus
  • 970 View
  • 85 Download


ABOUT
AUTHOR INFORMATION
ARTICLE CATEGORY

Browse all articles >

BROWSE ARTICLES
Editorial Office
#522, 27, Seochojungang-ro 24-gil, Seocho-gu, Seoul 06601, Korea
Tel: +82-2-717-0892    E-mail: psychiatryinvest@gmail.com                

Copyright © 2024 by Korean Neuropsychiatric Association.

Developed in M2PI

Close layer
prev next