Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis

Stogios, Nicolette; Smith, Emily R.; Bowden, Sylvie; Tran, Veronica; Asgariroozbehani, Roshanak; McIntyre, William Brett; Remington, Gary; Siskind, Dan; Agarwal, Sri Mahavir; Hahn, Margaret

doi:10.1038/s41386-021-01163-7

Cited by 23 publications

(19 citation statements)

References 63 publications

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“…Antipsychotic (AP) drugs, such as olanzapine (OLZ), are the cornerstone treatment for schizophrenia (Huhn et al., 2019; Pillinger et al., 2020), a severe mental illness affecting ∼1% of the population. In recent years, APs have been approved across a number of severe mental illnesses, and moreover have been increasingly prescribed for the management of a number of ‘off‐label’ conditions (Stogios et al., 2022). APs act through binding dopamine (D 2 ), serotonin (5‐HT 2A ) and muscarinic receptors (M 3 ) (Divac et al., 2014), amongst others.…”

Section: Introductionmentioning

confidence: 99%

Fasting or the short‐term consumption of a ketogenic diet protects against antipsychotic‐induced hyperglycaemia in mice

Shamshoum

Medak

McKie

et al. 2022

The Journal of Physiology

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support-information-section). OLZ Glucagon Blood sugar Ketogenic diet Fasting α cell Centrally mediated effects of OLZ on glucagon Direct effects of OLZ on the pancreasAbstract Antipsychotic (AP) medications, such as olanzapine (OLZ), are used in the treatment of schizophrenia and a growing number of 'off-label' conditions. A single dose of OLZ causes robust increases in blood glucose within minutes of treatment. The purpose of the current study was to investigate whether interventions that increase circulating ketone bodies (fasting, β-hydroxybutyrate (βHB), ketone esters or a ketogenic diet (KD)) would be sufficient to protect against the acute metabolic side effects of OLZ. We demonstrate that fasting or the short-term consumption of a KD Hesham Shamshoum joined Dr David Wright's laboratory to pursue his Doctorate in the

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Section: Introductionmentioning

confidence: 99%

Fasting or the short‐term consumption of a ketogenic diet protects against antipsychotic‐induced hyperglycaemia in mice

Shamshoum

Medak

McKie

et al. 2022

The Journal of Physiology

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“…According to our previous results and other reports, doses corresponding to 50% of the maximal physiological human dose were used. 32 All animals were housed under the same conditions for a period of 2 weeks prior to drug treatment. Rats were trained to self-administer a cookie dough mixture weighed 0.3 g (cookie dough mixed with the commercial diet: 25.5% cornstarch, 20.9% sucrose, 14.1% fat, 10.6% protein, 1.4% fiber, 2.5% crude ash and 25% moisture) without the drugs for one week.…”

Section: Methodsmentioning

confidence: 99%

Early Lipid Metabolic Effects of the Anti-Psychotic Drug Olanzapine on Weight Gain and the Associated Gene Expression

Chen¹,

Nakano²,

Hsu³

et al. 2022

NDT

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Background Atypical antipsychotics such as olanzapine often cause metabolic side effects such as obesity and diabetes, leading to an increased risk of nonalcoholic fatty liver disease. The aim of the present study was to investigate the effects of olanzapine treatment on hepatic lipid metabolism and its possible relationship with adipose tissue status. Methods Using a female rat model, we investigated the effects of chronic olanzapine administration on the regulation of carbohydrate and lipid metabolism including lipid biosynthesis, oxidation, efflux, and lipolysis in liver and adipose tissue. Results The body weight, liver mass and visceral adiposity after olanzapine treatment (2 mg/kg) for five weeks were not significantly different compared with vehicle controls. The serum level of triglycerides was higher in the vehicle controls than in olanzapine-treated rats. Unexpectedly, olanzapine treatment did not reduce glucose tolerance in our model. The expression of functional thermogenic protein uncoupling protein 1 (UCP1) was increased in brown adipose tissue (BAT) of the olanzapine group. Additionally, olanzapine treatment also reduced adipose inflammation in white adipose tissue (WAT). The transcription factor sterol regulatory element-binding protein (SREBP)-1c, a key early regulator of lipogenesis, was downregulated following olanzapine treatment. The expression of genes related to the triglycerides synthesis apparatus in the liver was upregulated in the olanzapine group. Olanzapine treatment induced genes involved in PPAR-α signaling and mitochondrial fatty acid oxidation in response to increased ATGL-mediated lipolysis in the liver. Conclusion Together, our findings suggest a complicated link between olanzapine therapy and metabolic disturbance and may garner interest in assessing the action of antipsychotic-induced metabolic disturbances.

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“…1,2 Quetiapine use has been linked to increased levels of low-density lipoprotein-cholesterol (LDL-C) and decreased high-density lipoprotein-cholesterol (HDL-C) based on randomized controlled trial (RCT) data in schizophrenia 3 and various off-label indications, for example, substance abuse disorders, generalized anxiety disorder (GAD), and obsessive-compulsive disorder. 4 However, patients included in RCTs receive much higher doses of quetiapine (150-800 mg/day) 3,4 than typically used off-label for anxiety or insomnia. Furthermore, the use of quetiapine might increase blood glucose levels, although this effect remains unclear, as relevant RCTs are generally short and blood glucose changes take more time.…”

Section: Introductionmentioning

confidence: 99%

Impact of low‐dose quetiapine‐use on glycosylated hemoglobin, triglyceride and cholesterol levels

Støvring

Andersen

Correll

et al. 2022

Acta Psychiatr Scand

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Objective Quetiapine use at standard doses has been associated with hyperglycemia and dyslipidemia. However, whether even frequently prescribed low‐dose quetiapine results in significant metabolic disturbances remains unclear. Thus, this study aimed to investigate the association between off‐label, low‐dose quetiapine and changes in glycosylated hemoglobin (HbA1c) levels/lipid parameters. Methods We identified new users of low‐dose quetiapine (≤50 mg tablets) in Denmark 2008–2018 with measurements of HbA1c, total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), or fasting triglycerides (fTG) within 365 days before and after quetiapine initiation. Mixed‐effects linear regression models were used to estimate coefficients (β) with 95% confidence intervals (95%CIs) for change in cardiometabolic parameters after quetiapine initiation. Inverse probability weighting was used to mitigate selection bias. Higher doses of quetiapine (>50 mg) were included in sensitivity analyses. Results Among 106,711 eligible new low‐dose quetiapine users (median age = 45 years, females = 55%), low‐dose quetiapine initiation was associated with increased fTG (β = 1.049[95%CI:1.027–1.072]) and decreased HDL‐C (β = 0.982[0.978–0.986]). Although HbA1c did not change significantly and TC and LDL‐C even decreased considering all subjects, all three metabolic parameters increased significantly among individuals with normal pre‐quetiapine initiation levels. The adverse metabolic effect of quetiapine on HbA1c, TC, LDL‐C, and HDL‐C was dose‐dependent, which was not the case for fTG. Conclusions Low‐dose quetiapine was associated with a significant increase in fTG and decreases in HDL‐C in all subjects, as well as with significant increases in HbA1c, TC, and LDL‐C among those with normal baseline values. The risk of metabolic worsening with quetiapine was dose‐dependent, except for fTG.

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Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis

Cited by 23 publications

References 63 publications

Fasting or the short‐term consumption of a ketogenic diet protects against antipsychotic‐induced hyperglycaemia in mice

Fasting or the short‐term consumption of a ketogenic diet protects against antipsychotic‐induced hyperglycaemia in mice

Early Lipid Metabolic Effects of the Anti-Psychotic Drug Olanzapine on Weight Gain and the Associated Gene Expression

Impact of low‐dose quetiapine‐use on glycosylated hemoglobin, triglyceride and cholesterol levels

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