Low-dose Quetiapine: Utilization and Cardiometabolic Risk

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Abstract

Antipsychotics are generally approved for treatment of severe mental disorders, such as schizophrenia, mania, or bipolar disorder. However, they are frequently used in other psychiatric disorders for their anxiolytic, sedative, or hypnotic properties. Of all antipsychotics, quetiapine has become the most widely used in many countries, and with high rates of off-label use. When this PhD project was initiated, there was only sparse evidence on adverse events with off-label, low-dose use of quetiapine, and the long-term safety was yet to be explored. This project set out to i) map the extent of off-label use of antipsychotics in Denmark, and ii) to investigate the safety of low-dose quetiapine with regards to long-term adverse events, such as diabetes and cardiovascular disease. The following paragraphs summarize the four studies that constitute the PhD. 

Study I assessed the occurrence of psychiatric, neurological, or cancer diagnoses (’relevant diagnoses’) among all individuals who filled prescriptions for antipsychotics in Denmark between 1997 and 2018. The main findings were as follows: i) the group without diagnoses of severe mental disorders comprised 2 of 3 users in 2018; ii) while the proportion of users without records of relevant diagnoses had decreased from 1997 to 2018, the use in other diagnostic groups had increased (e.g. major depression, neurotic or stress-related conditions, and sleep disorders); iii) antipsychotics such as chlorprothixene, flupentixol, levomepromazine, and quetiapine were commonly prescribed to individuals without relevant diagnoses, and iv) quetiapine was the most frequently used antipsychotic in 2018, both overall (51% of users) and among those without relevant diagnoses (58% of users in this group).

Study II assessed the risk of diabetes with off-label use of quetiapine in low-doses (≤50mg/day) among adults, using a newuser, active comparator-controlled cohort design. The incidence rate of diabetes was not higher among low-dose quetiapineinitiators than among a mentally ill reference-population of selective serotonin reuptake-inhibitor (SSRI) initiators. Furthermore, increasing cumulative doses of quetiapine, as low dose treatment, were not associated with an increased risk of diabetes. However, increasing cumulative dose was associated with increased risk of diabetes, when including off-label treatment with higher tablet strengths.

Study III assessed the risk of major adverse cardiovascular events (MACE: myocardial infarction, stroke, or death from cardiovascular causes) with off-label, low-dose use of quetiapine among adults in a new-user, active comparator-controlled cohort design. The risk of MACE was increased with initiation of low-dose quetiapine, compared to initiation of Z-drughypnotics or SSRIs. The increased risk of MACE was driven by an increased risk of death from cardiovascular causes among low-dose quetiapine-users, whereas no increase was found in the risk of myocardial infarction or stroke. However, the risk of stroke increased with continuous use.

Study IV investigated the effect of low-dose quetiapine-treatment on glycosylated hemoglobin A1c (HbA1c)-, triglyceride-, and cholesterol-levels in a new-user cohort design. Initiation of low-dose quetiapine was only associated with clear increases in fasting triglycerides and decreases in HDL cholesterol-levels, whereas HbA1c- and total/LDL cholesterol-levels did not change after initiation of low-dose quetiapine. However, among those with normal levels before initiation, use of low-dose quetiapine was associated with changes in both HbA1c- and cholesterollevels. Additionally, the study found that individuals with abnormal levels of HbA1c or cholesterols prior to initiation of lowdose quetiapine were more likely to be monitored after initiation of quetiapine, and that the proportion of low-dose quetiapineusers with available blood test results was low (<10%).

The present project contributes to the ongoing debate regarding the appropriateness and safety of off-label use of antipsychotic medications. First, it provides an updated and comprehensive assessment of antipsychotic use in Denmark, which can serve as a basis for future discussion, exploration, or intervention regarding off-label use of antipsychotics. Second, it provides novel data on the cardiometabolic safety of quetiapine in its increasingly common role – used in low doses as anxiolytic or hypnotic.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Hallas, Jesper, Principal supervisor
  • Andersen, Kjeld, Co-supervisor
  • Correll, Christoph U, Co-supervisor, External person
Publisher
DOIs
Publication statusPublished - 12. Sept 2022

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