Longitudinal impact of different treatment sequences of second-generation antipsychotics on metabolic outcomes: a study using targeted maximum likelihood estimation

Background Second-generation antipsychotics (SGAs) cause metabolic side-effects. However, patients’ metabolic profiles were influenced by many time-invariant and time-varying confounders. Real-world evidence on the long-term, dynamic effects of SGAs (e.g. different treatment sequences) is limited. We employed advanced causal inference methods to evaluate metabolic impact of SGAs in a naturalistic cohort.

We followed 696 Chinese patients with schizophrenia-spectrum disorders who received SGAs. Longitudinal targeted maximum likelihood estimation (LTMLE) was used to estimate the average treatment effects (ATEs) of continuous SGA treatment versus “no treatment” on metabolic outcomes, including total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), fasting glucose (FG), and body-mass-index (BMI), over 6-18 months at 3-month intervals. LTMLE accounted for both time-invariant and time-varying confounders. We also evaluated whether side-effects persisted after SGA discontinuation.

The average treatment effects (ATEs) of continuous SGA treatment on BMI and TG showed an inverted U-shaped pattern, peaking at 12 months and declining afterwards. Similar patterns were observed for TC and LDL, albeit the ATEs peaked at 15 months. For FG and HDL, the ATEs peaked at ∼6 months. The adverse impact of SGAs on BMI persisted even after medication discontinuation, yet other metabolic parameters did not show such lingering side-effects. Compared with other SGAs, clozapine and olanzapine showed greater metabolic side-effects.

Our real-world study suggests that metabolic side-effects may stabilize with prolonged continuous treatment. Clozapine and olanzapine confer greater cardiometabolic risks than other SGAs. The side-effects of SGAs on BMI may persist after drug discontinuation. These insights may guide antipsychotic choice and help improve the management of metabolic side-effects. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported partially by a National Natural Science Foundation China grant (81971706), a National Natural Science Foundation China (NSFC) Young Scientist Grant (31900495), the Lo Kwee Seong Biomedical Research Fund from The Chinese University of Hong Kong and the KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology and The Chinese University of Hong Kong, China. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval has been obtained from the New Territories West Cluster Ethics Committee (approval numbers: NTWC/CREC/823/10 and NTWC/CREC/1293/14) and the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (approval number: 2016.559). All participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The data that support the findings of this study are available on request from the corresponding author, HCS. The data are not publicly available due to their containing information that could compromise the privacy of research participants.