Interpreting variability in atypical antipsychotic levels: a practical review for TDM

Therapeutic drug monitoring (TDM) is a valuable tool for optimizing antipsychotic pharmacotherapy, especially in the context of interindividual variability in drug metabolism, adherence assessment, and treatment resistance.

Factors affecting TDM include genetic polymorphisms, age, sex, smoking status, drug-drug interactions, comorbidities (e.g. hepatic or renal impairment, obesity, and inflammation), physiological variations, and adherence. The pharmacokinetic parameters of antipsychotics and the role of active metabolites are important for accurately interpreting of TDM results. The metabolites norclozapine, paliperidone, dehydroaripiprazole, and didesmethyl-cariprazine contribute to the therapeutic effect. Norquetiapine has antidepressant effects, but also has strong anticholinergic adverse effects. The parent-to-metabolite ratio can serve as a marker of metabolic capacity, adherence patterns, and potential drug interactions.

Genotype-guided prescribing is expected to integrate more closely with TDM, using genetic information to select antipsychotics and estimate initial dosing while TDM reveals the patient's current functional metabolic phenotype shaped by adherence, inflammation, smoking, organ dysfunction, diet, and concomitant medications. The concept of phenoconversion can modify metabolic activity independently of genotype, making combined genotype-plus-phenotype assessment essential for individualized antipsychotic therapy. Future psychiatric TDM will increasingly integrate pharmacogenetics, pharmacokinetic modeling, and Bayesian forecasting.