Spotlight commentary: The role of therapeutic drug monitoring in optimizing treatment with antipsychotic medicines

Abstract

Creating an effective therapeutic regimen that is both personalized and suited to the patient involves establishing a solid network of communication and trust between the healthcare team and the patient. The success of a treatment is dependent on patient compliance and the clinician's expertise, along with their diligent observation of the patient's response to the prescribed medication. Any deficiency in these areas can lead to adverse effects and poor treatment outcomes. This is particularly true for psychiatric disorders, which are increasingly prevalent in today's world. Patients suffering from psychosis depend on medication to achieve functional daily living. This spotlight commentary aims to explore opportunities for better prescribing practices for antipsychotic medications by reviewing some recent articles in the field.

Antipsychotic drugs, a class of psychomodulatory agents, are primarily used to manage symptoms of psychosis. They are the first-line treatment for schizophrenia but are also beneficial for conditions like bipolar disorder, obsessive-compulsive disorder and dementia. Historically known as neuroleptics or major tranquilizers, these drugs are now categorized as typical (first-generation) and atypical (second-generation) antipsychotics. First-generation antipsychotics work by antagonizing dopamine receptors, while second-generation drugs affect both dopamine and serotonin signalling, as shown in Table 1.

Antipsychotic medications can lead to various somatic and psychological adverse effects, such as tremors, muscle rigidity, dizziness, weight gain, hematologic issues (e.g., agranulocytosis), hallucinations, severe anxiety, tardive dyskinesia and malignant neuroleptic syndrome. These adverse effects can compromise the quality of treatment, making dose management and therapeutic drug monitoring (TDM) essential strategies. TDM involves measuring drug levels at specific intervals to maintain a steady concentration in the patient's blood, thus improving individual dosing regimens. It is particularly useful for drugs with narrow therapeutic ranges, sizable pharmacokinetic variability, hard-to-monitor target concentrations and reported therapeutic and adverse effects.¹ However, despite its recognized value, TDM has not yet been fully integrated into psychiatric practice. Barriers such as the lack of well-established concentration–effect relationships for many psychoactive drugs and the complexity of its implementation in different age groups contribute to this gap. Overcoming these obstacles requires further research, enhanced clinician education and the development of practical tools to make TDM more accessible.

Patient cooperation is crucial during pharmacotherapy, but it hinges on the information provided by medical professionals. Recent research has addressed issues like patient adherence, suboptimal therapy and the need for dose monitoring, along with exploring new treatment targets in psychiatric pharmacology. While TDM is recognized for optimizing treatment by adjusting doses to improve efficacy and minimize harm, its adoption in psychiatry has been slow. One reason is the lack of universal agreement among clinicians on which antipsychotics require routine monitoring, despite strong Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) recommendations for drugs like clozapine and quetiapine. The variability in drug metabolism and response complicates the establishment of clear concentration–effect relationships for many antipsychotics.

TDM implementation also varies across countries, with wealthier healthcare systems offering broader access compared to low- and middle-income countries, where financial and infrastructure challenges limit its use. Though there is evidence that TDM reduces adverse drug reactions and enhances efficacy—particularly for antipsychotics with narrow therapeutic windows—more large-scale studies are needed to support its broader application. Addressing these disparities and further validating TDM's benefits across different healthcare settings remain key challenges.

A recent study by Fuente-Moreno et al.² investigated the overlap of prescription dosing instructions for antipsychotics and how different dosing strategies during these overlaps affect medication adherence estimates. It was found that despite overlapping prescriptions, dosing strategies did not significantly alter adherence estimates, with the highest dose selection during overlaps providing the most accurate estimate. This highlights the importance of refining dosing approaches to optimize treatment efficacy.

TDM plays a critical role in ensuring the safe and effective use of antipsychotic medications, especially in preventing drug–drug interactions and managing suboptimal prescribing patterns. For example, the use of TDM can help identify patients who may experience adverse reactions or fail to respond to standard doses of antipsychotic medications due to pharmacokinetic variability. Studies have shown that plasma concentrations of antipsychotics, such as clozapine, are more reliable indicators of therapeutic outcomes than prescribed doses, underscoring the value of TDM in tailoring treatments to individual patient needs.³ Additionally, TDM is particularly valuable in situations involving drug–drug interactions. For instance, patients on long-term antipsychotic therapy may require concurrent medications for comorbid conditions, increasing the likelihood of interactions that can affect drug efficacy and safety. Monitoring plasma concentrations can prevent these interactions from compromising treatment by adjusting doses accordingly.⁴

Solhaug et al.⁵ explored the impact of sex, age and cytochrome P450 genotypes on exposure to quetiapine (QUE) and its active metabolite N-desalkylquetiapine (NDQ). They found that older age, female sex and certain CYP2D6 genotypes were associated with higher NDQ exposure, increasing the risk of dose-dependent side effects. This suggests that TDM, alongside pharmacogenomics, could be particularly valuable in tailoring treatments for vulnerable populations. Roughley et al.⁶ discussed the necessity of adjusting risperidone doses based on age when treating Alzheimer's disease, advocating for TDM in the early phases of therapy to identify patients at increased risk of toxicity. Additionally, Hermans et al.⁷ linked aripiprazole blood levels in adolescents and children with autism spectrum disorders to unwanted side effects like weight gain, suggesting that TDM could improve safety in these patients.

The effects of vitamin D supplementation in patients with schizophrenia were assessed by Gaebler et al.⁸ to understand the impact on antipsychotic drug concentrations and psychopathology. While vitamin D can improve physical and mental health, it can also lower blood concentrations of antipsychotics metabolized by CYP3A4, such as aripiprazole and quetiapine, necessitating dose adjustments guided by TDM.

The significance of TDM was further underscored by Hao et al.,⁹ who developed a prediction model for quetiapine concentration in patients with depression and schizophrenia using real-world data and machine learning algorithms. This innovative study was the first to use artificial intelligence to predict blood concentrations of quetiapine, potentially aiding clinical medication guidance.

It is important to note, however, that while the studies discussed emphasize the potential of TDM in optimizing antipsychotic treatment, further work is needed to establish robust concentration–effect relationships, particularly for newer antipsychotics. Without such links, the full benefit of TDM may not be realized.

In conclusion, the successful management of psychiatric disorders relies on effective monitoring techniques and observation. TDM is particularly suited for managing complex conditions treated with antipsychotics, as demonstrated by the studies reviewed, which show TDM's role in reducing side effects and enhancing treatment efficacy, ultimately improving patient safety and outcomes. However, further work is needed to integrate TDM and pharmacogenomics more fully into psychiatric practice, with a focus on establishing clear concentration–effect relationships and expanding access to TDM across diverse healthcare settings.

All co-authors contributed equally to drafting of the manuscript and approved the final version.

No conflicts of interests to disclose.