In Mexico, the increasing incidence of anxiety disorders among school-aged children has become a growing concern for mental health professionals. Despite the widespread use of sertraline in this population, few studies have specifically examined its efficacy, pharmacokinetics, and safety in Mexican pediatric patients. This lack of local evidence limits the extrapolation of international findings to the national context, where significant clinical challenges persist regarding variability in therapeutic response, the occurrence of adverse events, and treatment adherence (22). Therefore, it is imperative to generate context-specific evidence that characterizes the pharmacokinetics of sertraline in Mexican pediatric patients, identifies the most prevalent genetic variants, and explores their associations with relevant pharmacokinetic and clinical parameters. In parallel, similar limitations have been reported in pediatric populations from other regions, including Asia, Africa, and the Middle East, where pharmacogenetic data remain scarce or are derived from small, heterogeneous cohorts (18–20). These shared evidence gaps highlight that the challenge of extrapolating pharmacogenetic findings from predominantly adult or European populations is not unique to Mexico, but rather reflects a broader global issue in pediatric psychopharmacology.

The present review aims to synthesize and analyze the available evidence on the impact of pharmacogenetics on the pharmacokinetics and safety of sertraline in children and adolescents with anxiety disorders. It examines the main genes involved in sertraline metabolism, the frequency and functional relevance of their variants, PopPK models applicable to pediatric cohorts, and the clinical implications of these findings for treatment optimization. This analysis seeks to provide a scientific and conceptual framework supporting the incorporation of pharmacogenomic tools into pediatric psychiatry and to promote the development of personalized, safe, and effective pharmacological strategies for managing anxiety disorders in this age group (Figure 1).

Sertraline is a SSRI widely employed in the treatment of various mood and anxiety disorders in both adults and children (24). Its use in pediatric and adolescent populations has increased steadily due to its favorable safety profile and demonstrated efficacy in reducing anxious and depressive symptoms (25). The mechanism of action of sertraline involves selective inhibition of the serotonin transporter (SERT), a membrane protein located on presynaptic serotonergic neurons. This transporter is responsible for the reuptake of serotonin (5-hydroxytryptamine, 5-HT) released into the synaptic cleft back into the presynaptic neuron for recycling or degradation (26). By blocking this process, sertraline increases serotonin availability in the synaptic space, enhancing serotonergic neurotransmission and thereby contributing to the regulation of mood, anxiety, and affective processing. Sustained elevation of synaptic serotonin levels has been correlated with gradual clinical improvement in various psychiatric conditions (27, 28) (Figure 2). From a pharmacodynamic perspective, sertraline exhibits high affinity for the SERT and low affinity for other receptor systems, including adrenergic, cholinergic, and dopaminergic receptors (29–31). This selectivity accounts for its lower incidence of collateral adverse effects compared with tricyclic antidepressants and earlier-generation agents.

Preclinical studies in animal models have shown that sertraline not only increases extracellular serotonin but also dopamine levels in specific brain regions, such as the nucleus accumbens and striatum, which may contribute to improvements in symptoms like anhedonia and loss of motivation, particularly in depressive disorders (32). Although these dopaminergic effects have not yet been conclusively demonstrated in humans through direct methods such as microdialysis or functional neuroimaging, experimental evidence suggests a complementary dopaminergic role in the therapeutic response to sertraline, highlighting opportunities for future clinical research. In pediatric patients, the therapeutic goal of sertraline is to reduce anxiety-related symptoms, including excessive worry, restlessness, difficulty sleeping, irritability, and associated somatic manifestations (33). In disorders such as generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), social anxiety disorder, and separation anxiety disorder, sertraline acts by restoring neurochemical balance within emotion-regulation circuits, thereby facilitating better school, social, and family adaptation (34).

Furthermore, sertraline has demonstrated efficacy in treating common comorbidities of childhood, such as major depressive disorder (MDD) and OCD (35). Systematic reviews and meta-analyses have identified sertraline as one of the SSRIs with the strongest evidence supporting both efficacy and safety in pediatric populations, especially when combined with psychotherapeutic interventions such as cognitive-behavioral therapy (CBT). In this context, treatment optimization with sertraline regarding dose titration, onset of action, tolerability, and risk of adverse events depends not only on general clinical factors but also on individual characteristics such as age, body weight, degree of hepatic maturation, and, increasingly recognized, the pharmacogenetic profile of the patient (36, 37).

Since its initial approval by the U.S. Food and Drug Administration (FDA) in 1991 for the treatment of major depressive disorder (MDD) in adults, sertraline has progressively expanded its therapeutic spectrum to encompass a variety of psychiatric conditions in both adult and pediatric populations. It is currently approved for the management of anxiety disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and MDD (38).

Anxiety disorders in the pediatric population

Sertraline is considered one of the safest and best-tolerated antidepressants within the class of SSRIs. However, its use may be associated with adverse events (AEs) that vary in frequency, intensity, and duration depending on individual patient characteristics, dosage, treatment duration, and progressively more recognized the pharmacogenetic profile of the individual (55, 56). In pediatric populations, AEs may manifest differently than in adults due to physiological factors such as immaturity of the central nervous system, developing hepatic and renal function, and variations in drug bioavailability. Therefore, close clinical monitoring during the initial treatment phase is essential (57, 58). Table 1 summarizes the most frequent and clinically significant AEs reported in children and adolescents treated with sertraline.

The most frequently reported side effects in pediatric populations primarily involve the gastrointestinal system, the central nervous system, and mood regulation. Gastrointestinal symptoms include nausea, vomiting, diarrhea, abdominal pain, dyspepsia, and loss of appetite. These typically occur during the first few weeks of therapy and tend to subside spontaneously or following dose adjustment (59). Neurological and mood-related AEs include headache, insomnia, somnolence, irritability, dizziness, fatigue, and psychomotor agitation. In some cases, hyperactivity or difficulty concentrating may occur, which can be misinterpreted as symptoms of ADHD (60). Sleep disturbances, as well as changes in appetite and body weight, have also been reported, although they are generally transient and reversible (61, 62).

Although infrequent, certain sertraline-related AEs have important clinical implications and warrant close monitoring. Among these, suicidal ideation and worsening of psychiatric symptoms are the most critical in pediatric psychiatry. In 2004, the U.S. Food and Drug Administration (FDA) issued a safety alert regarding the potential increased risk of suicidal ideation or behavior in children and adolescents treated with SSRIs, including sertraline. While the absolute risk remains low, intensive clinical monitoring is recommended during the first weeks of treatment and following any dosage adjustments (63). Another rare but potentially life-threatening AE is serotonin syndrome, which may occur due to overdose or coadministration with other serotonergic agents (64). This syndrome is characterized by hyperthermia, rigidity, autonomic instability, and altered mental status, requiring immediate medical attention. Additionally, cases of sexual dysfunction have been described in adolescents treated with sertraline, as well as mild-to-moderate dermatological reactions. Although uncommon, these may necessitate discontinuation of therapy if symptoms progress or significantly affect quality of life (65, 66).

Active monitoring during the first 2–4 weeks of treatment is essential to minimize the risk and severity of AEs. The main recommendations include:

Start with low doses and titrate gradually according to clinical response.

Optimizing sertraline therapy in pediatric patients remains a clinically significant challenge, owing to the high interindividual variability in both therapeutic response and adverse event incidence. This heterogeneity arises from multiple interacting factors, including physiological maturation, clinical comorbidities, and most notably the patient's pharmacogenetic profile (48). In this context, the therapeutic objective extends beyond symptom relief to include treatment safety, minimization of adverse events, and avoidance of both underexposure and overexposure to the drug (21).

Before initiating sertraline therapy, a comprehensive clinical assessment is essential. This evaluation should consider the patient's age, body weight, psychiatric diagnosis, symptom severity, comorbid medical conditions, and concomitant medications (68). In children and adolescents, it is recommended to start with low doses (e.g., 12.5–25 mg/day) and gradually titrate according to clinical response and tolerability. This stepwise strategy facilitates identification of the minimum effective dose while preventing excessive plasma concentrations and minimizing adverse effects, particularly in slow metabolizers (69).

Sertraline is primarily metabolized in the liver through enzymes of the cytochrome P450 system, notably CYP2C19, CYP2D6, and CYP2C9, with minor contributions from CYP3A4. Single nucleotide variants (SNVs) in these genes result in distinct metabolic phenotypes poor, intermediate, extensive, rapid, or ultrarapid directly affecting plasma concentrations and the therapeutic profile of the drug (70, 71).

Poor metabolizers (CYP2C19): exhibit markedly reduced hepatic clearance, leading to higher plasma levels and an increased risk of AEs. The CPIC recommends reducing the standard dose by at least 50% or selecting an alternative antidepressant if prior intolerance has been documented (50).

Implementing pharmacogenetically guided dosing strategies requires a multidisciplinary approach that integrates clinical, genetic, and pharmacokinetic information. Table 2 summarizes general dosing adjustment recommendations based on the patient's genetic profile, concomitant medications, and the presence of adverse effects or inadequate clinical response. These strategies should be applied under close psychiatric and pediatric supervision, ideally with the support of clinical pharmacogenomics services capable of interpreting genetic findings in the context of the patient's overall therapeutic plan.

PopPK modeling represents one of the most advanced tools for optimizing pharmacotherapy in drugs with a narrow therapeutic index, such as sertraline. This approach enables the estimation of individual pharmacokinetic parameters including clearance, volume of distribution, and half-life through mathematical models that integrate plasma concentrations, demographic characteristics, and genetic variability, even when only a limited number of biological samples are available (72). In the study by Zhang et al. (2024) (21), a population-based pharmacokinetic model was developed for children with anxiety disorders in China, incorporating both pharmacokinetic and genetic parameters, including CYP2C19 metabolic status, to design personalized dosing regimens. The model successfully optimized clinical efficacy and reduced the incidence of adverse effects, demonstrating the feasibility and clinical utility of PopPK approaches in pediatric psychiatry.

Beyond genetic testing and pharmacokinetic modeling, several complementary clinical tools can enhance the dynamic evaluation and adjustment of sertraline therapy. MDD, though not routinely applied to SSRIs, may be useful in cases of suboptimal response, suspected toxicity, or polypharmacy (73). In addition, systematic use of validated clinical rating scales such as the Pediatric Anxiety Rating Scale (PARS), the Children's Depression Inventory (CDI), and the Clinical Global Impression (CGI) allows for a quantitative assessment of symptom evolution, providing objective support for dose adjustments (74, 75). Finally, psychoeducation and adherence reinforcement are critical components of successful treatment outcomes. Active involvement of parents and caregivers throughout the therapeutic process facilitates the early detection of intolerance or adverse effects, improves treatment adherence, and strengthens trust in pharmacological management (76).

Despite the growing interest in tailoring selective serotonin reuptake inhibitor (SSRI) therapy to individual patients, the routine clinical implementation of pharmacogenetic testing and pharmacokinetic modeling remains limited in pediatric psychiatry. Economic constraints, logistical challenges, and insufficient training among healthcare professionals continue to represent major barriers to widespread adoption. In addition to these structural barriers, a critical limitation of the current evidence base is the underrepresentation of pediatric populations from diverse ethnic and geographic backgrounds, including Asian, African, and Middle Eastern regions (18–20). Differences in allele frequencies of key pharmacogenes such as CYP2C19 and CYP2D6 across populations may result in clinically relevant variability in sertraline pharmacokinetics, therapeutic response, and adverse event risk (10, 77). Addressing these gaps through multinational and multiethnic pediatric studies is essential to ensure equitable and globally applicable pharmacogenetically guided treatment strategies. However, with the rapid advancement of next-generation sequencing technologies and the progressive integration of personalized medicine initiatives worldwide, these tools are expected to become increasingly incorporated into standard therapeutic protocols. A key research priority involves the validation of genotype-guided dosing algorithms in well-designed, controlled pediatric clinical trials that reflect the genetic diversity of Latin American and Mexican populations. Establishing these frameworks would not only improve therapeutic outcomes but also reduce healthcare costs associated with avoidable adverse drug reactions or ineffective treatments.

Clinical practice supports initiating sertraline at 12.5–25 mg/day, with titration every 1–2 weeks based on response and tolerability. For patients weighing less than 30 kg or with a history of psychotropic hypersensitivity, even lower starting doses (6.25–12.5 mg/day) may be appropriate. Morning administration is advised to reduce the risk of insomnia. When genetic testing results are available, dosing should follow the recommendations of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) (14). Table 3 summarizes genotype-based dosing adjustment strategies. For example, a child carrying the **CYP2C192/2 (poor metabolizer) genotype may exhibit elevated serum levels within the first weeks of treatment, increasing the risk of adverse effects such as somnolence, nausea, or agitation. In such cases, a 50% dose reduction at initiation, combined with close clinical monitoring, can improve tolerability without compromising efficacy. Family psychoeducation plays a pivotal role during this phase. Informing caregivers about the expected treatment course, potential transient side effects, and the importance of adherence fosters treatment continuity and reduces unnecessary discontinuations.

Several limitations should be acknowledged when interpreting the findings of this review. First, most studies included did not involve representative samples of children under 12 years of age, restricting generalizability to this age group. Second, methodological heterogeneity across studies in design, sample size, and outcome variables precluded the performance of a quantitative meta-analysis. Additionally, the potential for publication bias cannot be excluded, as studies with negative or neutral findings are less likely to be published. Finally, there is a notable scarcity of data in Latin American and Mexican pediatric populations, limiting the applicability of results to local contexts and underscoring the need for region-specific research.