Endocrine and Growth Effects of Antipsychotic and Antiepileptic Medications in Children and Adolescents

 Corresponding author: Ashraf T. Soliman Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Endocrine and Growth Effects of Antipsychotic and Antiepileptic Medications in Children and Adolescents Ashraf T. Soliman 1, *, Laila Baker 1, Fawzia Alyafei 1, Shayma Ahmed 1, Noora AlHumaidi 1, Nada Alaaraj 1, Noor Hamed 1, Shaymaa Elsayed 2 and Ahmed Elawwa 2 1 Department of Pediatrics, Hamad Medical Center, Doha, Qatar. 2 Alexandria University Children’s Hospital, Alexandria, Egypt. World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 Publication history: Received on 22 September 2025; revised on 28 October 2025; accepted on 31 October 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.28.1.3695 Abstract Background: Antipsychotic and antiepileptic medications are increasingly prescribed to children and adolescents for psychiatric, neurodevelopmental, and seizure disorders. Because puberty, bone mineral accrual, and growth velocity are highly hormone-dependent, disruptions to neuroendocrine pathways during this stage can lead to clinically significant and potentially irreversible consequences. Despite common use, endocrine effects are under-recognized and inconsistently monitored in pediatric practice. Objective: To evaluate endocrine and growth abnormalities associated with antipsychotic and antiepileptic medications in children and adolescents over the past 25 years and to highlight clinical monitoring strategies that reduce risk. Methods: A literature search of PubMed, Scopus, and Google Scholar identified studies published from January 2000 to January 2025 evaluating endocrine or growth outcomes in patients under 18 years treated with antipsychotic or antiepileptic medications. Observational studies, randomized trials, and meta-analyses with extractable endocrine markers were included. Findings were synthesized narratively due to heterogeneity in outcome reporting. Results: Second-generation antipsychotics (SGAs) induce rapid and substantial metabolic effects. Olanzapine and risperidone consistently caused early weight gain, increasing BMI-SDS within the first weeks of therapy, accompanied by rising triglycerides, insulin resistance, and impaired glucose tolerance. Risperidone and paliperidone produced the highest prevalence of hyperprolactinemia, resulting in menstrual irregularities, galactorrhea, gynecomastia, and suppressed pubertal progression in susceptible youth. Chronic antipsychotic exposure was associated with reduced bone mineral density and lower IGF-1 activity, particularly when hyperprolactinemia persisted during adolescence. Aripiprazole demonstrated a more favorable endocrine profile with minimal prolactin elevation and lower obesity risk. Antiepileptic medications showed drug-specific endocrine toxicity. Hepatic enzyme-inducing agents (carbamazepine, phenytoin, phenobarbital) led to increased metabolism of thyroid hormones and vitamin D, contributing to subclinical hypothyroidism, impaired bone mineralization, and higher fracture risk. Valproate was strongly linked to central adiposity, insulin resistance, hyperandrogenism, and menstrual dysfunction in pubertal females. Topiramate often resulted in appetite suppression and metabolic acidosis with negative effects on bone health. Levetiracetam and lamotrigine generally demonstrated endocrine-neutral profiles, making them preferred options when hormonal vulnerability is anticipated. World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2259 Conclusion: Antipsychotic and antiepileptic medications impose measurable endocrine and growth burdens in children and adolescents, with metabolic, prolactin-mediated, thyroid-related, and bone health complications varying by drug class and mechanism. Routine monitoring of weight trajectory, puberty, thyroid markers, gonadal hormones, vitamin D status, and bone health is essential to minimize long-term developmental consequences. Treatment decisions should incorporate endocrine risk stratification and early preventive interventions to optimize patient outcomes. Keywords: Antipsychotics; Antiepileptic drugs; Pediatric growth; Endocrine dysfunction; Hyperprolactinemia; Thyroid abnormalities; Bone mineral density; Metabolic complications 1. Introduction Over the past decades, the use of antipsychotic and antiepileptic medications in children and adolescents has risen markedly across diagnostic categories including epilepsy, autism spectrum disorders, behavioural dysregulation, bipolar disorder, and psychosis, raising concerns about their long-term safety profiles during critical developmental periods (1). Because the hypothalamic–pituitary axes, bone accrual, growth plates, and pubertal processes are rapidly evolving during childhood and adolescence, exposure to medications with hormonal effects may alter growth velocity, final adult height, and reproductive health outcomes (2). Strong evidence now indicates that second-generation antipsychotics (SGAs) induce early and progressive metabolic disturbance — including weight gain, insulin resistance, dyslipidemia, and hyperprolactinemia — reflecting broad neuroendocrine disruption rather than simple caloric imbalance (3). Antiepileptic drugs (AEDs) are equally linked with endocrine dysregulation in youth, where thyroid dysfunction, suppressed gonadal hormones, altered IGF-1 pathways, and adverse effects on bone metabolism contribute to impaired growth and delayed maturation (4). In this developmental stage, even modest hormone deviations may produce lifelong consequences, affecting height potential, timing of puberty, bone strength, fertility, cardiometabolic disease risk, and psychosocial wellbeing (5). Despite the scale of exposure, the literature examining endocrine and growth complications is fragmented, often focusing on either psychiatric or epilepsy populations, with few reviews integrating the cumulative burden across both widely prescribed drug classes (6). Persistent hyperprolactinemia from antipsychotics may suppress gonadotropin-releasing hormone (GnRH), leading to delayed puberty, menstrual disturbance, decreased bone mineralization, and growth suppression (7). Meanwhile, hepatic enzyme-inducing AEDs accelerate metabolism of thyroid and sex hormones, reduce vitamin D availability, and disrupt growth plate signaling — biological pathways necessary for linear growth and pubertal progression (8). Although metabolic and endocrine monitoring recommendations exist, adherence is variable in practice, and clinicians frequently underestimate long-term risks owing to a lack of pediatric-specific evidence and structured guidance (9). Therefore, a timely synthesis is needed to evaluate and compare endocrine and growth abnormalities linked to antipsychotic and antiepileptic medications in youth, to guide safer prescribing, proactive monitoring, and early intervention strategies (10). Objectives To systematically review the endocrine and growth abnormalities reported in children and adolescents treated with antipsychotic medications over the past 25 years, focusing on metabolic, prolactin, thyroid, gonadal, IGF-1, pubertal, and bone health outcomes. To evaluate and summarize the evidence regarding endocrine and growth dysfunctions associated with antiepileptic (anti-seizure) medications in pediatric patients, including effects on thyroid function, sex steroid metabolism, vitamin D–calcium axis, bone mineralization, height velocity, and final height. World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2260 To compare and analyze the mechanisms, severity, clinical impact, and monitoring implications of endocrine/growth disturbances between these two major medication classes, in order to provide recommendations for safer prescribing and proactive surveillance in pediatric practice. 2. Materials and Methods 2.1. Study Design A structured mini review was conducted to identify and synthesize published evidence on endocrine and growth abnormalities associated with antipsychotic or antiepileptic drug use in children and adolescents. 2.2. Data Sources and Search Strategy • A comprehensive electronic search of the following databases was conducted: PubMed/MEDLINE, Scopus, and Google Scholar. • Date limits: January 2000 to January 2025 • Language: English only Key search terms (alone or combined using Boolean operators): • “antipsychotic”, “second-generation antipsychotic”, “atypical antipsychotic” • “antiepileptic”, “anti-seizure medication”, “AED” • “children”, “adolescents”, “pediatric” • “growth”, “height velocity”, “bone age” • “endocrine”, “prolactin”, “thyroid”, “gonadal”, “IGF-1”, “puberty” • “bone mineral density”, “vitamin D” • “metabolic syndrome”, “weight gain”, “insulin resistance” 2.3. Inclusion Criteria • Participants: Children or adolescents <18 years at medication initiation • Exposure: Antipsychotic or antiepileptic medications (any duration) • Outcomes: At least one reported endocrine or growth parameter • Study Type: Randomized trials, cohort studies, case-control studies, cross-sectional studies, case series (≥5 patients), and meta-analyses • Indexing: Published in PubMed-, Scopus-, or Google Scholar-indexed journals 2.4. Exclusion Criteria • Animal studies or in vitro research • Adult-only studies • Reports lacking specific hormonal or growth outcomes • Isolated case reports with <5 patients • Non-English publications • Abstracts without extractable data 2.5. Data Extraction Two reviewers independently extracted: • Study design, country, sample size • Medication type, dose, duration • Endocrine outcomes (prolactin, thyroid hormones, IGF-1, sex steroids, cortisol) • Growth outcomes (height SDS, height velocity, bone age, puberty) • Bone health (vitamin D, calcium, PTH, BMD) • Metabolic markers (BMI/BMI-SDS, lipids, glucose, HOMA-IR) • Reversibility of abnormalities, where available World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2261 2.6. Quality Assessment • Newcastle-Ottawa Scale for observational studies • Cochrane Risk of Bias Tool for randomized trials • Studies classified as low, moderate, or high risk of bias. 2.7. Synthesis Strategy Heterogeneity in study population, drug type, follow-up duration, and endocrine reporting precluded meta-analysis; therefore, a structured narrative synthesis approach was used. Figure 1 Prisma flow Diagram The PRISMA flow diagram illustrates a structured selection process where 412 records were identified, screened, and filtered to yield 15 studies that met the inclusion criteria for endocrine and growth outcomes in pediatric patients. 3. Results The literature review identified substantial evidence that antipsychotic and antiepileptic medications exert measurable and clinically relevant impacts on endocrine axes and growth physiology in children and adolescents. Because these agents are often used during critical developmental windows, even subtle changes in metabolic control, hormonal function, or linear growth may translate into long-term health consequences. The following results summarize and compare acute and chronic endocrine and growth abnormalities associated with these therapies, incorporating validated pediatric studies published over the past 25 years. World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2262 Table 1 Acute endocrine and growth abnormalities with antipsychotic medications in children and adolescents (2000– 2025) Drug / class Primary Mechanism Relevant to Endocrine System Acute clinical effect(s) Estimated pediatric prevalenc e / magnitud e* Onset timefra me Monitoring and clinical recommendatio ns Ref. Olanzapine Histamine-H1, 5HT2C antagonism → ↑ appetite, adipogenesis Rapid weight gain; early insulin resistance; rise in triglycerides 70–90% gain >7% baseline weight in 6–12 weeks 2–8 weeks Baseline/6–12 wk BMI, fasting glucose/lipids; anticipatory lifestyle counseling; consider metformin if rapid trajectory (2,7,11) Risperidon e D2 antagonism → suppressed tuberoinfundibu lar feedback Hyperprolactinemia; galactorrhea/amenorr hea; potential IGF1/sex-steroid suppression 200– 400% increase in prolactin within weeks 2–12 weeks Prolactin if symptomatic; monitor pubertal tempo; consider switching or dose reduction if persistent (1,9,12,1 9) Paliperido ne ER Active risperidone metabolite with sustained exposure Significant prolactin rise; mild metabolic changes Prolactin ↑ in >50% of treated youth 4–12 weeks Same as above; consider PRLsparing alternative if symptoms (12,13) Quetiapine Moderate 5HT2C blockade Moderate acute weight gain; mild dyslipidemia 30–50% weight gain in first 3 mo 4–12 weeks Track metabolic labs if BMI increases; reinforce lifestyle (2,7) Aripiprazo le Partial dopamine-D2 agonist Low prolactin burden; minimal early metabolic change <20–30% weight gain; PRL often normalize d 4–12 weeks First-line when endocrine risk is a concern; routine BMI/metabolic labs (2,7,14,1 5) Ziprasidon e Lower metabolic receptor affinity Minimal metabolic change; neutral on prolactin <10–20% mild changes 4–12 weeks ECG per label; episodic metabolic labs (2,7) Haloperido l (FGA comparato r) Strong D2 blockade Pronounced prolactin surge Comparabl e to risperidon e 1–8 weeks Avoid in prolactinsensitive conditions; check PRL if symptoms (1,12) Lurasidone High 5-HT7 and D2 affinity; low H1 Very low acute effect on BMI/metabolic labs ≈10% mild changes 6–12 weeks Consider in obesity-risk patients (14) World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2263 Pediatric studies consistently show early weight gain with olanzapine and early hyperprolactinemia with risperidone/paliperidone/amisulpride; aripiprazole, ziprasidone, and lurasidone exhibit lower acute metabolic burden, but routine growth, BMI, metabolic labs, and symptom-triggered prolactin checks remain essential. Corroborating pediatric meta-/cohort data include Correll 2009 JAMA for first-time SGAs and a 2022 meta-analysis on prolactin effects. Table 2 Chronic endocrine/growth abnormalities with antipsychotics (children & adolescents), 2000–2025 Drug / class Chronic endpoint(s) Pediatric findings (direction / typical pattern) Exposure duration (typical) Monitoring / management notes Ref. Secondgeneration antipsychotics (overall) Metabolic syndrome cluster; sustained weight/BMI increase Progressive weight gain with rising risk of insulin resistance, dyslipidemia, and metabolic syndrome in youth cohorts ≥6–12 months Baseline and periodic BMI, fasting glucose, lipids, BP; lifestyle program; consider pharmacologic mitigation if trajectory worsens (2,7,11,16) Olanzapine Weight/BMI; glucose/lipids Largest longer-term metabolic burden among SGAs (greatest weight/BMI increase; adverse lipid/glucose trends) ≥6–12 months Prefer alternatives in high-risk patients; intensified metabolic surveillance (2,7,11,16) Risperidone / Paliperidone Hyperprolactinemia and sequelae (menstrual irregularity, hypogonadism); potential bone effects Persistent prolactin elevation common; associations with menstrual disturbance and decreased bone mineral accrual reported ≥6–24 months Monitor symptoms (amenorrhea, galactorrhea, gynecomastia), pubertal progression; check prolactin if symptomatic; consider switch/partial agonist; bone health assessment if prolonged hypogonadism (1,12,17,18,19) Quetiapine Weight/BMI; lipids Moderate chronic weight gain and dyslipidemia risk, less than olanzapine but clinically relevant ≥6–12 months Continue metabolic surveillance; emphasize diet/activity (2,7,16) Clozapine Weight/BMI; glucose/lipids High chronic metabolic liability; diabetogenic signal in adolescents ≥6–12 months (often longer) Intensive metabolic monitoring; multidisciplinary management (2,16,20) Aripiprazole Metabolic burden; prolactin Lower long-term metabolic and prolactin ≥6–12 months Track BMI and labs; option when (2,7,12,15) World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2264 burden versus risperidone/olanzapine; still variable weight effects chronic prolactin elevation is a concern Ziprasidone / Lurasidone Weight/BMI; metabolic labs Generally favorable longer-term metabolic profile relative to higher-risk SGAs; weight/BMI effects typically small ≥6–12 months Use in patients at elevated metabolic risk; maintain routine surveillance (2,7,14) Firstgeneration antipsychotics (e.g., haloperidol) Prolactin; reproductive axis Chronic hyperprolactinemia typical; reproductive axis suppression possible ≥6–12 months Avoid when prolactinsensitive; monitor symptoms and prolactin as indicated (1,12) Across SGAs (mechanistic link) Growth / bone accrual Chronic hyperprolactinemia → hypogonadism → reduced bone mineral accrual; potential impact on height velocity over time ≥12–24 months Plot height SDS velocity; screen for prolonged hypogonadism; consider DXA when indicated (1,12,17,18,19) Table 2 shows that over 6–24 months, olanzapine displays the greatest sustained metabolic burden; risperidone/paliperidone carry the highest risk for persistent hyperprolactinemia with subsequent reproductive and bone concerns; aripiprazole, ziprasidone, and lurasidone tend to show lower chronic metabolic and prolactin burdens, though routine pediatric metabolic and endocrine surveillance remains essential. Figure 2 Combined acute and chronic endocrine and growth effects of antipsychotic medications in children and adolescents Figure 2 illustrates a clear differentiation in the endocrine and growth impacts of the three most widely prescribed second-generation antipsychotics in youth. Olanzapine shows the most significant acute metabolic burden, characterized by rapid weight gain that emerges within weeks of treatment initiation and continues to progress into the World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2265 chronic phase. Risperidone demonstrates the most pronounced prolactin elevation, reflecting its potent dopamine-2 receptor blockade in the tuberoinfundibular pathway, with potential risks for pubertal disruption and impaired bone mineral accrual if elevation persists. In contrast, aripiprazole consistently demonstrates a lower risk profile across both acute and chronic endocrine outcomes, supporting its use as a preferred option in children and adolescents with high metabolic vulnerability or existing endocrine disorders. Table 3 Acute growth and endocrine effects of antiepileptic medications (AEDs) in children and adolescents (2000– 2025) Drug / class Primary mechanism relevant to endocrine system Acute clinical effect(s) Estimated pediatric prevalence / magnitude* Onset timefram e Monitoring and clinical recommendatio ns Ref. Carbamazepi ne (CBZ) Hepatic enzyme induction → ↑ thyroid hormone clearance; ↑ vitamin D catabolism Subclinical hypothyroidism (↓FT4/↑TSH); early shift in bone turnover markers Thyroid signal common in cohorts on CBZ monotherapy 1–6 months TSH/FT4 at baseline and 3–6 months; consider dose/agent change if symptomatic (11,12 ) Oxcarbazepin e (OXC) Enzyme-inducing potential (weaker than CBZ) → altered thyroid economy Subclinical hypothyroidism in pediatric monotherapy cohorts Reported across OXC cohorts (less frequent than CBZ) 1–6 months Periodic TSH/FT4; recheck after dose changes (12) Phenytoin (PHT) / Phenobarbita l (PB) Strong enzyme induction → ↓ FT4; ↑ vitamin D catabolism Subclinical hypothyroidism; early biochemical bone effects Seen in pediatric series using enzyme inducers 1–6 months TSH/FT4 at 3–6 months; begin vitamin D/calcium optimization early (11,14 ) Valproate (VPA) Mitochondrial/ur ea-cycle and lipid effects; GABAergic weight/appetite effects Early weight gain; menstrual/androg en shifts (pubertal girls) reported; thyroid effects less consistent Weight gain signal in pediatric cohorts within months 1–6 months Plot BMI; counsel on nutrition/activity ; consider alternative if rapid gain or menstrual symptoms (11,15 ) Topiramate (TPM) Carbonic anhydrase inhibition; appetite suppression; renal bicarbonate loss Weight loss/reduced appetite; metabolic acidosis (↓HCO₃⁻); early bone marker changes possible Weight/appeti te effects frequent; acidosis in a subset Weeks to months Monitor weight, serum bicarbonate; review hydration; caution in underweight children (13,15 ) Levetiraceta m (LEV) Minimal hepatic enzyme effect; limited endocrine interactions Generally endocrine-neutral acutely; no consistent thyroid or prolactin effect Low Weeks to months Routine auxology; endocrine testing only if symptomatic (15) Lamotrigine (LTG) Minimal enzyme effect; weak Neutral on weight; no consistent Low Weeks to months Standard growth plotting; labs (15) World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2266 interaction with endocrine axes acute thyroid or prolactin change only if clinical concern Zonisamide (ZNS) Weak carbonic anhydrase inhibition; appetite suppression Appetite/weight reduction; possible mild metabolic acidosis Reported in pediatric series, less than TPM 1–3 months Monitor weight and bicarbonate if symptomatic (14,15 ) Table 3 highlights distinct acute endocrine profiles across antiepileptic drugs (AEDs) in children and adolescents. Enzyme-inducing agents (carbamazepine, phenytoin, phenobarbital) show the strongest early thyroid signal—typically subclinical hypothyroidism within 1–6 months—likely via increased hormone clearance; oxcarbazepine exhibits a milder version of this pattern (11,12,14). Valproate demonstrates early weight gain and occasional reproductive-axis changes in pubertal girls, warranting close BMI and menstrual surveillance (11,15). In contrast, topiramate (± zonisamide) often produces appetite/weight reduction and can precipitate metabolic acidosis within weeks, requiring bicarbonate monitoring, especially in underweight or high-activity youth (13–15). Levetiracetam and lamotrigine are largely endocrine-neutral acutely, supporting their use when growth or hormonal vulnerability is a concern (15). Table 4 Chronic endocrine and growth effects of antiepileptic medications (AEDs) in children and adolescents (2000– 2025) Drug / class Primary mechanism relevant to endocrine system Chronic clinical effect(s) Estimated pediatric prevalence / magnitude* Exposur e duratio n (typical) Monitoring and clinical recommendatio ns Ref. Carbamazepi ne (CBZ) Hepatic enzyme induction → ↑ clearance of thyroid hormones; ↑ vitamin D catabolism Persistent subclinical hypothyroidis m (↓FT4/↑TSH); reduced BMD/abnorm al bone markers; potential growthvelocity reduction Thyroid abnormality common in long-term CBZ monotherapy; bone marker/BMD effects reported across cohorts ≥12–24 months TSH/FT4 every 6– 12 mo; optimize vitamin D/calcium; weight-bearing exercise; consider DXA if additional risk factors or prolonged exposure (12,14,15 ) Oxcarbazepin e (OXC) Milder enzymeinducing effect than CBZ; altered thyroid economy Subclinical hypothyroidis m can persist; bone marker changes less pronounced than CBZ Thyroid abnormalities reported but generally less frequent than CBZ ≥12 months Annual thyroid panel; reassess after dose/agent changes; nutrition and activity counseling (12,15) Phenytoin (PHT) / Phenobarbital (PB) Strong enzyme induction → ↓ FT4; ↑ vitamin D catabolism and bone turnover Reduced BMD, vitamin D deficiency, elevated bone turnover markers; fracture risk signal in longer exposure Abnormal bone labs/BMD frequently observed with multi-year exposure ≥12–36 months Vitamin D (and calcium) optimization; periodic 25(OH)D and PTH; consider DXA for high-risk patients; encourage resistance/impac t activity (14,15) World Journal of Advanced Research and Reviews, 2025, 28(01), 2258–2274 2273 [20] Grover S, Nebhinani N, Chakrabarti S, Avasthi A. 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