Severe psychiatric disorders, including schizophrenia, bipolar disorder and related psychotic illnesses, are among the leading causes of long-term disability worldwide. Although antipsychotic medications remain indispensable for symptom control, relapse prevention and functional recovery, their long-term use is frequently complicated by adverse physical health outcomes. Among these, antipsychotic-associated weight gain (AAWG) represents one of the most common, distressing and clinically consequential adverse effects, contributing substantially to excess cardiometabolic morbidity and premature mortality in this population (1-3).

Individuals with severe mental illness experience a markedly reduced life expectancy compared with the general population, with cardiovascular disease accounting for a large proportion of excess deaths (1,2). Weight gain following the initiation of antipsychotics is a major modifiable contributor to this disparity. Clinically significant weight gain, often defined as a ≥7% increase from baseline body weight, has been reported with almost all antipsychotic agents, although the magnitude and trajectory of weight change vary across drugs and individuals (3-5). Notably, weight gain frequently emerges early in the course of treatment, progresses rapidly during the first months, and may persist long term, even when psychiatric symptoms are well-controlled (6,7).

Second-generation antipsychotics (SGAs), particularly olanzapine and clozapine, are consistently associated with the highest risk of AAWG and metabolic disturbances, including insulin resistance, dyslipidemia and impaired glucose tolerance (5,6). These adverse effects are not merely cosmetic; they are strongly associated with non-adherence to treatment, a reduced quality of life, stigma, and the early discontinuation of otherwise effective antipsychotic therapy (8,9). Consequently, AAWG represents a critical challenge at the intersection of psychiatric stability and physical health, underscoring the need for effective and acceptable management strategies.

The mechanisms underlying AAWG are multifactorial and involve the dysregulation of appetite control, satiety signaling, energy expenditure and peripheral metabolism. Antipsychotic medications interact with central neurotransmitter systems involved in energy homeostasis, including serotonergic, histaminergic, muscarinic and dopaminergic pathways, as well as peripheral metabolic processes that influence insulin sensitivity and lipid handling (10-12). The broader neurobiological framework of psychosis, including neurotransmission dysregulation, neuroinflammation, oxidative stress and mitochondrial dysfunction, is illustrated in Fig. 1. Although these mechanisms are central to psychotic disorders, only selected pathways are directly implicated in antipsychotic-associated weight gain (13).

From a clinical perspective, the trajectory of AAWG is particularly relevant. Longitudinal studies have demonstrated that the greatest proportion of weight gain occurs within the first 6-12 months of antipsychotic exposure, after which weight gain often plateaus at a higher set point (6,14). This pattern suggests that early intervention is crucial to prevent excessive long-term weight accumulation. Once a new weight set point is established, reversal becomes considerably more difficult, even with intensive lifestyle or pharmacological interventions (15). This understanding has critical implications for the timing and selection of preventive strategies.

Lifestyle modifications, including dietary counseling, increased physical activity and behavioral interventions, are is widely recommended as first-line management for AAWG in clinical guidelines (16-18). However, the real-world effectiveness of lifestyle interventions in patients with severe mental illness is often limited. Cognitive impairment, negative symptoms, sedation, social disadvantage and illness-related functional limitations can significantly reduce engagement and adherence (19,20). Moreover, structured lifestyle programs are resource-intensive and not consistently available, particularly in low- and middle-income countries. As a result, reliance on lifestyle modifications alone frequently fails to prevent clinically meaningful weight gain in routine psychiatric practice.

These limitations have prompted growing interest in adjunctive pharmacological strategies to mitigate AAWG. Among available options, metformin has emerged as the most extensively studied and consistently supported agent. Metformin is a well-established insulin-sensitizing drug with decades of use in the management of type 2 diabetes mellitus. Its mechanisms of action extend beyond glucose lowering and include effects on appetite regulation, gut hormone secretion, insulin sensitivity, and energy balance (12,21). Of note, metformin does not cause hypoglycemia when used as monotherapy and has a favorable safety profile when appropriately prescribed and monitored.

Evidence from randomized controlled trials and meta-analyses over the past two decades has demonstrated that metformin can attenuate AAWG and improve metabolic parameters in both diabetic and non-diabetic populations (22-25). More recent analyses have refined this understanding by highlighting the importance of timing. Meta-analyses and systematic reviews published within the past 5 years have indicated that metformin is particularly effective when initiated early in the course of antipsychotic treatment or in antipsychotic-naïve patients, where it can prevent further weight gain rather than attempting to reverse established obesity (24-27). This preventive effect is clinically meaningful, as even modest reductions in weight trajectory can translate into substantial long-term cardiometabolic benefit.

Perspectives in high-impact psychiatric literature, including Schizophrenia Bulletin, have emphasized the need to re-evaluate traditional stepwise algorithms that reserve metformin as a last-line option only after lifestyle modifications and antipsychotic switching have failed (18). Such approaches may inadvertently delay an effective intervention until the window for maximal benefit has passed. Instead, emerging evidence supports a more proactive and individualized approach, integrating metformin earlier in patients at a high risk of AAWG, particularly those prescribed high-risk antipsychotics or those experiencing rapid early weight gain.

Despite this growing evidence base, the real-world implementation of metformin for AAWG remains inconsistent. Clinician concerns regarding off-label use, perceived safety risks, pill burden, and uncertainty about long-term benefits continue to limit its uptake in psychiatric settings (28). In addition, the majority of available data are derived from controlled trials conducted in high-income countries, and there remains a relative paucity of prospective observational data reflecting routine clinical practice in diverse healthcare systems (13,19-21). This gap is particularly relevant in low- and middle-income countries, where resource constraints, limited access to structured lifestyle programs, and high reliance on metabolically adverse antipsychotics may amplify the burden of AAWG.

Furthermore, patient-centered considerations are increasingly recognized as essential in the management of AAWG. Qualitative research indicates that weight gain is among the most distressing side effects of antipsychotic treatment from the patient perspective, often perceived as more troubling than some psychiatric symptoms themselves (29). Patients frequently report a desire for early, effective interventions that acknowledge both physical and mental health priorities. Pharmacological strategies, such as metformin, which may reduce hunger and stabilize weight, are often viewed as acceptable and empowering when appropriately explained and monitored.

Against this background, there is a clear need for prospective, real-world studies evaluating the effectiveness of adjunctive metformin therapy for AAWG in routine psychiatric care. Such studies can complement randomized controlled trials by capturing broader patient populations, reflecting typical prescribing practices, and addressing pragmatic outcomes such as adherence and tolerability. Notably, observational data can help inform context-specific clinical decision-making, particularly in healthcare systems where guideline recommendations may not fully account for local constraints and patient preferences.

Therefore, the present prospective observational study was undertaken to evaluate the effectiveness of adjunctive metformin therapy, in combination with lifestyle modifications, in mitigating antipsychotic-associated weight gain in a real-world psychiatric population. By focusing on clinically meaningful outcomes such as changes in body weight and body mass index, and by situating the findings within contemporary evidence and evolving clinical perspectives, this study aims to contribute to the growing body of literature supporting earlier and more individualized management of AAWG.

In the present prospective observational study conducted in a real-world psychiatric setting, adjunctive metformin therapy was associated with a significant reduction in body weight and BMI among patients receiving antipsychotic treatment. Participants in the metformin group experienced a mean weight reduction of ~4 kg compared with those receiving lifestyle modification alone, supporting the effectiveness of metformin as an adjunctive strategy for managing AAWG. The study population reflects routine clinical practice, with a predominance of second-generation antipsychotics, particularly olanzapine and risperidone, agents well recognized for their high metabolic liability. Benzodiazepines, including clonazepam, were prescribed as concomitant medications and were not classified as antipsychotic agents for analytical purposes.

AAWG remains a major clinical challenge in long-term psychiatric care, contributing to increased cardiometabolic risk, reduced quality of life, and poor treatment adherence (14,15). Recent large-scale observational studies and meta-analyses have reaffirmed that SGAs such as olanzapine and clozapine are associated with the greatest magnitude of weight gain, particularly during the early phases of treatment (16,17). Contemporary evidence emphasizes that early and proactive intervention is critical, as weight gain trajectories established within the first 6-12 months are often sustained over time and difficult to reverse (18).

The findings of the present study are consistent with those of previous randomized controlled trials and meta-analyses published between 2021 and 2025, which demonstrate that adjunctive metformin significantly attenuates AAWG and improves metabolic parameters in patients receiving antipsychotic therapy (12,19-21). An updated meta-analysis by Zheng et al reported a clinically meaningful reduction in body weight and BMI with metformin compared with placebo, even among non-diabetic patients (21). Similarly, the study by Seifarth et al (20) confirmed moderate-quality evidence supporting metformin for reducing antipsychotic-related weight gain and insulin resistance. Other analyses have further highlighted that metformin is particularly effective when initiated early or in patients at high metabolic risk, reinforcing its role as both a preventive and therapeutic agent (21).

In the present study, longitudinal follow-up demonstrated a clear divergence in weight trajectories between groups. Patients receiving metformin exhibited a reduction in mean body weight from 60.45 to 57.98 kg, whereas those managed with lifestyle modifications alone experienced an increase from 58.24 to 60.94 kg. Corresponding changes in BMI mirrored these trends. These findings are consistent with previous randomized controlled trials and meta-analyses demonstrating significant reductions in body weight and BMI with adjunctive metformin in patients receiving antipsychotic therapy (3,21,24,27). Notably, these real-world data complement evidence from controlled trials by demonstrating effectiveness under routine prescribing conditions.

Mechanistically, metformin exerts its beneficial effects on weight regulation through multiple pathways, including improved insulin sensitivity, the suppression of hepatic gluconeogenesis, modulation of gut microbiota, and the enhancement of anorexigenic gut hormones such as glucagon-like peptide-1 and peptide YY (24,25). Recent translational studies suggest that these mechanisms may counteract antipsychotic-induced disruptions in appetite signaling and peripheral metabolism, thereby stabilizing weight trajectories in vulnerable patients (26). The observed benefits of metformin in non-diabetic populations further support its broader applicability in psychiatric practice (27).

An exploratory analysis in the present study suggested that patients with ongoing exposure to antipsychotics exhibited numerically lower weight gain compared with treatment-naïve individuals; however, this difference did not reach statistical significance and should be interpreted cautiously. Similar findings have been reported in recent cohort studies, where early metabolic changes were highly variable and influenced by baseline risk factors, antipsychotic type, and duration of exposure (28). These observations underscore the complexity of weight dynamics in psychiatric populations and highlight the need for individualized risk stratification.

Sex-based analysis revealed a higher adherence to metformin therapy among female patients, although no statistically significant difference in weight change between sexes was observed. Recent literature suggests that sex may influence medication adherence and health-seeking behaviors, with women often demonstrating greater engagement in weight-related interventions (29,30). However, adherence in the present study was assessed using self-report and pill counts rather than validated adherence instruments, limiting the strength of this conclusion. Nonetheless, these findings highlight the importance of considering psychosocial and behavioral factors when implementing metabolic interventions in psychiatric care.

Overall, the results of the present study add to the growing body of evidence supporting metformin as a safe and effective adjunctive intervention for mitigating AAWG, particularly when combined with lifestyle modification. Recent expert commentaries and consensus statements have increasingly advocated for earlier integration of metformin in high-risk patients, rather than reserving its use as a last-line option after significant weight gain has occurred (21,31). The present findings provide further real-world support for this evolving clinical approach.

Several limitations of the present study should be acknowledged. The single-center design may limit generalizability, and the 6-month follow-up period restricts assessment of long-term metabolic outcomes. The observational, non-randomized and non-blinded nature of the study introduces potential selection bias and residual confounding. Metformin dosing was guided by routine clinical practice, resulting in dose heterogeneity (500 mg to 1 g), which may have influenced treatment response. Lifestyle modifications were delivered as non-standardized counseling without objective adherence monitoring, limiting the ability to isolate the independent effects of metformin. Adherence assessment relied on patient self-report and pill counts rather than validated instruments, which may reduce precision, particularly in gender-based comparisons.

Despite these limitations, the present study provides valuable real-world evidence from a routine psychiatric setting. The findings should be interpreted with appropriate caution, and causal inferences cannot be definitively established. Future well-designed randomized controlled trials with longer follow-up are warranted to confirm these results, explore gender-specific adherence patterns, and evaluate the long-term cardiometabolic benefits of adjunctive metformin therapy.

In conclusion, the present prospective observational study demonstrated that adjunctive metformin therapy, when combined with lifestyle modifications, was associated with a statistically significant reduction in mean body weight and BMI among patients receiving antipsychotic treatment. Patients in the metformin group experienced a decrease in mean body weight from 60.45 to 57.98 kg, whereas those managed with lifestyle modifications alone showed an increase from 58.24 to 60.94 kg over the study period. These findings support the potential role of metformin in mitigating antipsychotic-associated weight gain in routine clinical practice. Although higher self-reported adherence to metformin therapy was observed among female patients, adherence was not assessed using validated instruments, and no statistically significant sex-based differences in weight outcomes were identified. Given the observational design, the findings should be interpreted with caution, and further well-designed randomized controlled trials are warranted to confirm these results and to evaluate long-term metabolic outcomes.