Biomedicine and Chemical Sciences

Schizophrenia is a persistent and severe mental illness characterised by a constellation of symptoms affecting thought, perception, emotion, and behaviour [1]. It exerts a profound impact not only on affected individuals but also on their families and society at large. Antipsychotic medication remains the mainstay of treatment for schizophrenia, aiming to improve overall functioning by reducing positive symptoms such as delusions and hallucinations [2].

Second-generation (atypical) antipsychotics — including olanzapine, risperidone, aripiprazole, quetiapine, and clozapine — are now the preferred first-line agents, largely because they are associated with fewer extrapyramidal side effects than first-generation (typical) antipsychotics [3]. However, the high prevalence of metabolic syndrome among individuals with schizophrenia remains a significant concern in mental health care [4]. Metabolic syndrome comprises a cluster of abnormalities, including central obesity, insulin resistance, dyslipidaemia, and hypertension; several studies have shown its prevalence to be higher in patients with schizophrenia than in the general population [5,6]. Olanzapine, in particular, can induce insulin resistance, impair glucose metabolism, and alter lipid metabolism, thereby contributing to metabolic syndrome and increased cardiovascular risk [7,8]. The present study was therefore undertaken to examine the role of olanzapine, prescribed for the treatment of schizophrenia, in inducing insulin resistance and impairing glucose metabolism — changes that may predispose patients to metabolic syndrome, diabetes, and cardiovascular disease.

MATERIALS AND METHODS

Place of Study

The study was conducted in the Department of Biochemistry and the Department of Psychiatry, Chhattisgarh Institute of Medical Sciences (CIMS), Bilaspur, Chhattisgarh.

Study Design

This was a hospital-based, prospective observational cohort study. Participants were recruited from the Psychiatric OPD, CIMS, Bilaspur, based on the following inclusion and exclusion criteria.

Inclusion Criteria

1. Adult patients aged 18–65 years diagnosed with schizophrenia according to DSM-5 or ICD-10 criteria.
2. Patients who had not previously received antipsychotic medication.
3. Patients with no prior history of metabolic syndrome.
4. Patients (or attendants, where applicable) able to provide informed consent and willing to participate in the study.

Exclusion Criteria

1. Patients with a diagnosis of other primary psychiatric or psychotic disorders.
2. Patients with a history of other severe medical conditions that could confound the assessment of metabolic syndrome.
3. Patients with a history of endocrine disorders or known metabolic abnormalities.
4. Pregnant or breastfeeding women.
5. Patients with a history of substance abuse or dependence within the preceding six months.

Sample Size

A total of 100 patients diagnosed with schizophrenia were enrolled, selected according to the inclusion and exclusion criteria above.

Duration of Study

The study was conducted over 24 months, commencing on 05.10.2023, following approval from the Scientific Research Review Committee and the Institutional Ethics Committee of CIMS, Bilaspur, Chhattisgarh.

Patients attending the Psychiatry OPD at CIMS who were newly diagnosed with schizophrenia (per DSM-5/ICD-10 criteria) and had not previously received antipsychotic treatment were invited to participate. Written informed consent was obtained from all participants. A structured proforma was used to record sociodemographic details, clinical history, comorbidities, lifestyle factors, and family history of schizophrenia and metabolic disorders. Blood samples were collected at baseline to assess fasting blood glucose and HOMA-IR and to exclude pre-existing metabolic syndrome. Patients who did not meet the inclusion criteria were excluded. Enrolled participants underwent a follow-up assessment at six months to evaluate changes in metabolic parameters and the development of insulin resistance.

Collection of Blood Sample

Venous blood was collected from each participant after an overnight fast, from the antecubital vein, into plain tubes; serum was separated by centrifugation at 2,000 rpm for 15 minutes. An additional sample was collected into fluoride tubes for glucose estimation. Fasting blood glucose was estimated by the GOD-POD spectrophotometric method using the ILAB 650 and ERBA 360 Chemistry Analyzers, and fasting insulin was measured by chemiluminescent immunoassay (CLIA) using the Beckman Coulter Access 2 Immunology Analyzer.

Insulin resistance was assessed using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), first described by Matthews et al. (1985) and calculated as:

HOMA-IR = [Fasting glucose (mg/dL) × Fasting insulin (mIU/mL)] / 405

Following six months of olanzapine therapy, patients were classified according to standard HOMA-IR cut-offs:

• 0.5–1.9: insulin-sensitive (optimal)
• Above 1.9: early insulin resistance
• Above 2.9: significant insulin resistance

Statistical Analysis

Data were analysed using Microsoft Excel and IBM SPSS Statistics (version 22.0, trial version). Descriptive statistics are reported as mean ± SD. The two-tailed t-test and one-way ANOVA were used to compare metabolic parameters, with p < 0.05 and F > 2.9 considered statistically significant.

RESULTS

Patients were assessed for changes in fasting blood glucose and HOMA-IR after six months of olanzapine therapy.

Comparison of FBS and HOMA-IR Before and After Treatment

As shown in Table 1, mean fasting blood glucose increased significantly from 99.8 ± 19.7 mg/dL at baseline to 109.7 ± 18.6 mg/dL at six months (p = 0.001). Similarly, mean HOMA-IR increased significantly from 0.9 ± 0.3 to 1.1 ± 0.3 (p = 0.002). These findings indicate a statistically significant deterioration in fasting glycaemic status and insulin sensitivity following six months of olanzapine therapy.

                Table 1. Comparison of FBS and HOMA-IR before (baseline) and after treatment (6 months)

        Change in FBS and HOMA-IR According to Sex

Table 2 compares the change in FBS and HOMA-IR between male (n = 53) and female (n = 47) patients after six months of olanzapine therapy. The mean increase in both parameters was numerically greater in female patients — FBS: 15.1 ± 1.4 vs. 10.5 ± 12.8 mg/dL; HOMA-IR: 0.18 ± 0.28 vs. 0.16 ± 0.27 — although neither difference reached statistical significance (p = 0.525 and p = 0.791, respectively).

Table 2. Difference in the change in FBS and HOMA-IR between male and female patients after 6         months of olanzapine therapy

Change in FBS and HOMA-IR According to Age Group

Table 3 presents the change in FBS and HOMA-IR stratified by age. The greatest mean increase in FBS was observed in the youngest age group (18–32 years: 10.6 ± 15.3 mg/dL), followed by the 33–46-year group (8.0 ± 11.1 mg/dL) and the 47–60-year group (4.6 ± 7.4 mg/dL); these differences were not statistically significant (F = 0.963, p = 0.385). Similarly, the mean change in HOMA-IR did not differ significantly across age groups (F = 0.477, p = 0.621).

Table 3. Difference in the change in FBS and HOMA-IR among patients by age group after 6 months of olanzapine therapy

DISCUSSION

The present prospective study evaluated the effect of six months of olanzapine therapy on fasting blood glucose (FBS) and insulin resistance (HOMA-IR) in patients with schizophrenia. Both parameters increased significantly over the treatment period, indicating that olanzapine adversely affects glucose metabolism and promotes insulin resistance even during the early phase of treatment.

Mean FBS rose from 99.8 ± 19.7 mg/dL at baseline to 109.7 ± 18.6 mg/dL at six months (p = 0.001), and mean HOMA-IR rose from 0.9 ± 0.3 to 1.1 ± 0.3 (p = 0.002), suggesting progressive impairment of insulin sensitivity following olanzapine initiation. This rise in fasting glucose and HOMA-IR is consistent with the hypothesis that insulin resistance precedes the clinical onset of overt diabetes [9].

These findings are consistent with those of Newcomer et al., who demonstrated that olanzapine produces significantly greater deterioration in insulin sensitivity and glucose tolerance than other atypical antipsychotics. Similarly, Houseknecht et al. proposed that olanzapine interferes directly with insulin signalling and glucose uptake in peripheral tissues, independent of weight gain. Together, these observations suggest that olanzapine-associated metabolic disturbance arises through both direct pharmacological effects and secondary mechanisms related to increased adiposity [10,11,12].

Several biological mechanisms may underlie these changes. Olanzapine has high affinity for serotonergic (5-HT2C), histaminergic (H1), dopaminergic (D2), and muscarinic receptors. Blockade of H1 and 5-HT2C receptors increases appetite and caloric intake, promoting weight gain and visceral adiposity [12,13]. In addition, olanzapine impairs insulin-mediated glucose uptake in skeletal muscle and adipose tissue, increases hepatic gluconeogenesis, alters adipokine secretion, and may impair pancreatic β-cell function — mechanisms that together contribute to insulin resistance and progressive glycaemic impairment [14,15].

Sex-stratified analysis showed a numerically greater increase in fasting blood glucose among female patients than male patients (15.1 ± 1.4 vs. 10.5 ± 12.8 mg/dL), though this difference did not reach statistical significance (p = 0.525); HOMA-IR likewise did not differ significantly by sex (p = 0.791). These findings suggest that the adverse metabolic effects of olanzapine occur irrespective of sex, in line with De Hert et al., who concluded that although women may experience greater weight gain in some populations, sex alone does not consistently predict olanzapine-induced insulin resistance [16,17].

Age-stratified analysis similarly showed no significant differences in the change in FBS (p = 0.385) or HOMA-IR (p = 0.621) across age groups, although younger patients showed a numerically greater rise in fasting glucose. This is consistent with the findings of Mitchell et al., who reported that metabolic abnormalities associated with second-generation antipsychotics occur across all age groups, underscoring the need for metabolic surveillance irrespective of patient age [17]. These findings carry important clinical implications. Patients with schizophrenia already have an elevated baseline risk of metabolic syndrome, owing to sedentary lifestyle, unhealthy dietary habits, smoking, and genetic susceptibility; olanzapine therapy further compounds this risk by promoting insulin resistance and hyperglycaemia. Regular metabolic monitoring should therefore form an integral part of psychiatric care, with baseline and periodic assessment of fasting plasma glucose, HbA1c, lipid profile, body weight, body mass index, waist circumference, and blood pressure to enable early detection and management of metabolic complications.

The strengths of this study include its prospective design, a uniform six-month follow-up period, and the simultaneous assessment of fasting blood glucose and HOMA-IR, which together provide a sensitive estimate of insulin resistance. Certain limitations should nonetheless be acknowledged: the study was conducted at a single tertiary care centre with a relatively modest sample size and a follow-up period limited to six months, and anthropometric indices (BMI, waist circumference), HbA1c, lipid profile, dietary intake, physical activity, and inflammatory biomarkers were not assessed. Future multicentre studies with larger cohorts and longer follow-up are warranted to clarify the long-term metabolic effects of olanzapine.

CONCLUSION

This study demonstrates that six months of olanzapine therapy in patients with schizophrenia results in a significant increase in fasting blood glucose and insulin resistance, irrespective of sex and age. On this basis, the following are recommended:

1. Patients with schizophrenia should be regularly monitored for metabolic syndrome risk factors.
2. Nutritional and lifestyle modification should be implemented for patients undergoing prolonged treatment with atypical antipsychotics such as olanzapine.
3. Where clinically appropriate, antipsychotics with a lower metabolic risk profile should be considered for patients at risk of developing insulin resistance and, consequently, metabolic syndrome.

REFERENCES

1. Farah FH. Schizophrenia: An overview. Asian J Pharm. 2018;12.
2. Rantala MJ, Luoto S, Borráz-León JI, Krams I. Schizophrenia: the new etiological synthesis. Neurosci Biobehav Rev. 2022;142.
3. van Os J, Kapur S. Schizophrenia. Lancet. 2009;374.
4. Lone S, Lone K, Khan S, Pampori RA. Assessment of metabolic syndrome in Kashmiri population with type 2 diabetes employing the standard criteria given by WHO, NCEP-ATP III and IDF. J Epidemiol Glob Health. 2017;7(4).
5. Yadav D, Mahajan S, Subramanian SK, Bisen PS, Chung CH, Prasad GB. Prevalence of metabolic syndrome in type 2 diabetes mellitus using NCEP-ATPIII, IDF and WHO definitions and its agreement in the Gwalior Chambal region of Central India. Glob J Health Sci. 2013;5(6).
6. Krishnamoorthy Y, Rajaa S, Murali S, Sahoo J, Kar SS. Association between anthropometric risk factors and metabolic syndrome among adults in India: a systematic review and meta-analysis of observational studies. Prev Chronic Dis. 2022;19.
7. Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol. 2018;17.
8. Hosseinpour-Niazi S, Afaghi S, Hadaegh P, Mahdavi M, Farhadnejad H, Tohidi M, et al. The association between metabolic syndrome and insulin resistance with risk of cardiovascular events in different states of cardiovascular health status. J Diabetes Investig. 2024;15(2).
9. Singh Y, Garg MK, Tandon N, Marwaha RK. A study of insulin resistance by HOMA-IR and its cut-off value to identify metabolic syndrome in urban Indian adolescents. J Clin Res Pediatr Endocrinol. 2013;5(4).
10. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19.
11. Casey DE, Haupt DW, Newcomer JW, Henderson DC, Sernyak MJ, Davidson M, et al. Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry. 2004;65.
12. Fernø J, Varela L, Skrede S, Vázquez MJ, Nogueiras R, Diéguez C, et al. Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. PLoS One. 2011.
13. Fountaine RJ, Taylor AE, Mancuso JP, Greenway FL, Byerley LO, Smith SR, et al. Increased food intake and energy expenditure following administration of olanzapine to healthy men. Obesity (Silver Spring). 2010.
14. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A. 2007;104(9).
15. Murotani T, Ishizuka T, Isogawa Y, Karashima M, Yamatodani A. Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system. Neuropharmacology. 2011;61(1–2).
16. De Hert MA, Van Winkel R, Van Eyck D, Hanssens L, Wampers M, Scheen A, et al. Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophr Res. 2006.
17. Mitchell AJ, Vancampfort D, Sweers K, Van Winkel R, Yu W, De Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders: a systematic review and meta-analysis. Schizophr Bull. 2013;39.

DECLARATIONS

Funding: None.

Conflict of Interest: The authors declare no conflict of interest.

Ethical Approval: The study was conducted in accordance with applicable ethical standards and approved by the appropriate ethics committee where required.

Informed Consent: Informed consent was obtained from all participants involved in the study where applicable.

Author Contributions: All authors contributed to the study conception, design, data collection, analysis, manuscript preparation, and approved the final version of the manuscript.

Data Availability: Data supporting the findings of this study are available from the corresponding author upon reasonable request.