Publication
Article
Psychiatric Times
Author(s):
Learn more about effective strategies for managing obesity and metabolic dysfunction in schizophrenia, focusing on dietary interventions and pharmacological treatments.
It is widely known that obesity, particularly abdominal obesity, significantly contributes to the progression of metabolic syndrome (MetS),1 with a prevalence as high as 75% in individuals with psychotic illness.2 Obesity-related metabolic disturbances significantly increase mortality in schizophrenia,3 with schizophrenia often preceding obesity, especially in younger patients.4
Antipsychotics can increase appetite, leading to higher carbohydrate consumption.5 Individuals with schizophrenia often consume a diet with a high glycemic load, which is recognized as a key driver of obesity and metabolic dysfunction.5 Weight gain can occur quickly after initiating antipsychotic treatment6 and can additionally disrupt glucose metabolism, alter cholesterol and triglyceride levels, and induce hypertension, which are key features of MetS.7 Insulin resistance, linked to obesity, is significantly higher in schizophrenia, increasing the risk of type 2 diabetes and negatively impacting brain function.8 In addition to possible medication effects, individuals with serious mental illness (SMI) face barriers such as financial constraints, reduced motivation, taste preferences, low social support, and limited access to healthy foods, all contributing to poor eating habits and reduced diet quality. Therefore, individuals with schizophrenia are also at higher risk of malnutrition, experiencing both deficiencies in micronutrients9 and inability to absorb the nutrients properly when increasing intake.10
Guideline-Directed Metabolic Management
The nature of obesity and metabolic dysfunction is multifaceted, and there are considerable challenges associated with achieving and sustaining successful outcomes. Weight gain prevention in schizophrenia is crucial, but interventions are understudied, and the conventional “eat less, move more” approach is deemed inadequate in individuals with SMI or in obesity medicine.11,12 Strategies involving medication dose reduction, discontinuation, or switching have shown modest weight reductions, with a mean change of −1.5 kg compared with unaltered treatment.13-15 However, switching may not be a viable option for certain patients, such as those receiving clozapine for difficult-to-treat schizophrenia.12 Two randomized controlled trials (RCTs), PHAstER and STEPWISE, found no evidence that structured lifestyle education programs prevent antipsychotic-induced weight gain (AIWG) in individuals with schizophrenia,16,17 indicating the need for more targeted interventions to address metabolic risks in this population.17
List of Key Questions Clinicians Can Ask a Patient With Schizophrenia
An international team from the University of California, Davis; Royal College of Surgeons in Ireland; and St John of God Hospital has developed clinical guidelines for preventing AIWG, focusing on metformin.12 Metformin is the best-supported pharmacological agent for managing weight gain in schizophrenia,18 with a mean weight reduction of about 3 kg when used off-label.18,19 It also improves metabolic parameters when started with antipsychotic treatment.20 The guidelines recommend initiating metformin concurrently with high-risk neuroleptics (eg, olanzapine or clozapine) or medium-risk neuroleptics (eg, quetiapine, paliperidone, or risperidone) when cardiometabolic risk factors are present or in individuals aged 10 to 25 years.
Metformin should be initiated with antipsychotics if a 3% increase in baseline body weight is observed during the first year of treatment.12 Behavioral interventions, including dietary and lifestyle modifications, should be consistently implemented alongside pharmacological strategies to mitigate AIWG.11
Glucagon-like peptide-1 (GLP-1) receptor agonists have shown a larger effect size than metformin in treating overweight or obesity, with a mean difference in weight loss of –6 kg.21,22 Although GLP-1 receptor agonists are recommended in national obesity guidelines due to high-certainty evidence,11,23 limited evidence exists in populations with SMI or schizophrenia. When clinically appropriate, these treatments should be made equally accessible to individuals with SMI as they are to those with obesity in the general population.
Toward Nutritional Interventions
Evidence suggests that patients with psychiatric disorders equally lack nutrition knowledge, food skills, or motivation to eat healthily despite higher rates of metabolic dysfunction. Several nutritional interventions have been used for weight loss, but not all have been thoroughly studied in schizophrenia. The Dietary Approaches to Stop Hypertension (DASH) diet, effective for weight loss, has not been thoroughly examined in relation to cardiovascular or psychopathological outcomes. However, a similar nutritional intervention to DASH has been reported to be effective in reducing excessive sodium and caloric intake in a sample of young patients with first-episode psychosis.24
Mediterranean diet (MedDiet) interventions, when combined with calorie restriction or exercise, promote weight loss and reduce cardiovascular risk, including insulin resistance markers. The MedDiet reduces inflammatory markers,25 which are believed to contribute to metabolic dysfunction, sometimes summarized as “metaflammation,” a condition thought to promote neuropsychiatric diseases.26 It is also believed to be neuroprotective and has shown promising results in a study on major depressive disorder.27 However, no clinical trials have been conducted on individuals with schizophrenia, indicating a significant research gap.
Ketogenic diets (KDs)—which are higher in fat, moderate in protein, and low in carbohydrates—are used to manage treatment-resistant epileptic seizures.28 They have been shown to reverse obesity and metabolic dysfunction mechanistically by lowering insulin levels and promoting ketosis,29,30 which enhances fat oxidation and insulin sensitivity, leading to weight loss and better metabolic control.31 KDs may also alleviate inflammation and improve lipid profiles.32 However, they require personalized medical monitoring and improved resources and support to ensure their effectiveness. Adherence demands commitment, but improved resources and support may enhance accessibility. Evidence suggests that KDs may target common pathophysiological mechanisms in neuropsychiatric disorders, including mitochondrial dysfunction, oxidative stress, inflammation, glucose hypometabolism, and neurotransmitter imbalances.33 Preliminary evidence suggests that KDs may offer dual benefits as both a metabolic therapy and a treatment for psychiatric symptoms in schizophrenia. Eight uncontrolled studies involving 52 patients, aged 18 to 82 years, with illness ranging from early to chronic stages, following KDs from 6 days to 12 years, showed improvements in psychiatric symptoms, with most patients showing improvements in symptoms measured by scales like the Positive and Negative Syndrome Scale, the Clinical Global Impression (CGI) scale, and the Hamilton Depression Rating Scale.33
A pilot study, involving 21 participants tracking their blood ketones weekly, found that dietary adherence to a KD improved their CGI scores by 31%, and 75% of participants entered recovery. Full adherence led to significant reductions in weight (12%), body mass index (BMI; 12%), waist circumference (13%), and visceral adipose tissue (36%).34 At this stage, RCTs are needed to compare the KD with active comparator interventions, with several trial protocols already published, including one at Stanford University.35
Enhancing Brain Metabolism
In individuals with psychiatric disorders, particularly schizophrenia, key metabolic pathways are disrupted by neuroinflammation, oxidative stress, and mitochondrial dysfunction.33,36,37 Noninvasive imaging in schizophrenia shows reduced creatine kinase flux, indicating impaired cerebral energy storage and utilization.38 Studies also show reduced mRNA expression of gene groups involved in mitochondrial oxidation metabolism and the ubiquitin-proteasome system.39 Elevated brain lactate levels are linked to reduced cognitive performance.40
Postmortem studies of the dorsolateral prefrontal cortex in schizophrenia also reveal increased lactate levels.41 Disruptions in glutamatergic signaling and neuronal energy affect Na+/K+-adenosine triphosphatase activity, reducing action potential generation and abnormal neurotransmitter release,42 which may contribute to impaired synaptic function and cognitive symptoms in schizophrenia.43 Individuals with schizophrenia exhibit abnormalities in central and peripheral glucose metabolism, including reduced cerebral glucose utilization.44
Exercise Interventions
Exercise interventions have shown viability in individuals with severe, chronic schizophrenia.44 A systematic review of 17 trials, involving 659 participants with nonaffective psychotic disorders, found that exercise did not significantly impact BMI, but it improved physical fitness, cardiometabolic risk factors, and psychiatric symptoms, particularly with 90 minutes of moderate to vigorous exercise per week. This level of exercise also enhanced functioning, comorbid conditions, and neurocognition,45 suggesting that an appropriately planned exercise could be an effective adjunctive treatment within a multimodal therapeutic approach.
Concluding Thoughts
Well-designed clinical studies are essential for evaluating metabolic interventions in managing schizophrenia and its associated obesity and metabolic dysfunction. A multifaceted, recovery-oriented approach, incorporating lifestyle changes and medications when appropriate, is essential. These treatments, supported by interdisciplinary teams, should be accessible for individuals with schizophrenia and personalized to each patient’s needs to promote sustainable recovery and overall wellness.
Dr Sethi is a founding director of the flagship Stanford Metabolic Psychiatry Clinic, a clinical associate professor at Stanford University, and the founder of Metabolic Psychiatry Labs Inc, a digital health platform translating research on metabolism-based psychiatric care into accessible clinical applications. Dr Liwinski is a clinical scientist and lecturer at University Psychiatric Clinics UPK Basel.
Resources
+ Clinicians interested in integrating metabolism-based care into psychiatric treatment can contact Stanford Metabolic Psychiatry directly via: https://www.metabolicpsychiatry.com/contact
+ To explore ongoing research or for patients interested in enrolling in studies, visit the trial page: https://clinicaltrials.gov/study/NCT06748950
References
1. Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabetic Medicine. 2006;23(5):469-480.
2. Galletly CA, Foley DL, Waterreus A, et al. Cardiometabolic risk factors in people with psychotic disorders: the second Australian national survey of psychosis. Aust N Z J Psychiatry. 2012;46(8):753-761.
3. Correll CU, Solmi M, Croatto G, et al. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry. 2022;21(2):248-271.
4. Vochoskova K, McWhinney SR, Fialova M, et al. Weight and metabolic changes in early psychosis-association with daily quantification of medication exposure during the first hospitalization. Acta Psychiatr Scand. 2023;148(3):265-276.
5. Peet M. Diet, diabetes and schizophrenia: review and hypothesis. Br J Psychiatry Suppl. 2004;47:S102-S105.
6. Holt RIG. The management of obesity in people with severe mental illness: an unresolved conundrum. Psychother Psychosom. 2019;88(6):327-332.
7. De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
8. Nicol GE, Yingling MD, Flavin KS, et al. Metabolic effects of antipsychotics on adiposity and insulin sensitivity in youths: a randomized clinical trial. JAMA Psychiatry. 2018;75(8):788-796.
9. Kim SR, Kim JY, Kim HY, et al. Factors related to malnutrition in community-dwelling patients with schizophrenia. Perspect Psychiatr Care. 2019;55(3):415-423.
10. Mangal DK, Shaikh N, Tolani H, et al. Burden of micronutrient deficiency among patients with type 2 diabetes: systematic review and meta-analysis. BMJ Nutr Prev Health. Published online January 29, 2025.
11. Breen C, O’Connell J, Geoghegan J, et al. Obesity in adults: a 2022 adapted clinical practice guideline for Ireland. Obes Facts. 2022;15(6):736-752.
12. Carolan A, Hynes-Ryan C, Agarwal SM, et al. Metformin for the prevention of antipsychotic-induced weight gain: guideline development and consensus validation. Schizophr Bull. 2024:sbae205.
13. Speyer H, Westergaard C, Albert N, et al. Reversibility of antipsychotic-induced weight gain: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2021;12:577919.
14. Siskind D, Gallagher E, Winckel K, et al. Does switching antipsychotics ameliorate weight gain in patients with severe mental illness? A systematic review and meta-analysis. Schizophr Bull. 2021;47(4):948-958.
15. Bak M, Drukker M, Cortenraad S, et al. Antipsychotics result in more weight gain in antipsychotic naive patients than in patients after antipsychotic switch and weight gain is irrespective of psychiatric diagnosis: a meta-analysis. PLoS One. 2021;16(2):e0244944.
16. Holt RIG, Gossage-Worrall R, Hind D, et al. Structured lifestyle education for people with schizophrenia, schizoaffective disorder and first-episode psychosis (STEPWISE): randomised controlled trial. Br J Psychiatry. 2019;214(2):63-73.
17. O’Donoghue B, Mifsud N, Castagnini E, et al. A single-blind, randomised controlled trial of a physical health nurse intervention to prevent weight gain and metabolic complications in first-episode psychosis: the Physical Health Assistance in Early Psychosis (PHAstER) study. BJPsych Open. 2022;8(6):e189.
18. Agarwal SM, Stogios N, Ahsan ZA, et al. Pharmacological interventions for prevention of weight gain in people with schizophrenia. Cochrane Database Syst Rev. 2022;10(10):CD013337.
19. de Silva VA, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
20. Yu O, Lu M, Lai TKY, et al. Metformin co-commencement at time of antipsychotic initiation for attenuation of weight gain: a systematic review and meta-analysis. Ther Adv Psychopharmacol. 2024;14:20451253241255476.
21. Vasiliu O. Therapeutic management of atypical antipsychotic-related metabolic dysfunctions using GLP-1 receptor agonists: a systematic review. Exp Ther Med. 2023;26(1):355.
22. Stevens H, Smith J, Bussey L, et al. Weight management interventions for adults living with overweight or obesity and severe mental illness: a systematic review and meta-analysis. Br J Nutr. 2023;130(3):536-552.
23. Cornier MA. A review of current guidelines for the treatment of obesity. Am J Manag Care. 2022;28(suppl 15):S288-S296.
24. Teasdale SB, Ward PB, Rosenbaum S, et al. A nutrition intervention is effective in improving dietary components linked to cardiometabolic risk in youth with first-episode psychosis. Br J Nutr. 2016;115(11):1987-1993.
25. Neale EP, Batterham MJ, Tapsell LC. Consumption of a healthy dietary pattern results in significant reductions in C-reactive protein levels in adults: a meta-analysis. Nutr Res. 2016;36(5):391-401.
26. Więckowska-Gacek A, Mietelska-Porowska A, Wydrych M, Wojda U. Western diet as a trigger of Alzheimer’s disease: from metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration. Ageing Res Rev. 2021;70:101397.
27. Bizzozero-Peroni B, Martínez-Vizcaíno V, Fernández-Rodríguez R, et al. The impact of the Mediterranean diet on alleviating depressive symptoms in adults: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2025;83(1):29-39.
28. Martin-McGill KJ, Jackson CF, Bresnahan R, et al. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev. 2018;11(11):CD001903.
29. Guevara-Cruz M, Hernández-Gómez KG, Condado-Huerta C, et al. Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: a randomized clinical trial. Clin Nutr. 2024;43(8):1914-1928.
30. Shai I, Schwarzfuchs D, Henkin Y, et al; Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008;359(3):229-241.
31. Volek JS, VanHeest JL, Forsythe CE. Diet and exercise for weight loss. Sports Med. 2005;35(1):1-9.
32. Volek JS, Phinney SD, Forsythe CE, et al. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids. 2009;44(4):297-309.
33. Anderson J, Ozan E, Chouinard VA, et al. The ketogenic diet as a transdiagnostic treatment for neuropsychiatric disorders: mechanisms and clinical outcomes. Curr Treat Options Psych. 2025;12(1):1.
34. Sethi S, Wakeham D, Ketter T, et al. Ketogenic diet intervention on metabolic and psychiatric health in bipolar and schizophrenia: a pilot trial. Psychiatry Res. 2024;335:115866.
35. Bai N. Pilot study shows ketogenic diet improves severe mental illness. Stanford Medicine. April 1, 2024. Accessed May 31, 2025. https://med.stanford.edu/news/all-news/2024/04/keto-diet-mental-illness.html
36. Bergman O, Ben-Shachar D. Mitochondrial oxidative phosphorylation system (OXPHOS) deficits in schizophrenia: possible interactions with cellular processes. Can J Psychiatry. 2016;61(8):457-469.
37. Hjelm BE, Rollins B, Mamdani F, et al. Evidence of mitochondrial dysfunction within the complex genetic etiology of schizophrenia. Mol Neuropsychiatry. 2015;1(4):201-219.
38. Du F, Cooper AJ, Thida T, et al. In vivo evidence for cerebral bioenergetic abnormalities in schizophrenia measured using 31P magnetization transfer spectroscopy. JAMA Psychiatry. 2014;71(1):19.
39. Altar CA, Jurata LW, Charles V, et al. Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry. 2005;58(2):85-96.
40. Rowland LM, Pradhan S, Korenic S, et al. Elevated brain lactate in schizophrenia: a 7 T magnetic resonance spectroscopy study. Transl Psychiatry. 2016;6(11):e967.
41. Sullivan CR, Mielnik CA, Funk A, et al. Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia. Sci Rep. 2019;9(1):5087.
42. Campbell I, Campbell H. A pyruvate dehydrogenase complex disorder hypothesis for bipolar disorder. Med Hypotheses. 2019;130:109263.
43. Sullivan CR, O’Donovan SM, McCullumsmith RE, Ramsey A. Defects in bioenergetic coupling in schizophrenia. Biol Psychiatry. 2018;83(9):739-750.
44. Dodd KJ, Duffy S, Stewart JA, et al. A small group aerobic exercise programme that reduces body weight is feasible in adults with severe chronic schizophrenia: a pilot study. Disabil Rehabil. 2011;33(13-14):1222-1229.
45. Firth J, Cotter J, Elliott R, et al. A systematic review and meta-analysis of exercise interventions in schizophrenia patients. Psychol Med. 2015;45(7):1343-1361.
Receive trusted psychiatric news, expert analysis, and clinical insights — subscribe today to support your practice and your patients.