Metabolic Health in Schizophrenia: Toward Nutritional and Metabolism-Based Strategies in Psychiatry

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

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

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