Managing Weight, Metabolic Syndrome, and Diabetes in Schizophrenia Patients

Schizophrenia patients face a hidden threat that lurks beneath their mental health symptoms: a troubling rise in cardiovascular disease and diabetes. Studies suggest that 60 percent of schizophrenia patients are overweight or obese. That stands in stark contrast to the 35 percent of the general population that falls into that category.

But that’s not all. The prevalence of type 2 diabetes is two to three times higher in individuals with schizophrenia. The metabolic side effects inherent in most antipsychotic drugs, lifestyle factors, and the underlying disease itself all pile on to make things worse. As a result, managing cardiometabolic health must be an integral part of the overall treatment regime.

Clinicians face a daunting challenge when they try to juggle effective symptom control while dodging these grave health risks.

Metabolic Burden in Schizophrenia

Multiple factors contribute to the increased risk of metabolic disorders in schizophrenia patients. Caregivers must consider the use of antipsychotic medications, social health determinants, genetic predispositions, and lifestyle choices.

About a third of individuals with schizophrenia have metabolic syndrome, with rates as high as 69 percent in those struggling with a chronic condition. Obesity, type 2 diabetes, and hypercholesterolemia are three to five times more prevalent in this population.

Additionally, schizophrenia patients are twice as likely to receive a cardiovascular disease diagnosis – and die from it. This exacerbates the already wide mortality gap between these individuals and the general population.

This underscores the desperate need for caregivers to get a better handle on the cardiovascular risks tied to schizophrenia.

Antipsychotic medications, certainly potent in managing psychotic symptoms, also bump up the risk of metabolic complications. Second-generation antipsychotics, in particular, can wreak havoc with the metabolism. Research has exposed side effects such as weight gain, altered glucose homeostasis, and dyslipidemia. All of these influence the risk of cardiovascular disease and type 2 diabetes.

Lifestyle factors – and the healthcare access disparities common in severe mental illness – exacerbate these adverse effects. And that can open the door to treatment non-adherence – or even outright abandonment – threatening long-term psychiatric outcomes.

Antipsychotic Selection and Therapy Adjustment

Clinicians can help patients stave off long-term complications while managing their symptoms effectively.

• Evaluate the metabolic risk profiles of antipsychotics before initiating treatment.
• Tailor antipsychotic choices based on individual risk factors.
• And consider options with lower metabolic risks when clinically appropriate. Second-generation antipsychotics – olanzapine and clozapine in particular – carry a higher risk of weight gain, insulin resistance, and dyslipidemia. Other second-generation antipsychotics, such as lurasidone and ziprasidone aripiprazole, and partial agonists aripiprazole, brexpiprazole, and cariprazine, tend to carry a lower metabolic burden.

Clinicians should initiate antipsychotic treatment at the lowest recommended dose and titrate slowly to the lowest effective dose, balancing efficacy with the potential for metabolic side effects. American Psychiatric Association (APA) guidelines recommend that patients on antipsychotics receive baseline and routine monitoring of body weight, body mass index (BMI) panel, and labs to assess lipids and glycemic control to identify and address metabolic issues early.

New Therapeutic Approaches to Weight Management

There’s no way to completely avoid added metabolic risks when prescribing antipsychotics. But clinicians can rely on f adjunctive treatments for weight management.

• Metformin has proved itself capable of preventing and treating antipsychotic-associated weight gain. Research has shown an average weight loss of 3.3 kg when patients taking antipsychotics took metformin compared with placebo. Aside from curbing weight gain, metformin’s ability to boost peripheral glucose uptake and cut hepatic glucose production can reduce insulin sensitivity.
• Glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for type 2 diabetes management, offer benefits of promoting weight loss, improving glycemic control, and treating metabolic complications such as metabolic-dysfunction associated steatotic liver dysfunction (formerly nonalcoholic fatty liver disease).
• Semaglutide 2.4 mg demonstrated a mean body weight change of 14.9 percent, compared with 2.4 percent in placebo-treated patients over 68 weeks in a phase 3 trial of adults with overweight or obesity.
• Tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist, has demonstrated an even greater weight impact. A 72-week phase 3 trial showed tirzepatide 15 mg weekly resulted in a mean weight loss of more than 20 percent. That’s compared to 3.1 percent with the placebo.  A 2017 study of schizophrenia patients treated with olanzapine or clozapine, prediabetes, and overweight or obesity, showed that liraglutide 1.8 mg daily decreased weight by an average of 5.3 kg compared with placebo over 16 weeks. Glucose tolerance normalized for 63.8 percent for those treated with liraglutide versus 16 percent of patients treated with placebo.

Novel Therapeutic Approaches

Metabolic complications associated with antipsychotic medications have driven demand for novel therapies with better metabolic profiles.

• Olanzapine/samidorphan (OLZ/SAM), which the FDA approved in 2021, reduces or prevents weight gain commonly while maintaining therapeutic efficacy by adding samidorphan, an opioid receptor blocker. A post-hoc analysis of the phase 3 trial ENLIGHTEN-2 trial showed OLZ/SAM carried a lower risk for worsening obesity, hypertension, and metabolic syndrome compared with olanzapine. [Correll 2023]
• Xanomeline-trospium (KarXT), a novel muscarinic M1/M4 receptors agonist, earned the FDA’s blessing in late September of this year. Recent pooled data from the EMERGENT-4 and EMERGENT-5 trials offer encouraging long-term metabolic outcomes, with an average weight reduction of 2.6 kg over one year of treatment. And crucial metabolic parameters, such as total cholesterol, triglycerides, and A1C, all remained stable throughout the treatment.
• Ulotaront, a trace amine-associated receptor 1 (TAAR1) agonist, also holds promise as a novel emerging drug class for schizophrenia. The FDA granted it the Breakthrough Therapy Designation in 2019. Data from a 26-week open-label extension study showed no clinically significant changes in weight, cholesterol, triglycerides, or A1C levels.

With the promising potential of emerging therapies to reduce the risk of weight gain, metabolic syndrome, and type 2 diabetes in schizophrenia patients, clinicians could soon have more available tools to improve care and long-term outcomes.