People with schizophrenia face a collection of challenges and, while an understandable emphasis is placed on psychosis, the metabolic risk factors of this multifactorial disorder must not be overlooked. An understanding of the relationship between diabetes and schizophrenia, combined with knowledge of effective treatment options, enables the clinician to provide more comprehensive and compassionate care to this vulnerable patient population.

Schizophrenia As a Multisystem Disorder

“While we are focused on schizophrenia as primarily a disorder of the brain…the brain is just one of the systems affected,” says Zachary Freyberg MD, PhD, an assistant professor of psychiatry and cell biology at the University of Pittsburgh, who completed his fellowship in schizophrenia research at Columbia University. The metabolic system is also affected.

In fact, patients with schizophrenia (and their first-degree relatives) are at a greater risk of developing diabetes than the general population. This propensity exists in medication-naive patients and is often compounded by the use of antipsychotics, many of which are known to have weight gain as a side effect.1

More on the diagnostic criteria for schizophrenia and treatment guidelines.

Diabetes and the Metabolic Links to Schizophrenia

According to Toby Pillinger, PhD, MRCP, a clinical research fellow at King’s College London Institute of Psychiatry, Psychology & Neuroscience, “People with schizophrenia present with a greater vulnerability for developing diabetes, right from the onset of illness.” Thus, “There needs to be a greater emphasis on lifestyle interventions that aim to minimize weight gain and associated metabolic disease in this population,” he advises. Such initiatives should be proactive rather than reactive – that is, offered early – and when medication is indicated, clinicians should aim to use those drugs that have fewer metabolic side effects.

There are three components that tend to lead to elevated diabetes in patients with schizophrenia:

  • Decreased insulin sensitivity is common in those diagnosed with schizophrenia. Recent advances in understanding the genetic commonality between schizophrenia and diabetes point to three genomic regions with loci from both diseases. Researchers have also identified 29 genes associated with both schizophrenia and type 2 diabetes (T2D).2
  • Antipsychotics – often considered a first-line treatment for psychosis – can contribute to insulin sensitivity as well as increase the risk of weight gain and the development of metabolic syndrome. Research has shown that in addition to facilitating weight gain, antipsychotics can increase sugar and cholesterol levels in the blood.3
  • Behavioral factors such as an increased incidence of smoking, disordered sleep, inactivity, and social isolation are commonly observed in those with schizophrenia and linked to increased risks for weight gain, metabolic syndrome, and T2D. Lifestyle factors such as low socioeconomic status also play a role.4,5

In addition to the increased risk instigated by schizophrenia, the following factors can increase the likelihood of developing type 2 diabetes in general:6

  • decreased levels of HDL
  • a diet high in processed foods and added sugars
  • Elevated triglyceride levels
  • Family history of diabetes and cardiovascular disease
  • Genetic predisposition
  • hypertension
  • higher waist to hip ratio
  • history of heart disease or stroke
  • obesity
  • polycystic ovary syndrome (PCOS)
    sedentary lifestyle
  • systemic inflammation

While having schizophrenia (or a first-degree relative with the disorder) does increase a patient’s risk for developing T2D –it does not guarantee it. Some studies in patients with schizophrenia who are medication-naïve show impaired glucose tolerance and higher insulin resistance when compared to healthy cohorts.7-9 Other studies suggest a dysregulation of the HPA axis in individuals with schizophrenia, leading to chronically increased cortisol levels.10

Decreased insulin sensitivity should be treated as part of the disorder, along with the positive, negative, and cognitive symptoms of schizophrenia.

Assessing and Treating Comorbid Diabetes in Patients with Schizophrenia

Monitoring & Patient Education

Recommendations from the American Psychiatric Association, American Diabetes Association (ADA), Canadian Diabetes Association (CDA), American Association of Clinical Endocrinologists (AACE), and the North American Association for the Study of Obesity (NAASO) all call for patients with schizophrenia to be closely monitored and treated for T2D. Yet, this population generally receives poorer care for T2D than the general population.11

While monitoring is important, early intervention is invaluable. A 6-week outpatient study examined the impact of the Diabetes Awareness and Rehabilitation Training (DART) program in patients with schizophrenia. The intervention included 90-minute sessions that educated participants about diet, exercise, and self-monitoring of blood glucose levels. Participants were also given pedometers and encouraged to track weekly weight changes. Simplified nutrition education was provided, including information about different food groups, portion sizes, label reading, healthy meal planning, and substituting sugar with fiber.

Outcomes were compared to patients who received usual care (UC), which included educational pamphlets from the ADA and continuous visits to their family physician. DART participants lost an average of 5.1 lbs during the trial compared to 6.8 lbs gained by the control group. At a 6-month follow-up, DART participants maintained positive outcomes. These findings suggest the value of education and of engaging patients in treatment plans.

Upon diagnosis of schizophrenia, it is advisable for patients to undergo a hemoglobin A1C (Hgba1c) test, which measures average blood sugar levels. If their A1C falls within prediabetic (5.7% to 6.4%) or diabetic range, (6.5% or higher), they should be referred to an endocrinologist and enrolled in one of the many health programs offered for diabetes.

Proactive Prescribing

Due to the strong links between schizophrenia and type 2 diabetes, some endocrinologists recommend a more proactive approach, however. Elena Christofides MD, FACE, chief executive officer of Endocrinology Associates and Endocrinology Research Associates, in Columbus, Ohio, shared her take.

“I believe they should be treated with insulin sensitizers (eg, pioglitazone) at the diagnosis of schizophrenia as opposed to waiting until they are diagnosed with diabetes,” she says. “This is an effective approach to prevent the development of diabetes by decreasing the metabolic disadvantages of antipsychotics,” says Dr. Christofides.

Various studies on the use of pioglitazone have shown favorable results. In one double-blind, placebo-controlled study, 54 patients with schizophrenia with (at least) impaired glucose and elevated triglycerides were treated with pioglitazone for 3 months. Researchers found an overall positive effect of pioglitazone in preventing deterioration in fasting glucose and improving HDL levels. Patients showed decreased fasting insulin levels, improved insulin sensitivity, lower triglycerides, and increased HDL. By the end of the study, 52% of the pioglitazone treated group had fasting glucose levels in the normal range. Additionally, PANSS depression scores were markedly improved.12

Given the high risk of developing T2D (especially while taking antipsychotics), pioglitazone, combined with lifestyle modifications,  may be an effective early intervention for those diagnosed with schizophrenia.

Dr. Freyberg also advises that individuals with schizophrenia see a nutritionist (as well as a psychiatrist and therapist) as part of their care plan, noting that sometimes – due to limits in the medical system – psychiatrists must act as the nutritionists. He further recommends that clinicians consider input and cooperation with caregivers to “help improve the chances of a constructive intervention.”

See also, other common clinical treatment challenges in schizophrenia, including medication adherence, metabolic effects, and comorbid mood disorders.

Can Diabetes Be Avoided When Patients Are on Antipsychotics? 

Determining the Root of Antipsychotic Risk in Type 2 Diabetes

Exactly how antipsychotics increase the risk for T2D is unclear. However, researchers like Dr. Freyberg are beginning to gain a greater understanding. His laboratory at the University of Pittsburgh seeks to elucidate the clinical efficacy of antipsychotics used to treat schizophrenia by studying the mechanisms of dopamine receptor signaling via D2 and D3 receptors.

“Antipsychotic drugs are not only targeting the brain, they are also targeting receptors outside the brain, including in the pancreas, including these beta cells that produce insulin,” says Dr. Freyberg. It’s widely accepted that an imbalance in dopamine – particularly too much dopamine in the striatum – drives psychosis and the main target of antipsychotics are thought to be D2 receptors.

“Dopamine and D2 receptors are also found in plentiful quantities outside the brain, particularly in the beta cells on the pancreas,” he adds. “These insulin-producing cells make their own dopamine and ordinarily use the dopamine to control insulin release through these same D2 receptors.” By blocking D2 receptors, antipsychotics may interfere with the production of insulin.

We also know that diabetes is mediated by insulin insensitivity – peripheral tissues do not efficiently utilize glucose – and by decreased insulin production by the pancreas, the latter of which is needed for peripheral tissues to absorb and utilize glucose.6

The action of antipsychotics on D2 receptors in the pancreas could help to explain why many people with schizophrenia are pre-diabetic and diabetic, even without being overweight (which is often but not always involved in T2D).

Dr. Christofides further explains that, in addition to the pancreas, some antipsychotics can alter hypothalamic functioning, causing a central effect that increases the risk for developing diabetes. The involvement of the hypothalamus is a likely result of antipsychotics targeting dopamine receptors, and in the case of second generations antipsychotics, serotonin receptors.13

Not All Antipsychotics Have the Same Metabolic Effects

When prescribing antipsychotics seems like the only option to successfully manage symptoms of schizophrenia, it’s important to remember that individual drugs differ in metabolic effect. According to Dr. Freyberg, “All antipsychotics decrease insulin sensitivity but to different degrees…. [They] heighten the odds of developing diabetes but if the patient is monitored effectively, the risk can be managed and, while all antipsychotics affect insulin sensitivity, not all antipsychotics cause weight gain.”

Dr. Pillinger’s work supports this view. He and his colleagues performed a meta-analysis of 100 RCTs to review which metabolic alterations occur in treatment with different antipsychotics. They investigated treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentration. Additionally, they performed a meta-regression analysis to examine the relationships between metabolic change and age, sex, ethnicity, and baseline weight.

The analysis showed that “marked differences exist between antipsychotics in terms of metabolic side effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Greater increases in glucose were predicted by higher baseline weight and male sex.”

The team further found that non-White ethnicity was associated with greater increases in total cholesterol compared to White ethnicity. Overall, improvements in symptom severity were associated with increases in weight, and LDL cholesterol as well as decreases in HDL cholesterol.3

Dr. Pillinger tells Psycom Pro, “Our research has shown that not all antipsychotics have the same potential to cause weight gain and metabolic dysregulation, so all things being equal, we should be prescribing those drugs that have better metabolic side-effect profiles first-line. Also, it is important to recognize that, overall, antipsychotics are associated with increased life expectancy in people with schizophrenia….  by reducing deaths by suicide and misadventure, and likely by improving longer-term engagement with physical health services.”

He explains that this increase in life expectancy outweighs the years lost because of increased metabolic and cardiovascular disease, pointing out that there is a net increase in years lived.

Editor’s Note: Dr. Pillinger’s team findings, combined with other work on the assessment, investigation, and management of physical health conditions in people with severe mental illness, were recently published in the Maudsley Guidelines for Physical Health.

There have been many other attempts to categorize which antipsychotics are better or worse –metabolically speaking. Generally, second-generation or atypical antipsychotics have a worse metabolic profile but their specific effects are heterogeneous. (See our antipsychotics prescribing primer)

Professional Takeaways

As is true with any disorder, it is important to treat the whole patient. Psychosis is often the most debilitating symptom of schizophrenia and should be managed accordingly. However, when other factors are of concern – such as insulin insensitivity, glucose intolerance, and weight gain – negative and cognitive symptoms need to be addressed, ideally from diagnosis onward.

“We know that early intervention (eg, diet, exercise, even medication) can slow progression from impaired glucose tolerance to diabetes in the general population; there is no reason to expect that this shouldn’t be achievable in people with schizophrenia too,” says Dr. Pillinger. Indeed, the research suggests this is achievable when patients receive proper monitoring, support, and guidance.

References
Last Updated: Oct 1, 2021