Insulin Resistance in Schizophrenia Occurs With and Without Antipsychotics

In the United States, rates of obesity continue to rise.
In the United States, rates of obesity continue to rise.
Researchers found data that showed patients with schizophrenia have an increased risk for metabolic disorders, and aripiprazole, lurasidone, and ziprasidone may offer the lowest risk for weight gain.

Patients with schizophrenia have an increased risk for death compared with the general population due to suicide, heart disease, and metabolic diseases, such as diabetes.1 Recent scientific evidence has linked metabolic syndrome in schizophrenia to the use of second-generation antipsychotics, with 1 small study showing that 11.66% of 120 patients developed metabolic syndrome after 4 months of antipsychotic treatment.2

At the same time, researchers from recent investigations indicated that rates of insulin resistance, impaired glucose tolerance, and hyperinsulinemia are also high in patients who have not used antipsychotics.3 In Reviews on Biomarker Studies of Metabolic and Metabolism-Related Disorders, researchers examined findings surrounding insulin resistance in schizophrenia with and without antipsychotic treatment to better understand the etiology of this disease and identify the best possible treatment outcomes.

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Antipsychotics and Insulin Resistance in Schizophrenia

Since the 1970s, antipsychotics in schizophrenia have been shown effective at improving cognitive and psychotic symptoms; however, side effects such as weight gain and metabolic syndrome have overshadowed these improvements. Clozapine and olanzapine, which researchers consider 2 of the most effective antipsychotics in schizophrenia treatment, have been found most likely to cause weight gain and disturbances in glucose and lipid metabolism.3 Results from a 2013 study showed that the rate of metabolic syndrome in schizophrenia was higher in patients who used clozapine compared with those who did not receive medication (51.9% vs 20.2%).3 Researchers of another study indicated that 43% of patients with schizophrenia who used clozapine developed type 2 diabetes.3

Researchers have linked the weight gain associated with clozapine to antagonism of the histaminergic H1 receptor, which increases the risk for insulin resistance and type 2 diabetes.3 Other factors linking weight gain with antipsychotics in schizophrenia include dosage and duration of treatment, stress, diet, and physical activity level. Of all the antipsychotics used to treat schizophrenia, clozapine and olanzapine are found to present the highest risk for weight gain, while aripiprazole, lurasidone, and ziprasidone may offer the lowest risk for weight gain.3

Insulin Resistance Without Antipsychotics in Schizophrenia

A number of metabolic abnormalities including insulin resistance are shown to affect patients with schizophrenia before they even begin antipsychotic therapy. Researchers of a 2003 study indicated that compared with healthy controls, 15.4% of drug-naive patients with schizophrenia had impaired fasting glucose tolerance, elevated insulin resistance, and significantly higher fasting plasma levels of glucose, insulin, and cortisol.4

Impaired glucose tolerance in schizophrenia has been identified in nonaffected relatives, which has led researchers to believe that metabolic syndrome may stem from a shared environmental or genetic background.3

Growth Hormone and Insulin Resistance

Researchers of multiple studies have indicated that patients with schizophrenia tend to exhibit changes in levels of growth hormone, which shares many elements of the same signaling pathways as insulin.3 Investigators of a case report published in 2014 found that 3 patients with schizophrenia who received antipsychotic therapy for several years developed acromegaly due to growth hormone-secreting pituitary macroadenoma. Researchers concluded that schizophrenia on its own or long-term antipsychotic therapy were closely associated with pituitary adenomas that secreted growth hormones.5

Cortisol and Insulin Resistance

Drug-naive patients with schizophrenia have also been shown to have higher circulating levels of cortisol and insulin compared with healthy controls.4 Additionally, when compared with healthy controls, ultrahigh-risk and drug-naive patients with first-episode schizophrenia have been found to have altered levels of cortisol, which suggests that altered cortisol may play a role in early phases of the disease.3 Researchers have yet to determine the exact mechanism and relationship between insulin and cortisol secretion in this population.

Gonadal Steroids and Insulin Resistance

Researchers of several studies have revealed that many steroid hormones of the hypothalamic-pituitary gonadal axis may affect the development and progression of schizophrenia. In a 2002 study, estrogen was found to be neuroprotective and contribute to the later onset of schizophrenia in women than in men, along with lower severity of symptoms.3 Researchers of another study conducted in 2005 found that compared with healthy controls, men with schizophrenia had significantly lower levels of testosterone, estrone, and estradiol.3

Other Hormones and Insulin Resistance

Patients with first-episode schizophrenia have been found to have increased serum concentrations of progesterone, prolactin, chromogranin A, and pancreatic polypeptide, in addition to the aforementioned hormones. For instance, insulin resistance in men has been linked to higher serum prolactin levels, while obese rats have shown increased levels of progesterone and hyperinsulinemia. Multiple researchers demonstrated links between these hormones and metabolic disturbances in patients with first-episode and chronic schizophrenia.3


Researchers have concluded that insulin resistance and metabolic syndrome can manifest in schizophrenia before and after the initiation of antipsychotics. Physical activity interventions have been effective at helping patients with schizophrenia manage and prevent metabolic syndrome, though compliance may be problematic, and plans for increasing compliance are recommended.3

Researchers have found that the use of metformin with antipsychotics is becoming more widespread, since metformin assists with mild weight loss and is effective at reducing insulin, fasting glucose, and triglyceride levels. Hormones and medications that target the hypothalamic-pituitary adrenal and hypothalamic-pituitary gonadal axes have also been effective at improving cognition in schizophrenia and keeping insulin resistance at bay.3


1. Ventriglio A, Gentile A, Stella E, Bellomo A. Metabolic issues in patients affected by schizophrenia: clinical characteristics and medical management. Front Neurosci. 2015;3(9):297.

2. Gautam S, Meena PS. Drug-emergent metabolic syndrome in patients with schizophrenia receiving atypical (second-generation) antipsychotics. Indian J Psychiatry. 2011;53(2):128-133.

3. Guest PC. Insulin resistance in schizophrenia. In: Reviews on Biomarker Studies of Metabolic and Metabolism-Related Disorders. Cham, Switzerland: Springer; 2019:1-16.

4. Ryan MC, Collins P, Thakore JH. Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry. 2003;160(2):284-289.

5. Iglesias P, Bernal C, Díez JJ. Curious cases: acromegaly and schizophrenia: an incidental association? Schizophr Bull. 2014;40(4):740-743.