Clinician Perspective: Examining the Link Between Antipsychotics and Diabetes

Life expectancy in individuals with schizophrenia is more than 20 times lower compared with the general population.¹ This may be due to poor physical health as well as elevated risk for suicide in this patient group.¹ While the use of antipsychotic drugs is linked with greater life expectancy in this population, these medications are also associated with metabolic side effects including obesity, dyslipidemia, and type 2 diabetes (T2D).²

A study published in 2012 found a 57% prevalence of metabolic syndrome in patients with schizophrenia vs 14% in the general population.³ In addition, the risk of developing antipsychotic-related metabolic side effects has been found to be higher in women compared with men. In research reported in 2005, 54.2% of women with schizophrenia had metabolic syndrome compared with 36.6% of men.⁴

“Variants in the … melanocortin 4 receptor (MC4R), the serotonin 2C receptor (HTR2C), the leptin, the neuropeptide Y (NPY) receptor, as well as the cannabinoid receptor 1 (CNR1) genes have been reported to be associated with increased antipsychotic induced weight gain,” according to a recent study published in the Nordic Journal of Psychiatry.⁵ The authors state the importance of early efforts to prevent T2D in patients with schizophrenia and note that obesity is the primary modifiable risk factor for T2D. “Apart from genetics and obesity, other risk factors for T2D include: age, unhealthy diet, physical inactivity, smoking, alcohol consumption, and obstructive sleep apnea,” they wrote.

These investigators studied the prevalence of elevated blood glucose levels, T2D, and dyslipidemia in Icelandic patients with schizophrenia who were taking clozapine and other antipsychotic medications. The sample included 188 patients taking clozapine (mean age, 51.2 years) and 395 patients who had never taken clozapine (mean age, 58.6 years).

Their results demonstrate a T2D prevalence of 14.3% in the clozapine group vs 13.7% in the no-clozapine group. In the clozapine group, women were 4.4-times more likely and men were 2.3-times more likely to have T2D than age-adjusted population controls. Among patients taking antipsychotics other than clozapine, women were 2.3-times more likely and men were 1.5-times more likely to have T2D compared to controls. Both groups showed significantly elevated triglycerides vs controls. 

“Clinicians must take active steps to reduce the risk of T2D and raised triglycerides in patients with schizophrenia,” the authors concluded.

For additional clinical insight, Psychiatry Advisor interviewed Kevin M. Pantalone, DO, ECNU, FACE, staff endocrinologist and director of clinical research in the department of endocrinology at Cleveland Clinic; and Christian Kohler, MD, clinical director of neuropsychiatry and associate professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania. 

Psychiatry Advisor: What is known about the association between antipsychotics and T2D risk, and what are the proposed underlying mechanisms?

Dr Pantalone: There is much literature to suggest that there is an elevated risk for T2D in patients with schizophrenia vs the general population and that this risk may be further increased in patients treated with antipsychotic medications. 

There are data from drug-naive patients — both from the era before the antipsychotic medications became available, as well as more recently — suggesting that there may be intrinsic metabolic risks associated with schizophrenia, largely related to genetics, lifestyle, and other factors. The use of antipsychotics appears to further increase that risk by causing significant metabolic side effects, including insulin resistance, dyslipidemia, obesity, and ultimately T2D.

The proposed mechanism is an increase in insulin resistance via the blocking of dopamine receptors. Many patients taking these therapies also have an increase in appetite that is centrally mediated and leads to weight gain. 

Dr Kohler: T2D is related to chronic dopamine blockade in the nigrostriatal system producing abnormal receptor functioning. TD2 is twice as common in [patients taking] the older first-generation antipsychotics than in the newer medications and is related to cumulative dose and years of exposure. Approximately 10% of persons taking first-generation antipsychotics experience TD2 at any given time.

Psychiatry Advisor: What are top takeaways for clinicians, and how is this risk addressed in clinical practice?

Dr Pantalone: It is important to weigh the risks vs benefits of all medications, including antipsychotics, especially when they are being used off-label. In recent years, these medications have increasingly been used for non-mental health-related disorders. Certainly, if the medications help to treat hallucinations or behaviors that could lead a patient with schizophrenia or another mental health disorder to harm oneself or others, then the benefit outweighs the associated risks. However, if being prescribed for other conditions, such as insomnia – as is rather common with [quetiapine] – one should consider using other therapies that are approved for that condition rather than the off-label use of an antipsychotic.   

Dr Kohler:  First-generation antipsychotics are no longer the first-line treatment for psychosis. Medication dosages should be kept as low as possible, and patients should be monitored for emergence of T2D using standard rating scales at 3- to 6-month intervals. 

Early emergence of T2D in the treatment course carries adverse consequences on social functioning. Patients should be monitored for T2D and protected from overexposure to medications. Early treatment of emergent T2D warrants close monitoring and change in antipsychotic medication, apart from a trial with specific medications such as valbenazine.

Psychiatry Advisor: What should be the focus of future research in this area?

Dr Pantalone: Additional research into the proposed mechanisms by which these drugs increase insulin resistance and negatively affect appetite control should be pursued, especially because their use is becoming more common.  This is happening primarily because patients and providers are becoming more comfortable talking about mental health disorders and related conditions. 

Dr Kohler:  Future studies should aim to identify persons at risk of developing T2D with antipsychotics through clinical examination, genetics, or serum markers. [Another area of focus should be] identifying medications that ameliorate T2D and can be given long-term without side effects. 

References

1. Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study).Lancet. 2009;374(9690):620-627.
2. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review.CNS Drugs. 2005;19(Suppl 1):1-93.
3. Sveinsson O, Thorleifsson K, Aspelund T, Kolbeinsson H. A study of risk factors for cardiovascular disease among schizophrenic patients using the rehabilitation mental health services at Kleppur.Laeknabladid. 2012;98(7-8):399-402.
4. McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res. 2005;80(1):19-32.
5. Ingimarsson O, MacCabe JH, Haraldsson M, Jónsdóttir H, Sigurdsson E. Risk of diabetes and dyslipidemia during clozapine and other antipsychotic drug treatment of schizophrenia in Iceland. Nord J Psychiatry. 2017;71(7):496-502.