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| Subscribe to Clinical Compass™ | VOLUME 3, ISSUE 7 - MARCH 25, 2008 | ||||||||||||||||||||||||
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Beware the Prevalence of Diabetes Mellitus by Eleanor Roberts, PhD Tuesday March 25th sees the 20th Annual American Diabetes Alert Day. Diabetes mellitus (DM) is a growing concern in the United States with around 200,000 deaths each year directly attributable to this disorder. There is an increased risk of comorbid type 2 DM (T2DM) in patients with various psychiatric disorders. For instance, the prevalence of T2DM in people with schizophrenia is estimated to be at least 2-3 fold higher than for the general population.(1) In one study, people with T2DM were shown to have depression prevalence rates of 20% compared with only 4% in healthy controls (p = .04).(2) Comorbidity can adversely affect both conditions(3) and may lead to an early death.(4) This is evidenced by an investigation that compared people with a single diagnosis versus a dual-diagnosis of T2DM and depression. They found that a dual-diagnosis conferred a 2.5-fold increased likelihood of death over a period of 8 years.(5) Comorbidity may be due to possible genetic predisposition, exacerbating disease-related factors, lifestyle factors such as poor nutritional choices and lack of exercise, and iatrogenic effects of some psychotropic medications.(6) With regard to the former, investigations have revealed an increased prevalence of T2DM-related factors in both first-episode and drug naïve patients with schizophrenia and their first-degree relatives. This is an intriguing finding considering the genetic links to psychiatric illnessess.(7) The exact relationship between depression and T2DM is not well elucidated, however it is known that symptoms involved in depression can impact insulin and glucose regulation and vice-versa. For instance, people with mood disorders, especially stress-related, are shown to have disturbances in hypothalamus-pituitary-adrenal axis modulation of glucocorticoids such as cortisol,(8) which can lead to downstream increases in blood glucose levels and to insulin resistance.(9) Neurobiological studies have indicated a link between depression and diabetes via the similar effects they have on the brain. For example, volume decreases of the hippocampus, amygdala, or orbitofrontal grey matter (OFGM) have been shown in people with either of these disorders.(8) These areas are involved in the processing and manifestation of emotions and their integration with working memory.(3) It does not follow though that everyone with T2DM develops depression. There is some evidence that those who have a predisposition to a mood disorder will manifest these neurobiological changes when T2DM is present. One study found that people comorbid for T2DM and depression had a correlation between decreased right OFGM volume and low performance on tests of executive functioning and attention/processing speed. There appeared to be a linear trend whereby although this measure in the group with T2DM alone was not significantly different from the controls, it was also not significantly different from the dual diagnosis patients, suggesting an additive effect of comorbidity. Also a factor in the development of T2DM in this cohort is lifestyle. On average people with schizophrenia or depression have higher levels of obesity, higher intake of sugar and fats, and lower levels of physical activity. These are well known to be factors in the development of both insulin resistance and reduced insulin sensitivity.(10) However, even though genetic-, medical- or lifestyle-related factors may contribute to the comorbidity of T2DM and a psychiatric disorder, increased odds for such comorbidity are most significantly associated with the use of second-generation antipsychotics (SGAs).(1) The morbidity rate of T2DM is correlated significantly with antipsychotic antagonism of 5HT2C and H1 receptors.(11, 12) Insulin resistance is also significantly associated with occupancy of 5HT2A receptors.(13) It is important to note that actions at these receptors alone can be enough to lead to the development of T2DM, without obesity.(14) However, SGAs are also linked to the development of T2DM by increasing the propensity of a person who is taking them to gain weight. One of the mechanisms for weight gain due to antipsychotics is thought to be via their action on hormones such as leptin. Leptin signals satiety to the hypothalamus, but over-stimulation can lead to leptin resistance, increased food consumption, and thus weight gain.(11, 15) The occurrence of resistance to both insulin and leptin, as well as glucose intolerance, is thought to occur through central effects of SGAs at the hypothalamus, and peripheral effects on adipocytes and skeletal muscle.(11, 13-15) There is conflicting evidence as to which SGAs increase the risk of T2DM. A study investigating 15,767 patients with schizophrenia who did not show T2DM/insulin sensitivity found that, compared to haloperidol, the hazard ratio for developing T2DM over the course of a year was 1.67 for quetiapine, 1.64 for olanzapine, and 1.60 for risperidone.(16) However, a 14 study meta-analysis found an increased T2DM risk for olanzapine only.(6) There are also associations between T2DM and clozapine,(1) and it is known that the high affinities of olanzapine and clozapine for the H1 receptor tightly correlate with their orexigenic effects, as well as with weight gain itself.(17) It may be that underlying genetic, medical, and lifestyle factors greatly influence the degree to which an antipsychotic can affect diabetes-related metabolism. There is increasing pressure on mental healthcare professionals to be aware of their patients’ overall medical health.(18, 19) People who are comorbid for a psychiatric disorder and T2DM tend to have poorer glycemic control, longer duration of T2DM, more medical complications, lower medication adherence, and a decreased quality of life.(2, 20) This is a population that is being underserved. In one survey only 30.3% of the people with schizophrenic and T2DM were receiving any diabetic medication.(1) This signals a need for mental healthcare professionals to be aware of the prevalence of T2DM in their psychiatric population. Recognition and control of T2DM in patients should include baseline medical assessments as well as long-term monitoring.(21) Not prescribing or switching off of medications such as olanzapine or clozapine may seem like a simple answer, however the fact that these are very effective medications does not always allow for these measures. In all cases, patient education on the importance of exercise and nutrition in the control of T2DM need to be both understood and utilized. In summary, the increased prevalence of T2DM and related indicators in patients with psychiatric disorders may be due to factors related to genetics, medical issues, lifestyle, and/or iatrogenic drug effects. These factors as a whole need to be investigated and addressed by mental healthcare professionals. Additional information regarding the relationship between antipsychotics and metabolic factors can be found in several archived neuroscienceCME activities including the neuroscienceCME TV activity Unmasking the Fallout of Antipsychotic-Induced Weight Gain. Do you have feedback for the author? Click here to send us an email. References
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