Study demonstrates link between mental illness and metabolic disorders

Article published in the Journal of Psychiatric Research shows more severe psychiatric and metabolic conditions in patients with bipolar disorder and low levels of adiponectin.

By Karina Toledo  |  Agência FAPESP – Recent studies have shown that psychiatric diseases, including bipolar disorder and depression, are often associated with metabolic disturbances such as type 2 diabetes, dyslipidemia and obesity. Scientific evidence also suggests that mental illness can influence metabolic disorders and vice versa.

This correlation has been observed by researchers at the Federal University of São Paulo (UNIFESP) in Brazil, according to a paper published recently in the Journal of Psychiatric Research.

The study, involving 59 patients with bipolar disorder, found that low levels of adiponectin were associated with more severe mental illness. Adiponectin is a protein hormone produced by adipose tissue that helps regulate glucose and lipid metabolism.

“Examining the medical history of these patients with low adiponectin levels, we noticed more frequent mood swings and psychiatric hospital admissions as well as persistent depressive symptoms and worse psychosocial functioning. They also had more metabolic disorders, such as glucose intolerance, diabetes and dyslipidemia,” said Elisa Brietzke, a professor at UNIFESP’s Medical School (EPM) and principal investigator for the project, which was supported by FAPESP.

If the findings are confirmed by future studies, Brietzke added, the level of adiponectin in the blood of patients with bipolar disorder could be used as a biomarker to help diagnose and treat the disease, with a low level of adiponectin indicating a worse condition from both the psychiatric and the metabolic standpoints.

These results also pave the way for new research designed to test interventions that modulate adiponectin levels in bipolar patients, she said.

The study was conducted at UNIFESP during Rodrigo Mansur’s PhD research. Mansur is currently a fellow at the University of Toronto in Canada. The initial aim was to compare blood levels of adiponectin and leptin between healthy and bipolar volunteers. Leptin is also a hormone secreted by adipose tissue, with an important role in metabolic regulation and appetite control.

“These hormones act locally and systemically,” Mansur said. “Receptors for these molecules are expressed in multiple brain regions, and their activation produces significant physiological effects. Both hormones appear to be part of inflammatory response control. Alterations in their production have been described in metabolic diseases such as obesity and type 2 diabetes. Our research focuses on the interface between mental disorders and metabolic diseases, so we’re particularly interested in mediators, mechanisms and systems that link the brain and periphery.”

Generally, no significant differences in levels of the two hormones were observed between bipolar patients and healthy volunteers, except when only women were observed: female bipolar patients had lower levels of adiponectin than women without the disorder.

In Brietzke’s opinion, however, the most interesting finding derived from a comparison of hormone levels between only bipolar patients. “There was a clear division into two subgroups: one with lower adiponectin and a more severe condition and the other with higher adiponectin and a more moderate condition,” she said.

Mansur added that the differences were found to be independent of confounding factors, such as age, smoking and use of antipsychotic drugs.

“The main interpretation is that there’s a direct association between metabolic multimorbidity and a more severe or complicated course of bipolar disorder,” Mansur said. “Adiponectin can therefore be understood as an indicator of metabolic dysfunction. But given the importance of adiponectin receptor signaling in the brain, it’s also possible that this molecule has a direct effect on the brain’s structure and functioning and hence on the treatment of bipolar disorder.”

As for leptin, no significant differences were found between any of the groups.

Central versus peripheral

The studies performed by the UNIFESP team are based on the hypothesis that the peripheral and central metabolisms are integrated, so that the presence of a metabolic comorbidity such as type 2 diabetes in bipolar disorder may be the effect – and/or the cause – of altered brain functioning.

“Evidence from many studies shows that even when metabolic disorders are not accompanied by mental illness, they involve cerebral abnormalities such as dysfunctions in the circuits that regulate emotional and cognitive processing,” Mansur said. “Psychiatric disorders, including depression and schizophrenia, are differentially affected by metabolic conditions, even after controlling for traditional risk factors such as sedentary lifestyle, diet, smoking and the use of medication.”

This result shows that the so-called monoaminergic model, which focuses solely on neurotransmitters and treatment with antidepressant and antipsychotic drugs, is highly insufficient, according to the researchers.

“These therapies can help a significant proportion of mentally ill patients, but they frequently fail,” Mansur said. “For example, studies show that up to 50% of patients with bipolar disorder respond unsatisfactorily. We urgently need broader theoretical models that are better suited to an understanding of the physiopathology of psychiatric disorders and can serve as a foundation for the development of genuinely innovative and transformative therapies.”

Mansur’s current activity in Canada includes participation in a study designed to test the efficacy of liraglutide in treating cognitive deficiencies in individuals with mood disorders.

Liraglutide, which was originally developed to treat type 2 diabetes, is a glucagon-like peptide 1 (GLP-1) receptor agonist. GLP-1 is a hormone secreted predominantly by the small intestine and released in response to food intake. GLP-1 also facilitates the use of glucose in multiple tissues, including those of the nervous system.

According to Mansur, preclinical trials have shown that liraglutide also has neuroprotective and neuroproliferative effects, protecting neurons from insults and stimulating the growth of dendrites and synaptic connections. These findings suggest a possible precognitive effect.

“Our preliminary data have shown an overall cognitive improvement in tests that measure executive functions, memory and processing speed,” he said. “We also observed an effect on the brain – an increase in a neural integrity marker – which correlates well with this cognitive improvement. An interesting point is that the improvement was most intense in patients with insulin resistance, suggesting that this population with metabolic problems is more responsive to interventions targeting a metabolic pathway.”

However, Mansur stressed that this is a pilot study involving a small number of patients and no placebo group. “The results are promising but preliminary and still in development,” he said.