Bipolar disorder ( BD) is a heterogeneous and genetically complex lifelong episodic illness with prevalence estimates in the range of 1-4% and variable clinical course. TB is associated with premature mortality , with the most common causes being cardiovascular disease (CVD) and suicide. Furthermore, TB patients are significantly more affected than the general population by obesity and its complications, such as type 2 diabetes (T2DM), cardiovascular diseases, and metabolic syndrome. In fact, the prevalence of metabolic syndrome in TB patients can double compared to that of the general population.
Insulin resistance ( IR) plays a vital role in the pathogenesis of T2DM, metabolic syndrome, and CVD. In the early stage of IR, insulin hypersecretion with normoglycemia occurs ; However, over time, the pancreas’s ability to increase insulin secretion is exhausted. Ultimately, IR represents a metabolic state in which peripheral organs resist the biological effect of insulin action. The “gold standard” method for measuring IR is the euglycemic-hyperinsulinemic clamp; however, given the complexity of this procedure, its routine clinical use is limited. Alternative measures based on fasting or fasting glucose and insulin levels are limited. after a 2-hour oral glucose tolerance test are widely used in clinical and research settings.
A recent meta-analysis revealed that 22.4% of people with BD had high fasting plasma glucose (FPG) cutoff values [FPG ≥ 100 mg/dL (FPG ≥ 100)] (95% CI, 16.7– 28.7%); diagnosis of impaired fasting glucose and suggestive of insulin resistance (IR). Furthermore, it revealed for people with TB an almost 1.6 times higher risk of developing T2DM and an equally high risk of obesity (RR = 1.67, 95% CI: 1.32–2.12, p < 0.001). .
Interestingly, IR has been identified in newly diagnosed TB patients, but not in their unaffected first-degree relatives or in comparison to matched non-TB controls. Furthermore, people with TB and IR are more likely to develop worse clinical outcomes with a longer course than euglycemic TB patients. For example, they cycle more rapidly and have a worse response to lithium and mood stabilizers . A recent systematic review provided qualitative evidence that impaired glucose metabolism (IGM) could be considered a risk factor for worse outcomes in BD, including a chronic disease course, worse global functioning, and rapid cycling. However, given the great heterogeneity between studies, a quantitative measure of the magnitude of the effect of IR on clinical outcomes in BD is not yet available.
Despite the prevalence of IR and its cardiometabolic consequences, to our knowledge, only a few studies have attempted to evaluate the degree of IR in subjects with TB or its effects on the clinical course. Furthermore, there is little and mixed evidence on the clinical interaction between BD and IR. Therefore, the following systematic review aims to provide information on the most current findings on the clinical correlates of IR in BD, including its impact on neuroimaging findings, cognitive domains, disease course, and response to treatment. A comprehensive understanding of IR in BD may help refine pathophysiological models of BD. Furthermore, it may encourage individualized interventions aimed at treating both metabolic and psychiatric abnormalities.
Background
Although insulin resistance (IR) and cardiometabolic syndrome are prevalent in patients with bipolar disorder (BD), only a few studies have attempted to accurately evaluate the degree and clinical impact of IR in BD.
Methods
A comprehensive search was conducted across multiple research databases through May 2022, following a predefined protocol (PROSPERO: CRD42022359259). We extracted neuroimaging findings, cognition, disease course, and treatment response of individuals with BD with evidence of IR compared to euglycemic individuals with BD.
Results
Of 1436 articles identified, 10 reports that met the inclusion criteria were included (n = 1183).
Bipolar disorder (BD) patients with insulin resistance (IR) showed worse verbal memory composite scores and executive function and exhibited smaller hippocampal volumes along with prefrontal neurochemical alterations compared to euglycemic BD patients.
Fixed effects meta-analysis revealed that BD patients with impaired glucose metabolism (IGM) were more likely to develop rapid and chronic cycling compared to euglycemic BD patients (k = 2, OR = 2.96, 95% CI 1.69–5.17, OR=2.88, 95% CI 1.59–5.21, p<0.001, respectively), with a trend toward significantly lower Global Assessment scores of functioning (k=5, MD=−4, 95% CI −8.23–0.23, p=0.06).
BD patients with impaired glucose metabolism (IGM) showed a higher rate of poor response to mood stabilizers compared to euglycemic BD patients (k = 2, OR = 6.74, CI 95%: 1.04–43.54, p = 0.04).
Limitations
The cross-sectional design and small sample sizes of the included studies limit the generalizability of the results.
Conclusion Insulin resistance (IR) is associated with worse clinical outcomes in bipolar disorder (BD) and inadequate response to treatment. The implementation of strategies to prevent and treat IR in TB is crucial to improve the prognosis of such a difficult-to-treat population. |
