The Alteration of Inflammatory Reflex and Its Association with Psychotropic Drugs in Bipolar Disorder from Acute Mania to Full Remission

Background: It is known that patients with bipolar disorder are at high risk of cardiovascular morbidity and have increased premature mortality from cardiovascular disease. An increase in the ratio of sympathetic to parasympathetic activity may be associated with more severe manic symptoms and unusual thought content. Cardiac function in manic patients is characterized by decreased HRV, reduced vagal tone, and a decline in heart rate complexity. Furthermore, there are increasing evidences that bipolar disorder and schizophrenia are associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. However, the involvement of above factors has been evaluated mostly in isolation. The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. The mechanisms underlying the sympathetic over-activity and systemic inflammatory activation can be explained by the dysfunctional inflammatory reflex. Up to date, there is none investigation to explore the inflammatory reflex in bipolar disorder. Aims: The goals of this study are (1) to explore the association between HRV and inflammatory markers related to inflammatory reflex from acute mania to full remission; (2) to determine what extent the antipsychotics, mood stabilizer, and anticholinergics affect the interaction between inflammatory markers and HRV in bipolar disorder. Methods: This is a 3-year proposal. Physically healthy and aged 18 to 45 years in-patients with bipolar I, manic episode without comorbid any other Axis I disorder will be recruited. Age (±2)- and sex- matched healthy schizophrenic patients and normal adults will be recruited as the comparison group and normal control group, respectively. The HRV and inflammatory markers, such as interleukin (IL)-1, IL-2, IL-6, TNF-, IL-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), sIL-6R, TNF-R1, high sensitivity C-reactive protein (hs-CRP), etc. of patients and normal controls will be measured. The HRV and inflammatory markers of bipolar patients along with schizophrenic ones will be measured in three phases; acute psychotic state (bipolar mania: YMRS>20 and HDRS-17<7; schizophrenia: a score of > 3 on delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness of PANSS ), partial remission, and full remission. The muscarinic pathway may be one of the major influencing factors. Based on the types of antipsychotics, we’ll divide patients into high muscarinic affinity (HMA) group and low muscarinic affinity (LMA) group for investigating the effects of medication on inflammatory reflex. The bipolar patients will receive either lithium or valproate therapy, and they will be divided into two groups for further analyses. Additional clinical data and level of physical activity will also be obtained by directly interviewing patients and reviewing medical records. Anticipated results: Based on the power analysis, 100 bipolar patients and matched controls will be recruited to provide sufficient power to meet the aims of study. There will be additional evidence to support the dysfunctional inflammatory reflex linking with alteration of immunomodulation and sympathovagal imbalance. In practice, the results will provide further knowledge to prevent CAD in patients with bipolar disorder.