Increased serum levels of NMDA receptor antibodies in female patients with bipolar disorder

Objective: Glutamatergic/GABAergic imbalance due to autoimmune antibodies targeting N-methyl-D-aspartate receptors (NMDA-R) is considered to be one of the shared pathways between bipolar disorder (BD) and autoimmune diseases. Evidence shows female vulnerability to autoimmune disorders, and suggests a sex-specific approach in autoimmunity research in BD. We aimed to assess serum concentrations of NMDA-R antibodies and density of NMDA and GABA receptors on platelets in euthymic patients with BD in comparison to healthy individuals; and to determine the impact of sex on serum concentrations of NMDA-R antibodies and the density of NMDA and GABA receptors on platelets. Method: NMDA antibody IgG were detected in serum samples of 27 DSM IV euthymic patients with bipolar disorder (16 females, 11 males) and 33 healthy individuals (17 females, 16 males), using ELISA method. The densities of NMDA and GABA receptors on platelets were investigated using immunocytochemical methods. Results: Patients with BD presented higher serum levels of NMDA-R antibodies in comparison to healthy individuals (p<0.001). The densities of NMDA and GABA receptor on platelets were similar in both groups. The NMDA-R antibody levels were influenced by both diagnosis and sex (F=5.813, df=1, p =0.020). Tserum lithium levels showed a significant linear association with the serum NMDA-R antibody levels even adjusting for age, sex, body mass index (F=-56.26, t=-2.52, p = 0.015, CI: -101.12/-11.40). Discussion: Our findings support a potential role of NMDA-R antibodies in the underlying pathophysiology of BD, particularly for females