Medication status modulates metabotropic glutamate receptor 5 availability in bipolar disorder and its associations with attention, anhedonia, and cognition

Bipolar disorder (BD) is a neuropsychiatric condition associated with affective and cognitive symptoms, impulsivity, and suicidality. The metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in BD, but the relationship between psychiatric medication use and mGlu5 availability remains unclear. Using 18 FFPEB positron emission tomography (PET), we measured mGlu5 in ventromedial prefrontal (vmPFC), orbitofrontal (OFC), and dorsolateral prefrontal (dlPFC) cortices, amygdala, and hippocampus in 48 individuals with BD (21 medicated) and 48 age and sex-matched healthy controls (HC). Group differences in mGlu5 availability were tested with analysis of covariance, controlling for cannabis and nicotine use. Clinical assessments of depression (MADRS), anhedonia (SHAPS), attention (Barratt Impulsiveness Scale), and cognition (Groton Maze Learning Test) were examined in relation to regional mGlu5 availability using linear regression. Significant group effects were observed across ROIs, showing lower mGlu5 in unmedicated BD relative to medicated BD and HC, with effects in the vmPFC ( p = 0.003), OFC ( p = 0.006), dlPFC ( p = 0.007), amygdala ( p = 0.009), and hippocampus ( p = 0.010). Across the full sample, lower OFC mGlu5 was associated with poorer executive function (β = −0.25, p = 0.044). In unmedicated BD, lower mGlu5 correlated with greater attentional difficulties (r's = −0.52 - -0.54, all p's < 0.05). In medicated BD, worse anhedonia correlated with lower mGlu5 (r's = −0.41–0.43, all p's < 0.05). These associations remained statistically significant after adjustment for depressive symptom severity, nicotine, and cannabis use. Findings indicate that medication status is associated with differences in mGlu5 availability in BD. mGlu5 availability in medicated participants was closer to that of HC, supporting further investigation of glutamatergic mechanisms as potential therapeutic targets in BD. • Unmedicated bipolar disorder shows lower mGlu5 across frontolimbic regions. • Medication status is associated with mGlu5 availability closer to healthy controls. • Lower OFC mGlu5 is associated with poorer executive function across participants. • mGlu5 may be a potential biomarker and therapeutic target in bipolar disorder.