Targeting the glutamatergic system is posited as a potentially novel therapeutic strategy for psychotic disorders. While studies in subjects indicate that antipsychotic medication reduces brain glutamatergic measures, they were unable to disambiguate clinical changes from drug effects.

To address this, we investigated the effects of a dopamine D2 receptor partial agonist (aripiprazole) and a dopamine D2 receptor antagonist (amisulpride) on glutamatergic metabolites in the anterior cingulate cortex (ACC), striatum and thalamus in healthy controls.

A double-blind, within-subject, cross-over, placebo-controlled study design with two arms (n = 25 per arm) was conducted. Healthy volunteers received either aripiprazole (up to 10 mg/day) for 7 days or amisulpride (up to 400 mg/day) and a corresponding period of placebo treatment in a pseudo-randomised order. Magnetic resonance spectroscopy (1H-MRS) was used to measure glutamatergic metabolite levels and was carried out at three different time points: baseline, after 1 week of drug and after 1 week of placebo. Values were analysed as a combined measure across the ACC, striatum and thalamus.

Aripiprazole significantly increased glutamate + glutamine (Glx) levels compared with placebo (β = 0.55, 95% CI [0.15, 0.95], P = 0.007). At baseline, the mean Glx level was 8.14 institutional units (s.d. = 2.15); following aripiprazole treatment, the mean Glx level was 8.16 institutional units (s.d. = 2.40) compared with 7.61 institutional units (s.d. = 2.36) for placebo. This effect remained significant after adjusting for plasma parent and active metabolite drug levels. There was an observed increase with amisulpride that did not reach statistical significance.

One week of aripiprazole administration in healthy participants altered brain Glx levels as compared with placebo administration. These findings provide novel insights into the relationship between antipsychotic treatment and brain metabolites in a healthy participant cohort.

High-fat diet (HFD) consumption during pregnancy can shape fetal brain development, increasing susceptibility to mental disorders. Nevertheless, the mechanisms underlying these negative outcomes remain unclear.

We hypothesize that mHFD induces inflammation and oxidative stress (OS) in the fetal brain, disrupting excitatory/inhibitory (E/I) balance in the adult brain. This results in altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, emotional regulation, and cognitive function. We tested the ability of N-acetyl-cysteine (NAC) - a powerful anti-oxidant and anti-inflammatory compound - to counteract mHFD effects.

Our mHFD model consists of female C57BL/6N mice fed either HFD (fat 58%, carbohydrate 25.5%, and protein 16.4%) or control diet (CD, fat 10.5%, carbohydrate 73.1% and protein 16.4%) before and during pregnancy (13 weeks). After 5 weeks on diets, half of them received NAC (1g/kg) for 8 weeks, until delivery.

Gene expression of Il-1b, Cd68, Tmem119, iNOS, and Arg1 was measured in fetal brains. Cognitive function and emotional phenotype were assessed in adult male and female offspring through the Morris Water Maze (MWM) and the Emergence test, respectively. HPA axis functionality was assessed by measuring plasma corticosterone levels by ELISA following acute stress. Gene expression of vesicular glutamate transporter 1 (Vglut1) and vesicular GABA transporter (Vgat) were assessed as markers of E/I balance.

Exposure to mHFD induced inflammation and OS in the fetal brain of both sexes, by increasing Il-1b and iNOS/Arg1. Additionally, Cd68 and Tmem119 were specifically increased in females. In adulthood, mHFD reduced latency to emerge from the shelter in the Emergence test in both sexes. In females, mHFD impaired cognitive function, reducing time spent in the MWM target zone, and increased HPA reactivity in response to acute stress. Furthermore, mHFD decreased Vgat expression in both sexes, resulting in an imbalanced Vglut1/Vgat ratio towards excessive excitatory input. Maternal NAC supplementation rescued this imbalance.

Overall, these data show that mHFD increases inflammation and OS in fetal brains, with greater effects in female offspring, inducing alterations in the E/I neuronal balance with concomitant disruptions of the neuroendocrine system and the emotional and cognitive profiles during adulthood. The supplementation with NAC was effective in rescuing the E/I imbalance as well as the behavioral phenotype.

None Declared

Bipolar disorder (BD) is characterised by heterogeneous phenotypic manifestations that may affect the achievement of a timely diagnosis delaying its therapeutic management. Increased circulating levels of pro-inflammatory cytokines and cortisol (CORT) have been observed in BD patients in addition to decreased levels of Brain-Derived-Neurotrophic Factor (BDNF) suggesting that the interaction among these mediators may play a role in the occurrence of affective episodes overall disrupting brain plasticity. However, knowledge on BD etiopathogenesis is still limited, including the causal relationship with inflammatory and neuroendocrine markers.

To assess whether variations in peripheral neuroendocrine and inflammatory markers during acute phases of the disease and euthymia might predict the occurrence of affective episodes; to evaluate whether the interplay among these biomarkers might be exploited as a signature of BD.

We are currently recruiting BD patients during depressive or manic/hypomanic phases together with age- and sex-matched healthy controls (CTRLs). Complete blood count, pro-inflammatory, anti-inflammatory cytokines and BDNF will be assessed in serum; salivary cortisol awakening response test will be used to evaluate hypothalamic-pituitary-adrenal axis activity. MADRS, YMRS and HAM-A will be used to assess psychiatric symptoms, PSP and C-SSRS for global functioning and suicidal risk, IPSS and SRRS for stress levels and CIRS to evaluate physical comorbidities. All assessments will be carried out at the time of recruitment (T0) and after 3 (T1) and 6 (T2) months.

Data have been so far collected on 28 BD patients (18 males, 10 females, age: 48.31±11.3) and 26 CTRLs (16 males, 10 females, age: 46.82±10.86). At T0, BD were characterised by a greater total number of white cells (7.83±1.86 BD vs. 6.78±1.87 CTRL, p<0.05), mean number of neutrophils (4.89±1.49 BD vs. 3.92±1.45 CTRL, p<0.05) and neutrophil/lymphocyte ratio (NLR) (2.52±1.1 BD vs. 1.9±0.69 CTRL, p<0.05). Moreover, BD patients showed overall a greater BMI (30.5±6.6 BD vs. 24.45±3.86 CTRL, p<.001). No difference was observed among groups with respect to sex and age.

Although preliminary, these results suggest that the active phases of BD are associated with a low-grade inflammatory state, potentially related to a different metabolic set-point in BD patients. Ultimately, this study will allow us to evaluate whether the presence of affective symptoms is correlated with fluctuations in the levels of inflammatory mediators, salivary cortisol and BDNF and to establish a reliable and highly predictive BD signature.

“Funded by: Bando Ricerca Indipendente ISS 2021-2023 to A. Berry project code ISS20-9286e4091f8e”

None Declared