2026 ECNP Congress

PS02-2085

Negative interaction between ceftriaxone and accelerated rTMS: implications for glutamatergic modulation in treatment-resistant depression

Marta Boffa — C. Cerri, A. Inserra, L.P. Padula, D. Voso, G. Di Lorenzo, L. De Risio, G. Martinotti2,, 6. 6,, 7. 6,, 8., M. Pettorruso, F. Zoratto · Istituto Superiore di Sanità, Centre for Behavioural Sciences and Mental Health, Rome, Italy

2026 ECNP Congress

Introduction

Treatment-resistant depression (TRD) remains a major clinical challenge, prompting the investigation of combined pharmacological and neuromodulation strategies. Accelerated repetitive transcranial magnetic stimulation (A-rTMS) is an established intervention for TRD[1], while ceftriaxone, a β-lactam antibiotic known to modulate glutamatergic transmission, has shown antidepressant-like effects in preclinical models of depression (MDD)[2][3]. Although both approaches exert beneficial effects when administered independently, their combined impact has not been previously investigated.

Aims

To evaluate the effects of ceftriaxone alone and in combination with A-rTMS on depressive- and anxiety-like behaviour in a preclinical model of TRD.

Methods

We used a validated TRD model consisting of socially-isolated Wistar-Kyoto rats subjected to a 4-week chronic mild stress (CMS) paradigm. Immediately after CMS completion, animals underwent a 2-day A-rTMS protocol. Animals were assigned to 4 groups: ceftriaxone+active-A-rTMS, ceftriaxone+sham-A-rTMS, vehicle+active-A-rTMS, vehicle+sham-A-rTMS.Ceftriaxone (200mg/kg) or vehicle (saline) were administered intraperitoneally (i.p.) for 8 consecutive days: during the last 6 days of CMS and on the 2 A-rTMS days (prior to stimulation). The A-rTMS protocol consisted of 4 sessions/day with a 55-min inter-session interval (10Hz, 40 pulses/train, 1600 pulses/session, 8 sessions, 16s inter-train interval). Sham groups were exposed to the same manipulation/acoustic effect. Behavioural tests investigating motivational- and apathy-like states, helplessness, social behaviour, anhedonia and anxiety-like behaviour were conducted over the 3 days following the last A-rTMS session. Statistical analyses were performed using two-way ANOVA, as appropriate. Post hoc comparisons (Tukey’s test) were reported where appropriate, including in the absence of significant interactions, given the conservative control for multiple comparisons.

Results

In sham-stimulated animals, ceftriaxone (vs vehicle) improved apathy-like state (splash test, ST; drug×rTMS: F(1,54)=10.122, p=0.0024, Tukey p<0.05), reduced helplessness (forced swim test, FST; F(1,52)=23.337, p<0.000, Tukey p<0.05), and increased motivation (novelty-seeking test, NST; F(1,52)=2.868, p=0.0963, Tukey p<0.05) and social engagement (social interaction test, SIT; F(1,48)=2.498, p=0.1206, Tukey p<0.05).In contrast, under active A-rTMS, ceftriaxone (vs vehicle) increased anxiety-like behaviour (light-dark test, LDT; F(1,49)=1.261, p=0.2670, Tukey p<0.05), reduced coping-related behaviour (FST; drug×rTMS: F(1,52)=23.337, p<0.0001, Tukey p<0.05), and decreased motivation (NST; F(1,52)=1.755, p=0.1910, Tukey p<0.05).Similarly, within ceftriaxone-treated animals, active A-rTMS (vs sham) increased apathy-like state (ST; drug×rTMS: F(1,54)=10.122, p=0.0024, Tukey p<0.05) and anxiety-like behaviour (LDT; F(1,49)=1.261, p=0.2670, Tukey p<0.05).Neither ceftriaxone alone nor its combination with A-rTMS affected anhedonia (female urine sniffing test, FUST; drug×rTMS×stimulus: F(1,44)=0.796, p=0.3773).

Conclusions.This is the first evidence that ceftriaxone alone exerts a broadly beneficial behavioural profile in a TRD model, improving apathy-, coping- and motivation-related behaviours, as well as social interaction, but not anhedonia. In contrast, its combination with active A-rTMS, compared to either treatment alone, worsened anxiety-, coping-, motivation- and apathy-like behaviours, and did not improve anhedonia, highlighting a negative interaction between the two interventions. These findings may be interpreted in light of the convergence of ceftriaxone and rTMS on glutamatergic mechanisms. Ceftriaxone enhances glutamate uptake via astrocytic GLT-1 upregulation[4], whereas rTMS modulates cortical excitability and synaptic plasticity, influencing glutamatergic neurotransmission and astrocyte-mediated glutamate regulation[5]. Together, these mechanisms may interact in a non-additive manner, potentially disrupting glutamate homeostasis and leading to impaired behavioural outcomes.

References

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