Long-term neuropsychiatric outcomes after neuromodulation in epilepsy patients: a systematic review and meta-analysis

Neuromodulation therapies, including vagus nerve stimulation (VNS), anterior nucleus of the thalamus deep brain stimulation (ANT-DBS), and responsive neurostimulation (RNS), have become established treatments for drug-resistant epilepsy. While seizure outcomes have been well-characterized, the long-term neuropsychiatric consequences of these interventions remain incompletely understood. This review aimed to compile available evidence on depression, anxiety, cognitive function, and quality of life following chronic neuromodulation therapy in adults and children with epilepsy.

We conducted a systematic search of PubMed, EMBASE, the Cochrane Library, and PsycINFO from inception through September 2025. Studies reporting neuropsychiatric outcomes after at least six months of VNS, ANT-DBS, or RNS therapy in patients with epilepsy were eligible. Random-effects meta-analysis was performed using standardized mean differences (SMDs). Heterogeneity was assessed via Cochran Q and I-squared statistics. Publication bias was evaluated with funnel plots and Egger regression.

From 2,847 records screened, 35 studies met inclusion criteria and 24 contributed to quantitative synthesis, encompassing 2,418 patients. The pooled effect on depression was a small but statistically significant improvement (SMD = -0.25; 95% CI: -0.43 to -0.07; p = 0.007). Subgroup analysis showed VNS had the largest antidepressant effect (SMD = -0.40; 95% CI: -0.69 to -0.10), while ANT-DBS (SMD = -0.18; 95% CI: -0.50 to 0.15) and RNS (SMD = -0.14; 95% CI: -0.47 to 0.19) showed non-significant trends toward improvement. Cognitive outcomes remained largely stable across all modalities, with no significant decline in overall cognitive performance (VNS: SMD = 0.07; DBS: SMD = 0.05; RNS: SMD = 0.02). Quality of life improved progressively, with clinically meaningful gains observed by the second year of treatment across modalities. Neuropsychiatric adverse events were most frequent in the ANT-DBS group, where 14.8% reported depressive symptoms during the blinded phase of the SANTE trial, though these diminished substantially over long-term follow-up.

Neuromodulation for drug-resistant epilepsy is associated with modest improvements in depression and quality of life without meaningful cognitive deterioration over follow-up durations of 6 months to 14 years. VNS demonstrated the most robust antidepressant signal, likely reflecting its established effects on monoaminergic brainstem circuits. Clinicians should monitor neuropsychiatric status, particularly during the early postimplantation period for ANT-DBS. Earlier intervention may optimize mood and quality of life benefits.