Was Kraepelin Prescient Regarding Excitation-Inhibition Imbalance in Schizophrenia?

Abstract Research on schizophrenia increasingly highlights altered excitation-inhibition (E/I) regulation in cortical circuits. Glutamatergic pyramidal cells propagate activity, whereas GABAergic interneurons periodically inhibit this activity. Their interaction supports gamma synchronization and the integration of information, while dysfunctional glutamatergic transmission (especially at the NMDA-receptor) disrupts information flow. This framework invites a restricted reconsideration of Kraepelin’s concept of dementia praecox. While Kraepelin erred in proposing a uniform, deteriorating course (schizophrenia is a heterogeneous neurodevelopmental spectrum disorder and many patients remain stable or recover) his emphasis on an early disturbance of mental integration in schizophrenia may have been prescient. Cognitive differences often precede psychosis, while genetic, experimental, postmortem, electrophysiological, and pharmacological findings converge on aberrations in the ecosystem of the NMDA-receptor in schizophrenic patients and members of high-risk groups for schizophrenia. D-serine, glycine, kynurenic acid, and redox state regulate are important co-regulators of the NMDA receptor and possible therapeutic targets. Negative trials of D-serine and glycine-transporter inhibitors, however, challenge simple augmentation strategies while leaving the developmental circuit hypothesis open, which would call for much earlier interventions. We argue that the decisive test for this hypothesis are biomarker-defined studies near illness onset; precisely when gamma synchronization or mismatch negativity already indicates impaired coordination. Excitation-inhibition imbalance thus gives Kraepelin’s clinical observation a modern and experimentally tractable form.