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This article proposes a critical period hypothesis, arguing that clozapine is most effective when started during a stage of illness in which network plasticity and synaptic substrate are still partially preserved. We outline a neurobiological continuum from first-line antipsychotic response to ultra-treatment resistance, emphasising dynamic changes in dopamine, glutamate, gamma-aminobutyric acid and muscarinic cholinergic systems. Observational studies suggest that earlier clozapine initiation is associated with better outcomes, particularly for negative symptoms and functioning. The hypothesis supports earlier recognition of treatment resistance and reduced avoidable delay.<\/jats:p>","DOI":"10.1177\/02698811261488465","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:40:18Z","timestamp":1790336418000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Early intervention with clozapine: Is there a neurobiological critical period for treatment-resistant schizophrenia?"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6845-5894","authenticated-orcid":false,"given":"Rajeev","family":"Krishnadas","sequence":"first","affiliation":[{"name":"University of Cambridge, UK"},{"name":"Cambridgeshire and Peterborough NHS Foundation Trust, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I Lam","family":"Leong","sequence":"additional","affiliation":[{"name":"University of Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Fraczek","sequence":"additional","affiliation":[{"name":"Cambridgeshire and Peterborough NHS Foundation Trust, UK"},{"name":"Department of Brain Sciences, Imperial College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-8955","authenticated-orcid":false,"given":"Emilio","family":"Fernandez-Egea","sequence":"additional","affiliation":[{"name":"University of Cambridge, UK"},{"name":"Cambridgeshire and Peterborough NHS Foundation Trust, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1640-7182","authenticated-orcid":false,"given":"Lena","family":"Palaniyappan","sequence":"additional","affiliation":[{"name":"Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"crossref","unstructured":"Agid O Arenovich T Sajeev G et al. 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