From immune dysregulation to precision immunotherapy in psychiatric disorders: A clinical-readiness framework for...

Immune dysregulation is reproducibly associated with major depressive disorder, bipolar disorder, and schizophrenia-spectrum disorders, but association does not establish a treatable immune mechanism. This critical narrative review distinguishes immune-associated psychiatric presentations, candidate inflammation-enriched psychiatric endotypes, and immune-driven neurological disease presenting with psychiatric symptoms. Targeted trials of tumor necrosis factor antagonism, interleukin-6-receptor blockade, and low-dose interleukin-2 provide preliminary, sometimes domain-specific signals, but primary clinical outcomes have often been negative or nonconfirmatory. Samples remain small, mechanistic evidence is incomplete, and no biologic immunotherapy has established clinical utility for routine treatment of a primary mood or psychotic disorder. C-reactive protein can support enrichment and pharmacodynamic assessment, but neither its elevation nor its reduction establishes a causal brain mechanism or predicts clinical benefit by itself. We propose a five-stage clinical-readiness framework: reproducible association, validated endotype, druggable mechanism with target engagement, biomarker-enriched proof of clinical mechanism, and replicated clinical utility. The framework guides evidence development and routine adoption rather than prohibiting earlier research or carefully governed exceptional care. Exceptional off-label use requires an individualized multidisciplinary assessment, explicit consent regarding uncertainty, prospective monitoring, and stopping rules; treatment resistance or suicide risk alone is not an indication for immunotherapy. Autoimmune encephalitis requires a separate, urgent diagnostic and therapeutic pathway. Progress in primary psychiatric disorders will depend on feasible biomarker strategies, prospective treatment-by-biomarker testing, mechanism-matched outcomes, and functional benefit and safety assessed over a clinically appropriate duration.