Th1/Th17-linked transcription factors TBX21 and RORC were associated with clinical response to rituximab in treatment-resistant schizophrenia.

BACKGROUND: One third of patients with schizophrenia do not achieve remission with current antipsychotic treatments. Converging data support an immune-mediated component in a subset of cases, overlapping with autoimmune CNS disorders. The B-cell-depleting monoclonal antibody rituximab is used in diseases such as multiple sclerosis and has been explored as an immunomodulatory strategy. We investigated plasma biomarkers, focusing on T-helper-related transcription factors, in relation to outcome after rituximab in schizophrenia.

METHODS: Nineteen severely ill, treatment-resistant patients (n = 9 with schizophrenia and n = 10 with obsessive-compulsive disorder [OCD]) included in an open-label pilot trial, received a single 1000 mg intravenous infusion of rituximab. Symptoms were assessed at baseline and week 12 using PANSS or Y-BOCS, global functioning with PSP, and improvement with CGI-I. Response was defined as "much" or "very much improved" on CGI-I at week 12. For the present analyses, we compared schizophrenia responders with a combined group of schizophrenia and OCD non-responders. Plasma and whole blood were collected at baseline and week 12. Multiplex cytokines and RT-qPCR for the expression of 13 genes coding for cytokines and T-cell-related transcription factors were analyzed, including Th1 and Th17 master regulators TBX21 (T-bet) and RORC (RORγt), respectively. We also constructed a composite rank score combining TBX21 and RORC expression (sum of their within-sample ranks).

RESULTS: Six out of eight schizophrenia patients were classified as responders and showed large symptomatic improvement (median PANSS change -70.1) and marked functional gain (median PSP +22.5). Within the analytic sample, schizophrenia responders (n = 6) had higher baseline TBX21 and RORC expression than non-responders (n = 8). Baseline TBX21 correlated with PSP improvement at week 12 (rs = 0.675, p < 0.01). The TBX21+RORC composite rank score showed the strongest association with outcome (higher in responders, p < 0.001; correlated with PSP gain, rs = 0.793, p < 0.001). Classical inflammatory markers, including IL-6, TNF-α and high-sensitivity C-reactive protein, did not differentiate responders.

DISCUSSION: Elevated baseline expression of the Th1- and Th17-associated transcription factors TBX21 and RORC - particularly their combined composite rank score - was associated with symptomatic and functional response to rituximab in treatment-resistant schizophrenia. The data suggest that a TBX21/RORC-defined, Th1/Th17-skewed T-cell signature may characterize a rituximab-responsive immunopsychiatric subtype of schizophrenia, in which B-cell depletion may secondarily modulate pathogenic T-cell response. These findings should be viewed as preliminary and hypothesis-generating for future controlled studies.