Specificity proteins 1 and 4 in peripheral blood mononuclear cells in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial.

Accumulating evidence suggests that Specificity Protein 1 (SP1) and 4 (SP4) transcription factors are involved in the pathophysiology of schizophrenia. The therapeutic use of selective oestrogen modulators such as raloxifene added to antipsychotic drugs in the treatment of postmenopausal women with schizophrenia has been investigated in a few clinical trials, which reported an improvement in negative, positive, and general psychopathological symptoms. We aimed to investigate the possible association between peripheral SP protein levels and symptom improvement in postmenopausal women with schizophrenia treated with adjuvant raloxifene. In a subgroup of 14 postmenopausal women with schizophrenia from a 24-week, randomized, parallel, double-blind, placebo-controlled clinical trial (NCT015736370), we investigated changes in SP1 and SP4 protein levels in peripheral blood mononuclear cells. Participants were randomized to either 60 mg/day adjunctive raloxifene or placebo. Psychopathological symptoms were assessed at baseline and at week 24 with the Positive and Negative Syndrome Scale (PANSS). The expression of SP proteins was evaluated by immunoblot, and changes in PANSS scores and protein levels were compared at baseline and after 24 weeks of treatment. An improvement in symptoms was observed in the intervention group, but not in placebo group. Post-treatment protein levels of SP4, but not SP1, correlated with improvements in general and total PANSS subscales in the raloxifene intervention group. A reduction in SP4 levels was found after raloxifene treatment. These results suggest that SP4 may be involved in raloxifene symptom improvement in postmenopausal women and could be a potential candidate for future studies investigating blood-based biomarkers for raloxifene effectiveness.

Specificity proteins 1 and 4, hippocampal volume and first-episode psychosis.

We assessed specificity protein 1 (SP1) and 4 (SP4) transcription factor levels in peripheral blood mononuclear cells and conducted a voxel-based morphometry analysis on brain structural magnetic resonance images from 11 patients with first-episode psychosis and 14 healthy controls. We found lower SP1 and SP4 levels in patients, which correlated positively with right hippocampal volume. These results extend previous evidence showing that such transcription factors may constitute a molecular pathway to the development of psychosis.

Phosphorylation of transcription factor specificity protein 4 is increased in peripheral blood mononuclear cells of first-episode psychosis.

BACKGROUND: Altered expression of transcription factor specificity protein 4 (SP4) has been found in the postmortem brain of patients with psychiatric disorders including schizophrenia and bipolar disorder. Reduced levels of SP4 protein have recently been reported in peripheral blood mononuclear cells in first-episode psychosis. Also, SP4 levels are modulated by lithium treatment in cultured neurons. Phosphorylation of SP4 at S770 is increased in the cerebellum of bipolar disorder subjects and upon inhibition of NMDA receptor signaling in cultured neurons. The aim of this study was to investigate whether SP4 S770 phosphorylation is increased in lymphocytes of first-episode psychosis patients and the effect of lithium treatment on this phosphorylation. METHODS: A cross-sectional study of S770 phosphorylation relative to total SP4 immunoreactivity using specific antibodies in peripheral blood mononuclear cells in first-episode psychosis patients (n = 14, treated with lithium or not) and matched healthy controls (n = 14) by immunoblot was designed. We also determined the effects of the prescribed drugs lithium, olanzapine or valproic acid on SP4 phosphorylation in rat primary cultured cerebellar granule neurons. RESULTS: We found that SP4 S770 phosphorylation was significantly increased in lymphocytes in first-episode psychosis compared to controls and decreased in patients treated with lithium compared to patients who did not receive lithium. Moreover, incubation with lithium but not olanzapine or valproic acid reduced SP4 phosphorylation in rat cultured cerebellar granule neurons. CONCLUSIONS: The findings presented here indicate that SP4 S770 phosphorylation is increased in lymphocytes in first-episode psychosis which may be reduced by lithium treatment in patients. Moreover, our study shows lithium treatment prevents this phosphorylation in vitro in neurons. This pilot study suggests that S770 SP4 phosphorylation could be a peripheral biomarker of psychosis, and may be regulated by lithium treatment in first-episode psychosis.