Abstract
A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.
Highlights
Antipsychotic drugs (APDs) remain the standard pharmacological treatment for schizophrenia (SCZ) and psychotic disorders, mainly by targeting dopamine neurotransmission[1,2,3]
We obtained peripheral blood mononuclear cells (PBMCs) isolated from blood samples from SCZ patients, which were obtained at the first episode of psychosis and after a 3-month period of treatment with APDs
ADAMTS2 expression, which is directly associated with dopaminergic signalling, primarily with the D1-class receptors and downstream through cAMP/cAMP response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK) signalling
Summary
Antipsychotic drugs (APDs) remain the standard pharmacological treatment for schizophrenia (SCZ) and psychotic disorders, mainly by targeting dopamine neurotransmission (primarily D2 receptors)[1,2,3]. Estimates suggest that one-fifth to one-half of patients have treatment-resistant SCZ and about 30–60% of these respond to clozapine[6,7,8]. Ruso-Julve et al Translational Psychiatry (2019)9:306 evidences suggest that D2 receptors is a direct target for all drugs used to treating SCZ, its blockade may not tackle the primary biological anomaly in a significant percentage of patients[9]. In this respect, the combined D1 and D2 receptors antagonism has been proposed to have synergic effects, which could account for the atypical clinical effectiveness of clozapine[10]. The glutamate hypothesis of SCZ led to explore its potential clinical application as targets for therapy[15]
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