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Role of intracellular mediators in clozapine induced ErbB1-ERK signalling in prefrontal cortical neurons: relevance to therapeutic efficacy.

Role of intracellular mediators in clozapine induced ErbB1-ERK signalling in prefrontal cortical neurons: relevance to therapeutic efficacy.

Here we investigate candidate intracellular mediators PI3K, Src, ß-arrestin and Ca2+ which may govern the ErbB1 transactivation pathway induced by clozapine. Methods: Primary murine frontal cortical neurons were exposed to wortmannin (PI3K inhibitor), monodansylcadaverine (MDC) (receptor endocytosis inhibitor) and BAPT-AM (Ca2+ inhibitor), and the effect on clozapine mediated ErbB1-ERK and Src phosphorylation examined by immunoelectrophoresis to assess mediator involvement. Results: Administration of wortmannin caused significant dose-dependent inhibition of ERK1/2 phosphorylation in the presence of clozapine (ERK1: clozapine 100±22% vs clozapine + 10 uM wortmannin 34±6%, p=0.0136).

In relation to ß-arrestin, MDC did not decrease clozapine induced ERK1/2 phosphorylation but rather elevated pERK1/2 levels (ERK2: clozapine 100±28% vs clozapine + 50 uM MDC 197±24%, p=0.0307). Similarly BAPTA-AM did not have a significant inhibitory effect on ERK activation following clozapine treatment of cells. Parallel detection of Src phosphorylation indicated a time disconnect with ERK phosphorylation. Conclusions: Clozapine modulates the PI3K/ Akt pathway, with aberrant signalling via ErbB4 documented in schizophrenia and Src a key component in the convergent ErbB1-dependent ERK signalling mechanism described. Therefore deficient ErbB1 signalling in schizophrenia may be augmented by clozapine with inverse action at ErbB4 receptors.

Conference: ASC2013, MAPrc
Areas of Interest / Categories: ASC 2013, MAPrc 2014

MAPrc 2014

The effect of symptomatic improvement on gamma synchrony in psychosis: a pilot study.

Impaired functional connectivity, as measured by synchronous gamma activity, has been observed in both the early and chronic stages of schizophrenia, as well as in unaffected first-degree relatives. This suggests gamma synchrony may be a trait-like marker of psychosis susceptibility, and not just a state-dependant characteristic. To conduct a pilot study into the short-term temporal stability of gamma synchrony and its relationship to symptomatic improvement in young patients who have been treated for recent onset psychosis. 20 medicated subjects underwent both clinical (PANSS) and electrophysiological (auditory oddball task during EEG) evaluation at both baseline and 8 weeks follow-up.

The effect of symptomatic improvement on gamma synchrony in psychosis: a pilot study.

Impaired functional connectivity, as measured by synchronous gamma activity, has been observed in both the early and chronic stages of schizophrenia, as well as in unaffected first-degree relatives. This suggests gamma synchrony may be a trait-like marker of psychosis susceptibility, and not just a state-dependant characteristic. To conduct a pilot study into the short-term temporal stability of gamma synchrony and its relationship to symptomatic improvement in young patients who have been treated for recent onset psychosis. 20 medicated subjects underwent both clinical (PANSS) and electrophysiological (auditory oddball task during EEG) evaluation at both baseline and 8 weeks follow-up.

Cerebral cortical grey matter deficits in schizophrenia and their associations with ageing, psychopathology, cognition and treatment response.

The diagnosis of schizophrenia lacks a broadly accepted biological basis and its heterogeneity may well represent a group of disorders with different aetiologies. Even so, brain imaging can map and quantify structural brain abnormalities in vivo as an intermediate (or endo-) phenotype of the disorder. To identify the degree of regional grey matter deficits in relation to age, the severity of psychopathology and cognitive/ neurological impairment, and treatment response in schizophrenia. Eighteen schizophrenia patients (32.2 years [SD 14.3], meeting DSM-IV criteria were examined. Eighteen pair-wise age (±2 years) and gender-matched healthy volunteers (31.9 years [SD 14.3]) served as control group.

A healthy lifestyle intervention among people with psychotic disorders: Results from a RCT.

People with psychotic disorders have higher rates of CVD risk factors compared to the general community. To our knowledge, this is the first RCT of its kind. To determine the efficacy of a multi-component intervention (smoking, diet and activity) delivered face to face compared to a largely telephone delivered intervention (smoking) among smokers with psychotic disorders. Participants with psychotic disorders residing in the community and smoking =15 cigarettes/day (CPD) were randomly assigned to either condition.

Schizophrenia and neurodevelopment – Where do we stand today?

The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood or adolescent periods. The objective is to place schizophrenia neuropathology in a neurodevelopmental context. This requires solid, scrutinized evidence of changes occurring during normal development of the cerebral cortex. We review literature on the development of the prefrontal cortex and chart major molecular and cellular events on a similar time line. Whilst neurogenesis, neuronal migration and myelination undergo most dramatic changes prenatally, these processes also extend into adolescence.

Serum epidermal growth factor levels are reduced in people with treatment resistant schizophrenia and modulated by clozapine treatment.

Up to 45% of patients with schizophrenia are treatment resistant to conventional drugs leaving clozapine as the only effective option. Its severe side-effects however limit it to a late stage option and the development of a biomarker to predict treatment response would be of high clinical utility. Our previous data demonstrate clozapine augments epidermal growth factor receptor (EGFR) signaling and hence we examined if EGF levels may be altered in treatment resistant schizophrenia (TRS) and are influenced by clozapine treatment. Study objectives: To determine if EGF levels are influenced by clozapine in TRS and can serve as a biomarker for clozapine response.

The Weight of Evidence: The Role of Metformin in Cardiometabolic Protection in Early Psychosis.

The relationship between weight gain and the treatment of first episode psychosis (FEP) with psychotropic medication is well established, with weight gain and increased cardiovascular risk as common sequelae. Such metabolic abnormalities create further disease burden and shorten the life expectancy of a population already dealing with mental illness. Antipsychotic-induced weight gain has been shown to commence within the first months of initiating treatment in drug-naïve youth, thus early intervention is necessary in order to attenuate the progression of metabolic abnormalities. Initial studies using metformin in this population have shown promising results.

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