By Will Boggs MD
NEW YORK—Synaptic and cognitive side effects appear to derive from antipsychotic-induced Hdac2 transcription via NF-kappaB, according to results of mouse and postmortem human studies.
“Clinicians know that antipsychotics decrease the risk of psychosis in schizophrenia patients, but these drugs do not improve or even deteriorate cognition,” Dr. Javier Gonzalez-Maeso from Virginia Commonwealth University School of Medicine, Richmond, told Reuters Health by email. “Our findings open a new line of treatment to improve cognition in these patients.”
Most people with schizophrenia have cognitive deficits that do not necessarily improve, and may even worsen, with antipsychotic drug regimens. How chronic antipsychotic treatment might contribute to cognitive impairment remains unclear.
Dr. Gonzalez-Maeso and colleagues previously showed that chronic treatment with the atypical antipsychotic drug clozapine induces upregulation of Hdac2 transcription in mice. In the present study, they explore the link between Hdac2 transcription and antipsychotic-induced cognitive side effects.
First, they showed that other atypical antipsychotics and antipsychotic-like drugs (clozapine, risperidone, quetiapine, sulpride, and volinanserin), but not the typical antipsychotic haloperidol, induce upregulation of Hdac2 transcription in mouse frontal cortex.
They then confirmed that upregulation of cortical HDAC2 expression disrupts synaptic modeling and cognition in mice and that virally mediated activation of frontal cortex NF-kappaB reduces synaptic plasticity via HDAC2.
Chronic clozapine treatment augmented binding of NF-kappaB to the Hdac2 promoter and enhanced NF-kappaB function via serotonin 5-HT-2A-receptor-dependent downregulation of inhibitor kappa-Balpha, according to the August 7 Nature Neuroscience online report.
The latter effect of chronic clozapine treatment appeared to rely on the MAPK-ERK signaling pathway.
“This pathway was affected in postmortem frontal cortex of people treated for schizophrenia, but not untreated people with schizophrenia,” Dr. Gonzalez-Maeso explained by email. “This means that it is a consequence of the treatment.”
Moreover, inhibiting frontal cortex NF-kappaB prevented the effects of chronic clozapine treatment on HDAC2 expression and cognitive deficits.
“Although our data revealed the basic signaling and neural circuit mechanism responsible for upregulation of Hdac2 transcription upon chronic atypical antipsychotic treatment, it will be interesting to expand this analysis in future studies to characterize the function of these transcriptional networks in synaptic plasticity and memory formation,” the researchers note.
“Collectively,” they conclude, “this study indicates that inhibition of the pathway by which the 5-HT2A receptor augments Hdac2 transcription via NF-kappaB may serve as a pharmacological approach to improve the currently limited therapeutic range of antipsychotic drug treatment. By extension, our findings emphasize the importance of compensatory pathways as one of the probable mechanisms that counteract positive clinical outcomes of compounds administered chronically.”
“These compensatory mechanisms may underlie other negative effects of therapeutic drugs given chronically,” Dr. Gonzalez-Maeso added.
Nat Neurosci 2017.
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