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Wednesday, August 23, 2017

The brain mechanism through which antipsychotic drugs cause cognitive damage has been identified

Researchers at CIBERSAM and the UPV/EHU-University of the Basque Country have detected inflammatory mechanisms of antipsychotic drugs in the brain leading to difficulties in memory, attention and task planning. This cognitive deterioration could lead to the "chronification" of the mental illness. "This finding opens up the means for furthering other drugs, which are still in the experimental phase but which may be able to inhibit these mechanisms and block the harmful effects," says Javier Meana, the UPV/EHU and CIBERSAM researcher. They do however warn that withdrawing antipsychotic treatments prematurely increases the risks of hallucinations and delusions

Researchers at the Network Centre for Biomedical Research into Mental Health (CIBERSAM) who belong to the Neuropsychopharmacology group of the University of the Basque Country (UPV/EHU) have, together with other international groups, unravelled the cell mechanisms that would account for the cognitive deterioration following the prolonged use, particularly in high doses, of atypical antipsychotic drugs in individuals with schizophrenia. The study, published this August in the journal Nature Neuroscience, shows that the blocking of the 5HT2A serotonin receptor brought about by antipsychotic drugs activates a significant inflammatory channel in the brain by altering the morphology and function of the synapses responsible for maintaining dynamic cognitive activity, a phenomenon known as synaptic plasticity.

Tests carried out on cell models, the brain tissue of deceased individuals with schizophrenia, and genetically modified animals subjected to treatment using drugs, revealed synaptic anomalies that lead to alterations of a cognitive nature, such as working memory difficulties and the capacity to distinguish between known and new objects.

The study also revealed that these cognitive deficits are due to a remodelling of the cerebral expression of different genes caused by changes in the activity of the HDAC2 proteins that repress the DNA expression.  As the UPV/EHU researcher Javier Meana explained, "this finding is opening up for us the means for furthering the design of drugs, which are still in the experimental phase but which are able to inhibit these proteins and thus block the cognitive damage caused by antipsychotic treatments".

A consortium of researchers from various international centres, including CIBERSAM and the UPV/EHU, have thus unravelled the cell mechanisms associated with the adverse effects of treatment with atypical antipsychotic drugs, in particular when administered in high doses. The cognitive problems associated with schizophrenia treatments and which could contribute towards the chronification of schizophrenia may include problems of sustained attention, lack of mental flexibility in the carrying out of tasks and difficulties in making future plans.

They are also linked to metabolic disorders

Treatment with atypical antipsychotic drugs, more modern than the so-called typical ones, has led to the disappearance of problems in the locomotor activity of the patients, but apart from cognitive problems, they also appear to generate a greater risk of metabolic disorders such as obesity and type 2 diabetes, thus increasing cardiovascular risk.  However, as Javier Meana explained, "these treatments cannot be withdrawn prematurely because that would facilitate the reappearance of hallucinations and deliria. The challenge is to avoid the adverse effects while maintaining the significant antipsychotic effectiveness they offer".

CIBERSAM

The Network Centre for Biomedical Research (CIBER) is a consortium that reports to the Carlos III Institute for Health (Ministry of the Economy and Competitiveness) and is co-funded through ERDF funding.  CIBER in its Subject Area of Mental Health (CIBERSAM) is made up of 25 clinical, pre-clinical and translational research groups. It is essentially geared towards the study of mental disorders, such as depression, schizophrenia, bipolar disorder as well as anxiety disorders and mental disorders in childhood and adolescence, and therapeutic innovation.

UPV/EHU's Neuropsychopharmacology Group

The UPV/EHU's Neuropsychopharmacology Group, which belongs to CIBERSAM and is attached to the BioCruces Institute for Research, is led by Prof Javier Meana. Its interest lies in focussing on the study of the factors that may unleash psychotic symptoms and the mechanisms that lead to cognitive deterioration in schizophrenia. The group is an international benchmark in the study of the biological substrates of mental illnesses and in the development of new and more effective treatments for them.

 

Bibliographic reference

Ibi D, de la Fuente Revenga M, Kezunovic N, Muguruza C, Saunders JM, Gaitonde SA, Moreno JL, Ijaz MK, Santosh V, Kozlenkov A, Holloway T, Seto J, García-Bea A, Kurita M, Mosley GE, Jiang Y, Christoffel DJ, Callado LF, Russo SJ, Dracheva S, López-Giménez JF, Ge Y, Escalante CR, Meana JJ, Akbarian S, Huntley GW, González-Maeso J.. Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects. Nature Neuroscience. DOI: 10.1038/nn.4616.
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