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," said 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 showed 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.

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".

The article titled, "Antipsychotic–induced Hdac2 transcription via NF–kappaB leads to synaptic and cognitive side effects," was published in the journal Nature Neuroscience.