Repeated co-treatment with antidepressants and risperidone increases BDNF mRNA and protein levels in rats

Recently, several clinical studies have suggested a beneficial effect of a combination of antidepressants (ADs) with antipsychotic drugs in drug-resistant depression. Moreover, preclinical and clinical studies indicated a role of brain-derived neurotrophic factor (BDNF) in the pathology of depression, as well as in the mechanism of action of ADs.

In the present study, we investigated the effect of repeated administration of ADs, escitalopram, fluoxetine or mirtazapine and a low dose of risperidone (an atypical antipsychotic drug) given separately or in combination, on the mRNA and protein levels of BDNF or cAMP response element binding (p-CREB) in the hippocampus and frontal cortex of male Wistar rats. ADs were given repeatedly (once daily for 14 days), separately or in combination with a low dose of risperidone. The tissue for biochemical assays was dissected 24h after the last dose of ADs.

The obtained results showed that repeated co-treatment with an inactive dose of risperidone and escitalopram or mirtazapine but not fluoxetine increased the BDNF mRNA expression in the hippocampus and frontal cortex. Moreover, combined treatment with an inactive dose risperidone and escitalopram elevated the protein levels of p-CREB in the frontal cortex. While, co-treatment with risperidone and fluoxetine or mirtazapine increased the protein levels of BDNF and p-CREB in both examined regions of the brain.

Our present findings suggest that enhancement levels of BDNF may be essential for the therapeutic effect of co-treatment with ADs and a low dose risperidone in patients with drug-resistant depression.