Electrical stimulus combined with venlafaxine and mirtazapine improves brain Ca²⁺ activity, pre-pulse inhibition, and immobility time in a model of major depressive disorder in schizophrenia

Background: The prevalence of major depressive disorder in patients with schizophrenia (SZ-MDD) has been reported to be about 32.6 %, but it varies considerably depending on the stage (early or chronic) and state (acute or post-psychotic) of schizophrenia. The exploration of ideal strategies for the treatment of major depressive disorder in the context of schizophrenia is urgently needed. Thus, the present study was conducted to investigate the treatment effects of clozapine, electrical stimulation (ECS; the mouse model equivalent of electroconvulsive therapy for humans), venlafaxine, and mirtazapine for SZ-MDD.

Methods: A mouse model of SZ-MDD was established with MK801 administration and chronic unpredictable mild stress exposure. Clozapine and ECS, alone and with mirtazapine and/or venlafaxine, were used as treatment strategies. In-vivo two-photon imaging was performed to visualize Ca²⁺ neural activity in the prefrontal cortex (PFC). Mouse performance on behavioral assays was taken to reflect acute treatment effects.

Results: ECS + venlafaxine + mirtazapine performed significantly better than other treatments in alleviating major depressive disorder, as reflected by PFC Ca²⁺ activity and behavioral assay performance. Clozapine + venlafaxine + mirtazapine did not have an ideal treatment effect. Brain Ca²⁺ activity alterations did not correlate with behavioral expression in any treatment group.

Conclusions: In this mouse model of SZ-MDD, ECS + venlafaxine + mirtazapine improved brain Ca2+ activity, pre-pulse inhibition, and immobility time. These findings provide useful information for the further exploration of treatment methods for patients with SZ-MDD, although the mechanisms underlying this comorbidity needed to be investigated further.