Abstract
Comorbid depressive disorders confound the diagnosis and therapy of schizophrenia. Using a murine model incorporating both MK801 and chronic unpredictable mild stress exposures, we successfully replicated both psychosis and depression. Ex vivo patch clamp recordings and in vivo calcium imaging demonstrated impaired neural activity in the prefrontal cortex (PFC). We then administered triple-drug combinations consisting of two antidepressants (mirtazapine and venlafaxine) plus an antipsychotic (either clozapine or olanzapine), and found improved PFC neuronal activity and performance in behavioral assays. Moreover, the addition of metformin to both psychotropic drug combinations brought further improvements in depressive and schizophrenic-like behaviors and physiological parameters. In summary, our data modeled the neuropathophysiology of schizophrenia with comorbid depression, and may inform drug intervention strategies.
Highlights
Depression frequently complicates schizophrenia, with a prevalence of 20% to 60% depending on the disease stage (Conley et al, 2007; Upthegrove et al, 2017)
Significant reductions in sucrose preference were demonstrated in both exposure groups compared to naïve mice (Figure 1B, 59.3 ± 7.3% for the chronic unpredictable mild stress (CUMS) + MK801 exposure group, 54.9 ± 4.3% for the MK801 + CUMS exposure group, and 79.2 ± 4.6% for the naïve group; P < 0.001 using Tukey post hoc comparison followed by one-way analysis of variance (ANOVA)), suggesting anhedonia phenotypes in both disease models
We evaluated schizophrenia-like phenotypes by examining sensory gating functions in the prepulse inhibition (PPI) test
Summary
Depression frequently complicates schizophrenia, with a prevalence of 20% to 60% depending on the disease stage (Conley et al, 2007; Upthegrove et al, 2017). Because the onset of depression can be an early predictor of suicidal behavior in later stages of psychosis (Upthegrove et al, 2010), it is of critical importance to determine both the neuropathophysiology and optimal drug intervention strategies for schizophrenia with comorbid depression. The lack of valid animal models of coexistent schizophrenia and depression is a major obstacle to the elucidation of pathogenesis and the preclinical evaluation of therapeutic candidates. Current models of schizophrenia display motor, cognitive, or sensory gating deficits rather than depressive behaviors (Nestler and Hyman, 2010). Behavioral assays showed higher despair, anhedonia and deficits of prepulse inhibition (PPI) (Zhou et al, 2020). This model of schizophrenia with comorbid depression provides a valuable tool for in vivo drug evaluation
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