Abstract
Depression is a prevalent psychiatric disorder with an increasing impact in global public health. However, a large proportion of patients treated with currently available antidepressant drugs fail to achieve remission. Recently, antipsychotic drugs have received approval for the treatment of antidepressant-resistant forms of major depression. The modulation of adult neuroplasticity, namely hippocampal neurogenesis and neuronal remodeling, has been considered to have a key role in the therapeutic effects of antidepressants. However, the impact of antipsychotic drugs on these neuroplastic mechanisms remains largely unexplored. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 3 weeks of stress exposure, animals were treated with two different antipsychotics: haloperidol (a classical antipsychotic) and clozapine (an atypical antipsychotic). We demonstrated that clozapine improved both measures of depressive-like behavior (behavior despair and anhedonia), whereas haloperidol aggravated learned helplessness in the forced-swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine, whereas haloperidol promoted a downregulation of these processes. Furthermore, clozapine was able to re-establish the stress-induced impairments in neuronal structure and gene expression in the hippocampus and prefrontal cortex. These results demonstrate the modulation of adult neuroplasticity by antipsychotics in an animal model of depression, revealing that the atypical antipsychotic drug clozapine reverts the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization.
Highlights
Major depression is a highly prevalent and complex psychiatric disorder that affects multiple behavioral domains, presenting a wide range of symptoms, namely depressed mood, anhedonia, anxiety and cognitive impairments that confer a severe disability and impaired quality of life in patients.[1,2,3] Strikingly, up to 60% of patients treated with the currently available therapies do not achieve full remission and evolve to treatment resistance.[4,5] Taking this into account, it is essential to explore new strategies to achieve full remission and to prevent the recurrence of depressive episodes
We examined whether stress-induced changes in neurogenesis at short-term[16,22] and long-term[26] are influenced by the different classes of antipsychotic drugs
The analysis of the effect of treatment in each time point of the sucrose preference test (SPT) revealed a significant effect at week 7 that survived to multiple comparisons (Bonferroni) (F2,44 = 15.818; Po 0.001), with post hoc analysis revealing significant differences between animals treated with vehicle and animals treated with clozapine (P o 0.001) and haloperidol (P o 0.001)
Summary
Major depression is a highly prevalent and complex psychiatric disorder that affects multiple behavioral domains, presenting a wide range of symptoms, namely depressed mood, anhedonia, anxiety and cognitive impairments that confer a severe disability and impaired quality of life in patients.[1,2,3] Strikingly, up to 60% of patients treated with the currently available therapies do not achieve full remission and evolve to treatment resistance.[4,5] Taking this into account, it is essential to explore new strategies to achieve full remission and to prevent the recurrence of depressive episodes. Multiple clinical studies have previously highlighted the potential beneficial effects of atypical antipsychotics in treatment-resistant depression.[6,7,8] In accordance, different atypical antipsychotic drugs have received approval from the Food and Drug Administration (FDA) for the treatment of antidepressant-resistant forms of major depression (either as monotherapy or augmentation),[9] a fact that supports their potential role in the emotional domain. Studies in animals confirm this view and show that the association of an atypical antipsychotic and a selective serotonin reuptake inhibitor synergistically increases the release of dopamine in prefrontal areas, improving motivation, pleasure and appetite.[10,11] until now the mechanisms by which atypical antipsychotics work in the treatment of this disorder remains unclear
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