Depression׳s causes play a role in individuals׳ different responses to antidepressant treatments, which require advancements. We investigated the mechanisms behind and responses to a highly effective antidepressant treatment, electroconvulsive therapy (ECT), in rat models with different (genetic or environmental) depression causes. Wistar Kyoto (WKY) rats and Wistar rats treated with chronic unpredictable mild stresses (CUMS) were used as genetic and environmental rat models of depression, respectively. The rats underwent electroconvulsive shock (ECS, the animal analog of ECT) or sham ECS. We performed a sucrose preference test, open field test, and Morris water maze to assess behavior. Hippocampal neuron numbers were measured with Nissl stain. Hippocampal BDNF, CREB, and p-CREB proteins were assayed with ELISA or western blotting. The main results showed that ECS impaired WKY rats׳ memories but improved CUMS rats׳ memories. It elevated hippocampal BDNF and CREB proteins only in CUMS rats, while it improved depressive behavior and hippocampal p-CREB protein levels in both rats, with more effective regulations in the CUMS rats. ECS did not change the hippocampal neuron number in both rats. These findings suggest that ECS exerted up-regulating effects on hippocampal BDNF and CREB (and its phosphorylation) in depressed rats, and the environmental model responded better.
Depression is responsible for a substantial proportion of worldwide disease burden, but clinical response to antidepressant treatments is still not satisfactory. Although pharmacotherapy has been the first-line treatment for depression, response to antidepressants varies between individuals (Keers and Uher, 2012), and more than half of patients fail to respond adequately to the first antidepressant they are prescribed (Trivedi et al., 2006). As a somatic treatment, electroconvulsive therapy (ECT) is known to be quicker and more effective than common antidepressants, but it is still not effective for up to 30% of patients with depression (Medda et al., 2009). Efficacy enhancements include exploring novel drugs and treatments, but there have been no significant advancements and robust response predictors to antidepressant treatments. ECT׳s mechanisms are complicated, and the cause of different individual responses to ECT for depression in terms of genes, environment, and their interaction are even more obscure.
Individual factors, especially depression׳s causes, play an essential role in different responses to antidepressant treatments (Uher, 2008, Keers and Aitchison, 2011 and Klengel and Binder, 2013). Depression results from an interaction between genes and environments. The mainstream “diathesis-stress” hypothesis for depression׳s etiopathogenesis of depression shows that the genetic or environmental factors can lead to the occurrence and development of different depression subtypes. Previous studies indicated that those with “endogenous” depression (occurring in the absence of a prior stressor) and those with “reactive” depression (occurring in response to a stressor) responded totally differently to somatic treatments, antidepressants, or psychotherapies (Keers and Uher, 2012).
The “neurotrophic hypothesis” suggests that reduced neurotrophins, including brain-derived neurotrophic factor (BDNF), result in decreased hippocampal function and ultimately depression. Neurogenesis-related genes, including BDNF, cyclic adenosine monophosphate response element-binding protein (CREB), and the pathway are essential in gene-cognition-environment interactions in depression׳s mechanism (Juhasz et al., 2011).
In the present study, we compared behavioral and molecular responses to electroconvulsive shock (ECS, the animal analog of ECT) between a genetic [Wistar Kyoto (WKY) rats, which are genetically hypersensitive to stressors, demonstrate depressive behaviors such as anhedonia, and are deemed a valid rat model of “endogenous” depression (Tejani-Butt et al., 2003)] and environmental [rats treated with chronic unpredictable mild stress (CUMS), which have similarities to patients with depression caused by chronic, low-level stresses, and are considered to simulate patients with “reactive” depression with good predictive, face, and construct validity] rat model of depression. We wished to reveal the profile and possible mechanism of different responses to ECT in rats with different depression causes.
Before ECS (or sham ECS) was administered, there were significant baseline SPP differences between groups [F(5, 66)=47.854, P<0.001]. Compared with groups S and SE, the baseline SPP in groups K, C, KE or CE were less (each P<0.001), while there were no significant differences between the four depressive rat groups (in groups K, C, KE or CE). There were no significant differences between the two healthy Wistar rat groups (in groups S and SE) ( Fig. 1A). After ECS (or sham ECS), there were significant differences in the SPP increase rate between groups [F(5, 66)=38.840, P<0.001]. The interaction between depression models (environmental or genetic) and treatment (sham ECS or ECS) was significant (F=24.113, P<0.001), and either the depression model effects or the ECS treatment effects were significant, respectively (models: F=27.352, P<0.001; ECS: F=107.970, P<0.001). Compared with group K, the values in both groups KE and CE were larger (KE: P=0.001; CE: P<0.001). Compared with group C, the values in both groups KE and CE were larger (KE: P=0.001; CE: P<0.001). Compared with group KE, the value of group CE was larger (P<0.001), but the values of groups S and SE were less (each P<0.001). Compared with group CE, both the values of groups S and SE were less (each P<0.001) ( Fig. 1B).
