Abstract
Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increase (P<0.001) in plasma PEDF in depressed patients compared with the controls that was further increased post-ECT (P=0.03). PEDF levels were not associated with mood scores. Chronic, but not acute, ECS increased PEDF mRNA in rat hippocampus (P=0.02) and dentate gyrus (P=0.03). This study identified alterations in blood levels of PEDF in depressed patients and further alterations following ECT, as well as in an animal model of ECT. These findings implicate PEDF in the biological response to ECT for depression.
Highlights
Electroconvulsive therapy (ECT) is the most effective treatment for severe, often treatment-resistant, and sometimes life-threatening, depression.[1,2] Of note, despite being in use since 1938, its mechanism of action is still not fully understood
A total of 47 protein spots were significantly altered following ECT in the low-abundance protein gels (Supplementary Figure 1), from which 25 spots were selected for identification using mass spectrometry and 32 proteins were identified
74 protein spots were significantly altered following ECT (Supplementary Figure 2), from which 20 spots were selected for identification by mass spectrometry and four proteins were identified
Summary
Electroconvulsive therapy (ECT) is the most effective treatment for severe, often treatment-resistant, and sometimes life-threatening, depression.[1,2] Of note, despite being in use since 1938, its mechanism of action is still not fully understood. Electroconvulsive stimulation (ECS), the animal model equivalent of ECT, has helped us begin to elucidate the neurobiological mechanisms of ECT. In this regard, ECS has been shown to bring about a wide range of molecular and cellular changes in the brain that may be involved in its action. ECS has been shown to bring about a wide range of molecular and cellular changes in the brain that may be involved in its action These include changes in monoamine neurotransmitters, synaptic plasticity, neurogenesis, hypothalamic–pituitary– adrenal-axis activity and the neuroinflammatory response.[3,4,5,6,7] the clinical utility of measuring molecular changes in the brains of patients is limited by the invasive nature of obtaining biopsies or cerebrospinal fluid (CSF). Blood has previously been shown to reflect brain-related protein levels, and it is known that exchanges can occur between the central nervous system and the periphery in both healthy and disease states.[8,9] peripheral blood represents a more clinically accessible tissue and provides a more minimally invasive, acceptable and inexpensive option for routine testing
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