RESUMEN
Depression is a highly prevalent and disabling psychiatric disorder. The hippocampus, which plays a central role in mood regulation and memory, has received considerable attention in depression research. Electroconvulsive therapy (ECT) is the most effective treatment for severe pharmacotherapy-resistant depression. Although the working mechanism of ECT remains unclear, recent magnetic resonance imaging (MRI) studies have consistently reported increased hippocampal volumes following ECT. The clinical implications of these volumetric increases and the specific cellular and molecular significance are not yet fully understood. This narrative review brings together evidence from animal models and human studies to provide a detailed examination of hippocampal volumetric increases following ECT. In particular, our preclinical MRI research using a mouse model is consistent with human findings, demonstrating a marked increase in hippocampal volume following ECT. Notable changes were observed in the ventral hippocampal CA1 region, including dendritic growth and increased synaptic density at excitatory synapses. Interestingly, inhibition of neurogenesis did not affect the ECT-related hippocampal volumetric increases detected on MRI. However, it remains unclear whether these histological and volumetric changes would be correlated with the clinical effect of ECT. Hence, future research on the relationships between cellular changes, ECT-related brain volumetric changes, and antidepressant effect could benefit from a bidirectional translational approach that integrates human and animal models. Such translational research may provide important insights into the mechanisms and potential biomarkers associated with ECT-induced hippocampal volumetric changes, thereby advancing our understanding of ECT for the treatment of depression.
RESUMEN
Introduction: Based on previous research on electroconvulsive therapy (ECT) we have proposed a model where disruption, potentiation, and rewiring of brain networks occur in sequence and serve as the underlying therapeutic mechanism of ECT. This model implies that a temporary disturbance of neuronal networks (disruption) is followed by a trophic effect (potentiation), which enables the rewiring of neuronal circuits to a more euthymic functioning brain. We hypothesized that disruption of neuronal networks could trigger biochemical alterations leading to a temporary decrease in N-acetylaspartate (tNAA, considered a marker of neuronal integrity), while choline (a membrane component), myo-Inositol (mI, astroglia marker), and glutamate/glutamine (Glx, excitatory neurotransmitter) were postulated to increase. Previous magnetic resonance spectroscopy studies, reporting diverse findings, have used two different referencing methods - creatine ratios and tissue corrected values referenced to water - for the quantification of brain metabolites. Changes in creatine during ECT have also been reported, which may confound estimates adopting this as an internal reference. Methods: Using MR spectroscopy, we investigated 31 moderately to severely depressed patients and 19 healthy controls before, during, and after ECT or at similar time points (for controls). We tested whether biochemical alterations in tNAA, choline, mI, and Glx lend support to the disrupt, potentiate, and rewire hypothesis. We used both creatine ratios and water-scaled values for the quantification of brain metabolites to validate the results across referencing methods. Results: Levels of tNAA in the anterior cingulate cortex decreased after an ECT treatment series (average 10.6 sessions) by 6% (p = 0.007, creatine ratio) and 3% (p = 0.02, water referenced) but returned to baseline 6 months after ECT. Compared to after treatment series tNAA levels at 6-month follow-up had increased in both creatine ratio (+6%, p < 0.001) and water referenced data (+7%, p < 0.001). Findings for other brain metabolites varied and could not be validated across referencing methods. Discussion: Our findings suggest that prior research must be interpreted with care, as several referencing and processing methods have been used in the past. Yet, the results for tNAA were robust across quantification methods and concur with relevant parts of the disrupt, potentiate, and rewire model.
RESUMEN
OBJECTIVE: The anticonvulsant hypothesis posits that ECT's mechanism of action is related to enhancement of endogenous anticonvulsant brain mechanisms. Results of prior studies investigating the role of the inhibitory neurotransmitter gamma-aminobutyric acid ("GABA+", GABA and coedited macromolecules) in the pathophysiology and treatment of depression remain inconclusive. The aim of our study was to investigate treatment-responsive changes of GABA+ in subjects with a depressive episode receiving electroconvulsive therapy (ECT). METHODS: In total, 41 depressed subjects (DEP) and 35 healthy controls (HC) were recruited at two independent sites in Norway and the USA. MEGA-PRESS was used for investigation of GABA+ in the anterior cingulate cortex. We assessed longitudinal and cross-sectional differences between DEP and HC, as well as the relationship between GABA+ change and change in depression severity and number of ECTs. We also assessed longitudinal differences in cognitive performance and GABA+ levels. RESULTS: Depressive episode did not show a difference in GABA+ relative to HC (t71 = -0.36, p = .72) or in longitudinal analysis (t36 = 0.97, p = .34). Remitters and nonremitters did not show longitudinal (t36 = 1.12, p = .27) or cross-sectional differences in GABA+. GABA+ levels were not related to changes in antidepressant response (t35 = 1.12, p = .27) or treatment number (t36 = 0.05, p = .96). An association between cognitive performance and GABA+ levels was found in DEP that completed cognitive effortful testing (t18 = 2.4, p = .03). CONCLUSION: Our results failed to support GABA as a marker for depression and abnormal mood state and provide no support for the anticonvulsant hypothesis of ECT. ECT-induced change in GABA concentrations may be related to change in cognitive function.