Since its introduction in 1938, the precise mechanism underlying the efficacy of electroconvulsive therapy (ECT) in treating severe psychiatric disorders remains elusive. This paper presents a comprehensive scoping review aimed to collate and summarize findings from clinical studies on neuroplastic changes induced by ECT. The review categorizes neuroplasticity into molecular, structural, and functional domains, offering a multilevel view of current research and its limitations. Molecular findings detail the varied responses of neurotrophic factors and neurotransmitters post-ECT, highlighting inconsistent evidence on their clinical relevance. Structural neuroplasticity is explored through changes in brain volume, cortical thickness, and white matter properties, presenting ECT as a potent stimulator of brain architecture alterations. Functional plasticity examines ECT's impact on brain function through diverse neuroimaging techniques, suggesting significant yet complex modifications in brain network connectivity and activity. The review emphasizes the multilevel nature of these neuroplasticity levels and their collective role in ECT's therapeutic outcomes. Methodological considerations-including sample size, patient heterogeneity, and variability in assessment timing-emerge as recurring themes in the literature, underscoring the need for more consistent and rigorous research designs. By outlining a cohesive framework of changes in neuroplasticity due to ECT, this review provides initial steps towards a deeper comprehension of ECT's mechanisms.

Electroconvulsive therapy (ECT) effectively treats severe psychiatric disorders such as depression, mania, catatonia, and schizophrenia. Although its exact mechanism remains unclear, ECT is thought to induce neurochemical and neuroendocrine changes. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have provided vital insights into ECT's neurobiological effects. This scoping review investigates the role of molecular imaging in understanding these effects. A systematic search across PubMed, EMBASE, Web of Science, Cochrane, and Scopus databases yielded 857 unique records, from which 45 peer-reviewed articles in English with longitudinal PET or SPECT measures in ECT patients were included. The review identifies 2 main research directions: ECT's impact on brain activity and neurotransmitters. Initial research assessed regional cerebral blood flow and regional glucose metabolism during ictal (during ECT), postictal (within 24 hours), short-term (within a week), and long-term (beyond a week) follow-up as markers of brain activity. Initial findings showed an anterior-posterior regional cerebral blood flow gradient during the ictal phase, with subsequent normalization of hypoperfusion in frontal and parietal regions, and persistent long-term effects. Later, research shifted to the monoamine hypothesis of depression, examining ECT's impact on serotonin and dopamine systems via PET imaging. Results on receptor availability post-ECT were mixed, showing both reductions and no significant changes, indicating variable effects. This scoping review further highlights the need to explore new targets, tailor methodologies for patient populations, and foster multicenter studies. Although SPECT has been valuable, advances in PET imaging now make it preferable, offering unparalleled insights into ECT's molecular and neurobiological mechanisms.

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.

This educational review article aims to discuss growing evidence from PET studies in the diagnosis and treatment of depression. PET has been used in depression to explore the neurotransmitters involved, the alterations in neuroreceptors, non-neuroreceptor targets (e.g., microglia and astrocytes), the severity and duration of the disease, the pharmacodynamics of various antidepressants, and neurobiological mechanisms of non-pharmacological therapies like psychotherapy, electroconvulsive therapy, and deep brain stimulation therapy, by showing changes in brain metabolism and receptor and non-receptor targets. Studies have revealed alterations in neurotransmitter systems such as serotonin, dopamine, GABA, and glutamate, which are linked to the pathophysiology of depression. Overall, PET imaging has furthered the neurobiological understanding of depression. Despite these advancements, PET findings have not yet led to significant changes in evidence-based practices. Addressing the reasons behind inconsistencies in PET imaging results, conducting large sample size studies with a more standardized methodological approach, and investigating further the genetic and neurobiological aspects of depression may better leverage PET imaging in future studies.

Electroconvulsive therapy (ECT) is an important treatment for depression. Although it is known as the most effective acute treatment for severe mood disorders, its therapeutic mechanism is still unclear. With the rapid development of neuroimaging technology, various neuroimaging techniques have been available to explore the alterations of the brain by ECT, such as structural magnetic resonance imaging, functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, single photon emission computed tomography, arterial spin labeling, etc. This article reviews studies in neuroimaging on ECT for depression. These findings suggest that the neurobiological mechanism of ECT may regulate the brain functional activity, and neural structural plasticity, as well as balance the brain's neurotransmitters, which finally achieves a therapeutic effect.

Approximately 40% of patients with major depressive disorder (MDD) had limited response to conventional antidepressant treatments, resulting in treatment-resistant depression (TRD), a debilitating subtype that yielded a significant disease burden worldwide. Molecular imaging techniques, such as positron emission tomography (PET) and single photon emission tomography (SPECT), can measure targeted macromolecules or biological processes in vivo. These imaging tools provide a unique possibility to explore the pathophysiology and treatment mechanisms underlying TRD. This work reviewed and summarized prior PET and SPECT studies to examine the neurobiology and treatment-induced changes of TRD. A total of 51 articles were included with supplementary information from studies for MDD and healthy controls (HC). We found that there were altered regional blood flow or metabolic activity in several brain regions, such as the anterior cingulate cortex, prefrontal cortex, insula, hippocampus, amygdala, parahippocampus, and striatum. These regions have been suggested to engage in the pathophysiology or treatment resistance of depression. There was also limited data to demonstrate the changes in the markers of serotonin, dopamine, amyloid, and microglia over some regions in TRD. Moreover, several observed abnormal imaging indices were linked to treatment outcomes, supporting their specificity and clinical relevance. To address the limitations of the included studies, we proposed that future studies needed longitudinal designs, multimodal approaches, and radioligands targeting specific neural substrates for TRD to evaluate their baseline and treatment-related alterations in TRD. Adequate data sharing and reproducible data analysis can facilitate advances in this field.

Mental disorders represent an increasing source of disability and high costs for societies globally. Molecular imaging techniques such as positron emission tomography (PET) represent powerful tools with the potential to advance knowledge regarding disease mechanisms, allowing the development of new treatment approaches. Thus far, most PET research on pathophysiology in psychiatric disorders has focused on the monoaminergic neurotransmission systems, and although a series of discoveries have been made, the results have not led to any material changes in clinical practice. We outline areas of methodological development that can address some of the important obstacles to fruitful progress. First, we point towards new radioligands and targets that can lead to the identification of processes upstream, or parallel to disturbances in monoaminergic systems. Second, we describe the development of new methods of PET data quantification and PET systems that may facilitate research in psychiatric populations. Third, we review the application of multimodal imaging that can link molecular imaging data to other aspects of brain function, thus deepening our understanding of disease processes. Fourth, we highlight the need to develop imaging study protocols to include longitudinal and interventional paradigms, as well as frameworks to assess dimensional symptoms such that the field can move beyond cross-sectional studies within current diagnostic boundaries. Particular effort should be paid to include also the most severely ill patients. Finally, we discuss the importance of harmonizing data collection and promoting data sharing to reach the desired sample sizes needed to fully capture the phenotype of psychiatric conditions.

Depression is heterogeneous and complex disease with diverse symptoms. Its neurobiological underpinning is still not completely understood. For now, there are still no validated, easy obtainable, clinically useful noninvasive biomarker(s) or biomarker panel that will be able to confirm a diagnosis of depression, its subtypes and improve diagnostic procedures. Future multimodal preclinical and clinical research that involves (epi)genetic, molecular, cellular, imaging, and other studies is necessary to advance our understanding of the role of monoamines, GABA, HPA axis, neurotrophins, metabolome, and glycome in the pathogenesis of depression and their potential as diagnostic, prognostic, and treatment response biomarkers. These studies should be focused to include the first-episode depression and antidepressant drug-naïve patients with large sample sizes to reduce variability in different biological and clinical parameters. At present, metabolomics study revealed with high precision that a neurometabolite panel consisting of plasma metabolite biomarkers (GABA, dopamine, tyramine, kynurenine) might represent clinically useful biomarkers of MDD.

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has a rapid antidepressant effect. Despite large research efforts, ketamine's mechanism of action in major depressive disorder (MDD) has still not been determined. In rodents, the antidepressant properties of ketamine were found to be dependent on both the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and the serotonin (5-HT)_1B receptor. Low 5-HT_1B receptor binding in limbic brain regions is a replicated finding in MDD. In non-human primates, AMPA-dependent increase in 5-HT_1B receptor binding in the ventral striatum (VST) has been demonstrated after ketamine infusion. Thirty selective serotonin reuptake inhibitor-resistant MDD patients were recruited via advertisement and randomized to double-blind monotherapy with 0.5 mg/kg ketamine or placebo infusion. The patients were examined with the 5-HT_1B receptor selective radioligand [¹¹C]AZ10419369 and positron emission tomography (PET) before and 24-72 h after treatment. 5-HT_1B receptor binding did not significantly alter in patients treated with ketamine compared with placebo. An increase in 5-HT_1B receptor binding with 16.7 % (p = 0.036) was found in the hippocampus after one ketamine treatment. 5-HT_1B receptor binding in VST at baseline correlated with MDD symptom ratings (r = -0.426, p = 0.019) and with reduction of depressive symptoms with ketamine (r = -0.644, p = 0.002). In conclusion, reduction of depressive symptoms in MDD patients after ketamine treatment is correlated inversely with baseline 5-HT_1B receptor binding in VST. Further studies examining the role of 5-HT_1B receptors in the antidepressant mechanism of action of ketamine should be conducted, homing in on the 5-HT_1B receptor as an MDD treatment response marker.