Long-acting second-generation injectable antipsychotics for the maintenance treatment of bipolar disorder: a narrative review.

INTRODUCTION: Non-adherence to medication significantly affects bipolar disorder outcomes. Long-Acting Injectable antipsychotics show promise by ensuring adherence and averting relapses. AREAS COVERED: This narrative review sought to evaluate the efficacy of second-generation injectable antipsychotics in bipolar disorder through searches in Embase, MEDLINE, and PsycInfo for randomized controlled trials and mirror-image studies.Risperidone and aripiprazole Long-Acting Injectables demonstrated effectiveness in preventing mood recurrences compared to placebos in adults with bipolar disorder. They showed superiority in preventing mania/hypomania relapses over placebos but did not appear to significantly outperform active oral controls. Notably, active controls seem to be more effective in preventing depression relapses than Long-Acting Injectables. Mirror-Image studies point toward the reduction of hospitalization rates following LAI initiation. EXPERT OPINION: The available evidence points thus toward the efficacy of LAIs, especially in managing manic episodes and reducing hospitalizations, The current evidence does not however immediately support prioritizing LAIs over oral medications in bipolar disorder treatment. More high-quality studies, especially comparing LAIs directly with active controls, are crucial to gain a comprehensive understanding of their efficacy. These findings highlight the need for further research to guide clinicians in optimizing treatment strategies for bipolar disorder.

Mechanism of Action of ECT in Depression.

Electroconvulsive therapy (ECT) remains the most potent antidepressant treatment available for patients with major depressive disorder (MDD). ECT is highly effective, achieving a response rate of 70-80% and a remission rate of 50-60% even in treatment-resistant patients. The underlying mechanisms of ECT are not fully understood, although several hypotheses have been proposed, including the monoamine hypothesis, anticonvulsive hypothesis, neuroplastic effects, and immunomodulatory properties. In this paper, we provide an overview of magnetic resonance imaging evidence that addresses the neuroplastic changes that occur after ECT at the human systems level and elaborate further on ECTs potent immunomodulatory properties. Despite a growing body of evidence that suggests ECT may normalize many of the structural and functional changes in the brain associated with severe depression, there is a lack of convergence between neurobiological changes and the robust clinical effects observed in depression. This may be due to sample sizes used in ECT studies being generally small and differences in data processing and analysis pipelines. Collaborations that acquire large datasets, such as the GEMRIC consortium, can help translate ECT's clinical efficacy into a better understanding of its mechanisms of action.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this common causal network (CCN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis (Principal Component Analysis, PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CCN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CCN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes. This evidence further supports that treatment interventions converge on a CCN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

An update on pharmacotherapy for recurrent depression in 2022.

INTRODUCTION: Major depressive disorder remains a major challenge due to its biopsychosocial burden with increased morbidity and mortality. Despite successful treatment options for the acute episode, recurrence rates are high, on average four times in a life span. AREAS COVERED: Both pharmacological as non-pharmacological evidence-based therapeutic options to prevent and treat recurrent depression are discussed. EXPERT OPINION: Although some risk factors for recurrence are well known, better evidence is needed. Antidepressant medication should be continued after acute treatment at its full therapeutic dose for longer periods, at least 1 year. There are no clear differences between classes of antidepressant medication when treatment is focused on preventing relapse. Bupropion is the only antidepressant with a proven efficacy to prevent recurrence in seasonal affective disorder. Recent findings conclude maintenance subanesthetic ketamine and esketamine treatment can be effective in sustaining antidepressant effect following remission. Furthermore, the pharmacological approach must be integrated with lifestyle interventions, especially aerobic exercise. Finally, combining pharma- and psychotherapy seems to improve outcome. Network and complexity sciences will help to decrease the high recurrence rates of MDD by developing more integrative and personalized approaches.

Reviewing the neurobiology of electroconvulsive therapy on a micro- meso- and macro-level.

BACKGROUND: Electroconvulsive therapy (ECT) remains the one of the most effective of biological antidepressant interventions. However, the exact neurobiological mechanisms underlying the efficacy of ECT remain unclear. A gap in the literature is the lack of multimodal research that attempts to integrate findings at different biological levels of analysis METHODS: We searched the PubMed database for relevant studies. We review biological studies of ECT in depression on a micro- (molecular), meso- (structural) and macro- (network) level. RESULTS: ECT impacts both peripheral and central inflammatory processes, triggers neuroplastic mechanisms and modulates large scale neural network connectivity. CONCLUSIONS: Integrating this vast body of existing evidence, we are tempted to speculate that ECT may have neuroplastic effects resulting in the modulation of connectivity between and among specific large-scale networks that are altered in depression. These effects could be mediated by the immunomodulatory properties of the treatment. A better understanding of the complex interactions between the micro-, meso- and macro- level might further specify the mechanisms of action of ECT.

White matter changes following electroconvulsive therapy for depression: a multicenter ComBat harmonization approach.

ECT is proposed to exert a therapeutic effect on WM microstructure, but the limited power of previous studies made it difficult to highlight consistent patterns of change in diffusion metrics. We initiated a multicenter analysis and sought to address whether changes in WM microstructure occur following ECT. Diffusion tensor imaging (DTI) data (n = 58) from 4 different sites were harmonized before pooling them by using ComBat, a batch-effect correction tool that removes inter-site technical variability, preserves inter-site biological variability, and maximizes statistical power. Downstream statistical analyses aimed to quantify changes in Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD), by employing whole-brain, tract-based spatial statistics (TBSS). ECT increased FA in the right splenium of the corpus callosum and the left cortico-spinal tract. AD in the left superior longitudinal fasciculus and the right inferior fronto-occipital fasciculus was raised. Increases in MD and RD could be observed in overlapping white matter structures of both hemispheres. At baseline, responders showed significantly smaller FA values in the left forceps major and smaller AD values in the right uncinate fasciculus compared with non-responders. By harmonizing multicenter data, we demonstrate that ECT modulates altered WM microstructure in important brain circuits that are implicated in the pathophysiology of depression. Furthermore, responders appear to present a more decreased WM integrity at baseline which could point toward a specific subtype of patients, characterized by a more altered neuroplasticity, who are especially sensitive to the potent neuroplastic effects of ECT.