A Mixed-Methods Feasibility Study of a Novel AI-Enabled, Web-Based, Clinical Decision Support System for the Treatment of Major Depression in Adults

The objective of this paper is to discuss perceived clinical utility and impact on physician-patient relationship of a novel, artificial-intelligence (AI) enabled clinical decision support system (CDSS) for use in the treatment of adults with major depression. Patients had a baseline appointment, followed by a minimum of two appointments with the CDSS. For both physicians and patients, study exit questionnaires and interviews were conducted to assess perceived clinical utility, impact on patient-physician relationship, and understanding and trust in the CDSS. 17 patients consented to participate in the study, of which 14 completed. 86% of physicians (6/7) felt the information provided by the CDSS provided a more comprehensive understanding of patient situations and 71% (5/7) felt the information was helpful. 86% of physicians (6/7) reported the AI/predictive model was useful when making treatment decisions. 62% of patients (8/13) reported improvement in their care as a result of the tool. 46% of patients (6/13) felt the app significantly or somewhat improved their relationship with their physicians; 54% felt it did not change. 71% of physicians (5/7) and 62% of patients (8/13) rated they trusted the tool. Qualitative results are analyzed and presented. Findings suggest physicians perceived the tool as useful in conducting appointments and used it while making treatment decisions. Physicians and patients generally found the tool trustworthy, and it may have positive effects on physician-patient relationships.

The Tryptophan Catabolite or Kynurenine Pathway’s Role in Major Depression

Kynurenine or tryptophan catabolite (TRYCAT) pathway contributes to the pathophysiology of major depression disorder (MDD) and major depressive episodes (MDE) in bipolar disorder and suicidal behaviors. The consequences of the overactivation of this pathway large reduced tryptophan (TRP) levels in peripheral blood and the CNS and increased levels of neurotoxic TRYCATs including kynurenine (KYN), 3-hydroxy kynurenine (3HK), quinolinic acid (QA), xanthurenic acid (XA), and picolinic acid (PA). However, other TRYCATs are protective, such as kynurenic acid (KA) and anthranilic acid (AA). Inflammation and cell-mediated immune activation along with oxidative and nitrosative stress (O&NS) may stimulate the first and rate-limiting enzyme of this pathway, namely indoleamine-2,3-dioxygenase (IDO). Therefore, during depression, balancing neuroprotective versus neurotoxic TRYCATs and balancing activation of the immune response system (IRS) versus the compensatory immune response system is crucial for achieving better treatment outcomes. Furthermore, targeting the causes of TRYCAT pathway activation (immune activation and O&NS) is probably the most effective strategy to treat depression. In the present review, we aim to provide a comprehensive explanation of the impact of TRYCATs in terms of pathophysiology and treatment of MDD and MDE.

Local and Transient Changes of Sleep Spindle Density During Series of Prefrontal Repetitive Transcranial Magnetic Stimulation in Patients With a Major Depressive Episode

The neuromodulatory effects of brain stimulation therapies notably involving repetitive transcranial magnetic stimulation (rTMS) on nocturnal sleep, which is critically disturbed in major depression and other neuropsychiatric disorders, remain largely undetermined. We have previously reported in major depression patients that prefrontal rTMS sessions enhanced their slow wave activity (SWA) power, but not their sigma power which is related to sleep spindle activity, for electrodes located nearby the stimulation site. In the present study, we focused on measuring the spindle density to investigate cumulative effects of prefrontal rTMS sessions on the sleep spindle activity. Fourteen male inpatients diagnosed with medication-resistant unipolar or bipolar depression were recruited and subjected to 10 daily rTMS sessions targeting the left dorsolateral prefrontal cortex (DLPFC). All-night polysomnography (PSG) data was acquired at four time points: Adaptation, Baseline, Post-1 (follow-up after the fifth rTMS session), and Post-2 (follow-up after the tenth rTMS session). Clinical and cognitive evaluations were longitudinally performed at Baseline, Post-1, and Post-2 time points to explore associations with the spindle density changes. The PSG data from 12 of 14 patients was analyzed to identify sleep spindles across the sleep stages II–IV at four electrode sites: F3 (frontal spindle near the stimulation site), F4 (contralateral homologous frontal region), P3 (parietal spindle in the hemisphere ipsilateral to the stimulation site), and P4 (contralateral parietal region). Statistical analysis by two-way ANOVA revealed that spindle density at F3 increased at Post-1 but decreased at Post-2 time points. Moreover, the local and transient increase of spindle density at F3 was associated with the previously reported SWA power increase at F3, possibly reflecting a shared mechanism of thalamocortical synchronization locally enhanced by diurnal prefrontal rTMS sessions. Clinical and cognitive correlations were not observed in this dataset. These findings suggest that diurnal rTMS sessions transiently modulate nocturnal sleep spindle activity at the stimulation site, although clinical and cognitive effects of the local changes warrant further investigation.

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Background: Major Depression is the leading cause of impairment worldwide. The understanding of its molecular underpinnings is key to identifying new potential biomarkers and drug targets to alleviate its burden in society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of Major Depression associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with Major Depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis using GTEx data and alteration of transcription factor binding sites with pattern matching approaches and chromatin accessibility data.Results: The fine-mapping of major depression genetic variants uncovered putative causally associated variants whose proximal genes were linked with Major Depression pathophysiology. Four genetic variants altering the expression of 5 genes were found by colocalization analysis, highlighting the role of SLC12A5, involved in chlorine homeostasis in neurons, and MYRF, related with central nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of the genomic variant rs62259947 in modulating the expression of P4HTM through the alteration of YY1 binding site, altogether regulating hypoxia response.Conclusions: The combination of GWAS signals, cis-eQTL, transcription factor binding site information and active regulatory regions in the chromatin, enabled the prioritization of putative causal genetic variants in Major Depression. Importantly, our pipeline can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.

Regulation of Life Extension Factor Klotho on Depressive-like Behaviors via Modulation of GluN2B Function in the Nucleus Accumbens

Klotho is a life extension factor that has an ability to regulate the function of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), whose dysfunction in the nucleus accumbens (NAc) underlies critical aspects of the pathophysiology of major depression. Here we study the functional relevance of klotho in the pathogenesis of depression. A chronic social defeat stress paradigm, where mice are either categorized as susceptible or unsusceptible group based on their performance in a social interaction test, was used in this study. We found that the expression of klotho was largely decreased in the NAc of susceptible mice when compared to control or unsusceptible group. Genetic knockdown of klotho in the NAc induced depressive-like behaviors in naive mice, while overexpression of klotho produced an antidepressive effect in normal mice and ameliorated the depressive-like behaviors in susceptible mice. Molecularly, knockdown of klotho in the NAc resulted in selective decreases of total and synaptic GluN2B expression that were identical to susceptible mice. Elevation of klotho in the NAc reversed the reductions of GluN2B expressions, as well as altered synaptic transmission and spine density in the NAc of susceptible mice. Furthermore, blockade of GluN2B with a specific antagonist abolished the beneficial effects of klotho elevation in susceptible mice. Collectively, we demonstrated that klotho in the NAc modulates depressive-like behaviors by regulating the function of GluN2B-containing NMDARs. These results reveal a novel role for klotho in the pathogenesis of depression, opening new insights into the molecular basis of major depression.

Volume of Amygdala Subregions and Clinical Manifestations in Patients With First-Episode, Drug-Naïve Major Depression

We examined amygdala subregion volumes in patients with a first episode of major depression (MD) and in healthy subjects. Covariate-adjusted linear regression was performed to compare the MD and healthy groups, and adjustments for age, gender, and total estimated intracranial volume showed no differences in amygdala subregion volumes between the healthy and MD groups. Within the MD group, we examined the association between amygdala subregion volume and the 17-item Hamilton Rating Scale for Depression (HAMD) score and the HAMD subscale score, and found no association in the left amygdala. In the right amygdala, however, there was an inverse linear association between the HAMD total and the HAMD core and lateral nucleus and anterior-amygdaloid-regions. Furthermore, an inverse linear association was seen between the HAMD psychic and the lateral nucleus, anterior-amygdaloid-regions, transition, and whole amygdala. The findings of this study suggest that the severity of MD and some symptoms of MD are associated with right amygdala volume. There have been few reports on the relationship between MD and amygdala subregional volume, and further research is needed to accumulate more data for further validation.