Pathogenesis of depression: Insights from human and rodent studies

Drs. Nelson and Papakostas Reply

Due to the clinical and etiological heterogeneity of major depressive disorder, it has been difficult to elucidate its pathophysiology. Current neurobiological theories with the most valid empirical foundation and the highest clinical relevance are reviewed with respect to their strengths and weaknesses. The selected theories are based on studies investigating psychosocial stress and stress hormones, neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate and gamma-aminobutyric acid (GABA), neurocircuitry, neurotrophic factors, and circadian rhythms. Because all theories of depression apply to only some types of depressed patients but not others, and because depressive pathophysiology may vary considerably across the course of illness, the current extant knowledge argues against a unified hypothesis of depression. As a consequence, antidepressant treatments, including psychological and biological approaches, should be tailored for individual patients and disease states. Individual depression hypotheses based on neurobiological knowledge are discussed in terms of their interest to both clinicians in daily practice and clinical researchers developing novel therapies.

Emerging cell death in depression: Mechanisms and therapeutic implications.

ObjectivesThe efficacy of treatment of major depressive disorder (MDD) is not satisfactory. Systemic inflammation may play an important role in MDD pathogenesis and treatment outcomes. Periodontal disease is the systemic inflammatory condition. Its prevalence may be as high as 45%. We aimed to assess the association of periodontal status with the outcome of 3‐month first‐line treatment of MDD with selective serotonin reuptake inhibitors.Material and MethodsWe performed the prospective cohort study during 2018/2019 at Psychiatric Hospital “Sveti Ivan,” Croatia, on a consecutive sample of 43 patients. The outcome was the MDD symptoms severity measured using the Hamilton Depression Rating Scale‐17. The periodontal status was indicated by the clinical attachment loss (CAL).ResultsBaseline periodontal status had a nonlinear significant and clinically relevant association with the MDD treatment outcome (R2 change of the quadratic term = 0.12; p = 0.027). In patients with good baseline periodontal status the severity of MDD symptoms was significantly improved. When the value of CAL was ≥4.44 mm, indicating the worse periodontal status, further increase in baseline CAL was associated with the worsening of MDD treatment outcomes independently of the baseline depression severity and 14 sociodemographic and clinical predictors of treatment outcome.ConclusionsPeriodontal healthcare is accessible, and should be utilize in an integrative, multidisciplinary approach not only for the sake of psychiatric patients' quality of life and prevention of periodontal disease, but for the sake of the outcomes of psychiatric treatment as well.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that is characterized by memory loss and cognitive impairment. Evidence shows that depression is a common co-occurrence in AD patients, and major depressive disorder (MDD) is considered a risk factor for AD. The crosstalk between the biological procedures related to the two disorders makes it very difficult to treat the comorbid conditions caused by them. Considering the common pathophysiological mechanisms underlying AD and MDD, antidepressant drugs may have beneficial therapeutic effects against their concurrence. In this study, we aimed to explore the potential drug candidates for the prevention and treatment of the comorbidity of AD and MDD. First, we screened the potential drugs for treating MDD by evaluating the distances of drug targets to MDD-related genes on the human protein-protein interaction network (PPIN) via a network-based algorithm. Then, the drugs were further screened to identify those that may be effective for AD treatment by analyzing their affinities with tau protein and Aβ42 peptide via molecular docking. Furthermore, the most stable binding modes were identified via molecular dynamics simulations, and the regulatory effects of drug candidates on genes involved in the pathogenesis of AD and MDD were analyzed. A total of 506 MDD-related genes were retrieved, and 831 drug candidates for MDD treatment were screened via the network-based approach. The results from molecular docking and molecular dynamics simulations indicated dihydroergotamine had the lowest binding affinity with tau protein and bromocriptine could form the most stable binding mode with Aβ42 peptide. Further analyses found that both dihydroergotamine and bromocriptine could regulate the expression of genes involved in the pathogenesis of AD and/or MDD in the brain. The exact mechanisms of the two drugs in treating AD and MDD, as well as their comorbidity, are still unclear, and further exploration is needed to evaluate their roles and mechanisms, both in vitro and in vivo. This study revealed that dihydroergotamine and bromocriptine may be the potential drug candidates for the treatment of the comorbidity of AD and MDD, and the therapeutic effects may be achieved by inhibiting the accumulation and aggregation of Aβ42 and tau protein and regulating the expression of disease-related genes in the brain.

Epigenetic changes caused by early life stress in the pathogenesis of depression.

As a first-line treatment for acute ischemic stroke (AIS), tenecteplase (TNK) can cause adverse effects, such as depression, in AIS patients. This study aims to elucidate the TNK target-related pathogenic mechanisms underlying major depressive disorder (MDD) in AIS patients. By analyzing six public peripheral blood bulk datasets from AIS and MDD patients using integrative bioinformatics methods (limma, non-negative matrix factorization (NMF), and machine learning), we identified TNK target-associated molecular subgroups and diagnostic models for MDD and AIS patients, respectively. Next, a hub gene involved in the pathogenesis of both MDD and AIS was identified, and its corresponding molecular characteristics were analyzed in the peripheral blood bulk profiles of MDD and AIS patients. In addition, to gain a deeper understanding of the molecular implications of the hub gene involved in the pathogenesis of MDD in AIS, we performed disease ontology (DO) analysis and virtual cell knockout (KO) of the hub gene using public AIS mouse brain single-cell datasets. Furthermore, a deep learning pipeline (DrugReflector) model and molecular docking were used to identify MDD-preventive therapeutic agents for AIS patients based on MDD and AIS public blood bulk data. Finally, the expression pattern of the hub gene was also evaluated in MDD and AIS cell models. Myeloperoxidase (MPO) can be considered an upregulated TNK target-associated gene involved in the pathogenesis of MDD in AIS patients, and BRD-K11973162 can be considered an MDD-preventive therapeutic candidate for AIS patients after TNK treatment. Our study is the first to identify MDD-associated diagnostic and therapeutic candidates for AIS patients after TNK treatment, providing a novel strategy for their clinical management.

TCF4 and RBFOX1 as peripheral biomarkers for the differential diagnosis and treatment of major depressive disorder

Neuroimaging-based subtypes of major depressive disorder in different sex and age groups: a potential link to sex hormone dynamics.

Many studies have predicted major depressive disorder (MDD) as the leading cause of global health by 2030 due to its high prevalence, disability, and illness. However, the actual pathophysiological mechanism behind depression is unknown. Scientists consider alterations in cytokines might be tools for understanding the pathogenesis and treatment of MDD. Several past studies on several inflammatory cytokine expressions in MDD reveal that an inflammatory process is activated, although the precise causes of that changes in cytokine levels are unclear. Therefore, we aimed to investigate resistin and G-CSF in MDD patients and controls to explore their role in the pathogenesis and development of depression. We included 220 participants in this study. Among them, 108 MDD patients and 112 age-sex matched healthy control (HCs). We used DSM-5 to evaluate study participants. Also, we applied the Ham-D rating scale to assess the severity of patients. Serum resistin and G-CSF levels were measured using ELISA kits (BosterBio, USA). The present study observed increased serum resistin levels in MDD patients compared to HCs (13.82 ± 1.24ng/mL and 6.35 ± 0.51ng/mL, p <0.001). However, we did not find such changes for serum G-CSF levels between the groups. Ham-D scores showed a significant correlation with serum resistin levels but not G-CSF levels in the patient group. Furthermore, ROC analysis showed a fairly predictive performance of serum resistin levels in major depression (AUC = 0.746). The present study findings suggest higher serum resistin levels are associated with the pathophysiology of MDD. This elevated serum resistin level may serve as an early risk assessment indicator for MDD. However, the role of serum G-CSF in the development of MDD is still unclear despite its neuroprotective and anti-inflammatory effects.

The cytokine network in the pathogenesis of major depressive disorder. Close to translation?

Major depressive disorder (MDD) is a severe illness that afflicts about 16.6% of people over their lifetime. MDD is highly correlated with suicidality, and often first presents in adolescence. Unfortunately, many pediatric patients suffering from MDD go undiagnosed, and current evidence-based treatment options in the U.S. are limited to psychotherapy and two selective serotonin reuptake inhibitors approved by the United States Food and Drug Administration. Molecular mechanisms have been shown to play a role in MDD pathogenesis, progression, and response to medication, yet few studies have explored the role of these pathways in pediatric MDD. In this review, we outline the gravity and importance of MDD in pediatric patients, some challenges in diagnosis and treatment, current treatments available for pediatric patients, and research to investigate differences between pediatric and adult MDD. We hope that this review will provide an outline of the current understanding and treatment of MDD in pediatric patients, and provide thoughtful insights for future work that could advance our understanding of MDD in pediatric populations, and also identify new therapeutic strategies.

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

Genome-wide transcriptomic and biochemical profiling of major depressive disorder: Unravelling association with susceptibility, severity, and antidepressant response

Major depressive disorder is a common debilitating mood disorder that affects quality of life. Prefrontal cortex abnormalities, an imbalance in neurotransmitters, neuroinflammation, and mitochondrial dysfunction are the major factors in the etiology of major depressive disorder. Despite the efficacy of pharmacotherapy in the treatment of major depressive disorder, 30%-40% of patients do not respond to antidepressants. Given this, exploring the alternative therapies for treatment or prevention of major depressive disorder has aroused interest among scientists. Transcranial photobiomodulation therapy is the use of low-power lasers and light-emitting diodes in the far-red to near-infrared optical region for stimulation of neuronal activities. This non-invasive modality improves the metabolic capacity of neurons due to more oxygen consumption and ATP production. Beneficial effects of transcranial photobiomodulation therapy in the wide range of neurological and psychological disorders have been already shown. In this review, we focus on some issue relating to the application of photobiomodulation therapy for major depressive disorder. There is some evidence that transcranial photobiomodulation therapy using near-infrared light on 10-Hz pulsed mode appears to be a hopeful technique for treatment of major depressive disorder. However, further studies are necessary to find the safety of this method and to determine its effective treatment protocol.