Molecular Mechanisms Associated with Antidepressant Treatment on Major Depression

Abstract

Major depressive disorder (MDD) is a complex and multifactorial psychiatric disorder that causes serious health, social, and economic concerns worldwide. The main treatment of the symptoms is through antidepressant (AD) drugs. However, not all patients respond properly to these drugs. Omic sciences are widely used to analyze not only biomarkers for the AD response but also their molecular mechanism. In this review, we aimed to focus on omics data to better understand the molecular mechanisms involving AD effects on MDD. We consistently found, from preclinical to clinical data, that glutamatergic transmission, immune/inflammatory processes, energy metabolism, oxidative stress, and lipid metabolism were associated with traditional and potential new ADs. Despite efforts of studies investigating biomarkers of response to ADs, which could contribute to personalized treatment, there is no biomarker panel available for clinical application. From clinical genomic studies, we found that the main findings contribute to the development of pharmacogenomic tests for AD efficacy for each patient. Several studies pointed at <i>DRD2</i>, <i>PXDNL</i>, <i>CACNA1E</i>, and <i>CACNA2D1</i> genes as potential targets for MDD treatment and the efficacy and rapid-antidepressant effect of ketamine. Finally, more in-depth studies of the molecular targets pointed here are needed to determine the clinical relevance and provide further evidence for precision MDD treatment.

Synaptotagmin-4 induces anhedonic responses to chronic stress via BDNF signaling in the medial prefrontal cortex

“…Previous studies have shown that Mapk1 -encoded protein expression is increased in the PFC in the Flinders sensitive line (FSL), a genetic rat model of depression 64 . Moreover, CACNA2D1 , which has been detected in human genome-wide association data as a candidate gene for depression 65 and bipolar disorder 66 , has been suggested to be a potential target for depression treatment and rapid antidepressant effects 67 . However, further research should be performed to address this potential.…”

Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment Options

“…However, it has been described that through this mechanism of action, endogenous opioid peptides that are involved in antidepressant functions may be released [ 74 ]. Furthermore, genetic studies have identified genes such as IRAK3 and NME7 that could influence esketamine’s efficacy, suggesting their involvement in processes related to immune response, stress regulation, and neuronal connectivity [ 75 , 76 ]. In addition to improving depressive symptoms, esketamine treatment has also shown improvements in other aspects of mental health, such as insomnia, and is not associated with weight gain [ 77 ], making it especially attractive for certain patients.…”

Postsynaptic Proteins at Excitatory Synapses in the Brain—Relationship with Depressive Disorders

“…These factors can discourage patients from taking antidepressants regularly or even lead to their discontinuation, significantly reducing the chance of remission and triggering several complications including suicide [ 14 ]. A better understanding of the molecular mechanisms underlying DDs, including MDD and bipolar disorder (BD), seems to be necessary to obtain new, more effective drugs (both antidepressant and anxiolytic profile) [ 3 , 15 , 16 , 17 ].…”