Molecular Basis of Late-Life Depression

Abstract

Late-life depression (LLD), compared to depression at a young age, is more likely to have poor prognosis and high risk of progression to dementia. A recent systemic review and meta-analysis of the present antidepressants for LLD showed that the treatment response rate was 48% and the remission rate was only 33.7%, thus implying the need to improve the treatment with other approaches in the future. Recently, agents modulating the glutamatergic system have been tested for mental disorders such as schizophrenia, dementia, and depressive disorder. Ketamine, a noncompetitive NMDA receptor (NMDAR) antagonist, requires more evidence from randomized clinical trials (RCTs) to prove its efficacy and safety in treating LLD. The metabotropic receptors (mGluRs) of the glutamatergic system are family G-protein-coupled receptors, and inhibition of the Group II mGluRs subtypes (mGlu2 and mGlu3) was found to be as effective as ketamine in exerting rapid antidepressant activity in some animal studies. Inflammation has been thought to contribute to depression for a long time. The cytokine levels not only increase with age but also decrease serotonin. Regarding LLD, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) released in vivo are likely to contribute to the reduced serotonin level. Brain-derived neurotrophic factor (BDNF), a growth factor and a modulator in the tropomyosin receptor kinase (Trk) family of tyrosine kinase receptors, probably declines quantitatively with age. Recent studies suggest that BDNF/TrkB decrement may contribute to learning deficits and memory impairment. In the process of aging, physiological changes in combination with geriatric diseases such as vascular diseases result in poorer prognosis of LLD in comparison with that of young-age depression. Treatments with present antidepressants have been generally unsatisfactory. Novel treatments such as anti-inflammatory agents or NMDAR agonists/antagonists require more studies in LLD. Last but not least, LLD and dementia, which share common pathways and interrelate reciprocally, are a great concern. If it is possible to enhance the treatment of LDD, dementia can be prevented or delated.

Involvement of inflammatory responses in the brain to the onset of major depressive disorder due to stress exposure

“…The relationship between IL-6 and MDD pathology has been reported previously (Maes et al, 2016;Ting et al, 2020;Kuo et al, 2021). Serum IL-6 concentration was significantly higher in patients with MDD and decreased only in the SSRI and SNRI reaction groups (Fei et al, 2021).…”

Pathomechanisms of Vascular Depression in Older Adults

“…Neuroradiological evidence of CSVD is a significant marker for cognitive deficits [ 57 , 58 ]. Although hemodynamic dysfunction may play a pathogenic role in the development of CI in patients with VaD [ 59 ], a number of other pathogenic factors, such as disorders of the glutamatergic system [ 19 ], stress-induced neurovascular pathology [ 60 ], mitochondrial dysfunction, lipid dysmetabolism [ 61 , 62 ], neuroimmune regulatory mechanisms [ 63 , 64 , 65 ], excitotoxicity, chronic inflammation [ 66 ], deficits of nerve growth factors [ 67 ], and others, may contribute to cognitive deficits in the presence of cerebrovascular burden, which is common in VaD [ 22 , 33 ]. Vascular risk factors, especially hypertension and diabetes, are higher in patients with LLD and affect the severity of depression and the degree of cognitive impairment [ 55 ].…”

“…The last decades have witnessed considerable advances in our understanding of the neurobiology of early- and late-onset depression and have shown that disturbances of fronto–subcortical functioning due to cerebrovascular and other brain disorders are implicated in LLD. However, its etiopathogenetic features and the molecular basis are still poorly understood [ 18 , 19 ].…”

Age-Related Alterations in the Behavior and Serotonin-Related Gene mRNA Levels in the Brain of Males and Females of Short-Lived Turquoise Killifish (Nothobranchius furzeri)

“…Age-related alterations in the brain's 5-HT system frequently accompany psychic disorders in senior patients [8]. The majority of knowledge concerning age-related changes in the brain's 5-HT system was based on results obtained from aged people (60 years old or older) using the PET assay and post mortem studies as well as experiments carried out on laboratory monkeys and rodents (see reviews) [9][10][11]. However, these studies are dramatically limited due to ethical norms and the relatively long lifespan of laboratory monkeys (>20 years old) and rodents (2 years old).…”