On the Mechanisms of Late-Life Depression

Major depressive disorder, more commonly known as depression, is all too prevalent a part of the human condition. Like many aspects of brain function, a great many layered mechanisms are investigated and debated by the research community, while still being poorly understood as a whole. Pharmaceutical treatments for depression are actually quite good for those people that they work for, but finding the right treatment can be a haphazard, experimental journey of years and different approaches for those who suffer. We might suspect that these treatments are essentially compensatory in nature, touching on mechanisms (such as serotonin levels) that are somewhat downstream from root causes.

That regular exercise reliably helps with depression is evidence for both inflammation and BDNF levels to be important, for their effects on neurogenesis among other mechanisms. Exercise reduces inflammation, and increases BDNF levels in the brain. But why do only some people need exercise in order to evade depression? Firm answers remain a challenge due to an incomplete understanding of the biochemistry of depression, or, for that matter, of much of the way in which the brain gives rise to the mind.

As pointed out by the authors of today's open access paper, depression in later life has a worse prognosis. This again points towards the role of inflammation and BDNF levels. With age, people exhibit a rising level of chronic inflammation. Some of this is avoidable, such as the inflammation originating from excess levels of visceral fat accompanying weight gain. Some of it is not, deriving from the aging of the immune system and molecular damage to tissues. BDNF levels decline with age, and one of the identified contributions to this decline is a changing gut microbiome, leading to reduced production of metabolites such as butyrate that enhance BDNF levels.

Molecular Basis of Late-Life Depression

Late-life depression, 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 late-life depression 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 late-life depression. 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 late-life depression, 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 late-life depression 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 late-life depression. Last but not least, late-life depression and dementia, which share common pathways and interrelate reciprocally, are a great concern. If it is possible to enhance the treatment of late-life depression, dementia can be prevented or delayed.

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