Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments

Abstract

Despite the extensive research conducted in recent decades, the molecular mechanisms underlying major depressive disorder (MDD) and relative evidence-based treatments remain unclear. Various hypotheses have been successively proposed, involving different biological systems. This narrative review aims to critically illustrate the main pathogenic hypotheses of MDD, ranging from the historical ones based on the monoaminergic and neurotrophic theories, through the subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune and endocrine explanations, until the most recent evidence postulating a role for fatty acids and the gut microbiota. Moreover, the molecular effects of established both pharmacological and non-pharmacological approaches for MDD are also reviewed. Overall, the existing literature indicates that the molecular mechanisms described in the context of these different hypotheses, rather than representing alternative ones to each other, are likely to contribute together, often with reciprocal interactions, to the development of MDD and to the effectiveness of treatments, and points at the need for further research efforts in this field.

The Complex Molecular Picture of Gut and Oral Microbiota–Brain-Depression System: What We Know and What We Need to Know

“…A plethora of scientific evidence has produced important results on the molecular bases of MDD, going far beyond the initial monoaminergic hypothesis starting in the 1950s. The different theories established successively focus on biological systems that are very different from each other, and none of the hypotheses proposed overcomes a major role in the development of MDD: from neurotrophic to subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune, oxidative stress; kynurenine (Kyn) pathway; clock gene machinery; and opioid and endocrine hypotheses ( 3 , 4 ). As MDD is a complex and multifactorial disorder, these several biological processes likely contribute all together to the development of the disease, interacting with mutual reinforcing effects.…”

“…After the HPA axis activation, the release of cortisol and catecholamines can affect: ( 1 ) gut permeability, ( 2 ) gut mobility, and ( 3 ) microbial composition. The increased permeability of the gut barrier and the decreased gut mobility define a leaky gut.…”

“…Different biological pathways can be activated when a peripheral inflammation, triggered by endotoxins, can propagate to the brain and initiate neuroinflammation: ( 1 ) peripheral cytokines send inflammatory signals to the brain via afferent nerves, ( 2 ) cytokines pass through permeable sections of the blood–brain barrier (BBB), and ( 3 ) activated immune cells migrate into the brain. It is important to underline that neuroinflammation may be especially insidious since it may last up to 40 times longer than the initial peripheral immune response ( 50 ).…”

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A1 and A2A Receptors, and Efficacy in Animal Models of Depression

“…Moreover, commonly used medications are associated with adverse reactions difficult to tolerate including cardiovascular, anticholinergic, neurologic, gastrointestinal, and other side effects. Another big drawback of antidepressant therapy currently in use is that its full efficacy begins to appear only after 4–6 weeks of treatment or even more [ 10 , 11 ]. Thus, the search for novel therapeutic strategies for the treatment of depression disorders represents an important research priority.…”

Beyond Haemostasis and Thrombosis: Platelets in Depression and Its Co-Morbidities

“…We will focus on the link between platelets and the pathophysiology of major depressive disorder (MDD), one of the leading causes of the disability and disease burden worldwide. MDD presents as a persistent low mood, with associated changes in behavior, cognition, sleep and appetite, impaired social and occupational functioning, increased risk of self-harm or suicide [ 17 , 18 ]. MDD is also associated with increased mortality due to several comorbidities, especially cardiovascular disease (CVD).…”