Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, utilizing SSRIs and SNRIs, with Esketamine emerging as a supplementary option in recent times. Nevertheless, there is a growing focus on exploring the relationship between inflammation and depression, revealing a strong correlation between the two. This insight prompts consideration of the anti-inflammatory properties of current antidepressants in their therapeutic application. Methods: A systematic literature search was conducted using the PubMed database to identify randomized controlled trials (RCTs) and clinical trials (CTs) that assessed the in vivo anti-inflammatory effects of SSRIs (fluoxetine, escitalopram, sertraline, and paroxetine), the SNRI venlafaxine, and esketamine/ketamine in human subjects undergoing treatment for depression. The included studies were evaluated based on changes in levels of pro-inflammatory and anti-inflammatory markers in response to the antidepressant treatments. Results: SSRIs, SNRIs, esketamine, and ketamine (a racemic mixture of S- and R-ketamine not formally approved for the treatment of depression) exhibit anti-inflammatory effects through diverse mechanisms, such as reducing pro-inflammatory cytokines or enhancing anti-inflammatory cytokines in serum or within specific brain regions like the hippocampus and prefrontal cortex. These actions are mediated through various inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome, the glutamatergic system, the gut–brain axis, the hypothalamic–pituitary axis, impaired neuroplasticity, and the kynurenine pathway. Conclusions: In summary, SSRIs, SNRIs, esketamine, and ketamine exert an anti-inflammatory role alongside their antidepressant effects via these intricate mechanisms.

Background: Monoamine neurotransmitters, including catecholamines (i.e., norepinephrine, epinephrine, and dopamine), and the indolamine serotonin play important roles in signaling in the central and peripheral nervous systems. Alterations in neurotransmission may be suggestive of neuroendocrine or psychiatric disorders, may reflect therapeutic responses, and are often considered relevant to mental health. Monoamine modulators and their metabolites are detectable in saliva, suggesting that saliva could represent an attractive, noninvasive, and cost-effective matrix for identifying and monitoring conditions in both healthy and diseased individuals. Accordingly, measuring salivary monoamine neurotransmitters may have scientific and possible clinical relevance. Summary: In this review, we summarize and critically evaluate current evidence on salivary dopamine, norepinephrine, epinephrine, serotonin, and their respective metabolites. Key Messages: Although further research is required to clarify their biological significance and clinical applicability, existing findings suggest that salivary monoamine measurement may hold potential, albeit with important limitations.