<unk><unk>  inhibition In the brain, messages are passed from a nerve cell to another via a chemical synapse, a small gap between the cells. The presynaptic cell that sends the information releases neurotransmitters including<unk>  into that gap. The neurotransmitters are then recognized by receptors on the surface of the recipient postsynaptic cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by monoamine transporters into the sending presynaptic cell, a process called<unk> .<unk> s inhibit the<unk>  of<unk> . As a result, the<unk>  stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. In the short run, this leads to an increase in signaling across synapses in which<unk>  serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of post-synaptic<unk>  receptors signals the pre-synaptic neuron to synthesize and release less<unk> .<unk>  levels within the synapse drop, then rise again, ultimately leading to downregulation of post-synaptic<unk>  receptors. Other, indirect effects may include increased norepinephrine output, increased neuronal cyclic AMP levels, and increased levels of regulatory factors such as BDNF and CREB. Owing to the lack of a widely accepted comprehensive theory of the biology of mood disorders, there is no widely accepted theory of how these changes lead to the mood-elevating and anti-anxiety effects of<unk> s.. Any direct effects of<unk> s are limited by their inability to cross the blood-brain barrier; their effects on<unk>  blood levels, which take weeks to take effect, appear to be largely responsible for their slow-to-appear psychiatric effects. Sigma receptor ligands +<unk> s at the human SERT and rat sigma receptors Medication σ1 σ2 σ1 / SERT Citalopram 1.16 292–404 Agonist 5,410 252–348 Escitalopram 2.5 288 Agonist Fluoxetine 0.81 191–240 Agonist 16,100 296–365 Fluvoxamine 2.2 17–36 Agonist 8,439 7.7–16.4 Paroxetine 0.13 ≥1,893 22,870 ≥14,562 Sertraline 0.29 32–57 Antagonist 5,297 110–197 Values are Ki (nM). The smaller the value, the more strongly thedrug binds to the site. In addition to their actions as<unk><unk> s of<unk> , some<unk> s are also, coincidentally, ligands of the sigma receptors. Fluvoxamine is an agonist of the σ1 receptor, while sertraline is an antagonist of the σ1 receptor, and paroxetine does not significantly interact with the σ1 receptor. None of the<unk> s have significant affinity for the σ2 receptor, and the SNRIs, unlike the<unk> s, do not interact with either of the sigma receptors. Fluvoxamine has by far the strongest activity of the<unk> s at the σ1 receptor. High occupancy of the σ1 receptor by clinical dosages of fluvoxamine has been observed in the human brain in positron emission tomography (PET) research. It is thought that agonism of the σ1 receptor by fluvoxamine may have beneficial effects on cognition. In contrast to fluvoxamine, the relevance of the σ1 receptor in the actions of the other<unk> s is uncertain and questionable due to their very low affinity for the receptor relative to the SERT. Anti-inflammatory effects The role of inflammation and the immune system in depression has been extensively studied. The evidence supporting this link has been shown in numerous studies over the past ten years. Nationwide studies and meta-analyses of smaller cohort studies have uncovered a correlation between pre-existing inflammatory conditions such as type 1 diabetes, rheumatoid arthritis (RA), or hepatitis, and an increased risk of depression. Data also shows that using pro-inflammatory agents in the treatment of diseases like melanoma can lead to depression. Several meta-analytical studies have found increased levels of proinflammatory cytokines and chemokines in depressed patients. This link has led scientists to investigate the effects of antidepressants on the immune system.<unk> s were originally invented with the goal of increasing levels of available<unk>  in the extracellular spaces. However, the delayed response between when patients first begin<unk>  treatment to when they see effects has led scientists to believe that other molecules are involved in the efficacy of these drugs. To investigate the apparent anti-inflammatory effects of<unk> s, both Kohler et al. and Więdłocha et al. conducted meta-analyses which have shown that after antidepressant treatment the levels of cytokines associated with inflammation are decreased. A large cohort study conducted by researchers in the Netherlands investigated the association between depressive disorders, symptoms, and antidepressants with inflammation. The study showed decreased levels of interleukin (IL)-6, a cytokine that has proinflammatory effects, in patients taking<unk> s compared to non-medicated patients. Treatment with<unk> s has shown reduced production of inflammatory cytokines such as IL-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ, which leads to a decrease in inflammation levels and subsequently a decrease in the activation level of the immune response. These inflammatory cytokines have been shown to activate microglia which are specialized macrophages that reside in the brain. Macrophages are a subset of immune cells responsible for host defense in the innate immune system. Macrophages can release cytokines and other chemicals to cause an inflammatory response. Peripheral inflammation can induce an inflammatory response in microglia and can cause neuroinflammation.<unk> s inhibit proinflammatory cytokine production which leads to less activation of microglia and peripheral macrophages.<unk> s not only inhibit the production of these proinflammatory cytokines, they also have been shown to upregulate anti-inflammatory cytokines such as IL-10. Taken together, this reduces the overall inflammatory immune response. In addition to affecting cytokine production, there is evidence that treatment with<unk> s has effects on the proliferation and viability of immune system cells involved in both innate and adaptive immunity. Evidence shows that<unk> s can inhibit proliferation in T-cells, which are important cells for adaptive immunity and can induce inflammation.<unk> s can also induce apoptosis, programmed cell death, in T-cells. The full mechanism of action for the anti-inflammatory effects of<unk> s is not fully known. However, there is evidence for various pathways to have a hand in the mechanism. One such possible mechanism is the increased levels of cyclic adenosine monophosphate (cAMP) as a result of interference with activation of protein kinase A (PKA), a cAMP dependent protein. Other possible pathways include interference with calcium ion channels, or inducing cell death pathways like MAPK and Notch signaling pathway. The anti-inflammatory effects of<unk> s have prompted studies of the efficacy of<unk> s in the treatment of autoimmune diseases such as multiple sclerosis, RA, inflammatory bowel diseases, and septic shock. These studies have been performed in animal models but have shown consistent immune regulatory effects. Fluoxetine, an<unk> , has also shown efficacy in animal models of graft vs. host disease.<unk> s have also been used successfully as pain relievers in patients undergoing oncology treatment. The effectiveness of this has been hypothesized to be at least in part due to the anti-inflammatory effects of<unk> s. Pharmacogenetics Large bodies of research are devoted to using genetic markers to predict whether patients will respond to<unk> s or have side effects that will cause their discontinuation, although these tests are not yet ready for widespread clinical use. Versus TCAs<unk> s are described as<unk> ' because they affect only the<unk>  pumps responsible for<unk> , as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well, and as a result,<unk> s have fewer side effects. There appears to be no significant difference in effectiveness between<unk> s and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of<unk> s. However,<unk> s have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. Further, they have fewer and milder side effects. Tricyclic antidepressants also have a higher risk of serious cardiovascular side effects, which<unk> s lack.<unk> s act on signal pathways such as cyclic adenosine monophosphate (cAMP) on the postsynaptic neuronal cell, which leads to the release of brain-derived neurotrophic factor (BDNF). BDNF enhances the growth and survival of cortical neurons and synapses.
Selective serotonin reuptake inhibitor
Atypical antidepressant
Tricyclic antidepressant
Tetracyclic antidepressant
Heterocyclic antidepressant
Glycine reuptake inhibitor
Serotonin–dopamine reuptake inhibitor
Dopamine reuptake inhibitor