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Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
The role of 5-HT in brain injury and the recovery of function after injury is not clear. Studies done in animal models of TBI suggest that acute synthesis of 5-HT increases after TBI and that this is associated with a decrease in local cerebral glucose utilization in the cerebral cortex.128 Additionally, inhibition of 5-HT synthesis with p-chlorophenylalanine was found to reduce cerebral blood flow changes, cerebral edema, and cell injury following TBI in animals.129 Such findings suggest that acute elevation of 5-HT may contribute to the damage after TBI. However, several other studies show that drugs that mimic the action of or increase the concentration of 5-HT at its receptors in the brain enhance the recovery of function after TBI. For example, some experimental agonists (i.e., repinotan and 8-OH-DPAT) as well as an approved agonist (buspirone) for the 5-HT1A receptor have been shown to improve learning deficits in rats following TBI.130,131 The SSRI antidepressant fluoxetine has also been shown to facilitate cognitive function in rats following TBI.132 Fluoxetine has also been found to reduce OCD in TBI patients.133 The antidepressant effects of SSRIs are also seen in TBI patients, just as they are in the noninjured population. Thus, it would appear that enhancing serotonergic neurotransmission is beneficial in TBI patients. However, more studies are needed before definitive conclusions can be reached regarding the use of serotonergic drugs for TBI patients. There is evidence that 5-HT enhances the expression of brain-derived neurotrophic factor (BDNF) and that BDNF promotes the growth of 5-HT neurons. These two signaling molecules seem to interact to enhance neuronal plasticity and prevent neurodegeneration.134 Thus, 5-HT may facilitate recovery of brain function after injury via increasing BDNF. There is evidence that this may also play a role in the antidepressant effects of SSRIs.
Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review
Published in Expert Opinion on Drug Safety, 2022
Javier De Diego-Adeliño, José Manuel Crespo, Fernando Mora, Adrián Neyra, Pedro Iborra, Luis Gutiérrez-Rojas, Selman F. Salonia
Antidepressant-induced nausea is thought to be mediated via 5-HT3 receptor activation in either the brain and/or the gut [131], and eventual desensitization of these receptors would dissipate nauseas within few days. Vortioxetine’s potent antagonism of 5-HT3 receptors should provide it with a neutral gastrointestinal profile from the beginning. However, basic research has proven that vortioxetine’s inhibitory activity at 5-HT3 receptors differs from other competitive antagonists, and it might induce a brief initial agonistic response [132]. Accordingly, some case-reports have suggested splitting daily dosage or even combining with a different 5-HT3 antagonist as mirtazapine to prevent the onset of nauseas [133]. On the other hand, 5-HT3 antagonists such as ondansetron or granisetron, commonly used to treat chemotherapy-induced emesis, are actually much better preventing vomiting than nausea and the physiopathological mechanisms underlying nausea appear much harder to describe than those underlying vomiting [134]. Beyond 5-HT3 receptors, there is evidence for an involvement of many other types of 5-HT receptors on emesis, including 5-HT1A, although their role is difficult to understand. In fact, some 5-HT1A agonists appear to have antiemetic properties but others, like buspirone or repinotan, can really cause nausea and vomiting [135]. Interestingly, in post-hoc analyses of the study of Jacobson [124], it was observed that nausea rates in patients previously treated with an SSRI, although transient, were significantly higher in those switching to vortioxetine (ranging 20–29.2%) than to escitalopram (ranging 3.3–6.1%). Desensitization of 5-HT3 receptors in such patients can be presupposed; therefore, it is reasonable to conclude that, besides its particular 5-HT3 binding pattern, other vortioxetine’s mechanisms of action, like 5-HT1A agonism, could be involved in transient treatment induced nausea associated with this multimodal acting AD.