Serotonin attributes

Many of the neuropsychiatric symptoms in early hepatic encephalopathy, such as altered sleep patterns, are signs that have classically been attributed to modifications of serotoninergic neurotransmission. Serotonin turnover, as indicated by the ratio of the concentrations of the metabolite 5-hydroxyindoleacetic acid to serotonin, is increased in brain in both human and experimental hepatic encephalopathy. 

Young TJ, et al. (2003) Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific cytotoxicity. J. Antimicrob. Chemofher. 51 1045-1047. 

The conventional antipsychotics have little effect on the negative psychotic symptoms such as autism, stupor and emotional withdrawal. The so-called atypical antipsychotics, or second-generation antipsychotics, like the heterocyclic compound risperidone, the benzamide sulpiride and several diben-zepines of which clozapine is the best known, have a broader spectrum which means that they also have an effect on the negative psychotic symptoms. Most share a common attribute of working on serotonin receptors as well as dopamine receptors. They have a low risk of extrapyramidal side effects. 

Nausea is a common early side effect of all SSRIs. Early nausea is probably attributable to the stimulation of serotonin type 3 (5-HT3) receptors in the gastrointestinal tract, which downregulate after several weeks of treatment. Hence this side effect is both dose dependent and transient. Some patients report less nausea if they take the medication with food. Although rarely needed, medication that blocks the 5-HT3 receptor (e.g., ondansetron) can be used to reduce SSRI-induced nausea. 

The combination of MAOIs with meperidine, and perhaps with other phenylpiperidine analgesics, also has been implicated in fatal reactions attributed to the serotonin syndrome. Aspirin, nonsteroidal anti-inflammatory drugs, and acetaminophen should be used for mild to moderate pain. Of the narcotic agents, codeine and morphine are safe in combination with MAOIs, although doses may need to be lower than usual. 

Abrupt discontinuation of TCAs commonly results in diarrhea, increased sweating, anxiety, and dizziness. These symptoms were previously attributed to cholinergic rebound, but the occurrence of similar symptoms after the discontinuation of many of the newer serotonergic antidepressants suggests that the pathophysiology may be more closely related to changes in serotonin. 

Serotonin has an effect on the hypothalamic control of pituitary function (see chapter 5), in central thermoregulation (attributed to the 5-HTj receptor), and in pain perception (probably the S-HTj receptor), where increased serotonergic function potentiates opiate analgesia. The administration of 5-HT reuptake inhibitors like fluoxetine increases the anorectic effect of 5-hydroxytryptamine and induces a selective suppression of nonprotein caloric intake in rats. The involvement of serotonin in endogenous psychiatric depression has been mentioned. 

Among FICAs, clomipramine is one of the more selective reuptake inhibitors of serotonin. Because plasma levels of its demethylated metabolite (which primarily works through the NE system) can in some patients exceed those of the parent compound, its therapeutic action cannot be solely attributed to serotonin uptake inhibition. 

Serotonin directly causes the contraction of vascular smooth muscle, mainly through 5-HT2 receptors. In humans, serotonin is a powerful vasoconstrictor except in skeletal muscle and heart, where it dilates blood vessels. At least part of this 5-HT-induced vasodilation requires the presence of vascular endothelial cells. When the endothelium is damaged, coronary vessels constrict. As noted previously, serotonin can also elicit reflex bradycardia by activation of 5-HT3 receptors on chemoreceptor nerve endings. A triphasic blood pressure response is often seen following injection of serotonin in experimental animals. Initially, there is a decrease in heart rate, cardiac output, and blood pressure caused by the chemoreceptor response. After this decrease, blood pressure increases as a result of vasoconstriction. The third phase is again a decrease in blood pressure attributed to vasodilation in vessels supplying skeletal muscle. Pulmonary and renal vessels seem especially sensitive to the vasoconstrictor action of serotonin. 

Considering the diverse effects attributed to serotonin and the heterogeneous nature of 5-HT receptors, other selective 5-HT antagonists... 

It is important to point out that basic sleep researchers make mistakes that are every bit as egregious and every bit as persistent as those of our clinical colleagues. From 1969 to 1975, it was widely held that serotonin promoted sleep. If that were true, then the SSRIs would be sedatives, not sleep saboteurs In fact, there is paradoxical sedation in a very high percentage of users, but this effect is not easily attributable to the enhancement of serotonergic efficacy. So strong was the serotonin hypothesis that it worked its way into textbooks, where it lived for fifteen years after it had been clearly shown that serotonin was actually a sleep inhibitor and, reciprocally, a wake-state enhancer. 

It is not clear, however, exactly how these drugs inhibit neurons involved in the polysynaptic pathways. There is preliminary evidence that one of these compounds (cyclobenzaprine) might block serotonin receptors on spinal interneurons, thereby decreasing the excitatory influence of serotonin on alpha motor neuron activity.50,55 Although this effect has been attributed to cyclobenzaprine in animals (rats), the effect of this drug and other muscle relaxants in humans remains to be determined. 

Venlafaxine is a potent inhibitor of serotonin reuptake and a weaker inhibitor of norepinephrine transport such that at lower therapeutic doses it behaves like an SSRI. At high doses (more than 225 mg/d) it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine reuptake inhibition. Doses in the range of 300 mg/d or greater may confer broader therapeutic effects than SSRIs, but a careful titration up to these doses is needed to control adverse effects. 

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