Serotonin syndrome controversies:A need for consensus

Serotonin syndrome(SS)is a drug-induced clinical syndrome resulting from increased serotonergic activity in the central nervous system.Although more than seven decades have passed since the first description of SS,it is still an enigma in terms of terminology,clinical features,etiology,pathophysiology,diagnostic criteria,and therapeutic measures.The majority of SS cases have previously been reported by toxicology or psychiatry centers,particularly in people with mental illness.However,serotonergic medications are used for a variety of conditions other than mental illness.Serotonergic properties have been discovered in several new drugs,including over-the-counter medications.These days,cases are reported in non-toxicology centers,such as perioperative settings,neurology clinics,cardiology settings,gynecology settings,and pediatric clinics.Overdoses or poisonings of serotonergic agents constituted the majority of the cases observed in toxicology or psychiatry centers.Overdose or poisoning of serotonergic drugs is uncommon in other clinical settings.Patients may develop SS at therapeutic dosages.Moreover,these patients may continue to use serotonergic medications even if they develop mild to moderate SS due to several reasons.Thus,the clinical presentation(onset,severity,and clinical features)in such instances may not exactly match what toxicologists or psychiatrists observe in their respective settings.They produce considerable diversity in many aspects of SS.However,other experts discount these new developments in SS.Since SS is a potentially lethal illness,consensus is required on several concerns related to SS.

Fluoxetine,a selective serotonin reuptake inhibitor used clinically,improves bladder function in a mouse model of moderate spinal cord injury

After spinal cord injury,the upward conduction of the spinal cord is lost,resulting in the loss of micturition control,which manifests as detrusor sphincter dyssynergia and insufficient micturition.Studies have shown that serotonergic axons play important roles in the control of the descending urination tract.In this study,mouse models of moderate spinal cord contusions were established.The serotonin agonists quipazine(0.2 mg/kg),8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DAPT,0.1 mg/kg),buspirone(1 mg/kg),sumatriptan(1 mg/kg),and rizatriptan(50 mg/kg),the serotonin reuptake inhibitors fluoxetine(20 mg/kg)and duloxetine(1 mg/kg),and the dopamine receptor agonist SKF-82197(0.1 mg/kg)were intraperitoneally administered to the model mice 35 days post-injury in an acute manner.The voided stain on paper method and urodynamics revealed that fluoxetine reduced the amount of residual urine in the bladder and decreased bladder and external urethral sphincter pressure in a mouse model of moderate spinal cord injury.However,fluoxetine did not improve the micturition function in a mouse model of severe spinal cord injury.In contrast,the other serotonergic drugs had no effects on the micturition functions of spinal cord injury model mice.This study was ethically approved by the Institutional Animal Care and Use Committee of Jiangsu Province Hospital of Chinese Medicine(approval No.2020DW-20-02)on September 11,2020.

Possible association of the 5-HTTLPR serotonin transporter promoter gene polymorphism with premature ejaculation in a Turkish population

We evaluated the genotypes of the serotonin transporter gene （5-HTT） in patients with premature ejaculation （PE） to determine the role of genetic factors in the etiopathogenesis of PE and possibly to identify the patient subgroups. A total of 70 PE patients and 70 controls were included in this study. All men were heterosexual, had no other disorders and were either married or in a stable relationship. PE was defined as ejaculation that occurred within 1 min of vaginal intromission. Genomic DNA from patients and controls was analyzed using polymerase chain reaction, and allelic variations of the promoter region of the serotonin transporter gene （5-HTTLPR） were determined. The 5-HTTLPR （serotonin transporter promoter gene） genotypes in PE patients vs. controls were distributed as follows： L/L 16% vs. 17%, L/S 30% vs. 53% and S/S 54% vs. 28%. We examined the haplotype analysis for three polymorphisms of the 5-HTTLPR gene： LL, LS and SS. The appropriateness of the allele frequencies in the 5-HTTLPR gene was analyzed by the Hardy-Weinberg equilibrium using the Z-test. The short （S） allele of the 5-HTTLPR gene was significantly more frequent in PE patients than in controls （P 〈 0.05）. We suggest that the 5-HTTLPR gene plays a role in the pathophysiology of all primary PE cases. Further studies are needed to evaluate the relationship between 5-HTTLPR gene polymorphism and patient subgroup （such as primary and secondary PE） responses to selective serotonin reuptake inhibitors as well as ethnic differences.

Differences of Plasma Levels of Tryptophan, Serotonin, 5-Hydroxyindole Acetic Acid, and Kynurenine between Healthy People and Patients of Major Monopolar Depression at Various Age and Gender

Background: It is not well analyzed whether there are differences in plasma levels of tryptophan (TRP) metabolites between healthy control people (HC) and patients of major monopolar depression (MMD). Methods: Ultra high-speed liquid chromatography/mass spectrometry has been used for the simultaneous determination of plasma levels of tryptophan metabolites in depressive patients. Results: There are no significant differences between plasma levels of TRP between HC and MMD. Plasma levels of TRP of HC are higher in young men, young women, old men, and old women in this order. Serotonin (5-HT) levels are higher in MMD than HC. Plasma levels of 5-HIAA of HC are also higher than those of patients of MMD. Plasma levels of kynurenine (KYN) of healthy old men and old women are higher than those of young men and old women. Plasma levels of KYN are higher in old women and young men of MMD than those of HC. Conclusion: Plasma levels of 5-HT are higher in patients of MMD than those of HC, which may suggest that use of drugs inhibiting the 5-HT transportation may increase plasma levels of 5-HT in MMD.

Molecular mechanism of noradrenaline during the stress-induced major depressive disorder

Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate.Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression.Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder（MDD） and several antidepressants functions by increasing the monoamine level at the synapses in the brain.However,it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant.Contrary to noradrenergic receptor stimulation,it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of antidepressant.In addition,enhanced noradrenaline（NA） release is central response to stress and thought to be a risk factor for the development of MDD.Moreover,fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus（LC）.However,it is unclear how they alter the firing activity of LC neurons.These inconsistent reports about antidepressant effect of NA-reuptake inhibitors（NRIs） and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD.In this review,we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD.We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons,hypothalamic-pituitary-adrenal axis（HPA-axis） and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.

Delayed atomoxetine or fluoxetine treatment coupled with limited voluntary running promotes motor recovery in mice after ischemic stroke

Currently, there is an unmet need for treatments promoting post-stroke functional recovery.The aim of this study was to evaluate and compare the dose-dependent effect of delayed atomoxetine or fluoxetine therapy(starting on post-stroke day 5), coupled with limited physical exercise(2 hours daily voluntary wheel running;post-stroke days 9 to 42), on motor recovery of adult male mice after photothrombotic stroke.These drugs are selective norepinephrine or serotonin reuptake inhibitors indicated for disorders unrelated to stroke.The predetermined primary end-point for this study was motor function measured in two tasks of spontaneous motor behaviors in grid-walking and cylinder tests.Additionally, we quantified the running distance and speed throughout the study, the number of parvalbumin-positive neurons in the medial agranular cortex and infarct volumes.Both sensorimotor tests revealed that neither limited physical exercise nor a drug treatment alone significantly facilitated motor recovery in mice after stroke.However, combination of physical exercise with either of the drugs promoted restoration of motor function by day 42 post-stroke, with atomoxetine being a more potent drug.This was accompanied by a significant decrease in parvalbumin-positive inhibitory interneurons in the ipsilateral medial agranular cortex of mice with recovering motor function, while infarct volumes were comparable among experimental groups.If further validated in larger studies, our observations suggest that add-on atomoxetine or fluoxetine therapy coupled with limited, structured physical rehabilitation could offer therapeutic modality for stroke survivors who have difficulty to engage in early, high-intensity physiotherapy.Furthermore, in light of the recently completed Assessment o F Fluoxet INe In s Troke recover Y(AFFINITY) and Efficacy o F Fluoxetine-a randomis Ed Controlled Trial in Stroke(EFFECTS) trials, our observations call for newly designed studies where fluoxetine or atomoxetine pharmacotherapy is evaluated in combination with structured physical rehabilitation rather than alone.This study was approved by the Texas Tech University Health Sciences Center Institutional Animal Care and Use Committee(protocol # 16019).

Comparison of Plasma Levels of Tryptophan Metabolites between Healthy People and Patients of Bipolar Depression at Various Age and Gender

Background: It is not well analyzed whether there are differences in plasma levels of tryptophan (TRP) metabolites between healthy control people (HC) and patients of type II bipolar depression (BDII). Methods: Ultra high-speed liquid chromatography/mass spectrometry has been used for the simultaneous determination of plasma levels of tryptophan metabolites in depressive patients. Results: Plasma levels of TRP are not different between HC and patients of BDII. Serotonin (5-HT) levels are higher in BDII than HC. Plasma levels of 5-HIAA of HC are higher than those of old women of BDII, but lower in young women of BDII. Plasma levels of kynurenine (KYN) of HC are not different from those of patients of BDII. Conclusion: Plasma levels of 5-HT are higher in patients of BDII than those of HC, which may suggest that use of drugs inhibiting the 5-HT transportation and lower transporter biding may increase plasma levels of 5-HT in patients of BD.

5-Hydroxytryptamine Changes under Different Pretreatments on Rat Models of Myocardial Infarction and/or Depression

Background：Psychocardiological researches have suggested a central role of 5-hydroxytryptamine （5-HT） on psychocardiological mechanism.This study aimed to further explore the central role of 5-HT and pretreatment effects of XinLingWan on rats with myocardial infarction （M I） and/or depression.Methods：Ninety Sprague-Dawley rats were randomly divided into three groups：MI group,depression group,and MI ＋ depression group （n 30 in each group）.Each group was then divided into three subgroups （n =10 in each subgroup）：a negative control subgroup （NCS）,a Western medicine subgroup （WMS）,and a traditional Chinese medicine subgroup （TCMS）,which were received pretreatment once a day for 4 weeks by saline,20 mg/kg sertraline mixed with 2 ml saline,and 40 mg/kg XingLingWan mixed with 2 ml saline,respectively.Different rat models were established after different pretreatments.Rats were then sacrificed for detection of serum 5-HT,platelet 5-HT,5-HT2.A receptors （5-HT2AR）,and serotonin transporter （SERT）.Data were analyzed by one-way analysis of variance （ANOVA） and least-significant difference （LSD） testing.Results：M I group：compared with NCS,there was a significant increase in WMS and TCMS of serum 5-HT （176.15 ± 11.32 pg/ml vs.334.50 ± 29.09 pg/ml and 474.04 ± 10.86 pg/ml,respectively,both P =0.000）,platelet 5-HT （129.74 ± 27.17 pg/ml vs.322.24 ± 11.60 pg/ml and 340.4 5 ± 17.99 pg/ml,respectively,both P =0.000）;depression group：compared with NCS,there was a significant increase in WMS and TCMS of serum 5-HT （194.69 ± 5.09 pg/ml vs.326.21 ± 39.98 pg/ml and 456.33 ± 23.12 pg/ml,respectively,both P =0.000）,platelet 5-HT （175.15 ± 4.07 pg/ml vs.204.56 ± 18.59 pg/ml and 252.03 ± 22.26 pg/ml,respectively,P =0.004 and P 0.000,respectively）;MI ＋ depression group：compared with NCS,there was a significant increase in both WMS and TCMS of serum 5-HT （182.50 ± 10.23 pg/ml vs.372.55 ± 52.23 pg/ml and 441.76 ± 23.38 pg/ml,respectively,both P =0.000） and platelet 5-HT （180.83 ± 11.08 pg/ml vs.221.12 ± 22.23 pg/ml and 265.37 ± 29.49 pg/ml,respectively,P =0.011 and P =0.000,respectively）.Conclusions：By elevating the amount of 5-HT and modulating 5-HT2AR and SERT levels in serum and platelets,XinLingWan and sertraline were found to exert pretreatment effect on rat models of MI and/or depression.