Viloxazine in the Treatment of Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children. Over the past twenty years, research on the disease and its characteristics and treatment options has grown exponentially. The first-line pharmacologic treatment of ADHD is stimulants, which have a response rate of ~70%. With the support of four phase 3 studies involving more than 1,000 pediatric patients 6–17 years old, the FDA has approved the non-stimulant, serotonin-norepinephrine modulating agent (SNMA) viloxazine in an extended-release capsule (viloxazine ER) for treatment of ADHD in children aged 6–17. Viloxazine modulates serotonergic activity as a selective 5-HT22B receptor antagonist and 5-HT2C receptor agonist and moderately inhibits norepinephrine transporter (NET), thus blocking the reuptake of norepinephrine. A phase 2 study by Johnson et al. found that once-daily dosing of viloxazine ER in 200, 300, or 400 mg dosages in children with ADHD for eight weeks resulted in a statistically significant reduction of ADHD-RS-IV total score. A post hoc analysis of data from four phase 3, randomized, placebo-controlled, double-blind, three-arm, clinical trials by Faraone et al. found that early response to viloxazine treatment, defined as a change in ADHD-RS-5 total score at week 2, best predicted the treatment response at week 6 [75% positive predictive power (PPP), 75% sensitivity]. Proper treatment of the symptoms and comorbidities associated with ADHD is crucial in improving a patient's quality of life, cognitive function, and overall therapeutic outcomes. Viloxazine's mechanism of action, clinical effects, and limited side effect profile point toward the drug's relevance in the treatment of ADHD.

Brain monoaminergic activity during predator inspection in the Trinidadian guppy (Poecilia reticulata)

To understand the processes underpinning social decision-making, we need to determine how internal states respond to information gathered from the social environment. Brain monoamine neurotransmitters are key in the appraisal of the social environment and can reflect the internal state underlying behavioural responses to social stimuli. Here we determined the effects of conspecific partner cooperativeness during predator inspection on brain monoamine metabolic activity in Trinidadian guppies (Poecilia reticulata). We quantified the concentration of dopamine, serotonin and their metabolites across brain sections sampled immediately after ostensibly experiencing cooperation or defection from social partners whilst inspecting a predator model. Our results indicate dopaminergic and serotonergic activity differs with the cooperativeness experienced; these different neurotransmission profiles are likely to affect the expression and regulation of downstream behaviours that ultimately contribute to the patterning of cooperative interactions among individuals in the population.

Curated Database and Preliminary AutoML QSAR Model for 5-HT1A Receptor

Introduction of a new drug to the market is a challenging and resource-consuming process. Predictive models developed with the use of artificial intelligence could be the solution to the growing need for an efficient tool which brings practical and knowledge benefits, but requires a large amount of high-quality data. The aim of our project was to develop quantitative structure–activity relationship (QSAR) model predicting serotonergic activity toward the 5-HT1A receptor on the basis of a created database. The dataset was obtained using ZINC and ChEMBL databases. It contained 9440 unique compounds, yielding the largest available database of 5-HT1A ligands with specified pKi value to date. Furthermore, the predictive model was developed using automated machine learning (AutoML) methods. According to the 10-fold cross-validation (10-CV) testing procedure, the root-mean-squared error (RMSE) was 0.5437, and the coefficient of determination (R2) was 0.74. Moreover, the Shapley Additive Explanations method (SHAP) was applied to assess a more in-depth understanding of the influence of variables on the model’s predictions. According to to the problem definition, the developed model can efficiently predict the affinity value for new molecules toward the 5-HT1A receptor on the basis of their structure encoded in the form of molecular descriptors. Usage of this model in screening processes can significantly improve the process of discovery of new drugs in the field of mental diseases and anticancer therapy.

Association Between The Loudness Dependence of The Auditory Evoked Potential and Age in Patients With Schizophrenia and Depression

Background The loudness dependence of the auditory evoked potential (LDAEP) reflects serotonin neurotransmission. Abnormality in serotonergic activity is dominant in patients with schizophrenia (SCZ) and major depressive disorder (MDD). Patients with SCZ show weak LDAEPs, reflecting high serotonergic activity. Some patients with MDD show high serotonergic activity. Although the changes in serotonin neurotransmission in the aging brain of SCZ and MDD have been observed, the relationship between central serotonergic activity and age remains unclear. The present study compared LDAEP between patients with SCZ and MDD, and healthy controls (HCs). We further examined whether age correlated with LDAEP and clinical symptoms, controlling usage of serotonin-related drugs. Methods A total of 105 patients with SCZ and MDD were enrolled (54 patients with SCZ and 51 patients with MDD). Thirty-five HCs were recruited. LDAEP was measured on midline channels (Fz, FCz, Cz, Pz, and Oz) among 62 electroencephalography channels. Positive and negative symptoms were assessed in patients with SCZ while depression and/or anxiety symptoms were evaluated in patients with MDD and HC. Results Patients with SCZ and MDD showed smaller mean LDAEP than that of HC group (p < 0.001). Age was positively correlated with LDAEPs in patients with SCZ and MDD. Conclusion Decreased serotonergic activity with aged brain could be indicated by LDAEP in patients with SCZ and MDD. Changes in LDAEP according to age would be a compensatory mechanism across progression of disease in SCZ and MDD.

Hijacking Dorsal Raphe to Improve Metabolism and Depression-like Behaviors via BDNF Gene Transfer in Mice

Moods and metabolism modulate each other. High comorbidity of depression and metabolic disorders such as diabetes and obesity poses a great challenge to treat such condition. Here we report the therapeutic efficacy of brain-derived neurotrophic factor (BDNF) by gene transfer in the dorsal raphe nucleus (DRN) in a chronic unpredictable mild stress model of depression (CUMS) and models of diabetes and obesity. In CUMS, BDNF-expressing mice displayed antidepressant- and anxiolytic-like behaviors, which are associated with augmented serotonergic activity. Both in the diet-induced obesity model (DIO) and in <i>db/db</i> mice，BDNF ameliorated obesity and diabetes, which may be mediated by enhanced sympathetic activity, not involving DRN serotonin. Chronic activation of DRN neurons via chemogenetic tools produced similar effects as BDNF in DIO mice. These results established the DRN as a key nexus in regulating depression-like behaviors and metabolism, which can be exploited to combat comorbid depression and metabolic disorders via BDNF gene transfer.

Hijacking Dorsal Raphe to Improve Metabolism and Depression-like Behaviors via BDNF Gene Transfer in Mice

Moods and metabolism modulate each other. High comorbidity of depression and metabolic disorders such as diabetes and obesity poses a great challenge to treat such condition. Here we report the therapeutic efficacy of brain-derived neurotrophic factor (BDNF) by gene transfer in the dorsal raphe nucleus (DRN) in a chronic unpredictable mild stress model of depression (CUMS) and models of diabetes and obesity. In CUMS, BDNF-expressing mice displayed antidepressant- and anxiolytic-like behaviors, which are associated with augmented serotonergic activity. Both in the diet-induced obesity model (DIO) and in <i>db/db</i> mice，BDNF ameliorated obesity and diabetes, which may be mediated by enhanced sympathetic activity, not involving DRN serotonin. Chronic activation of DRN neurons via chemogenetic tools produced similar effects as BDNF in DIO mice. These results established the DRN as a key nexus in regulating depression-like behaviors and metabolism, which can be exploited to combat comorbid depression and metabolic disorders via BDNF gene transfer.

Case series suggesting an association between sertraline and urinary side effects in a Sheffield child and adolescent mental health services (CAMHS) population

AimsTo suggest a link between sertraline and urinary side effects in a Sheffield Child and Adolescent Mental Health Service population.BackgroundEvidence suggests that Serotonin has an important role in bladder control through central and peripheral neurological pathways. Increased serotonergic activity leads to parasympathetic inhibition, which results in urine retention. It is through this mechanism of action and their effect on pre-synaptic serotonin 1A and peripheral 5-HT3 receptors that SSRIs were observed to have anti-enuretic effect. At low 5-HT concentrations, micturition is inhibited whereas at high levels, an excitatory effect is achieved. This may suggest a dose-dependent relationship between Sertraline and urinary side effects.MethodInclusion criteria:Under 18 years of ageOn SertralineReported urinary side effectsExclusion criteria:Above 18 yearsNot on SertralineAssociated urinary problemsDid not report urinary side effectsClinical records of eligible patients were accessed to gauge temporal relationship between initiation of sertraline and reported urinary side effects.ResultThree cases were identified in the authors’ clinical practice at Sheffield CAMHS that were suggestive of a link between sertraline and urinary side effects.ConclusionIt's important for clinicians to bear in mind the genitourinary side effects of SSRIs, which may be debilitating for patients in the CAMHS population. It's equally important for us as clinicians to educate young people and their parents about these potential side effects and how they can be managed. It has also been observed that higher doses of Sertraline have shown a possible link between onset of urinary side effects.

Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.

Loudness Dependence of Auditory-evoked Potentials, a Marker of Central Serotonergic Activity, is Affected by Fasting and Selective Uptake of Food

Serotonin is an important neuromodulator involved in many physiological processes including mood and satiety. In the brain, serotonin is manufactured from tryptophan, as serotonin itself cannot cross the blood–brain barrier. Previous research has shown that blood-tryptophan levels increase upon ingestion of carbohydrates and decrease upon protein consumption. How this translates into serotonin availability is as yet under-researched. Therefore, we examined the effect of fasting versus consuming carbohydrates or protein on central serotonergic activity using a repeated-measures crossover design in a sample of 37 healthy men. The loudness dependence of auditory-evoked potentials (LDAEP) serves as a noninvasive method to study central serotonergic activity. Blood-glucose levels and mood changes were also monitored before and after the nutritional intervention. The intervention had a significant nutrition-specific effect on LDAEP and blood-glucose levels. A significant difference emerged between the fasting condition and satiety, with LDAEP being lower during satiety, irrespective of the type of food. Thus, this indicator of serotonergic activity increased after food consumption, which was further related to mood improvement. Moreover, the LDAEP differed between the 2 measurements only for the carbohydrate testing day, suggesting that LDAEP can be selectively modulated by the type of nutrition consumed. Our data further indicate a high intraindividual stability of LDAEP, as the electrophysiological signals were very similar in the fasting condition across the 2 testing days. Together, these findings demonstrate that the LDAEP can serve as a biological marker for central serotonergic activity, while at the same time being sensitive to nutritional changes.