Insights from an academic endeavor into central nervous system drug discovery

Historically,"big pharma"did most central nervous system drug discovery R&D in-house.Yet,in modern times their"management reductionism"resulted in disappointing pipelines and pharma resided to(late)development,regulatory approval,and marketing(Thong,2015).This had significant consequences for financing and executing research,resulting in a larger role for funding by governments and patient-organizations and a shift of research to academia(Mazzucato,2013).

Advances in functional MRI research in bipolar disorder:from the perspective of mood states

Bipolar disorder is characterised by recurrent and alternating episodes of mania/hypomania and depression.Current breakthroughs in functional MRI techniques have uncovered the functional neuroanatomy of bipolar disorder.However,the pathophysiology underlying mood instability,mood switching and the development of extreme mood states is less well understood.This reviewpresents a comprehensive overviewof current evidence from functional MRI studies from the perspective of mood states.We first summarise the disrupted brain activation patterns and functional connectivity that have been reported in bipolar disorder,irrespective of the mood state.We next focus on research that solely included patients in a single mood state for a better understanding of the pathophysiology of bipolar disorder and research comparing patients with different mood states to dissect mood state-related effects.Finally,we briefly summarise current theoretical models and conclude this review by proposing potential avenues for future research.A comprehensive understanding of the pathophysiology with consideration of mood states could not only deepen our understanding of how acute mood episodes develop at a neurophysiological level but could also facilitate the identification of biological targets for personalised treatment and the development of new interventions for bipolar disorder.

Effects of Lycium barbarum polysaccharide on cytokines in adolescents with subthreshold depression:a randomized controlled study

Strong evidence has accumulated to show a correlation between depression symptoms and inflammatory responses.Moreover,anti-inflammatory treatment has shown partial effectiveness in alleviating depression symptoms.Lycium barbarum polysaccharide(LBP),derived from Goji berries,exhibits notable antioxidative and anti-inflammatory properties.In our recent double-blinded randomized placebo-controlled trial,we found that LBP significantly reduced depressive symptoms in adolescents with subthreshold depression.It is presumed that the antidepressant effect of LBP may be associated with its influence on inflammatory cytokines.In the double-blinded randomized controlled trial,we enrolled 29 adolescents with subthreshold depression and randomly divided them into an LBP group and a placebo group.In the LBP group,adolescents were given 300 mg/d LBP.A 6-week follow up was completed by 24 adolescents,comprising 14 adolescents from the LBP group(15.36±2.06 years,3 men and 11 women)and 10 adolescents from the placebo group(14.9±1.6 years,2 men and 8 women).Our results showed that after 6 weeks of treatment,the interleukin-17A level in the LBP group was lower than that in the placebo group.Network analysis showed that LBP reduced the correlations and connectivity between inflammatory factors,which were associated with the improvement in depressive symptoms.These findings suggest that 6-week administration of LBP suppresses the immune response by reducing interleukin-17A level,thereby exerting an antidepressant effect.

An open-label trial of divalproex sodium extended release for pediatric bipolar spectrum disorder in children age 6 - 12 years

Objective: To estimate the rate of response to divalproex sodium extended release in pediatric bipolar spectrum disorder in young children age 6 - 12. Methods: This was an 8-week, open-label treatment of youth with DSM-IV bipolar disorder with divalproex sodium extended release (ER) monotherapy. Severity of mania was assessed weekly with the Young Mania Rating Scale (YMRS). Results: The sample was 8.9 ± 2.0 years of age and predominantly male (83%). At study entry the mean YMRS score was 26.3 ± 4.5. Of the 18 subjects enrolled, 7 (39%) completed the 8 week course. We failed to find a clinically or statistically significant improvement with divalproex sodium ER. Pre-post comparisons at endpoint (LOCF) indicated an average response reduction of 6.1 ± 2.6 in the YMRS to a mean of 20.3 ± 8.1. Weight increased by 1.36 ± 0.7 kg (p = 0.08) from baseline to endpoint. Conclusion. Divalproex sodium ER monotherapy was associated with poor tolerability, was associated with clinically concerning weight gain but had modest therapeutic benefits in the management of symptoms of mania and depression in children with pediatric bipolar disorder.

Treating comorbid anxiety and depression: Psychosocial and pharmacological approaches

Comorbid anxiety with depression predicts poor outcomes with a higher percentage of treatment resistance than either disorder occurring alone. Overlap of anxiety and depression complicates diagnosis and renders treatment challenging. A vital step in treatment of such comorbidity is careful and comprehensive diagnostic assessment. We attempt to explain various psychosocial and pharmacological approaches for treatment of comorbid anxiety and depression. For the psychosocial component, we focus only on generalized anxiety disorder based on the following theoretical models:(1) "the avoidance model";(2) "the intolerance of uncertainty model";(3) "the meta-cognitive model";(4) "the emotion dysregulation model"; and(5) "the acceptance based model". For depression, the following theoretical models are explicated:(1) "the cognitive model";(2) "the behavioral activation model"; and(3) "the interpersonal model". Integration of these approaches is suggested. The treatment of comorbid anxiety and depression necessitates specific psychopharmacological adjustments as compared to treating either condition alone. Serotonin reuptake inhibitors are considered first-line treatment in uncomplicated depression comorbid with a spectrum of anxiety disorders. Short-acting benzodiazepines(BZDs) are an important "bridging strategy" to address an acute anxiety component. In patients with comorbid substance abuse, avoidance of BZDs is recommended and we advise using an atypical antipsychotic in lieu of BZDs. For mixed anxiety and depression comorbid with bipolar disorder, we recommend augmentation of an antidepressant with either lamotrigine or an atypical agent. Combination and augmentation therapies in the treatment of comorbid conditions vis-à-vis monotherapy may be necessary for positive outcomes. Combination therapy with tricyclic antidepressants, gabapentin and selective serotonin/norepinephrine reuptake inhibitors(e.g., duloxetine) are specifically useful for comorbid chronic pain syndromes. Aripiprazole, quetiapine, risperidone and other novel atypical agents may be effective as augmentations. For treatment-resistant patients, we recommend a "stacking approach" not dissimilar from treatment of hypertension In conclusion, we delineate a comprehensive approach comprising integration of various psychosocial approaches and incremental pharmacological interventions entailing bridging strategies, augmentation therapies and ultimately stacking approaches towards effectively treating comorbid anxiety and depression.

Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder

There is an increasing heavy disease burden of major depressive disorder(MDD)globally.Both high diagnostic heterogeneity and complicated pathological mechanisms of MDD pose significant challenges.There is much evidence to support anhedonia as a core feature of MDD.In the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition,anhedonia is further emphasised as a key item in the diagnosis of major depression with melancholic features.Anhedonia is a multifaceted symptom that includes deficits in various aspects of reward processing,such as anticipatory anhedonia,consummatory anhedonia,and decision-making anhedonia.Anhedonia is expected to become an important clinicopathological sign for predicting the treatment outcome of MDD and assisting clinical decision making.However,the precise neurobiological mechanisms of anhedonia in MDD are not clearly understood.In this paper,we reviewed(1)the current understanding of the link between anhedonia and MDD;(2)the biological basis of the pathological mechanism of anhedonia in MDD;and(3)challenges in research on the pathological mechanisms of anhedonia in MDD.A more in-depth understanding of anhedonia associated with MDD will improve the diagnosis,prediction,and treatment of patients with MDD in the future.

Efficacy of Lycium barbarum polysaccharide in adolescents with subthreshold depression: interim analysis of a randomized controlled study

Subthreshold depression is a highly prevalent condition in adolescents who are at high risk for developing major depressive disorder.In preclinical models of neurological and psychiatric diseases,Lycium barbarum polysaccharide(LBP)extracted from Goji berries had antidepressant effects including but not limited to anti-oxidative and anti-inflammatory properties.However,the effect of LBP on subthreshold depression is unclear.To investigate the clinical efficacy and safety of LBP for treating subthreshold depression in adolescents,we conducted a randomized,double-blind,placebo-controlled trial(RCT)with 29 adolescents with subthreshold depression recruited at The Fifth Affiliated Hospital of Guangzhou Medical University.The participants were randomly assigned to groups where they received either 300 mg LBP(LBP group,n=15,3 boys and 12 girls aged 15.13±2.17 years)or a placebo(placebo group,n=14,2 boys and 12 girls aged 15±1.71 years)for 6 successive weeks.Interim analyses revealed that the LBP group exhibited a greater change in Hamilton Depression Scale(HAMD-24)scores relative to the baseline and a higher remission rate(HAMD-24 total score≤7)at 6 weeks compared with the placebo group.Scores on the Beck Depression Inventory-II(BDI-II),Pittsburgh Sleep Quality Index(PSQI),Kessler Psychological Distress Scale(Kessler),and Screen for Child Anxiety-Related Emotional Disorders(SCARED)were similar between the LBP and placebo groups.No side effects related to the intervention were reported in either group.These results indicate that LBP administration reduced depressive symptoms in adolescents with subthreshold depression.Furthermore,LBP was well tolerated with no treatment-limiting adverse events.Clinical trials involving a larger sample size are needed to further confirm the anti-depressive effects of LBP in adolescents with subthreshold depression.This study was approved by the Medical Ethics Committee of the Fifth Affiliated Hospital of Guangzhou Medical University(Guangzhou,China;approval No.L2019-08)on April 4,2019 and was registered on ClinicalTrials.gov(identifier:NCT04032795)on July 25,2019.

Effects of the combination of second-generation antipsychotics on serum concentrations of aripiprazole and dehydroaripiprazole in Chinese patients with schizophrenia

Background Aripiprazole(ARI)is often prescribed alone or in combination with other second-generation antipsychotics(SGAs)to treat patients with schizophrenia.However,this may increase the potential clinical significance of drug-drug interactions.Therapeutic drug monitoring(TDM)is an important and fundamental tool both when administering ARI alone and in combination with other SGAs to monitor ARI pharmacokinetics,adjust the dosage and thereby achieve more effective and safer treatment.Aims This study retrospectively investigated the effects of four SGA comedications(clozapine,risperidone,quetiapine(QTP)and olanzapine)and other potential factors(sex,age and ARI dose)on the serum concentrations of ARI and dehydroaripiprazole(DARI)in Chinese patients with schizophrenia using TDM data.Methods High-performance liquid chromatography was used to test the serum concentrations of ARI,DARI and ARI+DARI.In addition,steady-state dose-adjusted serum concentrations(ie,concentration-to dose ratios,C:D ratios)of ARI,DARI and ARI+DARI;sex;age;ARI dose and SGA comedication dose between 299 inpatients with schizophrenia who received ARI or SGA comedication were all collected and analysed.Spearman’s correlation and multiple linear regression analysis were used to evaluate bivariate associations between ARI dose and serum ARI and DARI concentrations and describe the effect of independent variables on serum ARI and DARI concentrations,respectively.Results There were significant differences in the C:D ratios of ARI(χ^(2)=−3.21,p=0.001)and ARI+DARI(χ^(2)=−2.50,p=0.01)between the ARI and SGA groups,as well as in the C:D ratios of ARI(χ^(2)=−3.59,p<0.001)and ARI+DARI(χ^(2)=−3.10,p=0.002)between the female patients in the two groups.Of the four SGAs,only QTP had significant effects on the C:D ratios of ARI(Z=−4.12,p<0.001)and ARI+DARI(Z=−3.62,p<0.001)when compared with the ARI group in the whole sample and on the C:D ratios of ARI,DARI and ARI+DARI(Z=−3.96,p<0.001;Z=−2.22,p=0.03;Z=−3.75,p<0.001,respectively)in women when compared with their counterparts in the ARI group.Conclusion Comedication with SGAs resulted in lower C:D ratios of ARI and ARI+DARI compared with ARI monotherapy,and comedication with QTP resulted in lower C:D ratios of ARI and ARI+DARI than ARI monotherapy.Despite this statistical significance of our findings,whether the presently observed effect has clinical significance requires exploration by further research.TDM and dosage regulation of ARI should be performed in Chinese inpatients with schizophrenia who are receiving SGA comedication(especially QTP)to maintain a safe and effective dose-adjusted serum concentration of ARI and DARI.

Impact of Long-Term Treatment with OROS Methylphenidate on Pubertal Development in Adolescents with ADHD

The objective of this study was to examine whether stimulants impact pubertal development in adolescent Attention Deficit Hyperactivity Disorder (ADHD), an understudied subject. Pubertal staging data were collected during a 2-year open study of extended release methylphenidate in adolescents (N = 111) with ADHD. Tanner stages were compared to national estimates. The sample was primarily male, Caucasian, and a mean age of 14.8 years at baseline. The baseline Tanner stage for 70% of subjects was consistent with chronological age. For the majority of subjects who reached 12 - 20 months (N = 25) or 24 months (N = 21) endpoints, the Tanner stage at respective endpoints was consistent with age. We found that progression in Tanner stage was not associated with OROS MPH duration or dose (p > 0.10). Long-term treatment with extended release methylphenidate did not appear to adversely impact pubertal development in this sample of adolescents with ADHD.

Unforgettable Restaurant: helping older people who are living with disability and dementia return to society

On 25 January 2021,a special restaurant named the‘Unforgettable Restaurant’was opened in a prime locality of Shanghai,China;it emerged from a popular publicly broadcast welfare TV programme of the same name.1 This restaurant’s waiters are older patients with cognitive impairment,and the cumu-lative number of views for the programme has now exceeded 1.4 billion online.23 After the show was broadcast for two consecutive years,the filming party decided to open the restaurant officially,and the waiting duties were assumed by older people living with disability and dementia.

CBCL作为ADAH患儿精神病学共病的筛选工具

Aims: To examine the informativeness of the Child Behavior Checklist (CBCL) as a screening tool to identify comorbid and non-comorbid cases of attention deficit hyperactivity disorder (ADHD) in a paediatrically referred population. It was hypothesised that specific scales of the CBCL would help identify specific comorbidities within ADHD cases in the primary care setting. Methods: The sample consisted of children and adolescents 6-17 years old of both genders with ADHD (n = 121). A receiver operating curve (ROC) approach was used to determine which CBCL scales best differentiated between ADHD cases with and without its comorbidities with conduct, anxiety, and mood disorders. Results: ROC analysis showed that the CBCL Delinquent Behavior and Aggressive Behavior scales predicted the structured interview derived diagnoses of conduct and bipolar disorder, the Anxious/Depressed and Aggressive Behavior scales predicted major depression, and the Anxious/Depressed and Attention problems scales predicted anxiety disorders. Conclusions: These results extend to a paediatrically referred population with previously reported findings in psychiatric samples documenting good convergence between structured interview diagnoses and syndrome congruent CBCL scales. These findings support the utility of the CBCL as a screening tool for the identification of psychiatric comorbidity in ADHD youth in the primary care setting.

成人注意力不集中和多动症

注意力不集中和多动症（attention-deficit／hyperactivity disorder，ADHD）是一种患病率较高的疾病，全世界约有3％～9％的学龄儿童和4％的成人患有此病。过去认为，ADHD不会延续至成年，但是长期对照随访研究显示，该病存在于相当一部分幼年时被确诊为ADHD的成人。

The activity of antiparkinsonian drug hemantane in models of peripheral inflammation and lipopolysaccharide-induced neuroinflammation

A large body of literature supports the idea that inflammation exacerbates neurodegenerative pathology. This idea is also supported by the fact that intracerebral or intraperitoneal injection of lipopolysaccharide (LPS) induces symptoms of Parkinson’s disease in rats. The aim of this study is to evaluate the anti-inflammatory effects of the novel antiparkinsonian drug hemantane (N-2(adamantyl)hexamethylenimine hydrochloride), which is currently undergoing clinical trials, in models of peripheral inflammation and neuroinflammation and to investigate its ulcerogenic action, which is a common side effect of nonselective nonsteroidal anti-inflammatory drugs. Acetic acid-induced peritonitis in mice was used as a model of peripheral inflammation. Effect on the stomach was investigated in rats were deprived of food for 16 hours and then were treated with 0.2 LD50 of hemantane or the comparator drug diclofenac sodium per os. Injection of LPS in the left substantia nigra pars compacta in rats was chosen as a model of neuroinflammation. LPS-induced body weight loss, forelimb akinesia and behavioral changes caused by irritating odor were registered in rats. Hemantane in the dosage range of 10 - 40 mg/kg demonstrates anti-inflammatory activity and significantly decreases the intensity of exudative reaction in a model of acetic acid-induced peritonitis in mice. Additionally, at the dose of 0.2 LD50 orally it did not damage the gastric mucosa of rats. In a model of neuroinflammation induced by a unilateral injection of LPS, hemantane (10 mg/kg) prevents weight loss, development of forepaw akinesia contralateral to the operation, and smell disturbance in rats. Effectiveness of hemantane in the animal models of peripheral inflammation and neuroinflammation make it possible to suggest a new application of hemantane as a safe anti-inflammatory drug.

Dimensional Characteristics of Children and Adolescents with Mood Disorders and Autism Spectrum Disorders

Objective: We sought to identify clinical discriminators between predominantly mood disordered and predominantly autism spectrum disordered research subjects that may reflect phenotypic state and treatment response characteristics. Method: Participants were 26 boys and 4 girls aged 2 to 18 years (Mean Age = 7.70). Subjects with DSM-IV diagnoses of Major depression (N = 2), Bipolar Disorder (N = 4) and Mood Disorder not otherwise specified (NOS) (N = 11) represented the mood disorder group (MD) (N = 17, Mean Age = 8.2) and those with diagnoses of Autistic Disorder (N = 1), Asperger’s Disorder (7) or Pervasive Developmental Disorder (NOS) (N = 3) comprised the autism spectrum disorder (ASD) group (N = 9, Mean Age = 6.8). Primary outcome measurements were continuous actigraphic measurements collected over one to three week periods. Secondary outcomes included personality and observational measurements. Personality characteristics reflected significant cross-group impairments related to self-control and self-discipline and differed relative to intellectual measures. Observational measurements reflected greater general impairments among the ASD group. Results: Predominantly mood disordered children demonstrated greater impairments related to sleep (P = 0.000) and sleep onset latency (P = 0.000) and were more active than ASD children during evening periods (P = 0.000). ASD children had lower verbal functioning and greater deviations from the norm on measures of cognitive development (P = 0.003) and psychosis (P = 0.047). Conclusions: Sleep disturbances, evening activity levels and phase delayed sleep appear to differentiate predominant mood and autism spectrum disordered children suggesting future areas for further exploration of neurological and phenotypic treatment response characteristics.

Toward developing a simulated workplace laboratory for adults with high functioning autism spectrum disorders

Objective: Adults with high functioning autism spectrum disorders (HF-ASD) often experience difficulty in sustaining employment, yet little is known about workplace deficits in this population. This study aimed to assess the workplace performance of individuals with HF-ASDs in a previously validated laboratory workplace simulation environment. Method: Seven subjects of both sexes, ages 18 - 21 with a clinical diagnosis of ASD were brought in for a 10- hour workplace simulation, with a series of structured and unstructured tasks designed to elicit DSM-IV Attention Deficit and Hyperactivity Disorder (ADHD) symptoms and to provide objective measures of workplace performance. Results: HF-ASD participants performed significantly worse than Controls on several tasks throughout the day, particularly in the afternoon. Although HF-ASD subjects did not report elevated symptoms of ADHD, they completed significantly less of the unstructured tasks than Controls. Conclusion: These findings suggest that unstructured work activities and a lack of self-awareness are two primary areas of workplace deficits for individuals with HF-ASD.

Brain Signaling in Psychiatric Disorders: What Can They Tell Us in the Absence of Behavioral Differences?

This is a commentary on the often-observed phenomenon of observing task-based brain signaling differences between clinical populations and healthy control participants in the absence of any behavioral decrements in the clinical group. We offer several explanations for why brain-based differences amid normative performance may be of interest to researchers and clinicians. First, neural processing in the clinical group may not be as efficient as that in the control group. Second, differences in activation could reveal important differences in the cognition behind the (normative) behavior. Third, differences in activation may be prognostic biomarkers of injury or decline. In addition, we contend that similar behavior between groups is important in properly interpreting brain data. Finally, we offer caveats and future directions to further clarify brain mechanisms underlying behavior in clinical populations.

Nuclear receptors modulate inflammasomes in the pathophysiology and treatment of major depressive disorder

Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patients;therefore,there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms.Accumulated evidence has shown that immune inflammation,particularly inflammasome activity,plays an important role in the pathophysiology of MDD.In this review,we summarize the evidence on nuclear receptors(NRs),such as glucocorticoid receptor,mineralocorticoid receptor,estrogen receptor,aryl hydrocarbon receptor,and peroxisome proliferator-activated receptor,in modulating the inflammasome activity and depression-associated behaviors.This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD,and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.

Loneliness in Adolescents: A Flash Survey through Smartphones

Background: Loneliness has recently jumped to scholars’ attention due to a number of longitudinal studies’ results, impacting on health and quality of life of individuals, and political activities (such as the appointment of a dedicated ministry in the UK). All of these results have stimulated the need for better knowledge of the phenomenon and their consequences on different gender and age groups. Aim: So far, most of attention has been dedicated to the problem of older adults;however, younger individuals seem to also appear very vulnerable to loneliness. Method: This short communication is meant to open a window on adolescents’ feelings of being lonely or socially isolated, and does so through an investigation performed in the context of a conference on the very theme of loneliness. Results: Even at the age group considered in this study (individuals between 14 and 16 years old) loneliness appears to be a frequent problem. The contribution of the Internet and social media to this phenomenon needs to be clarified. Conclusions: Raising awareness on the seriousness of loneliness for an individual’s health and wellbeing appears today of paramount importance. Actions need to be taken at different levels to counteract the consequences of loneliness.

Endocannabinoid system: A newer molecular target for the treatment of alcohol-related behaviors

The cannabinoid(CB) receptors, endocannabinoids(e CB) and their synthesizing and catabolizing enzymes and the proteins involved in their transport, constitute what is now recognized as the e CB system. The e CBs are a class of lipids that have been identified as retrograde messengers and produce their effects via presynaptic CB receptors. The major function of the e CBs has been suggested to be that of modulating the release of several neurotransmitters implicated in a number of biological functions that include reward and reinforcement. There is now significant evidence to suggest that the e CB system plays an important role in the development of alcohol tolerance, dependence and re-lapse. Recent studies suggest that the pharmacological manipulation of the e CB system has the potential not only to block the direct reinforcing properties of alcohol but also alleviate behavioral abnormalities associated with relapse. There is also accumulating evidence that points to the possible utility of the e CB system targeted drugs in the treatment of alcoholismrelated behavioral disorders. The agents that block CB1 receptor function or inhibit the synthesis of e CBs are attractive candidate drugs that need to be explored. Further understanding of the role of the e CB system in molecular mechanism/s that underlies alcoholism-related behaviors should lead to a better treatment of this devastating disorder.

Comparison of the Analgesic Activity of Antiparkinsonian Aminoadamantane Derivatives Amantadine and Hemantane

The efficacy of some aminoadamantane derivatives used as neurodegeneration treatments is due to their ability to block NMDA receptors. But this mechanism of pharmacological action can also produce analgesic activity. Analgesic properties of two aminoadamantanes, amantadine (20 mg/kg) and hemantane (20 mg/kg), which were uncompetitive NMDA receptor antagonists, were assessed in rodent models of pain induced by different pain stimuli (tail-flick test, acetic twitches test in mice and formalin test in rats). Additionally, the anti-inflammatory properties of hemantane and amantadine were evaluated in mice with acetic peritonitis and in rats with hind paw edema induced by formalin injection. The results of our study demonstrate that the analgesic activity of the 1-aminoadamantane amantadine differs from the 2-aminoadamantane hemantane. The analgesic activity of amantadine administered intraperitoneally was more pronounced in the case of acute thermal pain in mice compared to hemantane, and only amantadine had a significant analgesic effect on the acute early phase of formalin pain in rats induced by the effect of the algogen on the primary sensory afferents. Hemantane was more effective than amantadine for relieving pain produced by inflammation owing to its pronounced anti-inflammatory activity: only hemantane decreased the amount of acetic twitches in mice that received drugs orally and was effective in the tonic phase of formalin pain in rats.