The impact of adult neurogenesis on affective functions: of mice and men.

In most mammals, new neurons are not only produced during embryogenesis but also after birth. Soon after adult neurogenesis was discovered, the influence of recruiting new neurons on cognitive functions, especially on memory, was documented. Likewise, the late process of neuronal production also contributes to affective functions, but this outcome was recognized with more difficulty. This review covers hypes and hopes of discovering the influence of newly-generated neurons on brain circuits devoted to affective functions. If the possibility of integrating new neurons into the adult brain is a commonly accepted faculty in the realm of mammals, the reluctance is strong when it comes to translating this concept to humans. Compiling data suggest now that new neurons are derived not only from stem cells, but also from a population of neuroblasts displaying a protracted maturation and ready to be engaged in adult brain circuits, under specific signals. Here, we discuss the significance of recruiting new neurons in the adult brain circuits, specifically in the context of affective outcomes. We also discuss the fact that adult neurogenesis could be the ultimate cellular process that integrates elements from both the internal and external environment to adjust brain functions. While we must be critical and beware of the unreal promises that Science could generate sometimes, it is important to continue exploring the potential of neural recruitment in adult primates. Reporting adult neurogenesis in humankind contributes to a new vision of humans as mammals whose brain continues to develop throughout life. This peculiar faculty could one day become the target of treatment for mental health, cognitive disorders, and elderly-associated diseases. The vision of an adult brain which never stops integrating new neurons is a real game changer for designing new therapeutic interventions to treat mental disorders associated with substantial morbidity, mortality, and social costs.

Early effects predict trajectories of response to esketamine in treatment-resistant depression.

BACKGROUND: The efficacy of esketamine in treatment-resistant depression (TRD) has been confirmed. However, its administration is expensive and restrictive, with limited knowledge on how long the treatment should be continued. Predicting the treatment outcome would benefit patients and alleviate the global treatment cost. We aimed to define distinct trajectories of treatment response and assess their predictability. METHODS: In this longitudinal study, two independent samples of patients with unipolar or bipolar TRD were treated with esketamine in real-world settings. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) before each esketamine administration. Latent class analyses were used to define trajectories of response. RESULTS: In the original sample (N = 50), we identified two classes whose trajectories depicted response and non-response, respectively. The model was validated in the confirmatory sample (N = 55). Class membership was influenced by a few baseline characteristics such as concomitant benzodiazepine medication, number of depressive episodes or polarity. On the other hand, after only two esketamine administrations, the MADRS score predicted the 90-day trajectory of response with an accuracy of 80 %. LIMITATIONS: This observational study is not placebo-controlled. Therefore, its results and their generalizability need to be confirmed in experimental settings. CONCLUSIONS: After the first administrations of esketamine, the MADRS score has a good capacity to predict the most plausible trajectory of response. While thresholds and their predictive values need to be confirmed, this finding suggests that clinicians could base on MADRS scores their decision to discontinue treatment because of poor remaining chances of treatment response.

Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine.

INTRODUCTION: Urgent action is needed to fight the ongoing coronavirus disease 2019 (COVID-19) pandemic by reducing the number of infected cases, contagiousness and severity. Chlorpromazine (CPZ), an antipsychotic from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and has antiviral activity against severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus. The aim of this in-vitro study was to test CPZ against SARS-CoV-2 in monkey and human cells. MATERIALS AND METHODS: Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in the presence of various concentrations of CPZ. Supernatants were harvested at day 2 and analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for the presence of SARS-CoV-2 RNA. Cell viability was assessed in non-infected cells. RESULTS: CPZ was found to have antiviral activity against SARS-CoV-2 in monkey VeroE6 cells, with a half maximal inhibitory concentration (IC50) of 8.2 µM, half maximal cytotoxic concentration (CC50) of 13.5 µM, and selectivity index (SI) of 1.65. In human A549-ACE2 cells, CPZ was also found to have anti-SARS-CoV-2 activity, with IC50 of 11.3 µM, CC50 of 23.1 µM and SI of 2.04. DISCUSSION: Although the measured SI values are low, the IC50 values measured in vitro may translate to CPZ dosages used in routine clinical practice because of the high biodistribution of CPZ in lungs and saliva. Also, the distribution of CPZ in brain could be of interest for treating or preventing neurological and psychiatric forms of COVID-19. CONCLUSIONS: These preclinical findings support clinical investigation of the repurposing of CPZ, a drug with mild side effects, in the treatment of patients with COVID-19.

The next psychoactive drugs: From imipramine to ketamine.

Since the 1950s, the therapeutic arsenal against depression has grown considerably. From the discovery of mono-amine oxidase inhibitors (MAOIs) to the antidepressant effect of ketamine, several pharmacological breakthroughs made the history of psychiatry. These discoveries oriented the research about the pathophysiology of depression, which is one of the most disabling diseases worldwide affecting 10 to 20% of general population. In this article, we offer a short historical review of the various therapeutic options developed over the past century and the consequences of these innovations. We then review the discovery of the antidepressant effects of ketamine (and its S-enantiomer, esketamine), the lastest development in depression treatment. Ketamine's effects are spectacular both in terms of their very short onset time, and because they are observed even in treatment-resistant depression. Just as MAOIs and tricyclic antidepressants allowed the "monoaminergic hypothesis of depression" to emerge, unravelling the mechanisms of ketamine's antidepressant effects should highlight the role of glutamatergic system and neuro-inflammation in the neurobiology of depression. Ketamine might also help to refine our understanding of the cognitive pathophysiology of depression and to deeply transform the clinical representations of depressive disorder.

Depuis les années 1950, l'arsenal thérapeutique permettant de lutter contre la dépression s'est considérablement enrichi. De la découverte des inhibiteurs de la mono-amine oxydase (IMAO) à celle de la kétamine, ces percées pharmacologiques ont marqué l'histoire de la psychiatrie et guidé la recherche sur la physiopathologie de la dépression, cette pathologie dévastatrice affectant entre 10 et 20 % de la population mondiale. Nous proposons dans cet article une courte revue historique des différentes options thérapeutiques développées au cours du siècle passé et des conséquences qu'ont eues ces innovations. Nous réalisons ensuite un état des lieux de la plus récente de ces découvertes, celle des effets antidépresseurs de la kétamine (et de son énantiomère S, l'eskétamine), spectaculaires de par leur délai d'action et leur efficacité même dans les formes les plus résistantes de dépression. De même que la découverte des IMAO et des tricycliques a permis de concevoir une théorie monoaminergique de la dépression, l'étude des mécanismes d'actions de la kétamine pourrait permettre de comprendre le rôle de la transmission glutamatergique ou de la neuro-inflammation dans la neurobiologie de cette pathologie, d'affiner nos connaissances sur sa physiopathologie cognitive, ou encore de transformer en profondeur les représentations des cliniciens sur cette maladie.

Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine.

Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is estimated that up to 30% of patients are resistant to conventional treatment. Recent comprehensive evidence has been accumulated which suggests that inflammation may be implied in the etiology of this disease. Here we investigated ketamine as an innovative treatment strategy due to its immune-modulating capacities. In a murine model of LPS-induced depressive-like behavior we demonstrated that a single dose of ketamine restores the LPS-induced depressive-like alterations. These behavioral effects are associated with i/ a reversal of anxiety and reduced self-care, ii/ a decrease in parenchymal cytokine production, iii/ a modulation of the microglial reactivity and iv/ a decrease in microglial quinolinic acid production that is correlated with plasmatic peripheral production. In a translational approach, we show that kynurenic acid to quinolinic acid ratio is a predictor of ketamine response in treatment-resistant depressed patients and that the reduction in quinolinic acid after a ketamine infusion is a predictor of the reduction in MADRS score. Our results suggest that microglia is a key therapeutic target and that quinolinic acid is a biomarker of ketamine response in major depressive disorder.

The association of ß-arrestin2 polymorphisms with response to antidepressant treatment in depressed patients.

The study of genetic polymorphisms involved in antidepressants (AD) response is essential to provide a personalized medicine approach in the field of depression. ß-arrestin 2 (ARRB2) is a candidate gene in the pharmacogenetics of AD as it is involved in the signaling cascade downstream of numerous neurotransmitter receptors. We investigated the association between five ARRB2 single nucleotide polymorphisms (SNPs): rs1045280, rs2036657, rs4790694, rs3786047 and rs452246, and response to AD treatment in a sample of 569 patients with a major depressive episode treated for 6months. We show that GG/GT patients for rs4522461 (n=534) and AA/AC patients for rs4790694 (n=244) have a lower response to AD than other genotype groups (HDRS score of 10.9 vs 8.0 after 6months, multivariate analysis: p=0.03; 12.2 vs 9.6, p=0.02, respectively). These data provide additional evidence that ß-arrestin 2 is a regulator of intracellular signal transduction processes involved in AD treatment.

No impact of eight NTRK2 genetic polymorphisms on 6-month antidepressant efficacy in depressed patients.

AIM: NTRK2 is the main receptor of the brain derived neurotrophic factor, which is involved in antidepressant efficacy. We assessed the impact of eight NTRK2 SNPs pertaining to response and remission after antidepressant treatment in depressed patients. PATIENTS & METHODS: In a naturalistic study, 569 patients with a major depressive episode requiring a new antidepressant treatment were genotyped for eight NTRK2 SNPs (rs1187352, rs1439050, rs1778933 rs2289656, rs2289657, rs2289658, rs3824519, rs56142442) and prospectively assessed for response and remission after 6 months of treatment. RESULTS: No association was shown between the NTRK2 SNPs and response/remission. CONCLUSION: There is no benefit to assess these eight TRKB SNPs to predict response/remission after antidepressant treatment in depressed patients.

Mother's Emotional and Posttraumatic Reactions after a Preterm Birth: The Mother-Infant Interaction Is at Stake 12 Months after Birth.

OBJECTIVES: Very preterm infants are known to be at risk of developmental disabilities and behavioural disorders. This condition is supposed to alter mother-infant interactions. Here we hypothesize that the parental coping with the very preterm birth may greatly influence mother-infant interactions. METHODS: 100 dyads were included in 3 university hospitals in France. Preterm babies at higher risk of neurodevelopmental sequelae (PRI>10) were excluded to target the maternal determinants of mother-infant interaction. We report the follow-up of this cohort during 1 year after very preterm birth, with regular assessment of infant somatic state, mother psychological state and the assessment of mother-infant interaction at 12 months by validated scales (mPPQ, HADS, EPDS, PRI, DDST and PIPE). RESULTS: We show that the intensity of post-traumatic reaction of the mother 6 months after birth is negatively correlated with the quality of mother-infant interaction at 12 months. Moreover, the anxious and depressive symptoms of the mother 6 and 12 months after birth are also correlated with the quality of mother-infant interaction at 12 months. By contrast, this interaction is not influenced by the initial affective state of the mother in the 2 weeks following birth. In this particular population of infants at low risk of sequelae, we also show that the quality of mother-infant interaction is not correlated with the assessment of the infant in the neonatal period but is correlated with the fine motor skills of the baby 12 months after birth. CONCLUSIONS: This study suggests that mothers' psychological condition has to be monitored during the first year of very preterm infants' follow-up. It also suggests that parental interventions have to be proposed when a post-traumatic, anxious or depressive reaction is suspected.