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Citalopram and escitalopram are structurally close-related antidepressants and both forms are widely used in the world. We aimed to comparatively evaluate the anti-neuroinflammatory and neuroprotective effects of escitalopram and citalopram in Parkinson's disease (PD) mouse model. Mice were randomly divided into six groups and received 6-hydroxydopamine (6-OHDA) or vehicle administration. The mice were then treated with escitalopram, citalopram or saline for consecutive 7 days. Behaviors, neuroinflammation, neurotransmitters, and neurotoxicity were assessed. Results showed that citalopram but not escitalopram worsened body weight loss and increased freezing time in the PD mice. Both drugs had no impact on the anxiety-like behaviors but ameliorated the depressive-like behaviors as in elevated plus maze and sucrose splash tests. Escitalopram but not citalopram ameliorated motor discoordination in the PD mice as in rotarod test. In accordance, escitalopram but not citalopram attenuated the 6-OHDA-induced nigrostriatal dopaminergic loss. Further mechanistic investigations showed that both drugs mitigated activations of microglia and astrocytes and/or levels of pro-inflammatory cytokines in the PD mice, but escitalopram showed appreciably better effects in the substantia nigra. Neurotransmitter examination in the prefrontal cortex suggested that the two drugs had comparable effects on the disturbed neurotransmitters in the PD mice, but citalopram was prone to disrupt certain normal homeostasis. In conclusion, escitalopram is moderately superior than citalopram to suppress neuroinflammation and to protect against dopaminergic neuronal death and motor discoordination in the 6-OHDA-induced PD mice. Our findings imply that escitalopram shall be prescribed with priority over citalopram to treat PD patients with depression as escitalopram may meanwhile provide greater additional benefits to the patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: A more in-depth understanding of the relationship between depressive symptoms, neurocognition and suicidal behavior could provide insights into the prognosis and treatment of major depressive disorder (MDD) and suicide. We conducted a network analysis among depressed patients examining associations between history of suicide attempt (HSA), core emotional major depression disorder, and key neurocognitive domains., Method: Depressed patients (n = 120) aged 18-65 years were recruited from a larger randomized clinical trial conducted at the Douglas Institute in Montreal, Canada. They were randomly assigned to receive one of two antidepressant treatments (i.e., escitalopram or desvenlafaxine) for 8 weeks. Core emotional MDD and key neurocognitive domains were assessed pre-post treatment., Results: At baseline, an association between history of suicide attempt (HSA) and phonemic verbal fluency (PVF) suggested that HSA patients reported lower levels of the latter. After 8 weeks of antidepressant treatment, HSA became conditionally independent from PVF. Similar results were found for both the HAM-D and the QIDS-SR core emotional MDD/neurocognitive networks., Conclusion: Network analysis revealed a pre-treatment relationship between a HSA and decreased phonemic VF among depressed patients, which was no longer present after 8 weeks of antidepressant treatment., Competing Interests: Declaration of competing interest All authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: There is growing evidence that adding non-steroidal anti-inflammatory drugs to some psychopharmacological treatments may help to improve symptoms in patients suffering from major depressive disorder. The present study examined the therapeutic efficacy of adding celecoxib to escitalopram and the safety of doing so., Method: In this double-blind randomized controlled trial, 60 patients with major depressive disorder were randomly assigned to either treatment with escitalopram plus celecoxib (intervention group) or escitalopram and placebo. All patients were evaluated blind to treatment group with the Hamilton Depression Rating Scale (HDRS) before the intervention as well at 4 and 8 weeks after initiating treatment. Chi-square and paired t-test were used to examine between-group differences at those assessment times., Results: There was no significant difference in depressive symptoms between intervention and placebo groups at baseline. However, at 4 and 8 weeks after the beginning of treatment, there were significant between-group differences in HDRS scores, favoring the intervention group. No between-group differences were found in treatment-related side effects., Conclusions: Adding celecoxib to escitalopram may improve symptoms of depression in patients with major depressive disorder without increasing the risk of drug-related side effects., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) has been subjected to relatively little research. However, a recent study based on target trial emulation suggested that sertraline may be more effective than escitalopram., Aims: To investigate whether sertraline, citalopram, and escitalopram differ in their effectiveness-assessed via the risk of psychiatric hospital admission and suicide following treatment initiation. The choice to focus on sertraline, citalopram, and escitalopram was made to limit confounding by indication, as the Danish depression treatment guideline from 2007 specifically listed these three SSRIs as first choice., Method: We conducted a target trial emulation based on data from Danish registers. We identified all individuals that initiated treatment for depression with sertraline, citalopram, or escitalopram in the period from January 1, 2007, to March 1, 2019. These individuals were followed until psychiatric hospital admission or suicide (separate analyses), death, 1 year after treatment initiation or end of data. Cox proportional hazards regression adjusted for relevant baseline covariates was performed to emulate randomized treatment allocation, comparing the rate of psychiatric hospital admission and suicide for individuals treated with sertraline (used as reference), citalopram or escitalopram, respectively. For escitalopram, we conducted a sensitivity analysis excluding data from the period during which the drug was sold under patent, as the price of the drug during that time likely entailed a different prescription pattern, increasing the risk of ("patent-related") confounding by indication., Results: We identified 56,865, 118,145, and 31,083 individuals initiating treatment with sertraline, citalopram, and escitalopram, respectively. Using sertraline as reference, the adjusted hazard rate ratio (aHRR) for psychiatric admission was 0.98 (95% CI = 0.91-1.05) for citalopram and 1.21 (95% CI = 1.10-1.32) for escitalopram. Notably, in the sensitivity analysis only including patients initiating treatment after the escitalopram patent had expired, the increased risk of psychiatric hospital admission associated with escitalopram treatment was no longer present (aHRR = 0.98, 95% CI = 0.82-1.18). The results of the analyses of suicide were inconclusive, due to few outcome events., Conclusions: Sertraline, citalopram, and escitalopram do not seem to have differential effectiveness in the treatment of depression. Taking potential patent-related, time varying, confounding by indication (via severity) into account is critical for pharmacoepidemiological studies, including those employing target trial emulation., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Selective Serotonin Reuptake Inhibitors (SSRIs) represent a diverse class of medications widely prescribed for depression and anxiety. Despite their common use, there is an absence of large-scale, real-world evidence capturing the heterogeneity in their effects on individuals. This study addresses this gap by utilizing naturalistic search data to explore the varied impact of six different SSRIs on user behavior., Methods: The study sample included ∼508 thousand Bing users with searches for one of six SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) from April-December 2022, comprising 510 million queries. Cox proportional hazard models were employed to examine 30 topics (e.g., shopping, tourism, health) and 195 health symptoms (e.g., anxiety, weight gain, impotence), using each SSRI as a reference. We assessed the relative hazard ratios between drugs and, where feasible, ranked the SSRIs based on their observed effects. We used Cox proportional hazard models in order to account for both the likelihood of users searching for a particular topic or symptom and the associated time to that search. The temporal aspect aided in distinguishing between potential symptoms of the disorder, short-term medication side effects, and later appearing side effects., Results: Differences were found in search behaviors associated with each SSRI. E.g., fluvoxamine was associated with a significantly higher likelihood of searching weight gain compared to all other SSRIs (HRs 1.85-2.93). Searches following citalopram were associated with significantly higher rates of later impotence queries compared to all other SSRIs (HRs 5.11-7.76), except fluvoxamine. Fluvoxamine was associated with a significantly higher rate of health related searches than all other SSRIs (HRs 2.11-2.36)., Conclusions: Our study reveals new insights into the varying SSRI impacts, suggesting distinct symptom profiles. This novel use of large-scale, naturalistic search data contributes to pharmacovigilance efforts, enhancing our understanding of intra-class variation among SSRIs, potentially uncovering previously unidentified drug effects., Competing Interests: Declaration of competing Interest NCJ has a received grant from Boehringer-Ingelheim. NCJ has edited a book through Academic Press and receives book royalties, and NCJ also receives speaking fees related to his research. MVH has worked as a paid consultant for Artisight and ChatNexus. EYT was previously employed by Microsoft Research., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Selective serotonin reuptake inhibitors (SSRIs) are widely used for depression based on the monoamine deficiency hypothesis. However, the clinical use of these agents is controversial, in part because of their variable clinical efficacy and in part because of their delayed onset of action. Because of the complexities involved in replicating human disease and clinical dosing in animal models, the scientific community has not reached a consensus on the reasons for these phenomena. In this work, we create a theoretical hippocampal model incorporating escitalopram's pharmacokinetics, pharmacodynamics (competitive and non-competitive inhibition, and serotonin transporter (SERT) internalization), inflammation, and receptor dynamics. With this model, we simulate chronic oral escitalopram in mice showing that days to weeks are needed for serotonin levels to reach steady-state. We show escitalopram's chemical efficacy is diminished under inflammation. Our model thus offers mechanisms for how chronic escitalopram affects brain serotonin, emphasizing the importance of optimized dose and time for future antidepressant discoveries., (© 2024. The Author(s).)

Clinical studies of major depression (MD) generally focus on group effects, yet interindividual differences in brain function are increasingly recognized as important and may even impact effect sizes related to group effects. Here, we examine the magnitude of individual differences in relation to group differences that are commonly investigated (e.g., related to MD diagnosis and treatment response). Functional MRI data from 107 participants (63 female, 44 male) were collected at baseline, 2, and 8 weeks during which patients received pharmacotherapy (escitalopram, N  = 68) and controls ( N  = 39) received no intervention. The unique contributions of different sources of variation were examined by calculating how much variance in functional connectivity was shared across all participants and sessions, within/across groups (patients vs controls, responders vs nonresponders, female vs male participants), recording sessions, and individuals. Individual differences and common connectivity across groups, sessions, and participants contributed most to the explained variance (>95% across analyses). Group differences related to MD diagnosis, treatment response, and biological sex made significant but small contributions (0.3-1.2%). High individual variation was present in cognitive control and attention areas, while low individual variation characterized primary sensorimotor regions. Group differences were much smaller than individual differences in the context of MD and its treatment. These results could be linked to the variable findings and difficulty translating research on MD to clinical practice. Future research should examine brain features with low and high individual variation in relation to psychiatric symptoms and treatment trajectories to explore the clinical relevance of the individual differences identified here., Competing Interests: B.N.F. has received grant/research support from Alternative Funding Plan Innovations Award, Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Hamilton Health Sciences Foundation, J. P. Bickell Foundation, Ontario Brain Institute, Ontario Mental Health Foundation, Society for Women's Health Research, Teresa Cascioli Charitable Foundation, Eli Lilly, and Pfizer and has received consultant and/or speaker fees from AstraZeneca, Bristol-Myers Squibb, Canadian Psychiatric Association, CANMAT, Daiichi Sankyo, Lundbeck, Pfizer, Servier, and Sunovion. R.M. has received consulting and speaking honoraria from AbbVie, Allergan, Janssen, KYE, Lundbeck, Otsuka, and Sunovion and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI, and OMHF. S.P. has been a consultant to Takeda, Bristol Myers Squibb, Lundbeck; has had a research contract with Assurex; and has equity in Mensante. R.W.L. has received speaker and consultant honoraria or research funds from AstraZeneca, Brain Canada, Bristol-Myers Squibb, the Canadian Institutes of Health Research (CIHR), the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Eli Lilly, Janssen, Lundbeck, Lundbeck Institute, Medscape, Otsuka, Pfizer, Servier, St. Jude Medical, Takeda, the University Health Network Foundation, Vancouver Coastal Health Research Institute, Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Healthy Minds Canada, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Unity Health, Viatris, and VGH-UBCH Foundation. S.H.K. has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, CIHR, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, and Sun Pharmaceutical and holds stock in Field Trip Health. D.J.M. has received consulting and speaking honoraria from Lundbeck and Genomind. C.S. has received consulting and speaking honoraria from Pfizer, Otsuka, Bayer, Eisai, and research grants from CAN-BIND, CIHR, OBI, and SEAMO. S.C.S. is a senior Scientific Advisor and shareholder in ADMdx, which receives NIH funding, and during the period of this research, he had research grants from Brain Canada, Canada Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), and the Ontario Brain Institute in Canada. Other authors declare no competing financial interests., (Copyright © 2024 van der Wijk et al.)

Background: To investigate the association between pre-trial expectancy, suggestibility, and response to treatment in a trial of escitalopram and investigational drug, COMP360, psilocybin, in the treatment of major depressive disorder (ClinicalTrials.gov registration: NCT03429075)., Methods: We used data ( n = 55) from our recent double-blind, parallel-group, randomized head-to-head comparison trial of escitalopram and investigational drug, COMP360, psilocybin. Mixed linear models were used to investigate the association between pre-treatment efficacy-related expectations, as well as baseline trait suggestibility and absorption, and therapeutic response to both escitalopram and COMP360 psilocybin., Results: Patients had significantly higher expectancy for psilocybin relative to escitalopram; however, expectancy for escitalopram was associated with improved therapeutic outcomes to escitalopram, expectancy for psilocybin was not predictive of response to psilocybin. Separately, we found that pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm., Conclusions: Overall, our results suggest that psychedelic therapy may be less vulnerable to expectancy biases than previously suspected. The relationship between baseline trait suggestibility and response to psilocybin therapy implies that highly suggestible individuals may be primed for response to this treatment.

Hepatocellular carcinoma (HCC) persists to be one of the most devastating and deadliest malignancies globally. Recent research into the molecular signaling networks entailed in many malignancies has given some prominent insights that can be leveraged to create molecular therapeutics for combating HCC. Therefore, in the current communication, an in-silico drug repurposing approach has been employed to target the function of PTP4A3/PRL-3 protein in HCC using antidepressants: Fluoxetine hydrochloride, Citalopram, Amitriptyline, Imipramine, and Escitalopram oxalate as the desired ligands. The density function theory (DFT) and chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters for the chosen ligands were evaluated to comprehend the pharmacokinetics, drug-likeness properties, and bioreactivity of the ligands. The precise interaction mechanism was explored using computational methods such as molecular docking and molecular dynamics (MD) simulation studies to assess the inhibitory effect and the stability of the interactions against the protein of interest. Escitalopram oxalate exhibited a comparatively significant docking score (-7.4 kcal/mol) compared to the control JMS-053 (-6.8 kcal/mol) against the PRL-3 protein. The 2D interaction plots exhibited an array of hydrophobic and hydrogen bond interactions. The findings of the ADMET forecast confirmed that it adheres to Lipinski's rule of five with no violations, and DFT analysis revealed a HOMO-LUMO energy gap of -0.26778 ev, demonstrating better reactivity than the control molecule. The docked complexes were subjected to MD studies (100 ns) showing stable interactions. Considering all the findings, it can be concluded that Escitalopram oxalate and related therapeutics can act as potential pharmacological candidates for targeting the activity of PTP4A3/PRL-3 in HCC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thirunavukkarasu C reports administrative support was provided by Pondicherry University. Thirunavukkarasu C reports a relationship with Pondicherry University that includes: employment. Thirunavukkarasu c has patent NIl pending to NIL. NIL, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT), but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI administration in primates and rodents, respectively. The effect of SSRI treatment on 5-HT1B receptor binding in patients with MDD has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect., Methods: Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3 to 4 weeks of treatment with the SSRI escitalopram 10 mg daily. Depression severity was assessed at time of PET and after 6 to 7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale., Results: We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (P = .036). Change in DBS [11C]AZ10419369 binding correlated with Montgomery-Åsberg Depression Rating Scale reduction after 3-4 (r = 0.78, P = .021) and 6-7 (r = 0.94, P < .001) weeks' treatment., Conclusions: Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Background: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling., Aims: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes., Methods: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored., Results/outcomes: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found., Conclusion: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: RCH is a scientific advisor to Usona Institute, Journey Collab’, Osmind, Maya Health, Beckley Psytech, Anuma, MindState, Entheos Labs. DE is a paid advisor for Aya Biosciences, Clerkenwell Health, Lophora Aps and Mindstate Design Lab. DJN has received consulting fees from Algernon and H. Lundbeck and Beckley Psytech, advisory board fees from COMPASS Pathways and lecture fees from Takeda and Otsuka and Janssen plus owns stock in Alcarelle, Awakn and Psyched Wellness. TB has received consulting fees from Adamo Biosciences. None of the other authors reported conflicts of interest.

Background: Newly identified multifunctional peptidergic modulators of stress responses: neuromedin U (NMU) and neuropeptide S (NPS) are involved in the wide spectrum of brain functions. However, there are no reports dealing with potential molecular relationships between the action of diverse anxiolytic or antidepressant drugs and NMU and NPS signaling in the brain. The present work was therefore focused on local expression of the aforementioned stress-related neuropeptides in the rat brain after long-term treatment with escitalopram and clonazepam., Methods: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 3 groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 5 mg/kg daily), and clonazepam (at single dose 0.5 mg/kg). All individuals were sacrificed under anaesthesia and the whole brain excised. Total mRNA was isolated from homogenized samples of amygdala, hippocampus, hypothalamus, thalamus, cerebellum and brainstem. Real time-PCR method was used for estimation of related NPS, NPS receptor (NPSR), NMU, NMU and receptor 2 (NMUR2) mRNA expression. The whole brains were also sliced for general immunohistochemical assessment of the neuropeptides expression., Results: Chronic administration of clonazepam resulted in an increase of NMU mRNA expression and formation of NMU-expressing fibers in the amygdala, while escitalopram produced a significant decrease in NPSR mRNA level in hypothalamus. Long-term escitalopram administration affects the local expression of examined neuropeptides mRNA in a varied manner depending on the brain structure., Conclusions: Pharmacological effects of escitalopram may be connected with local at least partially NPSR-related alterations in the NPS/NMU/NMUR2 gene expression at the level selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

We hypothesized that there is a relationship between the orexinergic system (OX) alterations and changes elicited by escitalopram or venlafaxine in adult rats subjected to maternal separation (MS). This animal model of childhood adversity induces long-lasting consequences in adult physiology and behavior. Male Wistar rats from the control and MS groups were injected with escitalopram or venlafaxine (10 mg/kg) IP from postnatal day (PND) 69-89. Adult rats were subjected to behavioral assessment, estimation of hypothalamic-pituitary-adrenal (HPA) axis activity and analysis of the OX system (quantitative PCR and immunohistochemistry) in the hypothalamus and amygdala. MS caused anxiety- and depressive-like behavior, endocrine stress-related response, and up-regulation of the OX system in the hypothalamus. Escitalopram, but not venlafaxine, increased the activity of hypothalamic OX system in the control rats and both drugs had no effect on OXs in the MS group. The disturbed signaling of the OX pathway may be significant for harmful long-term consequences of early-life stress. Our data show that the normal brain and brain altered by MS respond differently to escitalopram. Presumably, anti-anxiety and antidepressant effects of this drug do not depend on the activity of hypothalamic OX system., (Copyright © 2022 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

Acute lung injury (ALI) is a significant cause of morbidity and mortality worldwide. To search for a new treatment for acute lung injury, we investigated the effect of escitalopram on lipopolysaccharide (LPS)-induced ALI. Our results showed that escitalopram inhibited salt-inducible kinase 2 (SIK2) activity (IC 50  = 6.36 ± 0.93 μM) and triggered histone deacetylase 4 (HDAC4) dephosphorylation. Following its dephosphorylation, HDAC4 translocated into the nucleus, promoted deacetylation and cytoplasmic shuttling of p65, thus inhibited LPS-induced pro-inflammatory cytokine production. Moreover, escitalopram markedly ameliorated the inflammatory responses, reduced neutrophils infiltration and attenuated LPS-induced pulmonary injury in mice. Taken together, we identified a previously unexplored role for escitalopram in SIK2/HDAC4/NF-κB pathway, therefore escitalopram may be considered as a new treatment for ALI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity., Competing Interests: Declaration of competing interest There is no conflict of interest to declare with relevance to this work. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Sceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety., Aim of the Study: To obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression., Materials and Methods: The chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST., Results: Four main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5., Conclusions: Zembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST, as assessed in FSL rats. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Human serotine transporter (hSERT) is one of the most influential drug targets, and its allosteric modulators (e.g., escitalopram) have emerged to be the next-generation medication for psychiatric disorders. However, the molecular mechanism underlying the allosteric modulation of hSERT is still elusive. Here, the simulation strategies of conventional (cMD) and steered (SMD) molecular dynamics were applied to investigate this molecular mechanism from distinct perspectives. First, cMD simulations revealed that escitalopram's binding to hSERT's allosteric site simultaneously enhanced its binding to the orthosteric site. Then, SMD simulation identified that the occupation of hSERT's allosteric site by escitalopram could also block its dissociation from the orthosteric site. Finally, by comparing the simulated structures of two hSERT-escitalopram complexes with and without allosteric modulation, a new conformational coupling between an extracellular (Arg104-Glu494) and an intracellular (Lys490-Glu494) salt bridge was identified. In summary, this study explored the mechanism underlying the allosteric modulation of hSERT by collectively applying two MD simulation strategies, which could facilitate our understanding of the allosteric modulations of not only hSERT but also other clinically important therapeutic targets.

The metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists are reported to produce ketamine-like rapid-acting and sustained antidepressant-like effects in rodents. In this study, we compared the effects of single administration of the new mGlu2/3 receptor antagonist TP0178894 and the selective serotonin reuptake inhibitor (SSRI) escitalopram in the chronic social defeat stress (CSDS) model of depression, a model which has been shown to be resistant to treatment with a single dose of SSRI. In the tail suspension test and forced swimming test, high dose (3.0 mg/kg) of TP0178894 significantly attenuated the increased immobility time of these tests in CSDS susceptible mice, compared with vehicle-treated mice. In contrast, low doses (0.3 and 1.0 mg/kg) of TP0178894 and escitalopram (10 mg/kg) did not alter the increased immobility time of these two tests. In the sucrose preference test, TP0178894 (3.0 mg/kg) significantly improved the reduced sucrose preference of CSDS susceptible mice, three and seven days after a single dose. In addition, Western blot analyses showed that TP0178894 (3.0 mg/kg), but not low doses of TP0178894 and escitalopram, significantly attenuated the reduced expression of synaptic proteins [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA1) and postsynaptic density protein 95 (PSD-95)] in the prefrontal cortex from CSDS susceptible mice. This study suggests that TP0178894 shows rapid-acting and sustained antidepressant-like effects in CSDS model, as ketamine does., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia., Methods: In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5-p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90-92 rats were evaluated in the behavioral and biochemical tests., Results: BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests., Conclusion: The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram., (© 2021. The Author(s).)

Inducible nitric oxide synthase (iNOS) is an enzyme upregulated in the brain during neuroimmune stimuli which is associated with an oxidative and pro-inflammatory environment in several brain regions, including the hippocampal formation and the prefrontal cortex. The dentate gyrus of the hippocampal formation is the site of a process known as adult hippocampal neurogenesis (AHN). Although many endogenous and extrinsic factors can modulate AHN, the exact participation of specific proinflammatory mediators such as iNOS in these processes remains to be fully elucidated. Here, we investigated how the total genetic ablation of iNOS impacts the hippocampal neurogenic niche and microglial phenotype and if these changes are correlated to the behavioral alterations observed in iNOS knockout (K.O.) mice submitted or not to the chronic unpredictable stress model (CUS - 21 days protocol). Contrary to our initial hypothesis, at control conditions, iNOS K.O. mice displayed no abnormalities on microglial activation in the dentate gyrus. However, they did exhibit impaired newborn cells and immature neuron survival, which was not affected by CUS. The reduction of AHN in iNOS K.O. mice was accompanied by an increased positive coping response in the tail suspension test and facilitation of anxiety-like behaviors in the novelty suppressed feeding. Next, we investigated whether a pro-neurogenic stimulus would rescue the neurogenic capacity of iNOS K.O. mice by administering in control and CUS groups the antidepressant escitalopram (ESC). The chronic treatment with ESC could not rescue the neurogenic capacity or the behavioral changes observed in iNOS K.O. mice. Besides, in the ventromedial prefrontal (vmPFC) cortex there was no change in the expression or the chronic activation of PV neurons (evaluated by double labeling PV with FOSB) in the prelimbic (PrL) or infralimbic subregions. FOSB expression, however, increased in the PrL of iNOS K.O. mice. Our results suggest that iNOS seems essential for the survival of newborn cells and immature neurons in the hippocampus and seem to partially explain the anxiogenic-like behavior observed in iNOS K.O. mice. On the other hand, the iNOS ablation appears to result in increased activity of the PrL which could explain the antidepressant-like behaviors of iNOS K.O mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fernandes, Costa, Scomparin, Freire, Guimarães and Campos.)

Aims: Cilostazol (CLS) has shown antidepressant effect in cardiovascular patients, post-stroke depression, and animal models through its neurotrophic and antiinflammatory activities. Consequently, we aimed to investigate its safety and efficacy in patients with MDD by conducting double-blind, randomized, placebo-controlled pilot study., Methods: 80 participants with MDD (DSM-IV criteria) and Hamilton Depression Rating Scale (HDRS) score >20 were treated with CLS 50 mg or placebo twice daily plus escitalopram (ESC) 20 mg once daily for six weeks. Patients were evaluated by HDRS scores (weeks 0, 2, 4, and 6). Serum levels of CREB1, BDNF, 5-HT, TNF-α, NF- κB, and FAM19A5 were assessed pre- and post-treatment., Results: Co-administration of CLS had markedly decreased HDRS score at all-time points compared to the placebo group (p < 0.001). Early improvement, response, and remission rates after 6 weeks were significantly higher in the CLS group (90%, 90%, 80%, respectively) than in the placebo group (25%, 65%, 50% respectively) (p < 0.001). Moreover, the CLS group was superior to the placebo group in modulation of the measured neurotrophic and inflammatory biomarkers., Conclusion: CLS is safe and effective short-term adjunctive therapy in patients with MDD with no other comorbid conditions. Trial registration ID:NCT04069819., (© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Importance: Anxiety is common among patients with coronary heart disease (CHD) and is associated with worse health outcomes; however, effective treatment for anxiety in patients with CHD is uncertain., Objective: To determine whether exercise and escitalopram are better than placebo in reducing symptoms of anxiety as measured by the Hospital Anxiety and Depression-Anxiety Subscale (HADS-A) and in improving CHD risk biomarkers., Design, Setting, and Participants: This randomized clinical trial was conducted between January 2016 and May 2020 in a tertiary care teaching hospital in the US and included 128 outpatients with stable CHD and a diagnosed anxiety disorder or a HADS-A score of 8 or higher who were older than 40 years, sedentary, and not currently receiving mental health treatment., Interventions: Twelve weeks of aerobic exercise 3 times per week at an intensity of 70% to 85% heart rate reserve, escitalopram (up to 20 mg per day), or placebo pill equivalent., Main Outcomes and Measures: The primary outcome was HADS-A score. CHD biomarkers included heart rate variability, baroreflex sensitivity, and flow-mediated dilation, along with 24-hour urinary catecholamines., Results: The study included 128 participants. The mean (SD) age was 64.6 (9.6) years, and 37 participants (29%) were women. Participants randomized to the exercise group and escitalopram group reported greater reductions in HADS-A (exercise, -4.0; 95% CI, -4.7 to -3.2; escitalopram, -5.7; 95% CI, -6.4 to -5.0) compared with those randomized to placebo (-3.5; 95% CI, -4.5 to -2.4; P = .03); participants randomized to escitalopram reported less anxiety compared with those randomized to exercise (-1.67; 95% CI, -2.68 to -0.66; P = .002). Significant postintervention group differences in 24-hour urinary catecholamines were found (exercise z score = 0.05; 95% CI, -0.2 to 0.3; escitalopram z score = -0.24; 95% CI, -0.4 to 0; placebo z score = 0.36; 95% CI, 0 to 0.7), with greater reductions in the exercise group and escitalopram group compared with the placebo group (F1,127 = 4.93; P = .01) and greater reductions in the escitalopram group compared with the exercise group (F1,127 = 4.37; P = .04). All groups achieved comparable but small changes in CHD biomarkers, with no differences between treatment groups., Conclusions and Relevance: Treatment of anxiety with escitalopram was safe and effective for reducing anxiety in patients with CHD. However, the beneficial effects of exercise on anxiety symptoms were less consistent. Exercise and escitalopram did not improve CHD biomarkers of risk, which should prompt further investigation of these interventions on clinical outcomes in patients with anxiety and CHD., Trial Registration: ClinicalTrials.gov Identifier: NCT02516332.

Many voltammetry methods have been developed to monitor brain extracellular dopamine levels. Fewer approaches have been successful in detecting serotonin in vivo. No voltammetric techniques are currently available to monitor both neurotransmitters simultaneously across timescales, even though they play integrated roles in modulating behavior. We provide proof-of-concept for rapid pulse voltammetry coupled with partial least squares regression (RPV-PLSR), an approach adapted from multi-electrode systems (i.e., electronic tongues) used to identify multiple components in complex environments. We exploited small differences in analyte redox profiles to select pulse steps for RPV waveforms. Using an intentionally designed pulse strategy combined with custom instrumentation and analysis software, we monitored basal and stimulated levels of dopamine and serotonin. In addition to faradaic currents, capacitive currents were important factors in analyte identification arguing against background subtraction. Compared to fast-scan cyclic voltammetry-principal components regression (FSCV-PCR), RPV-PLSR better differentiated and quantified basal and stimulated dopamine and serotonin associated with striatal recording electrode position, optical stimulation frequency, and serotonin reuptake inhibition. The RPV-PLSR approach can be generalized to other electrochemically active neurotransmitters and provides a feedback pipeline for future optimization of multi-analyte, fit-for-purpose waveforms and machine learning approaches to data analysis., (© 2021. The Author(s).)

HIV-1 infection affects approximately 37 million individuals, and approximately 50% of seropositive individuals will develop symptoms of clinical depression and/or apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1-induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.

Previous neuroimaging studies have revealed abnormal functional connectivity of brain networks in patients with major depressive disorder (MDD), but findings have been inconsistent. A recent big-data study found abnormal intrinsic functional connectivity within the default mode network in patients with recurrent MDD but not in first-episode drug-naïve patients with MDD. This study also provided evidence for reduced default mode network functional connectivity in medicated MDD patients, raising the question of whether previously observed abnormalities may be attributable to antidepressant effects. The present study (ClinicalTrials.gov identifier: NCT03294525) aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Forty-one first-episode drug-naïve MDD patients were administrated antidepressant medication (escitalopram or duloxetine) for 8 weeks, with resting-state functional connectivity compared between posttreatment and baseline. To assess the replicability of the big-data finding, we also conducted a cross-sectional comparison of resting-state functional connectivity between the MDD patients and 92 matched healthy controls. Both Network-Based Statistic analyses and large-scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, indicating considerable antidepressant effects. Neither Network-Based Statistic analyses nor large-scale network analyses detected significant functional connectivity differences between treatment-naïve patients and healthy controls. In short, antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The purpose of this study was to evaluate the anxiolytic and antidepressant activity of ethanolic fruit extract of Pyrus communis (pear), in comparison with escitalopram in rodents (rats and mice). Thirty Wistar rats of about 200-250gm and albino mice of 25-30gm, male gender were divided into three groups each comprising of (n=10) animal respectively. Control group received distilled water, positive control received 10mg escitalopram & treated group received 200mg/kg/day of Pyrus communis ethanolic fruit extract orally for 30 days. They were evaluated by using the open field test, forced swim test (FST), plus maze test, light and dark test, hole poking test, stationary rod test, water maze test & cage crossing activity. Results were expressed as mean ± SD. Data was analyzed by using SPSS software (VERSION 21) one way ANOVA followed by Tukey test was used for post hoc analysis. Our result showed that fruit extract had significant antidepressant-like behavior in FST (p<0.001), open field (p<0.05), cage crossing (p<0.001) , significant anxiolytic activity in light and dark box test, plus-maze activity and significantly enhanced learning in water maze and stationary rod test when compared with control. The Pyrus communis fruit extract showed the anxiolytic and antidepressant-like profile in rats and mice. However, further studies need to be carried out in clinical trials for its use in different neuropsychological disorders.

Background: Selective serotonin reuptake inhibitors (SSRIs) show acute effects on the neural processes associated with negative affective bias in healthy people and people with depression. However, whether and how SSRIs also affect reward and punishment processing on a similarly rapid time scale remains unclear., Methods: We investigated the effects of an acute and clinically relevant dose (20 mg) of the SSRI escitalopram on brain response during reward and punishment processing in 19 healthy participants. In a doubleblind, placebo-controlled study using functional MRI, participants performed a well-established monetary reward task at 3 time points: at baseline; after receiving placebo or escitalopram; and after receiving placebo or escitalopram following an 8-week washout period., Results: Acute escitalopram administration reduced blood-oxygen-level-dependent (BOLD) response during punishment feedback in the right thalamus (family-wise error corrected [FWE] p = 0.013 at peak level) and the right caudate head (pFWE = 0.011 at peak level) compared to placebo. We did not detect any significant BOLD changes during reward feedback., Limitations: We included only healthy participants, so interpretation of findings are limited to the healthy human brain and require future testing in patient populations. The paradigm we used was based on monetary stimuli, and results may not be generalizable to other forms of reward., Conclusion: Our findings extend theories of rapid SSRI action on the neural processing of rewarding and aversive stimuli and suggest a specific and acute effect of escitalopram in the punishment neurocircuitry., Competing Interests: E. Forbes declares an honorarium for editorial activities for the Association for Psychological Science; paid consultancy for DSMB, Durham VA (sponsor), Otsuka (funder); an honorarium for mentoring activities as part of Research Centre, Brown University; research funding from the National Institutes of Health; and an honorarium for a grant review from the National Institutes of Health, all outside the published work. No other competing interests declared., (© 2021 CMA Joule Inc. or its licensors.)

Escitalopram and vortioxetine are efficacious antidepressants. They directly target serotonin (5-HT) system, but vortioxetine mechanism of action is distinct from the one of selective serotonin reuptake inhibitors (SSRIs). Treatment with SSRIs decrease platelet 5-HT concentration and increase peripheral brain-derived neurotrophic factor (BDNF) levels. Since vortioxetine has a multimodal mechanism of action, it is expected to have a greater effect on circulatory BDNF concentration, compared to conventional antidepressants. This longitudinal study aimed to explore and compare the effects of 4-weeks of treatment with vortioxetine and escitalopram on plasma BDNF and platelet 5-HT concentration in patients with major depressive disorder (MDD). The results revealed that vortioxetine significantly increased plasma BDNF concentration (p = .018) and significantly decreased platelet 5-HT concentration (p < .001). Treatment with escitalopram significantly decreased platelet 5-HT concentration (p < .001), but it did not affect plasma BDNF concentration (p = .379). Response to vortioxetine was not predicted by baseline plasma BDNF or platelet 5-HT concentration, but response to escitalopram was predicted by baseline platelet 5-HT concentration. These effects might be due to vortioxetine unique mechanism of action, but the clinical implications are unclear. It remains to be determined whether this finding extends during long-term vortioxetine treatment, and which, if any, clinical effects emerge from BDNF increase., (Copyright © 2020 Elsevier Inc. All rights reserved.)