The change of gut microbiota in MDD patients under SSRIs treatment.

The alterations in the gut microbiota have been reported to be correlated with the development of depression. The purpose of this study was to investigate the changes of intestinal microbiota in depressed patients after antidepressant treatment. We recruited 30 MDD patients (MDD group) and 30 healthy controls (control group). The MDD group received individualized treatment with escitalopram at a maximum dose of 20 mg/day. After depressive symptoms improved to a HAMD scale score > 50%, a fecal sample was collected again and used as the follow-up group. The differences of gut microbiota between patients and controls, the characteristics of gut microbiota under treatment and the potential differences in metabolic functions were thus investigated. The Firmicutes/Bacteroidetes ratio was significantly different within three groups, and the ratio of follow-up group was significantly lower than those of the other two groups. Alpha diversity was significantly higher in MDD group than those of the other groups, and the alpha diversity was not significantly different between control and follow-up groups. The beta diversity of some patients resembled participants in the control group. The metabolic function of gut microbiota after treatment was still different from that of the control group. This study suggests that the intestinal flora of depressed patients has a tendency to return to normal under escitalopram treatment.

Decreased thalamo-cortico connectivity during an implicit sequence motor learning task and 7 days escitalopram intake.

Evidence suggests that selective serotonin reuptake inhibitors (SSRIs) reorganize neural networks via a transient window of neuroplasticity. While previous findings support an effect of SSRIs on intrinsic functional connectivity, little is known regarding the influence of SSRI-administration on connectivity during sequence motor learning. To investigate this, we administered 20 mg escitalopram or placebo for 1-week to 60 healthy female participants undergoing concurrent functional magnetic resonance imaging and sequence motor training in a double-blind randomized controlled design. We assessed task-modulated functional connectivity with a psycho-physiological interaction (PPI) analysis in the thalamus, putamen, cerebellum, dorsal premotor, primary motor, supplementary motor, and dorsolateral prefrontal cortices. Comparing an implicit sequence learning condition to a control learning condition, we observed decreased connectivity between the thalamus and bilateral motor regions after 7 days of escitalopram intake. Additionally, we observed a negative correlation between plasma escitalopram levels and PPI connectivity changes, with higher escitalopram levels being associated with greater thalamo-cortico decreases. Our results suggest that escitalopram enhances network-level processing efficiency during sequence motor learning, despite no changes in behaviour. Future studies in more diverse samples, however, with quantitative imaging of neurochemical markers of excitation and inhibition, are necessary to further assess neural responses to escitalopram.

Escitalopram enhances synchrony of brain responses during emotional narratives in patients with major depressive disorder.

One-week treatment with escitalopram decreases amygdala responses to fearful facial expressions in depressed patients, but it remains unknown whether it also modulates processing of complex and freely processed emotional stimuli resembling daily life emotional situations. Inter-subject correlation (ISC) offers a means to track brain activity during complex, dynamic stimuli in a model-free manner. Twenty-nine treatment-seeking patients with major depressive disorder were randomized in a double-blind study design to receive either escitalopram or placebo for one week, after which functional magnetic resonance imaging (fMRI) was performed. During fMRI the participants listened to spoken emotional narratives. Level of ISC between the escitalopram and the placebo group was compared across all the narratives and separately for the episodes with positive and negative valence. Across all the narratives, the escitalopram group had higher ISC in the default mode network of the brain as well as in the fronto-temporal narrative processing regions, whereas lower ISC was seen in the middle temporal cortex, hippocampus and occipital cortex. Escitalopram increased ISC during positive parts of the narratives in the precuneus, medial prefrontal cortex, anterior cingulate and fronto-insular cortex, whereas there was no significant synchronization in brain responses to positive vs negative events in the placebo group. Increased ISC may imply improved emotional synchronization with others, particularly during observation of positive events. Further studies are needed to test whether this contributes to the later therapeutic effect of escitalopram.

Posttraumatic Distress Symptoms and Their Response to Treatment in Adults With Prolonged Grief Disorder.

OBJECTIVE: Posttraumatic stress disorder and prolonged grief disorder (PGD) arise following major life stressors and may share some overlapping symptomatology. This study aimed to examine the presence and response to treatment of posttraumatic stress symptoms (PTSS) in bereaved adults with a primary diagnosis of PGD. METHODS: A randomized controlled trial of 395 adults with PGD (defined as an Inventory of Complicated Grief score ≥ 30 plus confirmation on structured clinical interview) randomly assigned participants to either complicated grief treatment (CGT) with citalopram, CGT plus placebo, citalopram, or placebo between March 2010 and September 2014. This secondary analysis examined the presence of PTSS (per the Davidson Trauma Scale) at baseline and change in PTSS with treatment using longitudinal mixed-effects regression and examined the role of violent compared to nonviolent deaths (loss type). RESULTS: High levels of PTSS were present at baseline, regardless of loss type, and were associated with increased functional impairment (P < .001). CGT with placebo demonstrated efficacy for PTSS compared to placebo in both threshold (OR = 2.71; 95% CI, 1.13-6.52; P = .026) and continuous (P < .001; effect size d = 0.47) analyses, and analyses were suggestive of a greater effect for CGT plus citalopram compared to citalopram alone (threshold analysis: OR = 2.84; 95% CI, 1.20-6.70; P = .017; continuous analysis: P = .053; d = 0.25). In contrast, citalopram did not differ from placebo, and CGT plus citalopram did not differ from CGT plus placebo. CONCLUSIONS: Bereavement-related PTSS are common in bereaved adults with PGD in the context of both violent and nonviolent death and are associated with poorer functioning. CGT shows efficacy for PTSS, while the antidepressant citalopram does not. TRIAL REGISTRATION: : ClinicalTrials.gov identifier: NCT01179568.

Moderation of the transgenerational transference of antenatal stress-induced anxiety.

Maternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring's exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams' and pups' anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams' anxiety. Interestingly though, pups' exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.

Neuroplastic effects of a selective serotonin reuptake inhibitor in relearning and retrieval.

Animal studies using selective serotonin reuptake inhibitors (SSRIs) and learning paradigms have demonstrated that serotonin is important for flexibility in executive functions and learning. SSRIs might facilitate relearning through neuroplastic processes and thus exert their clinical effects in psychiatric diseases where cognitive functioning is affected. However, translation of these mechanisms to humans is missing. In this randomized placebo-controlled trial, we assessed functional brain activation during learning and memory retrieval in healthy volunteers performing associative learning tasks aiming to translate facilitated relearning by SSRIs. To this extent, seventy-six participants underwent three MRI scanning sessions: (1) at baseline, (2) after three weeks of daily associative learning and subsequent retrieval (face-matching or Chinese character-noun matching) and (3) after three weeks of relearning under escitalopram (10 mg/day) or placebo. Associative learning and retrieval tasks were performed during each functional MRI (fMRI) session. Statistical modeling was done using a repeated-measures ANOVA, to test for content-by-treatment-by-time interaction effects. During the learning task, a significant substance-by-time interaction was found in the right insula showing a greater deactivation in the SSRI cohort after 21 days of relearning compared to the learning phase. In the retrieval task, there was a significant content-by-time interaction in the left angular gyrus (AG) with an increased activation in face-matching compared to Chinese-character matching for both learning and relearning phases. A further substance-by-time interaction was found in task performance after 21 days of relearning, indicating a greater decrease of performance in the placebo group. Our findings that escitalopram modulate insula activation demonstrates successful translation of relearning as a mechanism of SSRIs in human. Furthermore, we show that the left AG is an active component of correct memory retrieval, which coincides with previous literature. We extend the function of this region by demonstrating its activation is not only stimulus dependent but also time constrained. Finally, we were able to show that escitalopram aids in relearning, irrespective of content.

Early escitalopram administration as a preemptive treatment strategy against spasticity after contusive spinal cord injury in rats.

In the majority of spinal cord injury (SCI) patients, spasticity develops in the subacute phase and chronically persists with muscle hypertonia. Among various pathological conditions underlying spasticity, upregulated expression of 5-HT receptors (5-HTR) on the spinal motor neurons due to 5-HT denervation is considered one of crucial factors for hyperexcitability of the spinal circuit. As a 5-HT signal modulator, selective serotonin re-uptake inhibitors (SSRIs) are ordinarily prescribed for diseases associated with 5-HT in the CNS, and are known for their ability to increase 5-HT levels as well as to desensitize 5-HTR. Here, we hypothesized that early SSRI administration as a preemptive treatment strategy would effectively prevent the onset of spasticity. We used a rat model of contusive SCI and administered escitalopram during the first 4 weeks after injury, which is the period required for spasticity development in rodent models. We performed a swimming test to quantify spastic behaviors and conducted the Hoffman reflex test as well as histological analyses for 5-HT2AR and KCC2 expressions. Four weeks of escitalopram administration suppressed spastic behaviors during the swimming test and reduced the population of spasticity-strong rats. Moreover, the treatment resulted in decreased immunoreactivity of 5-HT2AR in the spinal motor neurons. Result of the H-reflex test and membrane expression of KCC2 were not significantly altered. In summary, early escitalopram administration could prevent the onset of spastic behaviors via regulation of 5-HT system after SCI, but could not modulate exaggerated spinal reflex. Our results suggest a novel application of SSRIs for preventative treatment of spasticity.

Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor.

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.

The effectiveness of melissa officinalis l. Versus citalopram on quality of life of menopausal women with sleep disorder: a randomized double-blind clinical trial

Abstract Objective The present study aimed to assess the effect of Melissa Officinalis L. (a combination of lemon balm with fennel fruit extract) compared with citalopram and placebo on the quality of life of postmenopausal women with sleep disturbance. Methods The present study is a randomized, double-blind, placebo clinical trial among 60 postmenopausal women with sleep disturbance who were referred to a university hospital from 2017 to 2019. The participants were randomized to receive M. Officinalis L. (500 mg daily), citalopram (30 mg) or placebo once daily for 8 weeks. The Menopause-Specific Quality of Life (MENQOL) questionnaire was self-completed by each participant at baseline and after 8 weeks of the intervention and was compared between groups. Results The mean for all MENQOL domain scores were significantly improved in the M. Officinalis L. group compared with citalopram and placebo (p < 0.001). The mean ± standard deviation (SD) after 8 weeks in the M. Officinalis L., citalopram and placebo groups was 2.2 ± 0.84 versus 0.56 ± 0.58 versus 0.36 ± 0.55 in the vasomotor (p < 0.001), 1.02 ± 0.6 versus 0.28 ± 0.2 versus 0.17 ± 0.1 in the psychomotor-social (p < 0.001), 0.76 ± 0.4 versus 0.25 ± 0.1 versus 0.11 ± 0.1 in the physical and 2.3 ± 1.0 versus 0.35 ± 0.5 versus 0.41 ± 0.5 in the sexual domain, respectively. Conclusions The results revealed that M. Officinalis L. may be recommended for improving the quality of life of menopausal women with sleep disturbance. Trial registration The present study was registered by the name "Comparison of the efficacy of citalopram and compound of Asperugo procumbens and foeniculum vulgare in treatment of menopausal disorders" with the code IRCT2013072714174N1 in the Iranian Registry of Clinical Trials (IRCT).

The Effectiveness of Melissa Officinalis L. versus Citalopram on Quality of Life of Menopausal Women with Sleep Disorder: A Randomized Double-Blind Clinical Trial.

OBJECTIVE: The present study aimed to assess the effect of Melissa Officinalis L. (a combination of lemon balm with fennel fruit extract) compared with citalopram and placebo on the quality of life of postmenopausal women with sleep disturbance. METHODS: The present study is a randomized, double-blind, placebo clinical trial among 60 postmenopausal women with sleep disturbance who were referred to a university hospital from 2017 to 2019. The participants were randomized to receive M. Officinalis L. (500 mg daily), citalopram (30 mg) or placebo once daily for 8 weeks. The Menopause-Specific Quality of Life (MENQOL) questionnaire was self-completed by each participant at baseline and after 8 weeks of the intervention and was compared between groups. RESULTS: The mean for all MENQOL domain scores were significantly improved in the M. Officinalis L. group compared with citalopram and placebo (p < 0.001). The mean ± standard deviation (SD) after 8 weeks in the M. Officinalis L., citalopram and placebo groups was 2.2 ± 0.84 versus 0.56 ± 0.58 versus 0.36 ± 0.55 in the vasomotor (p < 0.001), 1.02 ± 0.6 versus 0.28 ± 0.2 versus 0.17 ± 0.1 in the psychomotor-social (p < 0.001), 0.76 ± 0.4 versus 0.25 ± 0.1 versus 0.11 ± 0.1 in the physical and 2.3 ± 1.0 versus 0.35 ± 0.5 versus 0.41 ± 0.5 in the sexual domain, respectively. CONCLUSIONS: The results revealed that M. Officinalis L. may be recommended for improving the quality of life of menopausal women with sleep disturbance. TRIAL REGISTRATION: The present study was registered by the name "Comparison of the efficacy of citalopram and compound of Asperugo procumbens and foeniculum vulgare in treatment of menopausal disorders" with the code IRCT2013072714174N1 in the Iranian Registry of Clinical Trials (IRCT).

Efficacy and safety of tipepidine as adjunctive therapy in major depressive disorder: A randomized, double-blind, placebo-controlled clinical trial.

AIM: Tipepidine, a synthetic, non-opioid expectorant, has been shown to improve depressive-like behavior in animal models of depression. In this study, we assessed the efficacy and tolerability of tipepidine combination therapy with citalopram in treatment of major depressive disorder (MDD). METHODS: In a randomized, double-blinded, placebo-controlled clinical trial, 62 patients with MDD were assigned into two parallel groups to receive citalopram (up to 40 mg/day) plus placebo or citalopram plus tipepidine (30 mg twice daily) for 6 weeks. Participants were assessed with the Hamilton Rating Scale for Depression (HAM-D) at baseline and Weeks 2, 4, and 6. RESULTS: Fifty-six patients completed the trial. The tipepidine group showed greater improvement in HAM-D scores from baseline to all three study time points (P = 0.048 for all). The remission and response-to-treatment rates were significantly higher in the tipepidine group (53.6% and 100%) compared to the placebo group (25.0% and 75%) at the study end-point (P = 0.029 and 0.005, respectively). The remission and response times in patients in the tipepidine group were also shorter compared with the placebo group (log-rank P = 0.020 and 0.004). There was no significant difference between the two groups in baseline parameters or frequency of side-effects. CONCLUSION: Tipepidine combination therapy with citalopram can effectively improve symptoms of patients with MDD in a shorter period of treatment. However, further studies with larger sample sizes and longer follow-up treatment are needed to confirm our findings.

Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression.

In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov-Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters' and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.

Escitalopram improves neural functional prognosis and endothelial dysfunction in patients with acute cerebral infarction.

BACKGROUND: Escitalopram is one of the most commonly used SSRIs at present, which has the characteristics of quick onset, less interactions with other drugs, and relative safety. OBJECTIVE: This study aims to investigate the effects of escitalopram on neural functional prognoses and endothelial dysfunction after acute ischemic stroke. METHODS: One hundred eligible patients afflicted with acute ischemic stroke were randomized into two groups: control and treatment groups. Patients in the treatment group received escitalopram in addition to the basic therapies in the control group over a period of 90 days. Neurological deficits were quantified using the National Institutes of Health Stroke Scale (NIHSS) score and Barthel index (BI) score, cognitive impairment was determined using the Mini-Mental State Examination (MMSE) score, depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAMD). Furthermore, post-stroke depression (PSD) was defined based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), with a HAMD score ≥17. Flow-mediated vascular dilatation (FMD) of the brachial artery was use as a surrogate indicator for endothelial dysfunction assessment with ultrasound. RESULTS: The mean NIHSS and HAMD scores on day 90 after treatment were significantly lower in the treatment group than in the control group (2.17±0.36 vs. 4.24±0.85; 5.81±1.35 vs. 10.43±4.91; P < 0.01), while the mean BI score and FMD were significantly higher in the treatment group (93.08±6.23 vs. 79.64±7.56, P < 0.01; 8.71±2.35 vs. 5.83±1.21, P < 0.05) than in the control group. The improvement in MMSE score was not significantly different between the two groups. CONCLUSIONS: Treatment with escitalopram early after ischemic stroke can improve neural functional prognoses and endothelial dysfunction. Escitalopram had less side effects, which is worthy of clinical prophylactic application.

Coprescribed Benzodiazepines in Older Adults Receiving Antidepressants for Anxiety and Depressive Disorders: Association With Treatment Outcomes.

OBJECTIVE: There is a paucity of data on the effects of coprescribed benzodiazepines on treatment response variability and adherence to antidepressant pharmacotherapy for depression and anxiety in late life. The objective of this transdiagnostic analysis was to examine the effect of benzodiazepines on treatment outcomes in older patients with generalized anxiety disorder (GAD) or major depressive disorder (MDD). METHODS: Secondary analyses of data from 2 clinical trials of antidepressant pharmacotherapy for GAD (escitalopram vs placebo, 2006-2009) or MDD (open treatment with venlafaxine, 2009-2014) were conducted. Participants included 640 adults aged 60+ years with DSM-IV-defined GAD (n = 177) or MDD (n = 463). Benzodiazepine data were collected at baseline. Adherence and treatment response were assessed over 12 weeks. The analysis addressed whether coprescribed benzodiazepines are associated with treatment response, antidepressant medication adherence, dropout, final dose of antidepressant medication, and report of antidepressant-related adverse effects. RESULTS: Participants with GAD and coprescribed benzodiazepines were treated with a lower mean dosage of escitalopram and were less likely to complete the trial; there was no difference in adherence or treatment response. Participants with MDD and coprescribed benzodiazepines were less likely to tolerate a therapeutic dose of venlafaxine and reported more medication-related adverse effects; there was no difference in adherence, dropout, or treatment response. CONCLUSIONS: Coprescription of benzodiazepines was associated with increased dropout in older patients with GAD and more medication-related adverse effects in older patients with MDD. However, with the systematic clinical attention offered in a clinical trial, they do not impede treatment response. Clinicians should be aware that a coprescribed benzodiazepine may be a marker of a more challenging treatment course. Trial Registration: Data analyzed were from studies with ClinicalTrials.gov identifiers NCT00892047 and NCT00105586.

Effect of escitalopram dose and treatment duration on CSF Aß levels in healthy older adults: A controlled clinical trial.

OBJECTIVE: To determine whether treatment with escitalopram compared with placebo would lower CSF ß-amyloid 42 (Aß42) levels. RATIONALE: Serotonin signaling suppresses Aß42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram. METHODS: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aß42 was used as the primary outcome in subsequent analyses. RESULTS: An overall 9.4% greater reduction in CSF Aß42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aß status (CSF Aß42 levels <250 pg/mL) was associated with smaller Aß42 reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aß42 levels >250 pg/mL). CONCLUSIONS: Short-term longitudinal doses of escitalopram decreased CSF Aß42 in cognitively normal older adults, the target group for AD prevention. CLINICALTRIALSGOV IDENTIFIER: NCT02161458. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aß42.

Expression and impact of Lsamp neural adhesion molecule in the serotonergic neurotransmission system.

Limbic system associated membrane protein (Lsamp) is a neural adhesion protein which has been recently found to be differentially expressed between serotonergic neuron subtypes. We have previously shown elevated serotonin (5-HT) turnover rate in Lsamp-deficient mice. The purpose of the current study was to elucidate the role of Lsamp in serotonergic neurotransmission. Chronic (18 days) administration of serotonin reuptake inhibitor (SSRI) escitalopram (10 mg/kg) significantly increased general activity in wild-type mice in the open field and protected exploration in Lsamp-/- mice in the elevated-plus maze. An important psychopathology-related endophenotype, elevated 5-HT turnover in the brain of Lsamp-deficient mice, was reproduced in the saline group. Escitalopram restored the elevated 5-HT turnover of Lsamp-deficient mice to a level comparable with their wild-type littermates, suggesting that high 5-HT turnover in mutants is mediated by the increased activity of serotonin transporter (SERT protein encoded by Slc6a4 gene). The baseline level of Slc6a4 transcript was not changed in Lsamp-deficient mice, however, our immunohistochemical analysis showed partial co-expression of Lsamp with both SERT and Tph2 proteins in raphe. Overactivity of SERT in Lsamp-/- mice is further supported by significant elevation of Maoa transcript and increase of DOPAC, another Mao A product, specifically in the raphe. Again, elevation of DOPAC was reduced to the level of wild-type by chronic SSRI treatment. The activity of Lsamp gene promoters varied in 5-HT producing nuclei: both Lsamp 1a and 1b promoters were active in the dorsal raphe; most of the expression in the median raphe was from 1b promoter, whereas Lsamp 1a promoter was almost exclusively active in the caudal subgroup of raphe nuclei. We suggest that Lsamp may have an impact on the integrity of serotonergic synapses, which is possibly the neurochemical basis of the anxiety- and sociability-related phenotype in Lsamp-deficient mice.

Escitalopram Alleviates Alzheimer's Disease-Type Tau Pathologies in the Aged P301L Tau Transgenic Mice.

BACKGROUND: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer's disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. OBJECTIVE: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. METHODS: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. RESULTS: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3ß and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. CONCLUSION: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3ß signaling pathway.

Sub-chronic vortioxetine (but not escitalopram) normalizes brain rhythm alterations and memory deficits induced by serotonin depletion in rats.

Major depressive disorder (MDD) is a chronic and disabling psychiatric disorder characterized by a wide range of signs/symptoms, including cognitive dysfunction. Vortioxetine (VOR) is a multimodal antidepressant drug with pro-cognitive actions in animal models and MDD patients. The VOR-mediated blockade of 5-HT3-R in a subpopulation of GABA interneurons enhances pyramidal neuron activity in rat medial prefrontal cortex, an effect possibly underlying its pro-cognitive action. Brain oscillations are involved in regulation of cognitive function. We therefore examined VOR effects on oscillatory activity in four brain areas of freely-moving rats (prelimbic cortex, PrL; nucleus accumbens, NAc; dorsal hippocampus, dHPC; paraventricular thalamic nucleus, PVA), in standard and in serotonin-depleted rats showing recognition memory deficits. 4-chloro-dl-phenylalanine (pCPA) markedly reduced low frequency oscillations (LFO, mainly 1 Hz oscillations) and enhanced theta oscillations in PrL and NAc. It also reduced gamma and high frequency oscillations (HFO) in PVA. Subchronic VOR and escitalopram (ESC) treatments had little effect on oscillatory activity in standard rats. However, VOR -but not ESC- prevented recognition memory deficits in 5-HT-depleted rats, and normalized LFO and theta powers in PrL and NAc. In parallel, VOR -but not ESC- prevented the deficit in PrL-dHPC gamma coherence, but not the decrease in gamma and HFO powers in PVA. Overall, this supports a prominent role of serotonergic neurotransmission on brain oscillatory activity, particularly in cortico-striatal pathways linked to short-term recognition memory. Further, VOR prevented pCPA-induced cognitive deficits by normalizing oscillatory activity at lower frequencies in the PrL-NAc pathway, also normalizing the PrL-dHPC coherence at gamma frequencies.