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Objectives: There is limited evidence about the factors influencing antidepressant (AD) prescription for the treatment of major depressive disorder (MDD) in Real World clinical practice in Italy. In this retrospective, population-based study, we set out to describe a patient cohort initiated on AD treatment for MDD and investigate the possible predictors of different ADs prescription in the primary care setting. Methods: Patients with a diagnosis of MDD who received an initial prescription of one of 11 selected ADs between 1-Apr-2017 and 31-Mar-2019 (index date) were identified from primary care electronic medical records in the Longitudinal Patient Database. Patients prescribed ≥1 AD in the 12 months before index date were excluded. Results were stratified by AD molecule. Multivariable logistic regression models estimated the association between patients’ demographic, clinical factors, and choice of AD molecule. Results: The study cohort comprised 8,823 patients (67.1% female; mean age 61.6 years). Previous AD treatments (prescribed in the 10 years before index date) had been received by 46.6% of patients (non-naïve patients). The most commonly reported psychiatric and medical comorbidities reported in the 12 months before index date were anxiety (8.4%) and hypertension (41.9%), respectively. Patients’ age was a significant predictor of AD molecule prescribed at index date in eight of the 11 molecules investigated while patients’ gender influenced clinician prescribing of bupropion, citalopram, fluoxetine, fluvoxamine, sertraline, and vortioxetine. Conclusions: Results from this Real World study provide useful information for clinicians on the clinical factors influencing AD prescription in patients treated for MDD in primary care.

Emotional blunting is theorized to be an adverse effect of antidepressants, particularly serotonin reuptake inhibitors, but this has not been firmly established. Another possibility is that emotional blunting represents a residual depressive symptom.We analyzed data from adult outpatients with acute major depressive disorder who participated in three 8-week randomized controlled trials. Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383) and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the "inability to feel" item from the Montgomery-Åsberg Depression Rating Scale.Emotional responsiveness improved, on average, in all treatment groups. Only a minority of participants (≤6 %) experienced more emotional blunting post-treatment, compared to baseline, with no significant differences between treatment groups, although roughly 20-25 % continued to report an inability to feel normal emotions at the final assessment. In Trials 1 and 2, emotional blunting was associated with poorer outcomes in terms of depressive symptoms, suicidal ideation, and sexual function, but these correlations were nearly identical in the placebo group.The trials were short and cannot speak to the possibility of emotional blunting from long-term treatment. Emotional blunting was measured with a single item.The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response. In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.

Selective serotonin reuptake inhibitors (SSRIs) have been associated with type 2 diabetes mellitus (T2DM) in youths, possibly via 5-HTUsing the UK Clinical Practice Research Datalink, we assembled a cohort of patients aged 5-24, newly prescribed a strong-affinity SSRI (citalopram, escitalopram, fluoxetine) or weak affinity (paroxetine, sertraline, fluvoxamine) between 1990 and 2019. We controlled for confounding using standardized mortality ratio weighting, estimated from calendar time-specific propensity scores. We used weighted Cox proportional hazards models to estimate hazard ratios (HRs) of incident T2DM with 95 % confidence intervals (CIs).The cohort included 347,368 new users of strong-affinity SSRIs and 131,359 of weak-affinity SSRIs. Strong-affinity SSRIs were not associated with an increased T2DM risk compared with weak-affinity SSRIs (incidence rate 2.8 vs 2.7 per 1000 person-years; HR 1.03, 95 % CI 0.85-1.25). T2DM risk did not vary with duration of use, age or sex. However, the HR was numerically higher in youths with normal or low weight (HR 1.30, 95 % CI 0.85-1.98) and with prior antipsychotic use (HR 1.62, 95 % CI 0.83-3.18).Median duration of SSRI use, in line with real-world SSRI prescribing, was relatively short.T2DM risk did not differ between strong- and weak-affinity SSRIs, providing reassurance for clinicians when choosing between SSRIs in youths.

Sustained attention describes our ability to keep a constant focus on a given task. This ability is modulated by our physiological state of arousal. Although lapses of sustained attention have been linked with dysregulations of arousal, the underlying physiological mechanisms remain unclear. An emerging body of work proposes that the intrusion during wakefulness of sleep-like slow waves, a marker of the transition toward sleep, could mechanistically account for attentional lapses. This study aimed to expose, via pharmacological manipulations of the monoamine system, the relationship between the occurrence of sleep-like slow waves and the behavioural consequences of sustained attention failures. In a double-blind, randomised-control trial, 32 healthy human male participants received methylphenidate, atomoxetine, citalopram or placebo during four separate experimental sessions. During each session, electroencephalography (EEG) was used to measure neural activity whilst participants completed a visual task requiring sustained attention. Methylphenidate, which increases wake-promoting dopamine and noradrenaline across cortical and subcortical areas, improved behavioural performance whereas atomoxetine, which increases dopamine and noradrenaline predominantly over frontal cortices, led to more impulsive responses. Additionally, citalopram, which increases sleep-promoting serotonin, led to more missed trials. Based on EEG recording, citalopram was also associated with an increase in sleep-like slow waves. Importantly, compared to a classical marker of arousal such as alpha power, only slow waves differentially predicted both misses and faster responses in a region-specific fashion. These results suggest that a decrease in arousal can lead to local sleep intrusions during wakefulness which could be mechanistically linked to impulsivity and sluggishness.Significance StatementWe investigated whether the modulation of attention and arousal could not only share the same neuromodulatory pathways but also rely on similar neuronal mechanisms; for example, the intrusion of sleep-like activity within wakefulness. To do so, we pharmacologically manipulated noradrenaline, dopamine, and serotonin in a four-arm, randomised, placebo-controlled trial and examined the consequences on behavioural and EEG indices of attention and arousal. We showed that sleep-like slow waves can predict opposite behavioural signatures: impulsivity and sluggishness. Slow waves may be a candidate mechanism for the occurrence of attentional lapses since the relationship between slow-wave occurrence and performance is region-specific and the consequences of these local sleep intrusions are in line with the cognitive functions carried by the underlying brain regions.

BACKGROUND: Anxiety is a common comorbidity in patients with coronary heart disease (CHD) and is associated with worse prognosis. However, effective treatment for anxiety in CHD patients is uncertain. The UNWIND randomized clinical trial showed that 12-week treatment of escitalopram was better than exercise training or placebo in reducing anxiety in anxious CHD patients. The longer-term benefits of treatment for anxiety are not known. METHODS: Patients were randomized to 12 weeks of Escitalopram (up to 20 mg), Exercise (3 times/wk), or placebo pill. At the conclusion of treatment, participants were followed for 6-months to determine the persistence of benefit on the primary anxiety endpoint assessed by the Hospital Anxiety and Depression Scale-Anxiety scale (HADS-A) and to assess the effects of treatment on major adverse cardiac events over a follow-up period of up to 6 years. RESULTS: Of the 128 participants initially randomized, 120 (94%) were available for follow-up. Participants randomized to the Escitalopram condition exhibited lower HADS-A scores (3.9 [3.1, 4.7]) compared to those randomized to Exercise (5.5 [4.6, 6.3]) (P = .007) and Placebo (5.3 [4.1, 6.5]) (P = .053). Over a median follow-up of 3.2 years (IQR: 2.3, 4.5), there were 29 adverse events but no significant between-group differences. CONCLUSION: In the UNWIND trial, 12 weeks of escitalopram treatment was effective in reducing anxiety. These beneficial effects were sustained for 6 months posttreatment. Although moderate or vigorous physical activity has a number of health benefits, exercise was not an effective treatment for anxiety in patients with CHD.

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This study aimed to determine the efficacy of non-hormonal therapy with citalopram vs fluoxetine for treating vasomotor syndrome (VMS) and urogenital syndrome of menopause (GSM) in Mexican women.A parallel prospective randomized clinical trial was conducted in 91 postmenopausal women with a total score on the Menopause Rating Scale (MRS) ≥ 17 and with the clinical diagnosis of VSM and GSM. Patients were randomly assigned to receive citalopram (n = 49) or fluoxetine (n = 42). Follow-up was carried out at 3 and 6 months.The citalopram group experienced a significant improvement compared to the fluoxetine group in the MRS total score (p 0.01), as well as in the psychological (p 0.001) and somatic (p 0.0001) domains at 3 and 6 months of follow-up. After 6 months of follow-up, the group that received citalopram decreased the relative risk (RR) to present VMS symptoms (RR = 0.30, CI 0.19-0.5, p = 0.0001), depressed mood (RR = 0.31, CI 0.15-0.6, p = 0.0002), irritability (RR = 0.40, CI 0.22-0.73, p = 0.002), anxiety (RR = 0.30, CI 0.13-0.69, p = 0.003), physical and mental exhaustion (RR = 0.35, CI 0.18-0.67, p = 0.001), sexual problems (RR = 0.18, CI 0.06-0.48, p = 0.0001), vaginal dryness (RR = 0.34, CI 0.14-0.80, p = 0.01), and urinary problems (RR = 0.36, CI 0.14-0.92, p = 0.043).We conclude that citalopram tends to improve VSM and GSM symptoms in postmenopausal Mexican women. Thus, we recommend the daily use of citalopram 20 mg. However, further studies will be required to support the results of the present work. These should include a larger number of patients and a placebo group.This clinical trial was retrospectively registered by the United States National Library of Medicine in the www.gov database on 04/20/2022. The given test Registration Number is NCT05346445.

Cigarette smoke exposure increases the production of free radicals leading to initiation of several pathological conditions by triggering the oxidative stress and inflammatory cascade. Olive fruit owing to its unique phytochemical composition possesses antioxidant, immune modulatory, and anti-inflammatory potential. Considering the compositional alterations in olive fruits during ripening, the current experimental trail was designed to investigate the prophylactic role of green and black olives against the oxidative stress induced by cigarette smoke exposure in rats. Purposely, rats were divided into five different groups: NC (negative control; normal diet), PC [positive control; normal diet + smoke exposure (SE)], drug (normal diet + SE + citalopram), GO (normal diet + SE + green olive extract), and BO (normal diet + SE + black olive extract). Rats of all groups were exposed to cigarette smoke except “NC” and were sacrificed for collection of blood and organs after 28 days of experimental trial. The percent reduction in total oxidative stress by citalopram and green and black olive extracts in serum was 29.72, 58.69, and 57.97%, respectively, while the total antioxidant capacity increased by 30.78, 53.94, and 43.98%, accordingly in comparison to PC. Moreover, malondialdehyde (MDA) was reduced by 29.63, 42.59, and 45.70% in drug, GO, and BO groups, respectively. Likewise, green and black olive extracts reduced the leakage of hepatic enzymes in sera, alkaline phosphatase (ALP) by 23.44 and 25.80% and 35.62 and 37.61%, alanine transaminase (ALT) by 42.68 and 24.39% and 51.04 and 35.41%, and aspartate transaminase (AST) by 31.51 and 16.07% and 40.50 and 27.09% from PC and drug group, respectively. Additionally, olive extracts also maintained the antioxidant pool, i.e., superoxide dismutase, catalase, and glutathione in serum. Furthermore, histological examination revealed that olive extracts prevented the cigarette smoke–induced necrosis, pyknotic alterations, and congestion in the lung, hepatic, and renal parenchyma. Besides, gene expression analysis revealed that olive extracts and citalopram decreased the brain and lung damage caused by stress-induced upregulation of NRF-2 and MAPK signaling pathways. Hence, it can be concluded that olives (both green and black) can act as promising antioxidant in alleviating the cigarette smoke–induced oxidative stress.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed treatments for depression, but their effects on serotonin reuptake and release are not well understood. Drosophila melanogaster, the fruit fly, expresses the serotonin transporter (dSERT), the major target of SSRIs, but real-time serotonin changes after SSRIs have not been characterized in this model. The goal of this study was to characterize effects of SSRIs on serotonin concentration and reuptake in Drosophila larvae. We applied various doses (0.1-100 μM) of fluoxetine (Prozac), escitalopram (Lexapro), citalopram (Celexa), and paroxetine (Paxil), to ventral nerve cord (VNC) tissue and measured optogenetically-stimulated serotonin release with fast-scan cyclic voltammetry (FSCV). Fluoxetine increased reuptake from 1 to 100 μM, but serotonin concentration only increased at 100 μM. Thus, fluoxetine occupies dSERT and slows clearance but does not affect concentration. Escitalopram and paroxetine increased serotonin concentrations at all doses, but escitalopram increased reuptake more. Citalopram showed lower concentration changes and faster reuptake profiles compared with escitalopram, so the racemic mixture of citalopram does not change reuptake as much as the S-isomer. Dose response curves were constructed to compare dSERT affinities and paroxetine showed the highest affinity and fluoxetine the lowest. These data demonstrate SSRI mechanisms are complex, with separate effects on reuptake or release. Furthermore, dynamic serotonin changes in Drosophila are similar to previous studies in mammals. This work establishes how antidepressants affect serotonin in real-time, which is useful for future studies that will investigate pharmacological effects of SSRIs with different genetic mutations in Drosophila.

Background Hypokalemia is a risk factor for drug-induced QT prolongation. Larger serum-to-dialysate potassium gradients during hemodialysis (HD) may augment the proarrhythmic risks of selective serotonin reuptake inhibitors (SSRIs). Methods We conducted a cohort study using 2007–2017 data from the United States Renal Data System and a large dialysis provider to examine if the serum-to-dialysate potassium gradient modifies SSRI cardiac safety. Using a new-user design, we compared 1-year sudden cardiac death (SCD) risk among HD patients newly treated with higher (citalopram, escitalopram) versus lower (fluoxetine, fluvoxamine, paroxetine, sertraline) QT-prolonging potential SSRIs, overall and stratified by baseline potassium gradient (≥4 versus Results The study included 25 099 patients: 11 107 (44.3%) higher QT-prolonging potential SSRI new users and 13 992 (55.7%) lower QT-prolonging potential SSRI new users. Overall, higher versus lower QT-prolonging potential SSRI use was not associated with SCD [weighted HR 1.03 (95% CI 0.86–1.24)]. However, a greater risk of SCD was associated with higher versus lower QT-prolonging potential SSRI use among patients with baseline potassium gradients ≥4 mEq/l but not among those with gradients Conclusions The serum-to-dialysate potassium gradient may modify the association between higher versus lower QT-prolonging SSRI use and SCD among people receiving HD. Minimizing the potassium gradient in the setting of QT-prolonging medication use may be warranted.

Depression is a common illness with no definite treatment.The study involved 2 experimental periods; 45-day (P1) followed by 30-day (P2). 40 adult albino rats were randomly divided into 4 groups. Grp 1 received saline orally while Grp 2 reserpine inraperitoneally (ip) during P1 and P2. Grps 3 and 4 received reserpine during P1, followed by reserpine plus B. monnieri, and reserpine plus citalopram ip during P2, respectively. Forced swimming test (FST) was performed at beginning and end of P1 and P2. Animals were sacrificed by end of P2 and brain taken for histopathological examination and ELISA estimation of serotonin, dopamine, norepinephrine, BDNF, MCP-1, FAS, and Bcl-2.During P1, reserpine prolonged immobility time (IT) in FST in Grps 2, 3, and 4. IT was subsequently lowered in Grps 3 and 4 but remained elevated in Grp 2 by end of P2. Serotonin, dopamine and norepinephrine were lowered in Grps 2, 3, and 4, but in Grps 3 and 4, levels were comparable to Grp1. BDNF and Bc1-2 were reduced in Grps 2, 3, and 4, with higher levels in Grps 3 and 4 than Grp 2. MCP-1 and FAS were elevated in Grps 2, 3, and 4, but levels were lower in Grps 3 and 4 than in Grp 2. Histopathology showed congested cerebral cortex in Grp 2 and normal cortex in other groups.Only adult male rats were involved and effects of co-administration of B. monnieri and citalopram were not characterized.B. monnieri improves depression comparable to citalopram in reserpine-induced depression.

Wistar-Kyoto (WKY) rats as an endogenous depression model partially lack a response to classic selective serotonin reuptake inhibitors (SSRIs). Thus, this strain has the potential to be established as a model of treatment-resistant depression (TRD). However, the SSRI resistance in WKY rats is still not fully understood. In this study, WKY and control rats were subjected to a series of tests, namely, a forced swim test (FST), a sucrose preference test (SPT), and an open field test (OFT), and were scanned in a 7.0-T MRI scanner before and after three-week citalopram or saline administration. Behavioral results demonstrated that WKY rats had increased immobility in the FST and decreased sucrose preference in the SPT and central time spent in the OFT. However, citalopram did not improve immobility in the FST. The amplitude of low-frequency fluctuation (ALFF) analysis showed regional changes in the striatum and hippocampus of WKY rats. However, citalopram partially reversed the ALFF value in the dorsal part of the two regions. Functional connectivity (FC) analysis showed that FC strengths were decreased in WKY rats compared with controls. Nevertheless, citalopram partially increased FC strengths in WKY rats. Based on FC, global graph analysis demonstrated decreased network efficiency in WKY + saline group compared with control + saline group, but citalopram showed weak network efficiency improvement. In conclusion, resting-state fMRI results implied widely affected brain function at both regional and global levels in WKY rats. Citalopram had only partial effects on these functional changes, indicating a potential treatment resistance mechanism.

The transcriptional effects of SSRIs and other serotonergic drugs remain unclear, in part due to the heterogeneity of postsynaptic cells, which may respond differently to changes in serotonergic signaling. Relatively simple model systems such as Drosophila afford more tractable microcircuits in which to investigate these changes in specific cell types. Here, we focus on the mushroom body, an insect brain structure heavily innervated by serotonin and comprised of multiple different but related subtypes of Kenyon cells. We use fluorescence activated cell sorting of Kenyon cells, followed by either or bulk or single cell RNA sequencing to explore the transcriptomic response of these cells to SERT inhibition. We compared the effects of two different Drosophila Serotonin Transporter (dSERT) mutant alleles as well as feeding the SSRI citalapram to adult flies. We find that the genetic architecture associated with one of the mutants contributed to significant artefactual changes in expression. Comparison of differential expression caused by loss of SERT during development versus aged, adult flies, suggests that changes in serotonergic signaling may have relatively stronger effects during development, consistent with behavioral studies in mice. Overall, our experiments revealed limited transcriptomic changes in Kenyon cells, but suggest that different subtypes may respond differently to SERT loss-of-function. Further work exploring the effects of SERT loss-of-function in other Drosophila circuits may be used help to elucidate how SSRIs differentially affect a variety of different neuronal subtypes both during development and in adults.

The effects of escitalopram vary markedly among MDD patients, and approximately one-third of patients fail to respond. A poor antidepressant response might be associated with excessively high C-reactive protein (CRP) levels, but the impact is not clear. We hypothesized that in adults with major depressive disorder, the peripheral biomarker, CRP, was associated with the response to escitalopram (SSRI).This was a prospective follow-up study. All 71 patients were treated with escitalopram for 12 weeks. Blood samples were collected at baseline and week 12. Remission was defined as a score of 7 or less on the HAMD-17 scale at week 12. Spearman correlations and multiple linear regressions were used to explore the relationship between continuous CRP levels and the HAMD-17 scores. Logistic regression was used to determine the predictors for remission. The restricted maximum likelihood (REML)-based mixed-effect model for repeated measures (MMRM) was used to examine the change of the HAMD-17 total scores between high and low CRP groups.Compared with the high CRP group (≥0.8 mg/l), the low baseline CRP group had a higher remission rate (22.73% vs. 48.89%, χ2 = 4.2, p = 0.0403). Logistic regression revealed that patients with lower CRPs were 3.920 times (95% CI: 1.142, 13.460) more likely to experience remission (p = 0.0300). The multiple linear regression model showed that the HAMD-17 total score reduction (baseline to week 12) was negatively correlated with the baseline CRP level (t = -2.00, p = 0.0494).We observed a predictive role of CRP for remission and symptomatic improvement after escitalopram treatment of MDD patients based on continuous or categorical CRP levels.

Fluoxetine (FL) is one of the selective serotonin reuptake inhibitors, which is used as an anti-depressant, as well as anti-panic drug. In this work, a sensor for label-free recognition of trace amounts of FL is introduced, which is based on an extended gate field-effect transistor (EGFET). This sensor enables the detection and accurate measurement of FL concentrations over wide dynamic range. The sensing part of the device is a Pt electrode covered by a sensitive polyvinyl chloride (PVC) membrane. The functionalized Pt electrode acting as an extended gate of the EGFET, is connected to the internal gate of a MOSFET transducer. The sensing element of the PVC membrane is the insoluble ion-pair of FL cation and tetraphenylborate anion. The sensor performance for detection of FL was characterized in different ionic strengths of the matrix solution. Then, the sensor capability to operate in physiological phosphate-buffered saline (PBS) was assessed, where the sensor indicated two linear dynamic ranges of its response, with different sensitivities in 10(-11) -10(-5) M and 10(-5) -10(-3) M ranges. Also the calculated detection limit for the sensor was 2.63x10(-12) M. Moreover, the selectivity of the sensor was examined and validated in the presence of Citalopram, which is another anti-depressant drug with a similar structure to FL. We proposed a comprehensive analytical mapping of current sensitivity in all working regimes of the EGFET, providing a guide to the design of optimized sensors in any integrated systems of interest. Finally, the sensor was successfully exploited to assay citalopram in its pharmaceutical formulation.

Background: Alterations in the serotonergic control of brain pathways responsible for facial emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched functional magnetic resonance imaging (fMRI) brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. Methods: We used REACT to estimate the dominant fMRI signal related to the serotonin (5-HT) transporter (SERT) distribution during processing of aversive facial emotion in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of SERT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A and 5-HT4 receptor maps. Results: Using REACT with the SERT map, we found a baseline group difference in the SERT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram ‘shifted’ the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Similar differences in SERT-enriched response were observed after controlling for other 5-HT maps. Conclusions: Our findings suggest that the SERT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.

Background Complex Regional Pain Syndrome (CRPS) is a neuropathic pain condition with no universally recognised treatment. The study evaluates the efficacy of a therapeutic protocol consisting of oral citalopram and lidocaine injections in patients affected by CRPS. Methods Between January 2010 and December 2014, 150 consecutive patients with CRPS were enrolled in the study and randomly assigned into three groups: group one - lidocaine injection and oral citalopram, group two - lidocaine injection and oral placebo, group three - injective and oral placebo. The Impairment Sum Score (ISS) was used to assess the severity of CRPS before, as well as at regular intervals after treatment commenced. Statistical significance (p Results The combined treatment proved to be more effective (ISS 47.6 to 12.6) than local anesthetic alone (ISS 47.5 to 21.5) and to placebo (ISS 47.2 to 29.9). Conclusion This study indicates that CRPS may be managed with well-tolerated association of oral citalopram and lidocaine injections.

Recent evidence suggests that treatment with antidepressants may promote functional recovery. However, the timeframe in which these pharmacological agents can influence stroke recovery is not well understood. This research investigated whether delayed administration of citalopram, used clinically in the management of post-stroke depression, could improve long-term functional recovery following experimental stroke. MacGreen mice carrying an enhanced green fluorescent protein reporter gene in monocyte and macrophage populations were subjected to 45 min occlusion of the middle cerebral artery. Animals were administered citalopram (10 mg/kg/day, n = 20) or saline (n = 20) starting 3 days after stroke for 28 days. Neurological deficits and skilled motor performance in the staircase task were recorded for 9 weeks post stroke. Grey and white matter structural lesions were quantified at Week 9, and enhanced green fluorescent protein immunohistochemistry was used to evaluate the effect of citalopram on inflammation. Twenty-five animals were included in the final analysis. Citalopram-treated animals (n = 13) showed a significant increase in impaired forepaw use in the staircase task compared with saline-treated animals (n = 12) 2, 3 and 7 weeks post stroke but no difference in neurological score at any time point examined. Citalopram treatment was associated with decreased monocyte/macrophage cell density and increased white matter tract integrity within the ipsilateral cortex. In conclusion, delayed administration of citalopram decreased brain inflammation and produced functional gains in our mouse model of stroke. Beneficial effects on skilled motor functions were long-lasting.

Neural health relies on cortical excitation-inhibition balance (EIB). Previous research suggests a link between increased cortical excitation and neuroplasticity induced by selective serotonin reuptake inhibitors (SSRIs). Whether there are modulations of EIB following SSRI-administration in the healthy human brain, however, remains unclear. Thus, in a randomized double-blind study, we administered a clinically relevant dose of 20 mg escitalopram for 7 days (time when steady state is achieved) in 59 healthy women (28 escitalopram, 31 placebo) on oral contraceptives. We acquired resting-state electroencephalography data at baseline, after a single dose, and at steady state. We assessed 1/f slope of the power spectrum as a marker of EIB, compared individual trajectories of 1/f slope changes contrasting single dose and 1-week drug intake, and tested the relationship of escitalopram plasma levels and cortical excitatory and inhibitory balance shifts. Escitalopram-intake was associated with decreased 1/f slope, indicating an EIB shift in favor of excitation. Furthermore, 1/f slope at baseline and after a single dose of escitalopram was associated with 1/f slope at steady state. Higher plasma escitalopram levels at a single dose were associated with better maintenance of these EIB changes throughout the drug administration week. These findings demonstrate the potential for 1/f slope to predict individual cortical responsivity to SSRIs and widen the lens through which we map the human brain by testing an interventional psychopharmacological design in a clearly defined endocrinological state.

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.

Background Some data suggests that citalopram has more risk of corrected QT interval (QTc) prolongation than other selective serotonin reuptake inhibitors. Consequently the U.S. Food and Drug Administration distributed a safety warning limiting the maximum dose for citalopram. There is also a suggestion that bupropion may decrease QTc in patients on drugs that increase QTc. The goals of this cross-sectional study were to examine (1) effects on QTc of citalopram compared to sertraline, bupropion, and tricyclic antidepressants; (2) dose dependent effects of citalopram; and (3) effects of bupropion on citalopram-mediated changes in QTc. Methods Records of subjects who received an EKG while taking one of the specified antidepressants were reviewed to collect demographic information, antidepressant history, and information about other confounders. Linear regression was used to examine the relationship between QTc and antidepressants. Results 487 subjects provided 798 EKG records. The sample was 95% male with an average age of 61 years. No differences were found in QTc between citalopram and other antidepressants. No dose relationship was detected between citalopram and QTc. Bupropion did not affect the relationship between citalopram and QTc (coefficient = -3.4; 95%CI = -14.2, 7.5; p = 0.54). Limitations Observational study designs are prone to biases from retrospective data collection. Some data subsets had small numbers of subjects. Conclusions No effect of citalopram on QTc was found at therapeutic doses. Neither was there evidence of a “QTc-sparing” effect of bupropion. The risk of adverse cardiovascular effects from citalopram at doses of 60 mg per day or less appears minimal.

Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([11C]-DASB, [123I]-ADAM, and [11C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis–Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis–Menten equation, SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose. All the studies were small, only a few investigated the same antidepressant, dose, and brain region, and few reported information on factors that may influence SERT occupancy. The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms. The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.

Funder: Lundbeckfonden (Lundbeck Foundation); doi: https://doi.org/10.13039/501100003554, Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of 'cold' cognition (including inhibition, cognitive flexibility, memory) and 'hot cognition' including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on 'cold' or 'hot' cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the 'blunting' effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339 .

У статті розглянуті сучасні аспекти патогенезу, ранньої діагностики та комплексного лікування тривожно-депресивних розладів при хворобі Паркінсона (ХП). На сьогодні науковці виділяють дві форми депресивних розладів при ХП залежно від наявності або відсутності зв’язку із флуктуаціями симптомів — депресію, що пов’язана із періодами вимикання, та депресію, що не пов’язана із періодами вимикання. Для корекції депресії при ХП застосовуються селективні інгібітори зворотного захвату серотоніну (СІЗЗС) — сертралін, пароксетин, циталопрам, міансерин, трициклічні антидепресанти (ТЦА) — амітриптилін, нортриптилін, іміпрамін, дезипрамін, селективні інгібітори зворотного захвату серотоніну та норадреналіну — дулоксетин, венлафаксин, селективний інгібітор зворотного захвату норадреналіну ребоксетин, пресинаптичний антагоніст α2-адренорецепторів міртазапін. У літературі наводяться суперечливі дані щодо ефективності тих чи інших антидепресантів. Основними препаратами для лікування депресії при ХП вважаються СІЗЗС та ТЦА. Мультидисциплінарний підхід до оптимізації лікування та догляду за пацієнтами із ХП може включати фізичну та трудотерапію, логопедичну та психологічну терапію. Все частіше у неврологічній практиці застосовуються психотерапевтичні методики на основі біоадаптивного управління, що є перспективним напрямком сучасної медицини й іменується біологічним зворотним зв’язком. Актуальним є раннє виявлення немоторних порушень при ХП, зокрема психоемоційних розладів, з метою їх своєчасної корекції для покращення якості життя пацієнтів із ХП та їх родичів. А також необхідні подальші наукові дослідження для оцінки клінічної ефективності антидепресантів при лікуванні тривожно-депресивних розладів у пацієнтів із ХП та оптимізації їх лікування з використанням у комплексній терапії сучасних немедикаментозних методів лікування, таких як когнітивно-поведінкова терапія та метод біоадаптивного управління.

OBJECTIVES: To evaluate the effects of modafinil on neuropathic pain induced by sciatic nerve cuffing in mice, and possible contribution of nitrergic/inflammatory and serotonergic systems. METHODS: Neuropathic pain was induced by applying a polyethylene cuff around the left sciatic nerve. Seven days later, mice received modafinil (50, 100, and 200 mg/kg; intraperitoneal [i.p.]) and morphine (10 mg/kg, i.p.) as control. Mice also received pretreatments of the nonselective nitric oxide (NO) synthase (NOS) inhibitor L-NAME, the selective neuronal NOS inhibitor 7-nitroindazole, the selective inducible NOS inhibitor aminoguanidine, and the selective serotonin reuptake inhibitor citalopram before modafinil (100 mg/kg). von Frey test was used to evaluate mechanical allodynia. Additionally, sciatic nerves were collected for histopathological analysis. Tissue levels of NO metabolites, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were assessed. RESULTS: Animals whose sciatic nerves were cuffed had a significantly (P

OBJECTIVE: To compare associations between individual antidepressants and newborn outcomes. DESIGN: Retrospective cohort study SETTING: Deliveries in a large, US medical system. POPULATION: Women who received at least one antidepressant prescription 3 months prior to conception through delivery. METHODS: Eligible women had maternal characteristics and newborn outcomes extracted from medical record data. Exposure was defined by the timing of the prescription during pregnancy. MAIN OUTCOME MEASURES: Newborn outcomes (any adaptation syndrome, neonatal intensive care unit (NICU) admission) were analyzed for each antidepressant and compared using standard statistics and multivariable regression compared to exposure to bupropion. Odds of outcomes based on timing of exposure were also explored. RESULTS: A total of 3,694 women were analyzed. Rates of any adaptation syndrome (p

Escitalopram is a selective serotonin reuptake inhibitor (SSRIs) antidepressant, drug that is currently used as first-line agents for the treatment of depression and it is also used in the treatment of other psychiatric disorders. The main goal of this study was to identify which brain areas are affected by escitalopram administration. This study was carried out on male Wistar rats that received escitalopram daily over 14 days and that were studied by 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG)-PET on the last day of treatment. Computed tomography (CT) images were acquired immediately before each PET scan and the main effects of drug administration were elucidated by Statistical Parametric Mapping. The results obtained indicated that repeated exposure to escitalopram increased metabolic activity in the retrosplenial and posterior cingulate cortices, while it decreased such activity in the ventral hippocampus, cerebellum, brainstem and midbrain regions, including the raphe nuclei and ventral tegmental area. Therefore, repeated exposure to escitalopram alters the activity of several brain areas closely related to the serotonergic system, and previously identified as key regions in the antidepressant effect induced by SSRIs. Furthermore, some of the changes found, such as the dampened metabolism in the ventral tegmental area, are similar to changes that have been described after treating with other fast-acting antidepressant approaches.

Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram.

Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD).Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed.Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F = 17.79, p = .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p .001) but not placebo (p = .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p = .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA) -VLPFC (F = 19.64, p .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F = 22.92, p = .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment.In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development.Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.

Stroke is a leading cause of death and neurological disability worldwide. Survivors of ischemic stroke usually suffer from impairment in motor function, visual field defect, speech disorders and depression. Cerebral levels of several neurotransmitters such as dopamine, 5-hydroxytriptamine (5-HT) or serotonin, norepinephrine (NE) and glutamate alter during ischemia and contribute to the pathophysiology of cerebral ischemia. The overall effect of serotonin in cerebral ischemia is still unclear but there are evidences that enhancement of serotonin activity in the hippocampus exerts protection against neuronal damage after ischemia. Besides, several studies showed that selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs) and serotonin agonists reduced cerebral infarct size and improved functional recovery after stroke. There are different mechanisms that may explain the neuroprotective effect of SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram in cerebral ischemia. They exert antioxidant, antiapoptotic and anti-inflammatory activities which are responsible for their effectiveness in stroke. In this review we will discuss in details the role of serotonin in ischemia and the proposed mechanisms of the neuroprotective role of SSRIs in stroke.

This review covers the latest advances in our understanding of psychosis in the elderly population with respect to diagnosis, epidemiology, and treatment. Major topics of discussion include late life psychiatric disorders such as schizophrenia, schizoaffective disorder, and delusional disorder as well as dementia-related psychosis. Clinical differences between early-onset and late-onset disorders are reviewed in terms of prevalence, symptomatology, and approach to treatment. Newly revised research and clinical criteria for dementia-related psychosis are referenced. The evidence base for emerging therapies including citalopram and pimavanserin in relation to conventional therapies such as atypical antipsychotics are discussed..

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring’s neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. A major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). Our present study shows that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms that drive adverse effects of perinatal SSRI exposure, and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia.

Background and Purpose: Stroke survivors have an increased risk of depression and bone fractures. Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of fractures in observational studies. Several randomized controlled trials (RCTs) reporting the effect of SSRIs on the risk of fractures in stroke survivors have been published recently but have not been subject to a meta-analysis. We aimed to determine the risk of fractures associated with the use of SSRIs, and the risk of falls, seizures, and recurrent strokes as possible mediators of fractures, in stroke survivors. Methods: We conducted a systematic review and meta-analysis of RCTs of SSRIs in stroke survivors according to a protocol registered in PROSPERO (CRD42020192632). Web of Science, EMBASE, PsycINFO, and Ovid Medline/PubMed bibliographic databases, clinical trial registers, and grey literature sources were searched. RCTs of SSRIs versus placebo or no intervention that report the risk of fractures in adult survivors of hemorrhagic or ischemic stroke were included. Two reviewers independently screened search results and extracted data. Meta-analyses were conducted for each outcome using the Mantel-Haenszel random-effects models. Results: The searches yielded 683 records, of which 4 RCTs of 6 months duration with a total of 6549 participants were included in the meta-analysis: 3 studies of fluoxetine and 1 study of citalopram. Treatment with an SSRI for 6 months increased the risk of fractures with a risk ratio of 2.36 (95% CI, 1.64–3.39) compared with placebo. The risk of falls, seizures, and recurrent stroke was not statistically significantly increased. Only studies of fluoxetine and citalopram were available for inclusion in the review, and hence the generalizability of the findings to other SSRIs is uncertain. Conclusions: Based on available RCTs of fluoxetine and citalopram, SSRIs used for 6 months doubled the risk of fractures in stroke survivors. Registration: URL: https://www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42020192632.

Background Cannabidiol (CBD), a major nonintoxicating constituent of cannabis, exhibits anxiolytic properties in preclinical and human studies and is of interest as a novel intervention for treating anxiety disorders. Existing first-line pharmacotherapies for these disorders include selective serotonin reuptake inhibitor and other antidepressants. Cannabidiol has well-described inhibitory action on cytochrome P450 (CYP450) drug-metabolizing enzymes and significant drug-drug interactions (DDIs) between CBD and various anticonvulsant medications (eg, clobazam) have been described in the treatment of epilepsy. Here, we examined the likelihood of DDIs when CBD is added to medications prescribed in the treatment of anxiety. Methods The effect of CBD on CYP450-mediated metabolism of the commonly used antidepressants fluoxetine, sertraline, citalopram, and mirtazapine were examined in vitro. Cannabidiol-citalopram interactions were also examined in vivo in patients (n = 6) with anxiety disorders on stable treatment with citalopram or escitalopram who received ascending daily doses of adjunctive CBD (200-800 mg) over 12 weeks in a recent clinical trial. Results Cannabidiol minimally affected the metabolism of sertraline, fluoxetine, and mirtazapine in vitro. However, CBD significantly inhibited CYP3A4 and CYP2C19-mediated metabolism of citalopram and its stereoisomer escitalopram at physiologically relevant concentrations, suggesting a possible in vivo DDI. In patients on citalopram or escitalopram, the addition of CBD significantly increased citalopram plasma concentrations, although it was uncertain whether this also increased selective serotonin reuptake inhibitor-mediated adverse events. Conclusions Further pharmacokinetic examination of the interaction between CBD and citalopram/escitalopram is clearly warranted, and clinicians should be vigilant around the possibility of treatment-emergent adverse effects when CBD is introduced to patients taking these antidepressants.

Bacterial resistance has become one of the most serious public health problems, globally, and drug repurposing is being investigated to speed up the identification of effective drugs. The aim of this study was to investigate the repurposing of escitalopram oxalate and clonazepam drugs individually, and in combination with the antibiotics ciprofloxacin and sulfamethoxazole–trimethoprim, to treat multidrug-resistant (MDR) microorganisms and to evaluate the potential chemical nuclease activity. The minimum inhibitory concentration, minimum bactericidal concentration, fractional inhibitory concentration index, and tolerance level were determined for each microorganism tested. In vitro antibacterial activity was evaluated against 47 multidrug-resistant clinical isolates and 11 standard bacterial strains from the American Type Culture Collection. Escitalopram oxalate was mainly active against Gram-positive bacteria, and clonazepam was active against both Gram-positive and Gram-negative bacteria. When associated with the two antibiotics mentioned, they had a significant synergistic effect. Clonazepam cleaved plasmid DNA, and the mechanisms involved were oxidative and hydrolytic. These results indicate the potential for repurposing these non-antibiotic drugs to treat bacterial infections. However, further studies on the mechanism of action of these drugs should be performed to ensure their safe use.

Stress is a well-known risk factor for anhedonia, and its impacts on social reward functions may be mitigated by its controllability. Moreover, there are questions about the effectiveness of selective serotonin reuptake inhibitors (SSRIs) on improving social hedonic functioning deficits characteristic of major depression. The current study in male Sprague–Dawley rats investigated the effects of uncontrollable stress on responses to social incentive stimuli and possible modulation by the SSRI escitalopram (ESC). The effects of inescapable foot-shocks on preferential responses to a conspecific, and to a compartment that was previously paired with the presence of a conspecific, were assessed in a Y-apparatus in rats that received 0, 5, or 10 mg/kg ESC. Although inescapable foot-shock exposure did not significantly alter the investigation of the conspecific, it did impair the response to the social-paired compartment and, importantly, this impairment was reversed by ESC. These results indicate that psychophysical stress can negatively impact reactivity to learned social rewards and that SSRI administration can have positive therapeutic effects.

Background Generalized anxiety disorder (GAD) is partly attibuted to the dysregulation of nuero-inflammation which can be mediated by adiponectin. We conducted this study was to explore the characteristics of peripheral adiponectin and its role in predicting treatment outcome in patients with generalized anxiety disorder (GAD) treated by escitalopram or venlafaxine. Methods A total of 70 untreated GAD inpatients who met the diagnosis criteria of the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) were enrolled and randomly selected for treatment with escitalopram (n=36) or venlafaxine (n=34) for 8 weeks. The serum adiponectin level of GAD and healthy controls (HCs) was measured by enzyme-linked immunosorbent assay (ELISA) before treatment. Hamilton Anxiety Rating Scale (HAM-A) assessment was conducted at baseline and at 1, 2, 4, and 8 weeks after treatment respectively. Serum adiponectin levels were compared between GAD patients and HCs, as well as between remission and nonremission cases; the correlation between baseline adiponectin level and HAM-A reduction rate were also analyzed. Results The serum adiponectin levels were higher in GAD patients compared to HCs (t=2.304; P=0.023), the serum adiponectin levels were higher in remission cases compared to nonremission cases (t=2.255, P=0.027), and the receiver operating characteristic (ROC) area in predicting treatment remission was 0.652±0.066 (P=0.029). The correlation between baseline adiponectin level and HAM-A reduction rate of GAD cases treated with escitalopram and venlafaxine in the endpoint was 0.362 (P=0.030) and -0.026 (P=0.883), respectively, and the ROC area of baseline adiponectin level in predicting treatment remission was 0.72±0.086 (P=0.024) and 0.473±0.102 (P=0.469), respectively. Conclusions Peripheral adiponectin is upregulated in GAD, and it seems higher baseline adiponectin level predicts a better treatment remission treated by escitalopram but not with venlafaxine, which suggests adiponectin maybe a potential key biomarker in Chinese GAD.

Trazodone is an efficacious atypical antidepressant acting both as an SSRI and a 5HT2A and 5HT2C antagonist. Antagonism to H1-histaminergic and alpha1-adrenergic receptors is responsible for a sleep-promoting action. We studied long-term gene expression modulations induced by chronic trazodone to investigate the molecular underpinning of trazodone efficacy. Rats received acute or chronic treatment with trazodone or citalopram. mRNA expression of growth factor and circadian rhythm genes was evaluated by qPCR in the prefrontal cortex (PFCx), hippocampus, Nucleus Accumbens (NAc), amygdala, and hypothalamus. CREB levels and phosphorylation state were evaluated using Western blotting. BDNF levels were significantly increased in PFCx and hippocampus by trazodone and in the NAc and hypothalamus by citalopram. Likewise, TrkB receptor levels augmented in the PFCx after trazodone and in the amygdala after citalopram. FGF-2 and FGFR2 levels were higher after trazodone in the PFCx. The CREB phosphorylation state was increased by chronic trazodone in the PFCx, hippocampus, and hypothalamus. Bmal1 and Per1 were increased by both antidepressants after acute and chronic treatments, while Per2 levels were specifically augmented by chronic trazodone in the PFCx and NAc, and by citalopram in the PFCx, amygdala, and NAc. These findings show that trazodone affects the expression of neurotrophic factors involved in antidepressant responses and alters circadian rhythm genes implicated in the pathophysiology of depression, thus shedding light on trazodone’s molecular mechanism of action.

Sleep deprivation may induce anxiety. On the other hand, anxiety disorders elicit main changes in the quality of sleep. Moreover, orexin and citalopram play a role in the modulation of insomnia and mood diseases. Thus, we planned preclinical research to evaluate the effect of combinations of orexin agents and citalopram on anxiety behavior in rapid eye movement (REM) sleep-deprived mice. For drug intracerebroventricular (i.c.v.) infusion, the guide cannula was surgically implanted in the left lateral ventricle of mice. REM sleep deprivation was conducted via water tank apparatus for 24 h. The anxiety behavior of mice was evaluated using the elevated plus maze (EPM). Our results revealed that REM sleep deprivation reduced the percentage of open arm time (%OAT) and the percentage of the open arm entries (%OAE) but not closed arm entries (locomotor activity) in the EPM test, presenting an anxiogenic response ( P 0.05). We found a sub-threshold dose of SB-334867, orexin-1 receptor antagonist, and orexin-1 which did not alter anxiety reaction in the REM sleep-deprived mice ( P 0.05). Intraperitoneal (i.p.) injections of citalopram (5 and 10 mg/kg) increased both %OAT and %OAE ( P 0.001) representing an anxiolytic effect, but not locomotor activity in the REM sleep-deprived mice. Interestingly, co-treatment of citalopram (1, 5 and 10 mg/kg; i.p.) and SB-334867 (0.1 µg/mouse; i.c.v.) potentiated the anxiolytic effect in the REM sleep-deprived mice. On the other hand, co-treatment of different dosages of citalopram along with a sub-threshold dose of orexin-1 did not alter %OAT, %OAE, and locomotor activity in the REM sleep-deprived mice. We found a synergistic anxiolytic effect of citalopram and SB-334867 in the REM sleep-deprived mice. These results suggested an interaction between citalopram and SB-334867 to prevent anxiogenic behavior in the REM sleep-deprived mice.

To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women. Searches were carried out in the PubMed, Cochrane Central, Embase, Lilacs, OpenGrey, and Clinical Trials databases. The searches were carried out by two of the authors, not delimiting publication date or original language. The following descriptors were used: The following data were extracted: author, year of publication, setting, type of study, sample size, intervention details, follow-up time, and results. A total of 218 articles were found, with 79 being excluded because they were repeated, leaving 139 articles for analysis: 90 were excluded in the analysis of the titles, 37 after reading the abstract, and 4 after reading the articles in full, and 1 could not be found, therefore, leaving 7 articles that were included in the review. Most of the studies analyzed have shown pain improvement with the help of neuromodulators for chronic pain. However, no improvement was found in the study with the highest statistical power. There is still not enough evidence that neuromodulatory drugs reduce the intensity of pain in women with CPP. Avaliar o efeito de drogas neuromoduladoras na intensidade da dor pélvica crônica em mulheres. As buscas foram realizadas nas bases de dados PubMed, Cochrane Central, Embase, Lilacs, OpenGrey e Clinical Trials. SELEçãO DOS ESTUDOS:: As buscas foram realizadas por dois dos autores, não delimitando data de publicação ou idioma de publicação. Foram usados os seguintes descritores: Foram extraídos os seguintes dados: autor, ano de publicação, local de origem, tipo de estudo, tamanho da amostra, detalhes da intervenção, tempo de seguimento e resultados. SíNTESE DOS DADOS:: Foram encontrados 218 artigos, sendo 79 deles excluídos por serem repetidos, restando 139 artigos para análise, dos quais 90 foram excluídos na análise dos títulos, 37 após a leitura do resumo e 4 após a leitura dos artigos na íntegra, e 1 não foi encontrado, restando, então, 7 artigos que foram incluídos na revisão. CONCLUSãO:: A maioria dos estudos analisados mostrou melhora da dor crônica com auxílio de neuromoduladores. No entanto, nenhuma melhora foi encontrada no artigo com maior poder estatístico. Ainda não há evidências suficientes de que drogas neuromoduladoras reduzam a intensidade da dor pélvica crônica em mulheres.

One of the biggest ambitions in the field of anorexia nervosa (AN) research is to find a reliable and effective pharmacological treatment. The fact that currently no pharmacological treatment is safe and effective in this disease is worrying and also challenging. On the basis of the progress in our understanding of AN neurobiology, we propose that escitalopram, a widely available drug, might be a safe and effective option that needs to be investigated. Escitalopram is the only selective serotonin reuptake inhibitor, without any catecholaminergic effect. As studies have shown decreased serotonergic and increased dopaminergic transmission in AN, we hypothesized that an ideal drug for AN management should boost serotonin levels to increase serotonergic and decrease dopaminergic transmission, the two main features of escitalopram action. Here, we present a short overview of pharmacological research in AN and discuss the theoretical rationale for escitalopram use in AN. We also call for double-blind, randomized, placebo-controlled trials to test whether this theoretical framework translates into clinical efficacy.

Residual antidepressants are of increasing concern worldwide, yet critical information on their long-term neurotoxic impacts on nontarget aquatic animals is lacking. Here, we investigated the long-term effects (from 0 to 150 days postfertilization) of the selective serotonin reuptake inhibitor citalopram (0.1-100 μg/L) on motor function, learning, and memory in zebrafish over two generations and explored the reversibility of the effect in F1 larvae. Unlike F0

As epidemiological studies become longer and larger, the field needs novel graphical methods to visualize complex longitudinal data. The aim of this study was to present the Slinkyplot, a longitudinal crosstabulation, to illustrate patterns of antidepressant use in a large prospective cohort of older adults with mild cognitive impairment.Data from the National Alzheimer's Coordinating Center are used to track switches between different states and types of antidepressant use. A Slinkyplot is populated with rows representing the state of medication use at each timepoint and columns representing the state at each subsequent visit.The constructed Slinkyplots display the common practice of switching on and off different antidepressants over time, with citalopram, sertraline, and bupropion most commonly used followed by switching to another SSRI or SNRI as second-line treatment.Slinkyplots are an innovative graphical means of visualizing complex patterns of transitions between different states over time for large longitudinal studies.

Background Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear. Methods In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models. Results CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3—4.1] vs. 0.4 [95% CI -0.5 – 1.3] vs. -0.1 [-95% CI -1.5—1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status. Conclusions Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.

Although obsessive-compulsive personality disorder (OCPD) is one of the most prevalent personality disorders, it is one of the least studied. There is debate as to whether pharmacotherapy is efficacious for OCPD. We aimed to systematically evaluate the efficacy and tolerability of pharmacotherapy for OCPD.This systematic review found two randomized controlled trials investigating pharmacotherapy of OCPD. In a study of major depression (n = 308) with comorbid OCPD (n = 71), citalopram was more effective for OCPD than sertraline with fewer drop-outs from treatment. In a small study of OCPD (n = 24), fluvoxamine was more effective than placebo, and there was a low drop-out rate. Risk of bias and quality assessment of these studies was not possible, and findings have very low levels of certainty.Two studies provide preliminary evidence in support of citalopram and fluvoxamine for OCPD. Further randomized controlled trials are required before firm conclusions can be drawn regarding efficacy of pharmacotherapy for OCPD.

Background Several studies investigated the role of selective serotonin reuptake inhibitors (SSRIs) in improving poststroke recovery; thus, we have decided to conduct this systematic review and meta‐analysis to investigate the efficacy and safety of SSRIs in poststroke recovery. Methods and Results In this meta‐analysis we searched the following databases: PubMed, Cochrane, Scopus, and Google Scholar. The studies were included if they were placebo‐controlled trials in design and reported SSRIs’ effects on poststroke depression, anxiety, disability, dependence, motor abilities, and cognitive functions. The quality of the included studies was assessed using the revised Cochrane risk‐of‐bias tool for randomized trials. The search yielded 44 articles that included 16 164 patients, and about half of the participants were treated with SSRIs. Our results showed that SSRIs had a significant effect on preventing depression (weighted mean difference [WMD], −7.05 [95% CI, −11.78 to −2.31]), treating depression according to the Hamilton Rating Scale for Depression score (WMD, −1.45 [95% CI, −2.77 to −0.14]), anxiety (relative risk, 0.23 [95% CI, 0.09–0.61]), dependence (WMD, 8.86 [95% CI, 1.23–16.48]), motor abilities according to National Institutes of Health Stroke Scale score (WMD, −0.79 [95% CI, −1.42 to −0.15]), and cognitive functions (WMD, 1.00 [95% CI, 0.12–1.89]). On the other hand, no significant effect of SSRIs on disability was observed. Additionally, we found that treating with SSRIs increased the risk of seizures (relative risk, 1.44 [95% CI, 1.13–1.83]), whereas there was no difference in the incidence of gastrointestinal symptoms or bleeding between SSRIs and a placebo. Conclusions Our study showed that SSRIs are effective in preventing and treating depression, and improving anxiety, motor function, cognitive function, and dependence in patients after stroke. These benefits were only reproducible with the citalopram subanalysis but not fluoxetine. Further well‐conducted placebo‐controlled trials are needed to investigate the safety and efficacy of citalopram among patients after stroke. Registration URL: www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42021285766.

Background To date, disproportionality analysis has been unable to demonstrate the increased bleeding risk associated with antidepressant drugs, especially selective serotonin reuptake inhibitors. Objective We hypothesised that a potential signal for an increased bleeding risk may be mitigated by the effects of agents other than antidepressant drugs that are strongly associated with haemorrhages, especially antithrombotics. In addition, we investigated if the use of more specific search terms of the Medical Dictionary for Regulatory Activities facilitates the detection of signals. Methods Pharmacovigilance data from the Uppsala Monitoring Centre were used to calculate substance-specific reporting odds ratios (RORs) for all types of bleeding and gastrointestinal bleeding. Reporting odds ratios were calculated with and without antithrombotic comedication. Results Regarding any type of bleeding, no signals were found in association with antidepressant drugs. Concerning upper gastrointestinal bleeding, signals were found related to citalopram (ROR: 1.56 [95% confidence interval 1.11–2.20]) and escitalopram (ROR: 1.52 [95% confidence interval 1.03–2.25]). After removal of reports related to antithrombotics, these signals could no longer be detected, but a new signal related to St. John’s Wort associated with haemorrhages was found (ROR: 1.50 [95% confidence interval 1.21–1.86]). Conclusions Antithrombotics seem unlikely to have a major impact on the detection of the bleeding risk of antidepressant drugs. The different categorisation of adverse drug reactions regarding the strength of a causal relationship between a drug and an event in the database may be relevant for this negative finding. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-021-00260-9.

Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter to correct a presumed deficit in extracellular serotonin signaling during depression. These agents bring clinical relief to many who take them; however, a significant and growing number of individuals are resistant to SSRIs. There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown. In this work, we use fast in vivo serotonin measurement tools to investigate the nexus between serotonin, inflammation, and SSRIs. Upon acute systemic lipopolysaccharide (LPS) administration in male and female mice, we find robust decreases in extracellular serotonin in the mouse hippocampus. We show that these decreased serotonin levels are supported by increased histamine activity (because of inflammation), acting on inhibitory histamine H3 heteroreceptors on serotonin terminals. Importantly, under LPS-induced histamine increase, the ability of escitalopram to augment extracellular serotonin is impaired because of an off-target action of escitalopram to inhibit histamine reuptake. Finally, we show that a functional decrease in histamine synthesis boosts the ability of escitalopram to increase extracellular serotonin levels following LPS. This work reveals a profound effect of inflammation on brain chemistry, specifically the rapidity of inflammation-induced decreased extracellular serotonin, and points the spotlight at a potentially critical player in the pathology of depression, histamine. The serotonin/histamine homeostasis thus, may be a crucial new avenue in improving serotonin-based treatments for depression. SIGNIFICANCE STATEMENT Acute LPS-induced inflammation (1) increases CNS histamine, (2) decreases CNS serotonin (via inhibitory histamine receptors), and (3) prevents a selective serotonin reuptake inhibitor (SSRI) from effectively increasing extracellular serotonin. A targeted depletion of histamine recovers SSRI-induced increases in extracellular hippocampal serotonin.

Objectives Genome-wide analyses of antidepressant response have suggested that genes initially associated with risk for schizophrenia may also serve as promising candidates for selective serotonin reuptake inhibitor (SSRI) efficacy. Protein tyrosine phosphatase, receptor-type, zeta-1 (PTPRZ1) has previously been shown to be associated with schizophrenia, but it has not been investigated as a predictor of antidepressant efficacy. The main objective of the study was to assess whether SSRI-mediated depressive and anxiety symptom remission in Chinese patients with major depressive disorder (MDD) are associated with specific PTPRZ1 variants. Methods Two independent cohorts were investigated, the first sample (N = 344) received an SSRI (i.e. fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, or paroxetine) for 8 weeks. The second sample (N = 160) only received escitalopram for 8 weeks. Hamilton Depression and Hamilton Anxiety Rating Scale scores at 8-weeks post-baseline in both cohorts were used to determine remission status. Five PTPRZ1 variants (rs12154537, rs6466810, rs6466808, rs6955395, and rs1918031) were genotyped in both cohorts. Results Anxiety symptom remission was robustly associated with PTPRZ1 rs12154537 (P = 0.004) and the G-G-G-G haplotype (rs12154537-rs6466810-rs6466808-rs6955395; P = 0.005) in cohort 2 but not cohort 1 (mixed SSRI use). Associations with depressive symptom remission did not survive correction for multiple testing. Conclusions These findings suggest that PTPRZ1 variants may serve as a marker of escitalopram-mediated anxiety symptom remission in MDD.