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Objective: This study investigated prescribing patterns of two cohorts of patients treated with selective serotonin reuptake inhibitors (SSRI) in primary care in Wales (UK), to better understand drivers for increased usage. Methods: This e‐cohort study included patients receiving a first READ‐coded SSRI prescription in SAIL in either 2005 or 2015. Patients were followed up for 3 years from date of SSRI prescription. Influence of age and other demographic data on prescribing patterns, and details of mental health or medication reviews that took place were identified. Results: In total 67,006 patients were included across the two cohorts; 29,534 in 2005, and 37,472 in 2015. Citalopram was the most commonly prescribed SSRI in both cohorts. A READ‐coded diagnosis relating to SSRI treatment could not be identified in 24,797 patients. The percentage of patients continuing treatment for 3 years was 6.9% and 11.3% in 2005 and 2015, respectively. In total, 21,150 (72%) patients in the 2005 cohort and 23,947 (64%) in the 2015 cohort received at least one medication review during follow‐up. Conclusions: The proportion of patients continuing longer term treatment was small, whilst the number of recorded mental health and medication reviews offers some reassurance that prescribing remained appropriate. [ABSTRACT FROM AUTHOR]

A 31‐week fetus was diagnosed with premature ductal constriction due to maternal treatment with sertraline. An emergent Cesarean section was performed at 32 gestational weeks. The baby was born in a severely depressed condition, with supra‐systemic pulmonary hypertension, requiring intubation, mechanical ventilation, and milrinone infusion. The patient's condition improved rapidly, allowing weaning from the ventilator and the inodilator therapy. The baby was discharged home at 38 weeks postmenstrual age, in good general condition, without any signs of pulmonary hypertension, requiring no respiratory support. The echo examinations on the first and third months after birth were normal. [ABSTRACT FROM AUTHOR]

Aim: Selective serotonin reuptake inhibitors (SSRIs) are among the most important antidepressants. However, there is limited research on predicting the occurrence of treatment‐resistant depression (TRD) after 5 years. Examining the predictive effect of TRD occurrence using resting‐state fMRI in patients initiating SSRIs treatment at the onset of major depressive disorder (MDD) could potentially enhance TRD management. Methods: A total of 60 first‐episode drug‐naive MDD patients who met the criteria, along with 41 healthy controls of Han Chinese ethnicity, were recruited. All MDD patients received SSRIs as the initial treatment for relieving depressive symptoms. Resting‐state fMRI scans were conducted for all subjects. Follow‐up assessments were conducted over a period of five years, during which MDD patients were categorized into treatment‐resistant depression (TRD) and non‐treatment‐resistant depression (NRD) groups based on disease progression. Amplitude of low‐frequency fluctuations (ALFF), fractional amplitude of low‐frequency fluctuations (fALFF), and Regional Homogeneity (ReHo) values were calculated and compared among the three groups. Additionally, receiver operating characteristic (ROC) curves were employed to identify potential predictors. Results: After 5 years of follow‐up, it was found that 43 MDD patients were classified as NRD, while 17 were classified as TRD. In comparison to TRD, NRD exhibited decreased ALFF in the left middle cingulum gyrus (MCG.L) and in the right middle frontal gyrus (MFG.R), as well as decreased ReHo in MCG.L. Furthermore, NRD showed increased fALFF in the left precuneus (PCUN.L). The area under the curve (AUC) values were as follows: 0.724 (MCG.L by ALFF), 0.732 (MFG.R), 0.767 (PCUN.L), 0.774 (MCG.L by ReHo), 0.878 (combined), 0.547 (HAMD), and 0.408 (HAMA) respectively. Conclusion: The findings suggest that PCUN.L, MFG.R, MCG.L, and the combined measures may indicate the possibility of developing TRD after 5 years when SSRIs are used as the initial therapy for relieving depressive symptoms in MDD patients. [ABSTRACT FROM AUTHOR]

This study evaluated the bioequivalence of the newly developed dapoxetine hydrochloride tablet relative to the marketed reference product by comparing their pharmacokinetic profiles under fasted and fed conditions. A total of 60 healthy Chinese male subjects participated in a single‐center, 2‐period, 2‐sequence, randomized, open‐label, self‐crossover study with a washout period of 14 days, 30 in the fasted group and 30 in the fed group. Following a single 30‐mg oral dose of the test or reference dapoxetine formulation, blood samples were collected before dosing to 72 hours after dosing. Liquid chromatography‐tandem mass spectrometry was performed to measure plasma concentration of dapoxetine and determine pharmacokinetic parameters through noncompartmental analysis. The vital signs and adverse events were also monitored during the study. The 90% confidence intervals of the geometric mean ratios for maximum plasma concentration, area under the plasma concentration‐time curve from time 0 to the last concentration time, and area under the plasma concentration‐time curve from time 0 extrapolated to infinity of the 2 dapoxetine formulations completely fell within the regulatory criteria for bioequivalence of 80%‐125%. In addition, both dapoxetine hydrochloride formulations were generally well tolerated. The generic dapoxetine hydrochloride tablet was bioequivalent to the marketed reference product in healthy Chinese men with no discernible safety differences. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to systematically review whether concurrent treatment with an SSRI and low‐dose ASA increases the risk of bleeding compared with treatment with an SSRI alone or ASA alone. Methods: Medline, Embase, the Cochrane Library, PsycINFO and Web of Science (from database inception to January 2023) were searched according to PICO: P = patients on treatment with an SSRI and/or low‐dose ASA; I = intervention: SSRI + ASA; C = comparison: ASA or SSRI alone; O = outcomes: bleeding/major bleeding. The included articles were assessed using checklists. Studies without major risk of bias formed the basis for the conclusions. Extracted data were pooled using random‐effects meta‐analyses. Certainty of evidence was assessed according to GRADE. Results: Twenty‐four studies met the PICO and were included. One randomized and six nonrandomized studies were assessed not to have major risk of bias. Regarding SSRI + ASA vs. ASA only, the pooled hazard ratio of three nonrandomized studies (n = 38 467) was 1.37 (95% confidence interval: 1.10; 1.70; I2 = 0%), and the pooled odds ratio of two nonrandomized studies (n = 28 296) was 0.95 (0.77; 1.19; I2 = 0%). Regarding SSRI + ASA vs. SSRI only, the randomized controlled trial (n = 1048) reported a hazard ratio of 1.82 (0.66; 5.02), the hazard ratio being 1.60 (1.24; 2.06) for ASA vs. placebo in patients without SSRI treatment; and one nonrandomized controlled study (n = 18 920) reported an incidence rate ratio of 1.03 (0.96; 1.12). Conclusions: The compiled evidence was too uncertain to support an interaction when an SSRI is added to low‐dose ASA. Low‐dose ASA added to an SSRI may imply an increased risk of bleeding primarily attributable to the initiation of ASA. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) signaling is known to be involved in the antidepressant‐like effects of conventional antidepressants, such as desipramine (DMI), a tricyclic antidepressant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor; however, the precise role of neuronal VEGF signaling in mediating these effects remains unclear. Using mice with excitatory neuron‐specific deletion of VEGF and its receptor, fetal liver kinase 1 (Flk‐1) in the forebrain, we examined the effects of forebrain excitatory neuron‐specific deletion of VEGF or Flk‐1 on the antidepressant‐like effects of repeated DMI and chronic FLX administration in the forced swim test (FST). Repeated intraperitoneal (i.p.) injections of DMI (10, 10, and 20 mg/kg at 24, 4, and 1 h before the FST, respectively) significantly decreased immobility in control mice; however, this effect was completely blocked in mice with neuron‐specific VEGF or Flk‐1 deletion. Although chronic treatment with FLX (18 mg/kg/day, i.p.) did not impact immobility in control mice 1 day after the 22nd injection, immobility was significantly reduced 1 day after the preswim and the 23rd FLX injection. However, in mice with neuron‐specific Flk‐1 deletion, chronic FLX treatment significantly increased immobility in the preswim and failed to produce antidepressant‐like effects. Collectively, these findings indicate that neuronal VEGF–Flk‐1 signaling contributes to the antidepressant‐like actions of conventional antidepressants. [ABSTRACT FROM AUTHOR]

Background and Aims: Benzodiazepines (BZDs) carry a risk for drug overdose and are prescribed alone or simultaneously with selective‐serotonin reuptake inhibitors (SSRIs) for the treatment of anxiety and depression in young adults. We aimed to measure risks of drug overdose following BZD treatment initiation, and simultaneous BZD and SSRI initiation, compared with SSRI treatment alone in young adults with depression or anxiety. Design, Setting, Participants: The cohort study used administrative databases covering privately (MarketScan, 1/1/2009–12/31/2018) and publicly (Medicaid, 1/1/2015–12/31/2016) insured young adults (18–29 years) in the United States. Those with depression or anxiety diagnoses newly initiating BZD or SSRI treatment (without BZD or SSRI prescriptions in prior year) were included. Simultaneous "BZD + SSRI" initiation was defined as starting BZD and SSRI treatment on the same day. The cohorts included 604 664 privately insured young adults (BZD = 22%, BZD + SSRI = 10%, SSRI = 68%) and 110 493 publicly insured young adults (BZD = 23%, BZD + SSRI = 5%, SSRI = 72%). Measurements: Incident medically treated drug overdose events were identified from emergency department and inpatient encounters (ICD poisoning codes) within 6 months of treatment initiation. Crude and propensity‐score adjusted cumulative incidence and hazard ratios (HR) were estimated. Sub‐analyses evaluated drug overdose intent. Findings Adjusted HRs of drug overdose for BZD vs. SSRI treatment was 1.36 (95% confidence interval [CI]:1.23–1.51) in privately and 1.59 (95%CI:1.37–1.83) in publicly insured young adults. The adjusted HRs of drug overdose for BZD + SSRI treatment vs. SSRI treatment were 1.99 (95%CI:1.77–2.25) in privately and 1.98 (95%CI:1.47–2.68) in publicly insured young adults. Conclusions: Among young adults in the United States, initiating benzodiazepine treatment for anxiety and depression, alone or simultaneously with selective‐serotonin reuptake inhibitors (SSRI), appears to have an increased risk of medically treated drug overdose compared with SSRI treatment alone. These associations were observed in publicly and privately insured individuals. [ABSTRACT FROM AUTHOR]

Perinatal mood disorders are a tremendous burden to childbearing families and treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants is increasingly common. Exposure to SSRIs may affect serotonin signaling and ultimately, microbes that live in the gut. Health of the gut microbiome during pregnancy, lactation, and early infancy is critical, yet there is limited evidence to describe the relationship between SSRI exposure and gut microbiome status in this population. The purpose of this Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA)‐compliant scoping review is to assess evidence and describe key concepts regarding whether SSRI exposure affects the maternal and infant gut microbiome. Sources were collected from PubMed, Web of Science, and Scopus databases, and an additional gray literature search was performed. Our search criteria returned only three sources, two rodent models and one human subjects research study. Results suggest that fluoxetine (SSRI) exposure may affect maternal gut microbiome dynamics during pregnancy and lactation. There were no available sources to describe the relationship between perinatal SSRI exposure and the infant gut microbiome. There is a significant gap in the literature regarding whether SSRI antidepressants affect the maternal and infant gut microbiome. Future studies are required to better understand how SSRI antidepressant exposure affects perinatal health. [ABSTRACT FROM AUTHOR]

Aim: Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression‐like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. Methods: Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI‐treated group data. Results: Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). Conclusion: Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant‐like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings. [ABSTRACT FROM AUTHOR]

Aims: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women. Methods: We conducted a randomized, double‐blind, placebo‐ and active‐controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine), 8 mg reboxetine (and placebocitalopram), or two placebos. Study drugs were administered at a 1‐h interval due to a difference in estimated time to peak plasma concentration (tmax). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated tmax for both study drugs (one timepoint). Results: Compared to placebo, citalopram increased OUP by 6.6 cmH20 (95% confidence interval [CI] 0.04–13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH20 (95% CI: 1.3–12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH20 in resting condition compared to placebo (95% CI: 23.5–36.5, p < 0.001), and 27.0 cmH20 (95% CI: 21.2–32.8, p < 0.001) in squeezing condition. Conclusion: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI. [ABSTRACT FROM AUTHOR]

Serotonin (5‐HT) accumulates in the heart during myocardial ischaemia and induces deleterious effects on the cardiomyocytes. We aimed to investigate whether carrier‐mediated 5‐HT efflux contributed to the increase in interstitial 5‐HT level during ischaemia. Using microdialysis technique applied to the heart of anaesthetised Wistar rats, myocardial interstitial concentration of 5‐HT was measured by electro‐chemical detection coupled with high‐performance liquid chromatography (HPLC‐ECD) while simultaneously various pharmacological agents, which create a similar condition to ischaemia, were locally administered by reverse‐microdialysis. Sodium cyanide‐induced chemical anoxia increased dialysate 5‐HT concentration. A similar increase in dialysate 5‐HT concentration was induced by ouabain, an inhibitor of sodium‐potassium ATPase and reserpine, an inhibitor of vesicular monoamine transporter. Fluoxetine, a selective serotonin reuptake inhibitor raised the baseline level of 5‐HT, and neither sodium cyanide nor the combination of ouabain and reserpine induced further increase in 5‐HT in the presence of fluoxetine. The results indicate that reverse transport of 5‐HT via SERT, which is caused by an impaired ion gradient, contributes to the rise in interstitial level of 5‐HT during ischaemia suggesting carrier‐mediated 5‐HT efflux occurs in the heart in vivo. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) have anti‐inflammatory properties that may have clinical utility in treating severe pulmonary manifestations of COVID‐19. SSRIs exert anti‐inflammatory effects at three mechanistic levels: (a) inhibition of proinflammatory transcription factor activity, including NF‐κB and STAT3; (b) downregulation of lung tissue damage and proinflammatory cell recruitment via inhibition of cytokines, including IL‐6, IL‐8, TNF‐α, and IL‐1β; and (c) direct suppression inflammatory cells, including T cells, macrophages, and platelets. These pathways are implicated in the pathogenesis of COVID‐19. In this review, we will compare the pathogenesis of lung inflammation in pulmonary diseases including COVID‐19, ARDS, and chronic obstructive pulmonary disease (COPD), describe the anti‐inflammatory properties of SSRIs, and discuss the applications of SSRIS in treating COVID‐19‐associated inflammatory lung disease. [ABSTRACT FROM AUTHOR]

Pharmaceuticals are ubiquitous in aquatic environments, yet little is known regarding their impacts on ecological processes. Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed human antidepressants and have been shown to alter crayfish behavior. These behavioral alterations are particularly relevant as crayfish play a central role in freshwater ecosystems and often reach high biomass in anthropogenically influenced environments commonly exposed to pharmaceutical contamination. Using a 14‐d artificial stream experiment, we exposed spinycheek crayfish (Faxonius limosus) to citalopram, a common SSRI, at an environmentally realistic concentration (0.5 µg/L). We used a Y‐shaped flume to quantify the effects of SSRI exposure on crayfish behavior and food/conspecific preference. We also tested the interacting effects of citalopram and crayfish on habitat‐specific and whole‐stream ecosystem functions and biomass. Crayfish exposed to SSRIs exhibited increased boldness (time to emerge from shelters; P < 0.05) and spent more time orienting to food resources than nonexposed crayfish. Crayfish increased water column chlorophyll a (P < 0.01) and benthic organic matter (P = 0.03). Furthermore, crayfish potentially increased water column respiration (P = 0.09) and potentially decreased nitrate uptake (P = 0.05). SSRI exposure exhibited a potential effect of decreasing benthic chlorophyll a (P = 0.07), but there were no significant CRAY+SSRI interactions. Neither crayfish nor SSRI treatments affected whole‐stream metabolism. These results suggest that citalopram has the potential to affect algal biomass but did not affect ecosystem functioning. However, alterations to crayfish behavior driven by SSRI exposure could lead to subsequent ecosystem‐level effects as crayfish did affect various response metrics. We were unable to detect the effects of altered crayfish behavior at the ecosystem scale during our study, likely due to the short time frame (2 weeks) of our experiment. Further work is needed to quantify longer‐term ecosystem consequences of sublethal effects of pharmaceuticals, but these results show that ecological responses to pharmaceuticals should consider the entire ecosystem. [ABSTRACT FROM AUTHOR]

Objective: Since several recent meta‐analyses report a dose‐response relationship for the antidepressant effect of the selective serotonin reuptake inhibitors (SSRIs), we investigated how these drugs are dosed in clinical practice. Methods: Through linkage of nation‐ or region‐wide registers, we describe SSRI doses in 50,365 individuals residing in Region Västra Götaland, Sweden, with an incident diagnosis of depression and initiating SSRI treatment between 2007 and 2016. The primary question was to elucidate to what extent these individuals had been prescribed a daily dose that according to recent meta‐analyses is required to elicit the maximum antidepressant effect, that is >20 mg citalopram, >10 mg escitalopram, >10 mg fluoxetine, >10 mg paroxetine or >50 mg sertraline. Results: In all, 21,049 (54%) out of 38,868 individuals <65 years of age, and 9,131 (79%) out of 11,497 individuals ≥65 years of age, never received an SSRI dose reported to exert maximum antidepressant effect. These prescribing practices were seen for citalopram, escitalopram and sertraline, but not for fluoxetine and paroxetine, and were frequent in both primary and secondary/tertiary care. Suggesting that doses here defined as maximum efficacy doses, when prescribed, are usually not intolerable, between 59% and 68% of individuals <65 years of age received such a dose also for the subsequent prescription, that is as frequently as in those prescribed a sub‐maximum efficacy dose (52–69%). Conclusion: Most patients being prescribed an SSRI to treat their depression never receive the dose that according to recent meta‐analyses is most likely to effectively combat their condition. The lack of consensus regarding effective dosing of SSRIs may have contributed to this state of affairs. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic and recurrent gastrointestinal (GI) disorder with an unknown aetiology and pathogenesis. Regarding the effectiveness of antidepressants on UC in animal models of depression and the known anti‐inflammatory effects of escitalopram this study was conducted to evaluate the beneficial effects of escitalopram on an acetic acid‐induced UC model without depression. UC model was induced by intra rectal (i.r.) administration of 4% acetic acid in rats after 24 hours of fasting. Animals were treated with three doses of escitalopram (5, 10 and 20 mg/kg). Prednisolone (4 mg/kg) was used as a reference drug in UC. Histological and oxidative stress markers were measured in all groups. Results showed significant increase in superoxide dismutase (SOD) activity and glutathione (GSH) levels, as well as significant decrease in myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, macroscopic factors (ulcer surface area, ulcer severity and weight‐to‐colon ratio) and microscopic and histological parameters (severity and extent of inflammation, cryptic destruction and severity of tissue involvement) in escitalopram treated rats (10, 20 mg/kg) compared to the UC group. In conclusion, the results of our study are in support of beneficial anti‐inflammatory and antioxidant effects of escitalopram in UC. [ABSTRACT FROM AUTHOR]

The association between selective serotonin reuptake inhibitor (SSRI) exposure and cancer incidence has been investigated; however, no epidemiological study has investigated the association between exposure to individual SSRIs and kidney cancer incidence. The aim of this study is to examine whether SSRI use affected the risk of kidney cancer. We conducted a population‐based retrospective cohort study using data from Taiwan's National Health Insurance Research Database. After adjusting for sex, age, urbanization level, comorbidity and medication use through propensity score matching, we identified 222 024 SSRI users and 221 361 SSRI nonusers. A robust Cox proportional hazards model was used to examine the associations between use of individual SSRIs and the risk of kidney cancer with 1‐ and 2‐year induction periods. The result showed that SSRI users tended to be associated with a lower risk of kidney cancer with a 2‐year induction period than nonusers; however, the association was not statistically significant (adjusted hazards ratio [aHR] = 0.88, 95% confidence interval [CI] = 0.77‐1.01). We further examined the effects of individual SSRIs and observed a significantly lower risk of kidney cancer associated with the use of citalopram (aHR = 0.67, 95% CI = 0.47‐0.96) and paroxetine (aHR = 0.75, 95% CI = 0.58‐0.97) with the 2‐year induction period. These findings support that SSRIs are associated with decreased kidney cancer risk and indicate that citalopram and paroxetine have protective effects in depressed patients with kidney cancer. What's new?: Patients with kidney cancer may be at an increased risk of developing depression. In turn, depression is a risk factor for poor outcomes in kidney cancer. In addition to their antidepressant effects, serotonin reuptake inhibitor (SSRI) have been suggested to exhibit antineoplastic effects. This study is the first to demonstrate the effects of individual SSRIs on kidney cancer risk, showing that citalopram and paroxetine may play a role in reducing the risk of kidney cancer. The results suggest that citalopram and paroxetine should be preferentially considered for the management of depressed patients with a high risk of developing kidney cancer. [ABSTRACT FROM AUTHOR]

Depression is a frequent and debilitating comorbidity that affects heart failure (HF) patients. Up to 30% of HF patients suffer from depression and even more have depressive symptoms. Moreover, depression carries a risk for HF, especially in high-risk groups, and is significantly associated with worse quality of life and clinical outcomes. The pathophysiology of depression and HF is poorly understood, but both diseases share several mechanisms and risk factors, including dysregulation of platelet reactivity, inflammation, neuroendocrine function, arrhythmias, high-risk behaviours, and social factors. Current HF guidelines advise to screen HF patients for depression and several screening questionnaires are available. Ultimately, the diagnosis of depression is based on DSM-5 criteria. Depression treatment consists of non-pharmacological and pharmacological therapies. Non-pharmacological therapies, such as exercise training and cognitive-behavioural therapy, have been shown to have beneficial effects on depressive symptoms. Selective serotonin reuptake inhibitors, the mainstay of antidepressant therapy, appear to be safe in HF but have not shown superiority over placebo in HF in short- and long-term randomized clinical trials. New therapies to treat depression are under investigation and may offer the opportunity to improve depression management in HF, including N-methyl-D-aspartate receptor antagonists, repetitive transcranial magnetic stimulation and omega-3 supplementation. New technologies may offer several advantages for the screening and diagnosis of depression but they remain to be tested in future research. In this review, we examine the intersection of depression and HF, summarize the epidemiology and pathophysiology, and discuss new opportunities to diagnose and treat HF patients with depression. [ABSTRACT FROM AUTHOR]

Objective: Evaluate whether selective serotonin reuptake inhibitor (SSRI) use during pregnancy, as well as prior or current untreated psychiatric illness is associated with postpartum haemorrhage (PPH).Design: National register-based cohort study based on data from the Swedish Pregnancy Register.Setting: Sweden, nationwide coverage.Population: A total of 31 159 pregnant women with singleton deliveries after gestational week 22+0 between January 2013 and July 2017.Methods: Pregnant women with self-reported SSRI use at any time point during pregnancy were compared with non-SSRI-treated women with prior or current psychiatric illness, as well as wiith healthy women with no psychiatric illness or reporting SSRI use.Main Outcome Measures: Postpartum haemorrhage defined as blood loss >1000 ml during the first 2 hours postpartum reported by the delivering midwife or obstetrician.Results: Postpartum haemorrhage prevalence was 7.0% among healthy women, 7.6% among women with prior or current psychiatric illness and 9.1% among women treated with SSRI. The unadjusted odds for PPH among women with prior or current psychiatric illness and women on SSRI treatment were increased by 9 and 34%, respectively, compared with healthy unmedicated women without a history of psychiatric illness (odds ratio [OR] 1.09, 95% CI 1.04-1.14 and OR 1.34, 95% CI 1.24-1.44, respectively). The estimates remained unchanged after adjustment for several confounders (such as maternal age, body mass index [BMI], parity, prior caesarean section, smoking, occupation and country of birth) and potential covariates (such as delivery mode, polyhydramnion, preterm delivery, labour dystocia and infant birthweight >4000 g).Conclusions: Higher risk for PPH was observed both among women treated with SSRI during pregnancy and among women with prior or current psychiatric illness.Tweetable Abstract: SSRI use at any point during pregnancy and prior or current history of psychiatric illness was associated with an increased likelihood for PPH. [ABSTRACT FROM AUTHOR]

Key points: During maximal effort contractions, intense serotonin release via the raphe‐spinal pathway spills over from the somato‐dendritic compartment to activate inhibitory 5‐HT1A receptors on the axon initial segment of motoneurons to reduce motoneuronal output.We investigated whether the same mechanism of central fatigue is present for low‐intensity contractions, whereby weak serotonergic drive over an extended period may cause accumulation of serotonin and exacerbate central fatigue.Enhanced availability of serotonin did not directly influence motor pathways or motor performance during prolonged submaximal contraction.However, perceptions of muscle fatigue were greater, and the fatigue‐induced lengthening of the silent period elicited via motor cortical stimulation was reduced with enhanced availability of serotonin.We propose that sustained low‐intensity serotonergic neurotransmission influences supraspinal processes associated with fatigue, without directly influencing the output of the motor system during submaximal exercise. Enhanced availability of serotonin (5‐HT) exacerbates central fatigue that occurs during maximal effort contractions. However, it is unknown if 5‐HT release contributes to central fatigue during prolonged submaximal contractions. Hence, we assessed the effect that enhanced availability of 5‐HT has on sustained low‐intensity fatiguing contractions. Fifteen individuals (22.3 ± 2.1 years) ingested the 5‐HT reuptake inhibitor paroxetine in a human, double‐blinded, placebo‐controlled, repeated‐measures design. Participants performed a low‐intensity isometric elbow flexion for 30 min (15% of maximal voluntary contraction, MVC). Throughout the protocol, brief MVCs were performed and muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of the brachial plexus, and motor point stimulation of the biceps were obtained. Ratings of perceived fatigue were also acquired. Paroxetine did not influence torque or voluntary activation during brief MVCs performed throughout the low‐intensity contraction. However, paroxetine increased the perception of fatigue throughout the contraction (P = 0.005), and shortened the biceps silent period elicited via TMS during sustained submaximal contraction (P = 0.003) and brief MVCs (P = 0.011). Overall, it appears that prolonged low‐intensity contractions do not cause intense 5‐HT release onto motoneurons, and therefore, 5‐HT does not activate inhibitory extra‐synaptic 5‐HT1A receptors of motoneurons to reduce their output. Although motor performance was unaffected by paroxetine, perceived fatigue was greater and intracortical inhibitory activity was reduced following the enhancement of endogenous concentrations of 5‐HT during sustained submaximal contraction. Thus, 5‐HT affects supraspinal processes during low‐intensity contractions without directly altering motor pathways projecting to the muscle. Key points: During maximal effort contractions, intense serotonin release via the raphe‐spinal pathway spills over from the somato‐dendritic compartment to activate inhibitory 5‐HT1A receptors on the axon initial segment of motoneurons to reduce motoneuronal output.We investigated whether the same mechanism of central fatigue is present for low‐intensity contractions, whereby weak serotonergic drive over an extended period may cause accumulation of serotonin and exacerbate central fatigue.Enhanced availability of serotonin did not directly influence motor pathways or motor performance during prolonged submaximal contraction.However, perceptions of muscle fatigue were greater, and the fatigue‐induced lengthening of the silent period elicited via motor cortical stimulation was reduced with enhanced availability of serotonin.We propose that sustained low‐intensity serotonergic neurotransmission influences supraspinal processes associated with fatigue, without directly influencing the output of the motor system during submaximal exercise. [ABSTRACT FROM AUTHOR]

Study Objective: The potential for maternal antidepressant use to influence the risk of spontaneous abortion, one of the most important adverse pregnancy outcomes, is not clear. We aimed to assess whether first trimester antidepressant exposure was associated with an increased risk of spontaneous abortion. Design: Community‐based prospective cohort study (Right from the Start). Setting: Eight metropolitan areas in North Carolina, Tennessee, and Texas. Participants: A total of 5451 women (18 years of age or older) who were planning to conceive or were pregnant (before 12 weeks of completed gestation) and were enrolled in the study between 2000 and 2012; of those women, 223 used antidepressants (selective serotonin reuptake inhibitors [SSRIs] only [170], SSRIs and non‐SSRIs [9], and non‐SSRIs only [44]) during their first trimester, and 5228 did not (never users). Measurements and Main Results: First trimester antidepressant use was determined during a first trimester telephone interview. Spontaneous abortion was self‐reported and verified by medical records. The association of first trimester antidepressant use and spontaneous abortion was assessed by using Cox proportional hazard regression. Among the 5451 women enrolled, 223 (4%) reported first trimester antidepressant use, and 659 (12%) experienced a spontaneous abortion. SSRIs were the most common class of antidepressants used (179 [80%]). Compared with women who never used antidepressants during the first trimester of pregnancy, women who reported antidepressant use were 34% (adjusted hazard ratio [aHR] 1.34, 95% confidence interval [CI] 0.97–1.85) more likely to experience a spontaneous abortion after adjusting for covariates. Women who reported ever using SSRIs were 45% (aHR 1.45, 95% CI 1.02–2.06) more likely to experience a spontaneous abortion compared with never users. When time of loss relative to the time of interview was taken into consideration, the association between first trimester SSRI use and spontaneous abortion was significant only among those with losses before the interview (aHR 1.49, 95% CI 1.04–2.13) but was not significant among those with losses after the interview (aHR 0.43, 95% CI 0.06–3.15). Conclusion: The association between use of first trimester antidepressants, particularly SSRI use, and spontaneous abortion was significant only among women whose exposure status was assessed after loss. In this instance, reporting bias may create a spurious association. Future studies should take the timing of data collection relative to the timing of loss into consideration. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are psychoactive pharmaceuticals that have been detected intact in natural waters globally. Laboratory experiments have reported that several SSRIs inhibit fish foraging behavior, but data for the SSRI escitalopram are lacking. The objectives of the present study were to determine whether escitalopram affects feeding behavior in zebrafish and whether possible sex differences exist. We exposed female and male zebrafish (Danio rerio) to 0.00, 0.10, and 1.50 µg/L of escitalopram in flow‐through tanks for a 3‐wk exposure period. We used a video tracking system with high temporal and spatial resolution to collect data on zebrafish swimming patterns in test tanks containing a food source. The results show a more pronounced effect of escitalopram in males compared with females. At the assumed most environmentally relevant concentration (0.10 µg/L), male average feeding time/visit and maximum feeding duration were significantly reduced by 27 and 42%, respectively. In addition, male total feeding duration was also significantly reduced (by 73%) at the highest concentration (1.50 µg/L). In females, only the maximum feeding duration was significantly reduced (by 41%) in the 0.10 µg/L treatment group. Hence, we reject our initial hypothesis that female feeding behavior is more vulnerable to escitalopram. There was no effect of escitalopram on length or weight among the experimental groups. The present study demonstrates that escitalopram, like other SSRIs, can inhibit fish foraging behavior and therefore potentially disturb natural food chains. Finally, our study suggests that SSRIs can both be sex and behavior specific. Environ Toxicol Chem 2019;38:1902–1910. © 2019 SETAC. [ABSTRACT FROM AUTHOR]

Aim: To estimate the risk of gastrointestinal (GI) bleeding associated with serotonin reuptake inhibitors (SSRIs) by level of kidney function. Methods: We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified patients with chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml min–1 1.73 m–2 for ≥3 months), and a comparison group of patients without it. Patients with CKD were further classified as stage 3a (eGFR 45–59 ml min–1 1.73 m–2), 3b (30–44 ml min–1 1.73 m–2) and 4/5 (<30 ml min–1 1.73 m–2). We excluded prevalent SSRI users at cohort entry. Exposure was time‐dependent SSRI prescription and outcome was first hospitalization for GI bleeding. We estimated adjusted rate ratio (aRR) and rate difference (aRD) of GI bleeding comparing periods with and without SSRI prescription at each level of kidney function. Results: The aRRs and aRDs were: (i) no CKD (n = 202 121) aRR: 1.66 (95%CI 1.37–2.01), aRD: 2.0/1000 person–years (5.5 vs. 3.5/1000 person–years in period with and without SSRIs); (ii) CKD stage 3a (n = 153 316) aRR: 1.86 (1.62–2.15), aRD: 4.2/1000 person–years (8.3 vs. 4.1/1000 person–years); (iii) CKD stage 3b (n = 46 482) aRR: 1.61 (1.27–2.04), aRD: 4.8/1000 person–years (9.9 vs. 5.1/1000 person–years); and (iv) CKD stage 4/5 (n = 11 197) aRR: 1.84 (1.14–2.96), aRD: 7.9/1000 person–years (15.3 vs. 7.4/1000 person–years). While there was no evidence of increase in the aRR (P = 0.922), there was strong evidence that the aRD increased as kidney function deteriorated (P = 0.001). Conclusions: While the relative risk was constant, the excess risk of GI bleeding associated with SSRIs markedly increased among patients with decreased kidney function. [ABSTRACT FROM AUTHOR]

Abstract: Glioblastoma multiforme (GBM) is recognized as a most aggressive brain cancer with the worst prognosis and survival time. Owing to the anatomic location of gliomas, surgically removing the tumour is very difficult and avoiding damage to vital brain regions during radiotherapy is impossible. Therefore, therapeutic strategies for malignant glioma must urgently be improved. Recent studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) have cytotoxic effect on certain cancers. Considering as a more superior SSRI, escitalopram oxalate exhibits favourable tolerability and causes generally mild and temporary adverse events. However, limited information is revealed about the influence of escitalopram oxalate on GBM. Therefore, an attempt was made herein to explore the effects of escitalopram oxalate on GBM. The experimental results revealed that escitalopram oxalate significantly inhibits the proliferation and invasive ability of U‐87MG cells and significantly reduced the expressions of cell cycle inhibitors such as Skp2, P57, P21 and P27. Notably, escitalopram oxalate also induced significant apoptotic cascades in U‐87MG cells and autophagy in GBM8401 cells. An animal study indicated that escitalopram oxalate inhibits the proliferation of xenografted glioblastoma in BALB/c nude mice. These findings implied that escitalopram oxalate may have potential in treatment of glioblastomas. [ABSTRACT FROM AUTHOR]

Objectives To determine whether discontinuation of chronic antidepressant therapy is associated with a higher risk of antidepressant discontinuation syndrome ( ADS) symptoms in patients admitted to the intensive care unit ( ICU) when compared with those who were continued on therapy and to identify factors associated with increased risk of ADS in this population. Design Single-center retrospective observational cohort study. Setting ICUs in a tertiary care hospital. Patients A total of 106 adult patients, admitted to the ICU between September 2013 and August 2014, who had a length of stay of 72 hours or longer and who were receiving chronic selective serotonin inhibitors ( SSRIs) or serotonin-norepinephrine reuptake inhibitors ( SNRIs) before admission. Measurements and Main Results Patients were classified as continued or discontinued from therapy based on initiation of home SSRI/ SNRI therapy within 48 hours of admission. The primary end point was incidence of ADS symptoms. Type of symptoms, receipt of symptom-related therapies, and length of stay were also assessed. Sequential logistic regression analysis was used to determine the impact of discontinuation while controlling for other risk factors. Therapy was discontinued in 38.7% of patients. The risk of developing ADS symptoms was higher in discontinued patients (unadjusted odds ratio [ OR] 2.6, 95% confidence interval [ CI] 1.12-6.07, p=0.024). After adjusting for covariates, the odds of ADS increased (adjusted OR 3.8, 95% CI 1.3-11.7, p=0.018). Female sex was associated with an increase in risk of ADS ( OR 3.4, 95% CI 1.2-10.0, p=0.026). Affective symptoms were the most prevalent type reported (34.1% vs 10.8%, p=0.005). Use of symptom-related therapies and length of stay did not differ between groups. Conclusion Abrupt discontinuation of SSRI/ SNRI therapy increases the risk of ADS symptoms in critically ill patients, particularly in females. These results underscore the importance of continuation of home antidepressant therapy even in the setting of critical illness. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors ( SSRIs) are first-line pharmacotherapy for mood and anxiety disorders. The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene SLC6A4, two polymorphic sites termed 5- HTTLPR and STin2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of SSRI efficacy and tolerability. This review summarizes approximately 15 years of study of these polymorphisms as they relate to SSRI tolerability phenotypes. Four online databases (PubMed, Cochrane CENTRAL, Psyc INFO, and Pharm GKB) were searched for articles on polymorphisms of SLC6A4 including 5- HTTLPR and STin2 by using a systematic approach. Specific and general psychopharmacology terms, along with adverse effect and tolerability concepts, added to the search strategy. The Human Gene Mutation Database was checked for additional references. Forty studies met the inclusion criteria. While null and occasionally opposite associations are reported, the low expression 5- HTTLPR S allele is generally associated with greater adverse drug reaction burden during SSRI therapy. The most convincing evidence is in studies of antidepressant-induced mania and gastrointestinal adverse events. Studies of STin2 are sparse and have conflicting findings. In conclusion, the S allele of 5- HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body of evidence include assay errors, dissimilar grouping of genotypes, the role of ethnicity in associations, and study methodological differences. The clinical utility of serotonin transporter genotypes is not yet delineated but will ultimately depend on genotypic effects on both tolerability and efficacy of SSRIs. [ABSTRACT FROM AUTHOR]

Although reports of pharmaceutical bioconcentration in aquatic organisms are increasing, less is known about trophic transfer in aquatic food webs. The bioaccumulation and trophodynamics of sertraline and fluoxetine, 2 selective serotonin reuptake inhibitors (SSRIs) frequently detected in aquatic environments, were tested by exposing constructed aquatic food chains to SSRIs under controlled laboratory conditions. Both of these ionizable, weak base pharmaceuticals showed lower bioaccumulation factors (BAFs) with increasing trophic level (i.e., no biomagnifications) in 2 3-level food chains ( Acer platanoides, fed to Asellus aquaticus, in turn fed to Notonecta glauca or Pungitius pungitius). Mean sertraline BAFs in A. platanoides, A. aquaticus, N. glauca, and P. pungitus were 2200 L/kg, 360 L/kg, 26 L/kg, and 49 L/kg, respectively, and mean fluoxetine BAFs 1300 L/kg, 110 L/kg, 11 L/kg, and 41 L/kg, respectively. The weak influence of diet was further demonstrated by measured BAFs being equal to or lower than measured bioconcentration factors (BCFs). Organism lipid content was not positively correlated with BAFs, suggesting that other processes are driving interspecific differences in SSRI bioaccumulation. The empirically derived parameter values were introduced into a proposed bioaccumulation model, and a poor correlation was found between modeled and empirical BAFs (predicted r2 = -0.63). In conclusion, the apparent lack of biomagnification of these ionizable pharmaceuticals suggests that environmental concern should not necessarily focus only on higher trophic levels, but also on species showing high BCFs at any trophic level. Environ Toxicol Chem 2017;36:1029-1037. © 2016 SETAC [ABSTRACT FROM AUTHOR]

Introduction The occurrence of female sexual dysfunction ( FSD) in patients with major depressive disorder ( MDD) receiving selective serotonin reuptake inhibitors ( SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population. Methods This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction. Results The prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage ( P = 0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism ( P = 0.030) using additive genetic model, with even stronger association when using the recessive model ( P = 0.013). Discussion This study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs. [ABSTRACT FROM AUTHOR]

Objectives: A series of preclinical studies have suggested that selective serotonin reuptake inhibitor antidepressants not only stimulate neurogenesis but also have neuroprotective effects. The present study primarily aimed to investigate whether escitalopram would decelerate the brain atrophy of patients with mild-to-moderate Alzheimer's disease (AD). We also assessed the effects of escitalopram on the cognitive function and neuropsychiatric symptoms of these participants.Methods: Seventy-four probable AD patients without major depression were recruited from four dementia clinics of university hospitals and randomly assigned in a 1:1 ratio. Each group received 20 mg/day of escitalopram or placebo for 52 weeks. The primary outcome measures were the change rates of hippocampal and whole brain volume on magnetic resonance imaging for 52 weeks. The Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory, and Cornell Scale for Depression in Dementia (CSDD) were also applied.Results: We did not find any significant differences in the changes of hippocampal or whole brain volume between the groups. Escitalopram showed significant beneficial effects on the CSDD score at 28 weeks compared with placebo (t = -2.17, df = 50.42, p = 0.035), but this finding did not persist throughout the study.Conclusion: The findings of the present study do not support the role of escitalopram as a progression-delaying treatment for AD. However, the negative results of the present trial should be interpreted cautiously because of the relatively small sample size. Further large-scale escitalopram trials targeting the earlier stages of AD, even prodromal AD, are still needed. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background The main treatments in a majority of headache patients are pharmacologic therapies. As a result, it is imperative to have strong background in pharmacotherapy used to treat headaches in order to provide optimal therapy and avoid drug interactions. One of the main reasons for failure of pharmacologic treatment of headaches is drug-drug interactions (DDIs). While there are many distinct pathways and mechanisms in which DDIs can occur, most occur through alterations within the cytochrome P450 pathways (CYP). Drugs that cause induction, inhibition, or are simply substrates for these pathways are responsible for many of the DDIs. Aim/Results We review and discuss the important and potential DDIs of commonly used headache medication often encountered in clinical practice. We divide the drugs into two classes, abortive and preventive. Within each group we select the most commonly used drugs and provide a detailed discussion of the mechanisms of interaction for each. Also included are commonly used herbal supplements, which can interact with headache medications. Conclusion Drug-drug-interactions are a major concern when developing a treatment regimen for patients suffering from headaches. There is a growing need for physician attention to the pharmacokinetics of drugs to improve the quality of patient care. It is vital that prescribing physicians be aware of the DDIs associated with the commonly prescribed headache medications to optimize patient care and therapy results. [ABSTRACT FROM AUTHOR]

Introduction Genes that regulate the catecholamine metabolism pathways are potential targets for research in the antidepressant treatment response. This study was intended to determine whether antidepressant responses to selective serotonin reuptake inhibitors ( SSRIs) are associated with genetic polymorphisms of the tyrosine or tryptophan gene in Chinese major depressive disorder ( MDD) patients. Methods A total of 290 MDD patients were recruited and received a 6-week SSRIs randomized double-blinded treatment. Allele, genotype, and haplotype frequencies were compared between responders and nonresponders in catecholamine genes. Results Genotype frequency of the rs1800544 polymorphism in the DRD4 gene was significantly different between responders and nonresponders after false discovery rate correction ( P = 0.042). The frequency of the DRD4 rs1800544 CG genotype was significantly higher ( P = 0.003) in responders (51.4%) than in nonresponders (35.8%), and patients with the CG genotype showed an 81.7% response rate. In comparison, the response rates were 73.9% and 52.2% in patients with the GG genotype and the CC genotype, respectively. The frequencies of the DRD4 rs1800544 CC and GG genotypes were significantly lower ( P = 0.003) in responders (7.7%, 40.9%) than in the nonresponders (19.4%, 44.8%). No significant difference was found between two groups either in genotype or allele frequencies of single nucleotide polymorphisms in the TPH, SLC6A2, SLC6A3, or DRD2 genes. No significant difference was found between two groups in TPH, SLC6A2, SLC6A3, DRD2, or DRD4 gene haplotypes. Discussion Polymorphisms of the DRD4 gene appear to be associated with SSRI treatment response in Chinese MDD patients. [ABSTRACT FROM AUTHOR]

Background: Cognitive behavioral therapy (CBT) and pharmacotherapy are efficacious for the short-term treatment of panic disorder. Less is known about the efficacy of these therapies for individuals who do not respond fully to short-term CBT.Method: The current trial is a second-step stratified randomized design comparing two treatment conditions-selective serotonin reuptake inhibitor (SSRI; paroxetine or citalopram; n = 34) and continued CBT (n = 24)-in a sample of individuals classified as treatment nonresponders to an initial course of CBT for panic disorder. Participants were randomized to 3 months of treatment and then followed for an additional 9 months. Only treatment responders after 3 months were maintained on the treatment until 12-month follow-up. Data analysis focused on panic disorder symptoms and achievement of response status across the first 3 months of treatment. Final follow-up data are presented descriptively.Results: Participants in the SSRI condition showed significantly lower panic disorder symptoms as compared to continued CBT at 3 months. Results were similar when excluding individuals with comorbid major depression or analyzing the entire intent-to-treat sample. Group differences disappeared during 9-month naturalistic follow-up, although there was significant attrition and use of nonstudy therapies in both arms.Conclusions: These data suggest greater improvement in panic disorder symptoms when switching to SSRI after failure to fully respond to an initial course of CBT. Future studies should further investigate relapse following treatment discontinuation for nonresponders who became responders. Clinicaltrials.gov Identifier: NCT00000368; https://clinicaltrials.gov/show/NCT00000368. [ABSTRACT FROM AUTHOR]

The effects of antidepressants on wildlife are currently raising some concern because of an increased number of publications indicating biological effects at environmentally relevant concentrations (<100 ng/L). These results have been met with some scepticism because of the higher concentrations required to detect effects in some species and the perceived slowness to therapeutic effects recorded in humans and other vertebrates. Because their mode of action is thought to be by modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. The authors highlight studies on the effects of antidepressants, particularly on crustacean and molluskan groups, showing that they are susceptible to a wide variety of neuroendocrine disruptions at environmentally relevant concentrations. Interestingly, some effects observed in these species can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans to several selective serotonin reuptake inhibitors can invoke changes in swimming behavior within hours. In mollusks, exposure to selective serotonin reuptake inhibitors can induce spawning in male and female mussels and foot detachment in snails within minutes of exposure. In the light of new studies indicating effects on the human brain from selective serotonin reuptake inhibitors using magnetic resonance imaging scans, the authors discuss possible reasons for the discrepancy in former results in relation to the read-across hypothesis, variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different targets and differential sensitivity to receptors. Environ Toxicol Chem 2016;35:794-798. © 2015 SETAC [ABSTRACT FROM AUTHOR]

Objective Examine therapeutic potential of a selective serotonin reuptake inhibitor ( SSRI) and a norepinephrine reuptake inhibitor ( NERI) in an animal model of comorbidity between epilepsy, depression-like, and impulsive-like impairments. Methods Epilepsy was induced in male Wistar rats by LiCl and pilocarpine. An SSRI fluoxetine ( FLX), and an NERI reboxetine ( RBX) were administered either alone or as a combination over 1 week. Depressive-like and impulsive-like behaviors were examined using the forced swim test. Fast scan cyclic voltammetry was used to analyze serotonergic transmission in the raphe nucleus ( RN)-prefrontal cortex ( PFC) pathway, and noradrenergic transmission in locus coeruleus ( LC)- PFC, and LC- RN projections. Monoamine levels in PFC were measured using high-performance liquid chromatography (HPLC). Functional capacities of 5- HT1A receptors and α2A adrenoreceptors in PFC were analyzed by autoradiography. Results Epileptic rats showed behavioral signs of depression and hyperimpulsivity, suppressed serotonergic and noradrenergic tones, decreased levels of serotonin (5- HT), and norepinephrine ( NE); 5- HT1A receptor and α2A adrenoreceptors functions remained intact. FLX failed to improve behavioral deficits, but effectively raised 5- HT level and marginally improved RN- PFC serotonergic transmission. RBX reversed impulsive-like behavior, normalized content of NE and noradrenergic tone in LC- PFC and LC- RN. FLX- RBX combination fully reversed depressive-like behavior, and normalized RN- PFC serotonergic transmission. None of the treatment modified the function of 5- HT and NE receptors. Significance Depressive- and impulsive-like behaviors in the pilocarpine model of epilepsy stem respectively from dysfunctions of serotonergic and noradrenergic ascending pathways. At the same time, epilepsy-associated depression is SSRI resistant. The finding that an SSRI- NERI combination exerts antidepressant effect, along with RBX-induced improvement of LC- RN noradrenergic transmission point toward the involvement of LC- RN noradrenergic input in enabling therapeutic potential of FLX. Medications that improve serotonergic and noradrenergic transmission, such as serotonin-norepinephrine reuptake inhibitors may be effective in treating epilepsy-associated SSRI-resistant depression, as well as concurrent depression and attention-deficit/hyperactivity disorder ( ADHD). [ABSTRACT FROM AUTHOR]

Study Objective Second-generation antidepressants have been shown to improve cognition and depression symptomatology, which are the major risk factors for dementia; however, little is known about the comparative effectiveness of antidepressants in reducing the risk of dementia. Thus, the objective of this study was to evaluate the long-term comparative effectiveness of different antidepressant classes in reducing the risk of dementia in elderly nursing home residents with depression. Design Propensity score-adjusted retrospective cohort study. Data Source Multistate Minimum Data Set-linked Medicare Parts A, B, and D data files. Patients A total of 25,108 nursing home residents (65 years and older) with a diagnosis of depression and without a dementia diagnosis who were Medicare beneficiaries and new users of selective serotonin reuptake inhibitors ( SSRIs; 19,952 [79.5%]), serotonin-norepinephrine reuptake inhibitors ( SNRIs; 2381 [9.5%]), or tetracyclic antidepressants (2775 [11.1%]) between 2007 and 2010. Measurements and Main Results New users of SSRIs, SNRIs, and tetracyclics were followed over a 2-year period for the occurrence of dementia. A Cox proportional hazards regression model was used to evaluate the comparative effectiveness of SNRIs and tetracyclics in reducing the risk of dementia, with the SSRI class used as the reference category after controlling for propensity scores and their interactions terms. The unadjusted incidence of dementia was 8.2% for SSRI users, 6.0% for SNRI users, and 7.2% for tetracyclic users. The propensity score-adjusted Cox model did not find any significant difference in the risk of dementia in elderly nursing home residents who used SNRIs (hazard ratio [ HR] 0.99, 95% confidence interval [ CI] 0.84-1.19) or tetracyclics ( HR 1.01, 95% CI 0.87-1.17) compared with the SSRI users. Conclusion This study did not find any significant differences in reducing the risk of dementia among the new users of second-generation antidepressant classes. Further studies are needed to evaluate the profiles of second-generation antidepressants on cognition in this vulnerable population. [ABSTRACT FROM AUTHOR]

Aims Amino acids are important body metabolites and seem to be helpful for understanding pathogenesis and predicting therapeutic response in major depressive disorder ( MDD). We performed amino acid profiling to discover potential biomarkers in major depressive patients treated with selective serotonin reuptake inhibitors ( SSRIs). Methods Amino acid profiling using aTRAQ™ kits for Amino Acid Analysis in Physiological Fluids on a liquid chromatography-tandem mass spectrometry ( LC- MS/ MS) system was performed on 158 specimens at baseline and at 6 weeks after the initiation of SSRI treatment for 68 patients with MDD and from 22 healthy controls. Results Baseline alpha-aminobutyric acid ( ABA) discriminated the patients according to the therapeutic response. Plasma glutamic acid concentration and glutamine/glutamic acid ratio were different between before and after SSRI treatment only in the response group. Comparing patients with MDD with healthy controls, alterations of ten amino acids, including alanine, beta-alanine, beta-aminoisobutyric acid, cystathionine, ethanolamine, glutamic acid, homocystine, methionine, O-phospho-L-serine, and sarcosine, were observed in MDD. Conclusion Metabolism of amino acids, including ABA and glutamic acid, has the potential to contribute to understandings of pathogenesis and predictions of therapeutic response in MDD. [ABSTRACT FROM AUTHOR]

Background Serotonergic system is believed to play a role in levodopa‐induced‐dyskinesias pathogenesis, and serotonin transporter has been evaluated as potential target. Aim of the study To retrospectively investigate the potential effect of selective serotonin reuptake inhibitors (SSRIs) during dopaminergic treatment, in the development of dyskinesias in patients with Parkinson's disease (PD). Methods One hundred and thirty‐five consecutive patients with PD, with 10‐year follow‐up since diagnosis. Age at PD onset, duration of levodopa treatment, maximum daily dose, and SSRIs exposure were collected. Risk, latency, and severity of dyskinesias were evaluated comparing patients with and without SSRIs exposure. Results Forty‐nine patients received SSRIs for a variable period, 86 were never treated; no significant difference between the groups was observed (P = 0.897) in the prevalence of dyskinesias. Considering latency between PD diagnosis and dyskinesias onset, patients exposed to SSRIs developed dyskinesias later (6.48 ± 1.99 vs 5.70 ± 1.89 years, P = 0.020). The median dyskinesia severity score was 0 in the exposed group vs 1 in non‐exposed patients (P = 0.025). Multivariate analysis demonstrated SSRIs exposure as the only independent predictor, protecting from severe dyskinesia. Conclusions Use of SSRIs in patients with PD did not protect from dyskinesias; however, exposure may delay the onset and reduce the severity, confirming modulation of the serotonergic system as possible antidyskinetic strategy. [ABSTRACT FROM AUTHOR]

The article discusses a study which evaluates the impact of selective serotonin reuptake inhibitors (SSRIs) to the delay of low risk myelodysplastic syndrome (LR-MDS) prognosis and prolong survival of LR-MDS patients. SSRIs were found to have an influence on the survival outcome of patients regardless of the disease-modifying agents they have received. A substantial favorable survival was also retained for patients taking SSRIs.

Introduction Previous studies have shown that varying acute-phase treatment periods of fluoxetine and paroxetine can result in varying antidepressive effects. We therefore did a meta-analysis to ascertain the efficacy of fluoxetine versus paroxetine for depression by varying acute-phase treatment periods. Methods PubMed, CCTR, Web of Science, Embase, CBM-disc, and CNKI were searched up to March 2013. The key search terms were 'depression,' 'paroxetine,' and 'fluoxetine.' No language restriction was imposed. Results We included 17 studies with 3,110 patients. Three treatment period subgroups were created: 6, 8/10, and 12 weeks. In the 6-week subgroup, paroxetine was more efficacious than fluoxetine (odds ratio [ OR]: 0.74; P < 0.05). In the 8/10-week subgroup, two drugs displayed comparative efficacy ( OR, 0.85; P > 0.05). In the 12-week subgroup, fluoxetine was more efficacious than paroxetine ( OR: 1.25; P < 0.05). There were no significant differences in acceptability. Significant heterogeneity and potential publication bias did not exist. Conclusions Patients' economic conditions, individual preference, and side effects of fluoxetine and paroxetine can be obstacles of successful treatment. Inappropriate acute-phase treatment, such as inadequate treatment periods, may result in pseudoresistance. Clinicians should take these information into consideration when prescribe fluoxetine or paroxetine for patients. Our results can aid clinicians in making an optimal treatment plan to increase odds of response. [ABSTRACT FROM AUTHOR]

AIMS: Our goal was to evaluate the association between antidepressant use and the risk of coronary heart disease (CHD) among subjects with no history of coronary heart disease. METHODS: A search of Medline, EMBASE, PsycINFO and the Cochrane Library was performed in January 2013. Two authors independently reviewed and selected eligible observational studies, based on predetermined selection criteria. Pooled relative risks (RRs) with confidence intervals (CIs) were calculated using random-effects or fixed-effects models. RESULTS: Sixteen observational studies (seven case-control studies and nine cohort studies) were included in the final analysis. There was no association between selective serotonin reuptake inhibitor use and the risk of CHD overall [odds ratio (OR), 0.93; 95% CI, 0.65-1.33] or in subgroup meta-analysis of case-control studies (OR, 0.91; 95% CI, 0.60-1.37) and cohort studies (RR, 0.96; 95% CI, 0.59-1.55). The use of tricyclic antidepressant was associated with an increased risk of CHD overall (OR, 1.51; 95% CI, 1.07-2.12), but it was observed only in case-control studies (OR, 1.56; 95% CI, 1.24-1.96) and low-quality studies (OR, 1.49; 95% CI, 1.20-1.85) in the subgroup meta-analyses. CONCLUSIONS: This meta-analysis of observational studies in subjects with no history of CHD suggests that neither selective serotonin reuptake inhibitor nor tricyclic antidepressant use is associated with an increased risk of CHD. [ABSTRACT FROM AUTHOR]

Aims Citalopram ( CT) and escitalopram ( S- CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder ( MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S- CT and their metabolites in MDD patients treated with CT or S- CT. Methods Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms ( SNPs) were modelled as additive allelic effects. Results Genome-wide significant associations were observed for S- CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10−9) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10−16), supporting the important role of these cytochrome P450 ( CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. Conclusions In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S- CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors. [ABSTRACT FROM AUTHOR]

Aim We utilized single-voxel 1H magnetic resonance spectroscopy to determine biochemical abnormalities related to major depressive disorder ( MDD) in the bilateral dorsolateral prefrontal cortex, anterior cingulate cortex ( ACC), and cerebellar hemisphere before and after antidepressant treatment. Methods Fifteen adult MDD patients and 15 age- and sex-matched healthy controls were involved. Magnetic resonance spectroscopy of the brain was conducted in all subjects at the beginning of the study and the depressed subjects were reassessed after 8 weeks of antidepressant treatment. Results At baseline, N-acetyl aspartate ( NAA), total glutamine plus glutamate ( Glx) and myo-inositol ( MI) levels in the bilateral ACC were significantly lower in MDD patients than in controls ( P < 0.05/3). MI in the bilateral cerebellar hemisphere were also decreased in patients compared with controls. After the treatment, the lower NAA, Glx and MI in ACC were normalized in MDD patients and the NAA and Glx increased compared to baseline values. The MI levels in the bilateral cerebellar hemisphere were also normalized in patients. MI and choline levels in the right cerebellar hemisphere were elevated compared to those at baseline. Conclusion Our study suggests that metabolic abnormalities in the ACC and cerebellar hemisphere are implicated in MDD. Antidepressants may alter the local metabolic abnormalities in these areas. [ABSTRACT FROM AUTHOR]

Depression is a frequent side-effect of interferon-based treatment of patients with chronic viral hepatitis, that may lead to reduction or discontinuation of treatment. Clinical trials data showed the importance of therapy of psychiatric disorders for a successful antiviral treatment. Emerging evidence suggests that interferon may cause depression affecting serotonin synthesis via increased activity of indoleamine 2,3-dioxygenase. Serotonin reuptake inhibitors significantly improve mood disorders, but the use of these drugs requires caution because some studies reported the emergence of mania in patients treated for depression during antiviral therapy. Therefore, this review will examine and discuss the putative role of serotonin and its metabolism in the development of depression during antiviral therapy, focusing on pharmacological interventions to reduce side-effects. [ABSTRACT FROM AUTHOR]

ABSTRACT Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is the inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI, sertraline, is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline directly to inhibit hepatic drug metabolism is relatively weak compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. The study examined whether sertraline produces time-dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6β-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting the formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with the reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with MI complex formation. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Low serotonin function is associated with alcoholism, leading to speculation that increasing serotonin function could decrease ethanol consumption. Mice with one or two deletions of the serotonin transporter ( SERT) gene have increased extracellular serotonin. To examine the relationship between SERT genotype and motivation for alcohol, we compared ethanol self-administration in mice with zero (knockout, KO), one ( HET) or two copies ( WT) of the SERT gene. All three genotypes learned to self-administer ethanol. The SSRI, fluvoxamine, decreased responding for ethanol in the HET and WT, but not the KO mice. When tested under a progressive ratio schedule, KO mice had lower breakpoints than HET or WT. As work requirements were increased across sessions, behavioral economic analysis of ethanol self-administration indicated that the decreased breakpoint in KO as compared to HET or WT mice was a result of lower levels of unconstrained demand, rather than differences in elasticity, i.e. the proportional decreases in ethanol earned with increasing work requirements were similar across genotypes. The difference in unconstrained demand was unlikely to result from motor or general motivational factors, as both WT and KO mice responded at high levels for a 50% condensed milk solution. As elasticity is hypothesized to measure essential value, these results indicate that KO value ethanol similarly to WT or HET mice despite having lower break points for ethanol. [ABSTRACT FROM AUTHOR]

Objective We investigated the plasma levels of interleukin (IL)-6 and 5-HTT polymorphisms in patients with major depressive disorder (MDD). This is the first report, to our knowledge, of an investigation into the association between 5-HTT gene polymorphism, plasma IL-6 levels, and responses to selective serotonin reuptake inhibitors (SSRIs) in Japanese patients with MDD. Method One-hundred and eighteen patients (51 male, 67 female) who met the DSM-IV criteria for MDD were enrolled. Their ages ranged from 24 to 78 (mean ± SD = 44 ± 12) years. The patients were treated with SSRIs (paroxetine in 66 cases, sertraline in 42 cases) for 8 weeks. Results The plasma levels of IL-6 were significantly higher in the SSRI responders than in the nonresponders ( p = 0.0328), and the changes in plasma IL-6 levels correlated significantly with the changes in severity of depressive state ( p = .0.007). No difference was found in baseline and the changes in plasma IL-6 levels between the patients with a 5-HTT gene (5-HTTLPR) L-carrier and those with S/S. Conclusion These results suggest that the plasma levels of IL-6 reflect the severity of MDD and that plasma IL-6 levels might be another biological-state marker for the depressive state. In addition, the 5-HTTLPR polymorphism might be independent of plasma IL-6 levels. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Amphetamine withdrawal in both humans and rats is associated with increased anxiety states, which are thought to contribute to drug relapse. Serotonin in the ventral hippocampus mediates affective behaviors, and reduced serotonin levels in this region are observed in rat models of high anxiety, including during withdrawal from chronic amphetamine. This goal of this study was to understand the mechanisms by which reduced ventral hippocampus serotonergic neurotransmission occurs during amphetamine withdrawal. Serotonin synthesis (assessed by accumulation of serotonin precursor as a measure of the capacity of in vivo tryptophan hydroxylase activity), expression of serotonergic transporters, and in vivo serotonergic clearance using in vivo microdialysis were assessed in the ventral hippocampus in adult male Sprague Dawley rats at 24 h withdrawal from chronic amphetamine. Overall, results showed that diminished extracellular serotonin at 24 h withdrawal from chronic amphetamine was not accompanied by a change in capacity for serotonin synthesis ( in vivo tryptophan hydroxylase activity), or serotonin transporter expression or function in the ventral hippocampus, but instead was associated with increased expression and function of organic cation transporters (low-affinity, high-capacity serotonin transporters). These findings suggest that 24 h withdrawal from chronic amphetamine reduces the availability of extracellular serotonin in the ventral hippocampus by increasing organic cation transporter-mediated serotonin clearance, which may represent a future pharmacological target for reversing anxiety states during drug withdrawal. [ABSTRACT FROM AUTHOR]

Objective: Seasonality of completed suicides with a peak in spring and early summer is a well-documented finding. The circannual serotonergic functioning is hypothesized to be central in this phenomenon. Antidepressant medications exert their pharmacological action mainly by regulating serotonin. Our aim is to study the amplitude of the seasonal effect among suicide victims positive for different classes of antidepressants or without any antidepressants at the time of death. Method: By using Swedish Registers, 12 448 suicides with forensic data for antidepressive medication and information on in-patient-treated mental disorder were identified during 1992-2003. Seasonality was estimated with a Poisson regression variant of the circular normal distribution of completed suicides. Results: Higher suicide seasonality was found for individuals treated with selective serotonin reuptake inhibitor (SSRIs) compared to those with other antidepressant treatment or without any antidepressant treatment. The finding is more evident for men and violent suicide methods and those without history of in-patient treatment. Conclusion: Our results provide preliminary support for the serotonergic hypothesis of suicide seasonality and raise the question of a possible accentuation of the natural suicide seasonality in patients treated with SSRIs, a hypothesis that warrants further investigation. [ABSTRACT FROM AUTHOR]

Major depressive disorder ( MDD) affects 121 million people globally and is one of the leading causes of functional disability worldwide. As a recurrent disorder, MDD is associated with significant morbidity and functional disability as well as high direct and indirect costs to the health care system. Although several drug therapies are available for treating MDD, many patients do not achieve a sustained remission. Vilazodone was approved by the United States Food and Drug Administration in 2011 and has a distinctive pharmacology profile, as the drug is a selective serotonin reuptake inhibitor and serotonin 5- HT1A receptor partial agonist. In two 8-week, double-blind, placebo-controlled trials, vilazodone's overall rate of response was similar to other antidepressants for the treatment of MDD. Compared with placebo, remission rates were not significantly different in one trial and were not reported in the second trial. Vilazodone was generally well tolerated, with nausea and diarrhea being the most frequent adverse events reported. Postmarketing studies and further active comparative studies will provide additional insight to the potential benefits and safety of this novel drug. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are among the many pharmaceuticals detected in aquatic ecosystems. Although the acute effects of SSRIs on select organisms have been reported, little is understood about the chronic effects of these drugs on amphibians, which are particularly sensitive to environmental pollutants. Serotonin plays important roles in many physiological functions, including a wide array of developmental processes. Exposure to SSRIs during development may cause developmental complications in a variety of organisms, but little is known about the degree of exposure necessary to cause deleterious effects. Here, we sought to gain a better understanding of the effects of SSRIs on amphibian development by use of a combined laboratory and outdoor mesocosm study. Tadpoles in a laboratory setting were exposed to a low (0.029 µg/L) and a high (0.29 µg/L) concentration of the common SSRI fluoxetine from stages 21 and 22 through completion of metamorphosis. Tadpoles in outdoor mesocosms were exposed to fluoxetine concentrations ranging from 0.1 to 0.3 µg/L. Exposed tadpoles in the laboratory showed delayed development compared with controls when stage was assessed throughout the experiment. Control tadpoles also gained weight faster than treatment tadpoles, which may be explained by reduced food intake. Mesocosm tadpoles exhibited similar trends, but no significant differences were detected. These results indicate that ecologically relevant levels of fluoxetine may cause developmental delays in amphibians. Environ. Toxicol. Chem. 2010;29:2845-2850. © 2010 SETAC [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 114, 697–705. Effects of the antidepressant fluoxetine on stimulation-dependent synaptic vesicle exocytosis were examined in cultured primary hippocampal neurons. Synaptic vesicles were fluorescently labeled in vitro with FM1–43, washed and subsequently destained in two consecutive cycles. Exocytosis was triggered by electric field stimulation and imaged by fluorescence microscopy. In control preparations, the second staining-destaining cycle caused a significant reduction of relative fluorescence loss, number of active synapses and half-decay time ( t50). These fatigue effects were largely prevented by short-term administration of 1 μM fluoxetine, which was present before and during the second stimulation cycle. Fluoxetine concentrations above 10 μM inhibited exocytosis almost completely but showed no other toxic effects on neurons. Stressed neurons, grown under hyperosmotic conditions, were even more fatigue-protected by fluoxetine. These observations support the idea that therapeutic concentrations of fluoxetine enhance the recovery of neurotransmission from exhausting stimuli in healthy and in hyperosmotically stressed neurons as well. [ABSTRACT FROM AUTHOR]