Individual Selective Serotonin Reuptake Inhibitors Research Articles

Integrated physio-biochemical and transcriptomic analysis reveals the joint toxicity mechanisms of two typical antidepressants fluoxetine and sertraline on Microcystis aeruginosa

Selective serotonin reuptake inhibitor (SSRI) antidepressants are of increasing concern worldwide due to their ubiquitous occurrence and detrimental effects on aquatic organisms. However, little is known regarding their effects on the dominant bloom-forming cyanobacterium, Microcystis aeruginosa. Here, we investigated the individual and joint effects of two typical SSRIs fluoxetine (FLX) and sertraline (SER) on M. aeruginosa at physio-biochemical and molecular levels. Results showed that FLX and SER had strong growth inhibitory effects on M. aeruginosa with the 96-h median effect concentrations (EC50s) of 362 and 225 μg/L, respectively. Besides, the mixtures showed an additive effect on microalgal growth. Meanwhile, both individual SSRIs and their mixtures can inhibit photosynthetic pigment synthesis, cause oxidative damage, destroy cell membrane, and promote microcystin−leucine−arginine (MC-LR) synthesis and release. Moreover, the mixtures enhanced the damage to photosynthesis, antioxidant system, and cell membrane and facilitated MC-LR synthesis and release compared to individuals. Furthermore, transcriptomic analysis revealed that the dysregulation of the key genes related to transport, photosystem, protein synthesis, and non-ribosomal peptide structures was the fundamental molecular mechanism underlying the physio-biochemical responses of M. aeruginosa. These findings provide a better understanding of the toxicity mechanisms of SSRIs to microalgae and their risks to aquatic ecosystems.

Dose of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding in older adults.

Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of upper gastrointestinal bleeding (UGIB) in older patients but little is known about the risk associated with individual SSRI drugs and doses. To quantify the risk of UGIB in relation to individual SSRI use in older adults. We conducted a nested case-control study within a cohort of 9565 patients aged ⩾65 years prescribed SSRIs from 2000 to 2013 using claims data of universal health insurance in Taiwan. Incident cases of UGIB during the follow-up period were identified and matched with three control subjects. Conditional logistic regression was used to estimate the odds ratio (OR) of UGIB associated with individual SSRI use and cumulative dose. UGIB risk increased with the increasing cumulative doses of SSRIs (adjusted OR: 1.28, 95% confidence interval (CI): 1.02-1.62 for the highest vs. the lowest tertile). Compared with users of other SSRIs, fluoxetine users were at an increased risk of UGIB (adjusted OR: 1.25, 95% CI: 1.03-1.50) with a dose-response manner, whereas paroxetine users had 29% decreased odds (95% CI: 0.56-0.91). The increased risk was only observed among current fluoxetine users. Fluoxetine therapy was associated with an increased risk of UGIB in a dose-response manner among older adults.

Reduced risk of mortality among COVID-19 patients with in-hospital selective serotonin reuptake inhibitor administration

Abstract Objectives The anti-inflammatory properties of selective serotonin reuptake inhibitors (SSRI)s, particularly fluvoxamine, have been hypothesized to reduce clinical deterioration in patients with COVID-19 when administered early in the disease course. The objective of this analysis was to examine the effect of maintenance SSRI administration, including variation among different medications, on the outcomes of hospitalized patients with COVID-19. Methods Retrospective analysis of disease progression and mortality risk of over 230,000 patients hospitalized with COVID-19 at facilities associated with a large healthcare system in the United States. Key findings Receipt of SSRIs during the hospital encounter occurred in approximately 10.6% (n = 24,690) of COVID-19 patients. When matched for patient characteristics, disease severity and other treatments, receipt of any SSRI was associated with a 30% reduction in the relative risk of mortality (RR: 0.70, 95% confidence interval [CI]: 0.67–0.73; adjusted P-value <0.001). Similar reductions in the relative risk of mortality were seen with nearly every individual SSRI; for sertraline-treated patients, the most commonly used SSRI in the data set, there was a 29% reduction in the relative risk of mortality (RR: 0.71, 95% CI: 0.66–0.77; adjusted P-value <0.001). Conclusions In total, this retrospective analysis suggests that there is a significant association between SSRI antidepressants and reduced morality among patients hospitalized with COVID-19.

A systematic review and meta-analysis on the efficacy outcomes of selective serotonin reuptake inhibitors in depression in Alzheimer’s disease

BackgroundDepressive symptoms are the most common neuropsychiatric symptoms in patients with Alzheimer’s disease (AD). However, despite being common, no definite consensus recommendations exist for the management of depression in AD.ObjectiveTo assess the effects of selective serotonin reuptake inhibitors (SSRIs) on the alleviation of depressive symptoms in patients with AD.Material and methodsMedline, Scopus, Web of Science, Google Scholar, and PsychINFO were electronically searched from inception until October 2022. Response to therapy and mean depression scores between the treatment (or before) and placebo (or after) groups were the primary outcomes. For depression scores, the standard mean deviation and accompanying 95% confidence interval were determined. The risk of bias was determined using the funnel plot, trim and fill, Egger’s and Begg’s analyses.ResultsSSRIs attenuated depressive symptoms in patients with AD (0.905 SMD, 95%CI, 0.689 to 1.121, p < 0.000). At individual SSRI level, escitalopram, paroxetine, and sertraline significantly alleviated depressive symptoms in AD patients (0.813 SMD, 95%CI, 0.207 to 1.419, p = 0.009, 1.244 SMD, 95%CI, 0.939 to 1.548, p < 0.000, and 0.818 SMD, 95%CI, 0.274 to 1.362, p < 0.000). The funnel plot, trim and fill, Begg’s test (p = 0.052), and Egger’s test (p = 0.148), showed no significant risk of publication bias.ConclusionOur meta-analysis supports the use of SSRIs for the alleviation of depression in patients with AD. However, we recommend larger randomized clinical trials that would compare the efficacy of different SSRIs in AD patients with depression.

Dose-response effects of selective serotonin reuptake inhibitor monotherapy for the treatment of depression: systematic review of reviews and meta-narrative synthesis

ObjectiveTo assess and clarify the relations between selective serotonin reuptake inhibitor (SSRI) dose efficacy, acceptability (early treatment discontinuation (dropouts)), and tolerability (reported adverse drug effects), and critically evaluate methods previously...

Pharmacotherapy for post traumatic stress disorder (PTSD).

Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in the use of medication in its treatment. To assess the effects of medication for reducing PTSD symptoms in adults with PTSD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 11, November 2020); MEDLINE (1946-), Embase (1974-), PsycINFO (1967-) and PTSDPubs (all available years) either directly or via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR). We also searched international trial registers. The date of the latest search was 13 November 2020. All randomised controlled trials (RCTs) of pharmacotherapy for adults with PTSD. Three review authors (TW, JI, and NP) independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. We contacted investigators to obtain missing data. We stratified summary statistics by medication class, and by medication agent for all medications. We calculated dichotomous and continuous measures using a random-effects model, and assessed heterogeneity. We include 66 RCTs in the review (range: 13 days to 28 weeks; 7442 participants; age range 18 to 85 years) and 54 in the meta-analysis. For the primary outcome of treatment response, we found evidence of beneficial effect for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.74; 8 studies, 1078 participants), which improved PTSD symptoms in 58% of SSRI participants compared with 35% of placebo participants, based on moderate-certainty evidence. For this outcome we also found evidence of beneficial effect for the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine: (RR 0.45, 95% CI 0.22 to 0.94; 1 study, 26 participants) in 65% of people on mirtazapine compared with 22% of placebo participants, and for the tricyclic antidepressant (TCA) amitriptyline (RR 0.60, 95% CI 0.38 to 0.96; 1 study, 40 participants) in 50% of amitriptyline participants compared with 17% of placebo participants, which improved PTSD symptoms. These outcomes are based on low-certainty evidence. There was however no evidence of beneficial effect for the number of participants who improved with the antipsychotics (RR 0.51, 95% CI 0.16 to 1.67; 2 studies, 43 participants) compared to placebo, based on very low-certainty evidence. For the outcome of treatment withdrawal, we found evidence of a harm for the individual SSRI agents compared with placebo (RR 1.41, 95% CI 1.07 to 1.87; 14 studies, 2399 participants). Withdrawals were also higher for the separate SSRI paroxetine group compared to the placebo group (RR 1.55, 95% CI 1.05 to 2.29; 5 studies, 1101 participants). Nonetheless, the absolute proportion of individuals dropping out from treatment due to adverse events in the SSRI groups was low (9%), based on moderate-certainty evidence. For the rest of the medications compared to placebo, we did not find evidence of harm for individuals dropping out from treatment due to adverse events. The findings of this review support the conclusion that SSRIs improve PTSD symptoms; they are first-line agents for the pharmacotherapy of PTSD, based on moderate-certainty evidence. The NaSSA mirtazapine and the TCA amitriptyline may also improve PTSD symptoms, but this is based on low-certainty evidence. In addition, we found no evidence of benefit for the number of participants who improved following treatment with the antipsychotic group compared to placebo, based on very low-certainty evidence. There remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.

A comparative analysis of selective serotonin reuptake inhibitors and fall risk in older adults.

One in five older adults (age 65+) uses an antidepressant medication. However, little is known about how fall risk differs between commonly prescribed medications. We examine the comparative association between individual selective serotonin reuptake inhibitors (SSRI) and self-reported falls in older adults. We used data from 2010-2017 Medicare Current Beneficiary Surveys, a nationally representative survey of Medicare beneficiaries. We included participants from three different panels surveyed over two successive years. Participants were limited to community-dwelling Medicare beneficiaries 65+, enrolled in Medicare Part D, and taking an SSRI (n=1023) during baseline years. Participants were asked about demographic and health characteristics, medication use (including dose, frequency, duration of use) and self-reported falls as any fall or recurrent falls in the past year. We compared individual SSRI (citalopram or escitalopram vs sertraline) use by the average monthly total standardized daily dose (TSDD) and self-reported falling, controlling for potential confounders. Descriptive analysis and multivariable logistic regressions were conducted using SAS-callable SUDAAN. Citalopram/escitalopram (n=460 users; 45.0% of all SSRI users) and sertraline (n=294 users; 28.7% of all SSRI users) were the most commonly prescribed SSRIs. Overall, 36.3% of citalopram/escitalopram users and 39.4% of sertraline users reported a fall in the year following medication use. There were no statistically significant differences between sertraline and citalopram/escitalopram users of either low or medium TSDD levels in the risk of self-reported any or recurrent falls. However, users of high TSDD of sertraline (>75 mg) had a lower risk of recurrent falls compared to high TSDD citalopram (>30 mg) or escitalopram (>15 mg) daily for 30 days. These findings suggest a potential comparative safety benefit of sertraline compared to citalopram/escitalopram at high doses related to recurrent falls. Additional comparative studies of individual antidepressants may better inform fall risk management and prescribing for older adults.

Drug treatment for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials

ObjectiveTo identify drug classes and individual selective serotonin reuptake inhibitors (SSRIs) with high rates of remission and low risk of adverse events in the treatment of panic disorder with or...

Association between selective serotonin reuptake inhibitors and kidney cancer risk: A nationwide population-based cohort study.

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.

Association of Selective Serotonin Reuptake Inhibitors With the Risk of Type 2 Diabetes in Children and Adolescents

Concerns exist that use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of developing type 2 diabetes (T2D) in adults, but evidence in children and adolescents is limited. In the absence of a randomized clinical trial, evidence must be generated using real-world data. To evaluate the safety of SSRI use in children and adolescents with respect to the associated risk of T2D. This cohort study of patients aged 10 to 19 years with a diagnosis for an SSRI treatment indication was conducted within the nationwide Medicaid Analytic eXtract (MAX; January 1, 2000, to December 31, 2014) and the IBM MarketScan (January 1, 2003, to September 30, 2015) databases. Data were analyzed from November 1, 2018, to December 6, 2019. New users of an SSRI medication and comparator groups with no known metabolic adverse effects (no antidepressant exposure, bupropion hydrochloride exposure, or psychotherapy exposure). Within-class individual SSRI medications were compared with fluoxetine hydrochloride. Incident T2D during follow-up. Intention-to-treat effects were estimated using Cox proportional hazards regression models, adjusting for confounding through propensity score stratification. As-treated effects to account for continuous treatment were estimated using inverse probability weighting and marginal structural models. A total of 1 582 914 patients were included in the analysis (58.3% female; mean [SD] age, 15.1 [2.3] years). The SSRI-treated group included 316 178 patients in the MAX database (publicly insured; mean [SD] age, 14.7 [2.1] years; 62.2% female) and 211 460 in the MarketScan database (privately insured; mean [SD] age, 15.8 [2.3] years; 63.9% female) with at least 2 SSRI prescriptions filled, followed up for a mean (SD) of 2.3 (2.0) and 2.2 (1.9) years, respectively. In publicly insured patients, initiation of SSRI treatment was associated with a 13% increased hazard of T2DM (intention-to-treat adjusted hazard ratio [aHR], 1.13; 95% CI, 1.04-1.22) compared with untreated patients. The association strengthened for continuous SSRI treatment (as-treated aHR, 1.33; 95% CI, 1.21-1.47), corresponding to 6.6 (95% CI, 4.2-10.4) additional cases of T2D per 10 000 patients treated for at least 2 years. Adjusted HRs were lower in privately insured patients (intention-to-treat aHR, 1.01 [95% CI, 0.84-1.23]; as-treated aHR, 1.10 [95% CI, 0.88-1.36]). Findings were similar when comparing SSRI treatment with psychotherapy (publicly insured as-treated aHR, 1.44 [95% CI, 1.25-1.65]; privately insured as-treated aHR, 1.21 [95% CI, 0.93-1.57]), whereas no increased risk was observed compared with bupropion treatment publicly insured as-treated aHR, 1.01 [95% CI, 0.79-1.29]; privately insured as-treated aHR, 0.87 [95% CI, 0.44-1.70]). For the within-class analysis, no medication had an increased hazard of T2D compared with fluoxetine. These findings suggest that children and adolescents initiating SSRI treatment may be at a small increased risk of developing T2D, particularly publicly insured patients. The magnitude of association was more modest than previously reported, and the absolute risk was small. The potential small risk should be viewed in relation to the efficacy of SSRIs for its major indications in young patients.

Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects

Antidepressants are commonly used during pregnancy, but limited information is available about individual antidepressants and specific birth defect risks. To examine associations between individual antidepressants and specific birth defects with and without attempts to partially account for potential confounding by underlying conditions. The population-based, multicenter case-control National Birth Defects Prevention Study (October 1997-December 2011) included cases with selected birth defects who were identified from surveillance systems; controls were randomly sampled live-born infants without major birth defects. Mothers of cases and controls participated in an interview after the expected delivery date. The data were analyzed after the completion of the National Birth Defects Prevent Study's data collection. Self-reported antidepressant exposure was coded to indicate monotherapy exposure to antidepressants. We used multivariable logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations between maternal antidepressant use and birth defects. We compared early pregnancy antidepressant-exposed women with those without antidepressant exposure and, to partially account for confounding by underlying maternal conditions, those exposed to antidepressants outside of the birth defect development critical period. This study included 30 630 case mothers of infants with birth defects and 11 478 control mothers (aged 12-53 years). Early pregnancy antidepressant use was reported by 1562 case mothers (5.1%) and 467 control mothers (4.1%), for whom elevated aORs were observed for individual selective serotonin reuptake inhibitors (SSRIs) and selected congenital heart defects (CHD) (eg, fluoxetine and anomalous pulmonary venous return: aOR, 2.56; 95% CI, 1.10-5.93; this association was attenuated after partially accounting for underlying conditions: aOR, 1.89; 95% CI, 0.56-6.42). This pattern was observed for many SSRI-CHD combinations. Associations between SSRIs and non-CHD birth defects often persisted or strengthened after partially accounting for underlying conditions (eg, citalopram and diaphragmatic hernia: aOR, 5.11; 95% CI, 1.29-20.24). Venlafaxine had elevated associations with multiple defects that persisted after partially accounting for underlying conditions (eg, anencephaly and craniorachischisis: aOR, 9.14; 95% CI, 1.91-43.83). We found some associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. Our results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor Use as a Predictor of a Diagnosis of Restless Legs Syndrome.

Because restless legs syndrome (RLS) is a problematic syndrome, demonstrating an association between use of selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) and RLS may help direct patient care. The goals of this study were (1) to establish the incidence of RLS in mental health patients being treated with SSRIs or SNRIs in a local Veterans Affairs medical center and (2) to evaluate the frequency with which certain SSRIs or SNRIs are associated with RLS and the trend in frequency of the diagnosis since the revision of the criteria for RLS offered by the International Restless Leg Syndrome Study Group (IRLSSG), the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the International Classification of Sleep Disorders, Revised (ICSD-3). A retrospective chart review was used to evaluate the number of patients receiving SSRI/SNRI therapy with and without a diagnosis of RLS, with the date of the RLS diagnosis and initiation of SSRI/SNRI therapy noted. The frequency with which certain SSRIs/SNRIs were associated with RLS, and the frequency of RLS diagnoses since January 2012 were also noted. Descriptive statistics and logistic regression were used for data analysis. A total of 254 charts were reviewed. A majority of the patients (89.8%) were male, and 14 (5.5%) were diagnosed with RLS. A logistic regression equation approached significance in predicting RLS (P=0.053). Age and sex emerged as significant predictors of RLS. The prevalence of any individual SSRI or SNRI being associated with RLS was indeterminable. No difference was seen in the number of RLS diagnoses since the refining of the IRLSSG, DSM-5, and ICSD-3 criteria. The use of SSRIs/SNRIs does not seem to be associated with a diagnosis of RLS. In addition, the diagnosis of RLS does not seem to have become more common since the revision of the diagnostic criteria for the disorder.

Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy: A Review of Current Evidence.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant medications worldwide. However, over the past decade, their use during pregnancy, a period of extreme vulnerability to the onset of depression, has become highly concerning to patients and their healthcare providers in terms of safety to the developing fetus. Exposure to SSRIs in pregnancy has been associated with miscarriage, premature delivery, neonatal complications, birth defects-specifically cardiac defects-and, more recently, neurodevelopmental disorders in childhood, specifically autism spectrum disorders. Studies addressing the effect of individual SSRIs indicate a small but higher risk for birth defects with maternal fluoxetine and paroxetine use. Though the excess in absolute risk is small, it may still be of concern to some patients. Meanwhile, antenatal depression itself is associated with adverse perinatal outcomes, and discontinuing antidepressant treatment during pregnancy is associated with a high risk of relapse of depression. Whether the observed adverse fetal effects are related to the mother's medication use or her underlying maternal illness remains difficult to determine. It is important that every pregnant woman being treated with an SSRI (or considering such treatment) carefully weighs the risks of treatment against the risk of untreated depression for both herself and her child. The importance of recognizing a higher risk for the development of adverse outcomes lies in the potential for surveillance and possibly a timely intervention. Therefore, we recommend that pregnant women exposed to any SSRI in early pregnancy be offered options for prenatal diagnosis through ultrasound examinations and fetal echocardiography to detect the presence of birth defects. Tapering off or switching to other therapy in early pregnancy, if appropriate for the individual, may also be considered on a case-by-case basis.

Use of selective serotonin re-uptake inhibitors and the heart rate corrected QT interval in a real-life setting: the population-based Rotterdam Study.

Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QTc prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults. This study, which was part of the prospective Rotterdam Study (period 1991-2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QTc F (QT corrected according to Fridericia) measured during use of individual SSRIs with QTc F measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older. We included 12 589 participants with a total of 26 620 ECGs of which 436 ECGs were made during SSRI use. The mean QTc F was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QTc compared with ECGs recorded during non-use (+12.8 ms, 90% CI 7.5, 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg citalopram. Although no SSRI class effect was observed, use of citalopram was associated with a longer QTc F, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QTc F prolongation.

Aerobic treatment of selective serotonin reuptake inhibitors in landfill leachate

Pharmaceuticals used in human medical care are not completely eliminated in the human body and can enter the municipal sewage sludge system and leachate water from landfill both as the parent compound and as their biologically active metabolites. The selective serotonin reuptake inhibitors (SSRIs) have a large potential for unwanted effects on nontarget organisms in the environment. Leachates from active or old closed landfills are often treated with continuous stirring and simple aeration in a pond/lagoon before infiltration into the environment. The aim of this work was to simulate the reduction of five SSRIs (citalopram, fluoxetine, paroxetine, sertraline and fluvoxamine) and three of their metabolites (desmethylcitalopram, didesmethylcitalopram and norfluoxetine) during aerobic treatment of leachate from landfills. This landfill leachate-simulation experiment was performed to see what happens with the pharmaceuticals during aerated treatment and continuous stirring of landfill leachate for 120 h. It is important to establish whether different pollutants such as pharmaceuticals can be removed (oxidized or otherwise degraded) or not before infiltration into the environment. All the SSRIs had a significant concentration reduction during the aeration treatment process. Total SSRI concentrations were reduced significantly during aerobic treatment, and the individual SSRIs were reduced by 89% to 100% after 120 h. Among the high-concentration samples, fluoxetine (10 mg L−1) was the least degraded with 93% concentration reduction. Among the low-concentration samples, paroxetine was the least degraded with 89% concentration reduction. Fluvoxamine and citalopram were most effectively eliminated and were completely removed from both the high- and low-concentration samples. The samples were also investigated for the metabolites desmethylcitalopram, didesmethylcitalopram and norfluoxetine but only norfluoxetine in the high-concentration fluoxetine sample was detected. Our results suggest that aeration is an effective method for eliminating pharmaceuticals such as SSRIs from landfill leachate water. Comparing the results of all SSRIs with different treatment methods, paroxetine and fluvoxamine seem to be the easiest compounds to eliminate independent of method, while fluoxetine and sertraline seem to be the most stable.

Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot.

Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. Previous studies have suggested that SSRIs may increase the risk of birth defects, including clubfoot. Using data from a population-based case-control study, we evaluated whether SSRI use increased the risk of clubfoot. Mothers were interviewed within 1 year after delivery about sociodemographic factors, pregnancy events, and exposures. They were specifically asked if they experienced depression or anxiety or if they took any of the following SSRIs: citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or fluoxetine. We used logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). We included a total of 622 clubfoot cases and 2002 nonmalformed controls born between 2006 and 2011 in Massachusetts, New York, and North Carolina. For the 2nd or 3rd lunar month of pregnancy (the relevant gestational period), SSRI use for a period of more than 30 days was higher in case mothers (5%) than control mothers (3%). After adjustment for maternal smoking and body mass index, the OR for any SSRI use and clubfoot was 1.8 (95% CI = 1.1-2.8). When individual SSRIs were examined, ORs were elevated for sertraline (1.6 [0.8-3.2]), paroxetine (9.2 [0.7-484.6]), and escitalopram (2.9 [1.1-7.2]). Our data suggest an increased risk of clubfoot occurrence in relation to SSRI use. Drug-specific risks varied widely, and some estimates were unstable.

Prenatal Antidepressant Exposure and Risk of Spontaneous Abortion – A Population-Based Study

PurposeTo estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy.MethodsFrom the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression.ResultsOf the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10–1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80–1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population.ConclusionWe identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.

Use of quetiapine in child and adolescent populations – Response to letter from Dr Lambe

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Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations

It has been suggested that the commonly prescribed class of antidepressants selective serotonin reuptake inhibitors (SSRIs) are associated with birth defects. However, the teratogenic effect of individual SSRIs has not been previously compared using meta-analysis. To determine the strength of the association between individual SSRIs and major, minor, and cardiac malformation among infants born to women taking these medications. Electronic search of CINAHL, EMBASE, Medline, PsycINFO, and ISI Web of Science using the search terms (SSRI OR antidepressant) AND (obstetric outcome OR malformation OR birth outcome OR teratogen), supplemented by manual searching of published references and requests of primary researchers for unpublished data. There were 115 studies identified by electronic search and reviewed in full text, which yielded 16 papers reporting 36 data samples for major malformations, nine papers reporting 26 data samples for cardiac malformations, and four papers reporting seven data samples for minor malformations. Fluoxetine (OR 1.14, 95% CI 1.01-1.30) and paroxetine (OR 1.29, 95% CI 1.11-1.49) were associated with increased risk of major malformations. Paroxetine was associated with increased risk of cardiac malformations (OR 1.44, 95% CI 1.12-1.86). Sertraline and citalopram were not significantly associated with congenital malformation. Between-sample heterogeneity was low and a range of methodological considerations had no significant impact on effect size. There was little evidence of publication bias. Fluoxetine and paroxetine should be avoided in the first trimester and among those at risk of an unplanned pregnancy.

Comparative safety of selective serotonin reuptake inhibitors among pediatric users with respect to adverse cardiac events

This study aims to perform a comparative safety study assessing the risk of ventricular arrhythmia, cardiac arrest, or sudden death among pediatric selective serotonin reuptake inhibitor (SSRI) users. Using US claims data from 1997 to 2009, new pediatric (age < 18 years) users of SSRI monotherapy were identified. Adverse cardiac outcomes occurring within 12 months of SSRI initiation were identified using a previously validated International Classification of Disease, ninth edition algorithm. Cox proportional hazard analysis was used to estimate the risk for each SSRI, using fluoxetine as the referent group, adjusting for the propensity to receive an individual SSRI, demographics, and exposure covariates. Over the study period, 113,714 subjects met the inclusion criteria and contributed 40,639 person-years of SSRI exposure time. Sertraline (33%) and fluoxetine (29%) were the most commonly prescribed SSRIs. Forty events occurred within 12 months of SSRI initiation. The crude incidence rate was highest for escitalopram (19.5/10,000 person-years) and lowest for fluoxetine (4.2/10,000 person-years). The median time to event ranged from 45 to 86 days. The adjusted risk of adverse event, relative to fluoxetine, was highest for citalopram Hazard Ratio (HR) = 3.53, 95% confidence interval [CI] = 1.09–11.46) and escitalopram (HR = 3.30, 95%CI = 1.08–10.14) and lowest for paroxetine (HR = 1.34, 95%CI = 0.30–5.99) and sertraline (HR = 2.14, 95%CI = 0.75–6.16). The incidence of adverse cardiac events among pediatric SSRI users was low. However, the risk of an adverse outcome was higher for citalopram and escitalopram users as compared with fluoxetine users. Future studies should focus on confirming these findings and identifying modifying risk factors to optimize medication selection for this population.