Do selective serotonin reuptake inhibitors cause suicide? : Authors' reply to Raven
Ontology highlight
ABSTRACT:
SUBMITTER: Cipriani A
PROVIDER: S-EPMC557945 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundIt is unclear whether the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressant drugs reduce the risk of suicide in people with depression. We explored the association between exposure to SSRIs and risk of suicide completion or attempt.MethodsWe conducted a systematic review of observational studies that reported completed or attempted suicide in depressed individuals who were exposed to SSRIs compared with those who were not exposed to antidepressants. We assessed the overall risk of completed or attempted suicide.ResultsEight studies involving more than 200 000 patients with moderate or severe depression were included in the meta-analysis. Although exposure to SSRIs increased the risk of completed or attempted suicide among adolescents (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.51-2.44), the risk was decreased among adults (OR 0.57, 95% CI 0.47-0.70). Among people aged 65 or more years, exposure to SSRIs had a protective effect (OR 0.46, 95% CI 0.27-0.79). Sensitivity analyses did not change these findings. In particular, for studies that used completed suicide as an outcome, exposure to SSRIs was associated with increased risk among adolescents (OR 5.81, 95% CI 1.57-21.51) and decreased risk among adults (OR 0.66, 95% CI 0.52-0.83) and older people (OR 0.53, 95% CI 0.26-1.06).InterpretationBased on data from observational studies, use of SSRIs may be associated with a reduced risk of suicide in adults with depression. Among adolescents, use of SSRIs may increase suicidality.
| S-EPMC2630355 | biostudies-literature
Project description:Given the failure to develop disease-modifying therapies for Alzheimer's disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.
| S-EPMC6862425 | biostudies-literature
Project description: Not available
| S-EPMC6953348 | biostudies-literature
Project description:The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD.
| S-EPMC4331562 | biostudies-literature
Project description:The neurosteroid 3alpha-hydroxysteroid-5alpha-pregnan-20-one (allopregnanolone) acts as a positive allosteric modulator of gamma-aminobutyric acid at gamma-aminobutyric acid type A receptors and hence is a powerful anxiolytic, anticonvulsant, and anesthetic agent. Allopregnanolone is synthesized from progesterone by reduction to 5alpha-dihydroprogesterone, mediated by 5alpha-reductase, and by reduction to allopregnanolone, mediated by 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). Previous reports suggested that some selective serotonin reuptake inhibitors (SSRIs) could alter concentrations of allopregnanolone in human cerebral spinal fluid and in rat brain sections. We determined whether SSRIs directly altered the activities of either 5alpha-reductase or 3alpha-HSD, using an in vitro system containing purified recombinant proteins. Although rats appear to express a single 3alpha-HSD isoform, the human brain contains several isoforms of this enzyme, including a new isoform we cloned from human fetal brains. Our results indicate that the SSRIs fluoxetine, sertraline, and paroxetine decrease the K(m) of the conversion of 5alpha-dihydroprogesterone to allopregnanolone by human 3alpha-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3alpha- and 3alpha, 17beta-reduced or -oxidized androgens mediated by 3alpha-HSD type II(Brain). Another antidepressant, imipramine, was without any effect on allopregnanolone or androstanediol production. The region-specific expression of 3alpha-HSD type II(Brain) and 3alpha-HSD type III mRNAs suggest that SSRIs will affect neurosteroid production in a region-specific manner. Our results may thus help explain the rapid alleviation of the anxiety and dysphoria associated with late luteal phase dysphoria disorder and major unipolar depression by these SSRIs.
| S-EPMC23979 | biostudies-literature
Project description:BackgroundAlthough selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain.Methods and findingsFrom Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08-1.32, p < 0.001, absolute risk = 1.0%). With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19-1.73, p < 0.001, absolute risk = 3.0%). However, there were no significant associations in those aged 25-34 y (HR = 1.20, 95% CI 0.95-1.52, p = 0.125, absolute risk = 1.6%), in those aged 35-44 y (HR = 1.06, 95% CI 0.83-1.35, p = 0.666, absolute risk = 1.2%), or in those aged 45 y or older (HR = 1.07, 95% CI 0.84-1.35, p = 0.594, absolute risk = 0.3%). Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16-1.41, p < 0.001), non-violent crime convictions (HR = 1.22, 95% CI 1.10-1.34, p < 0.001), non-violent crime arrests (HR = 1.13, 95% CI 1.07-1.20, p < 0.001), non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22-1.36, p < 0.001), and emergency inpatient or outpatient treatment for alcohol intoxication or misuse (HR = 1.98, 95% CI 1.76-2.21, p < 0.001). With age and sex stratification, there was a significant association between SSRIs and violent crime convictions for males aged 15 to 24 y (HR = 1.40, 95% CI 1.13-1.73, p = 0.002) and females aged 15 to 24 y (HR = 1.75, 95% CI 1.08-2.84, p = 0.023). However, there were no significant associations in those aged 25 y or older. One important limitation is that we were unable to fully account for time-varying factors.ConclusionsThe association between SSRIs and violent crime convictions and violent crime arrests varied by age group. The increased risk we found in young people needs validation in other studies.
| S-EPMC4570770 | biostudies-literature
Project description:Background and Purpose- Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications and conflicting reports on outcome after stroke. We sought to evaluate whether pre-intracerebral hemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome. Methods- Through post hoc analysis of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage), SSRI use was categorized into no use, pre-ICH only, pre- and post-ICH use (termed "continuous"), and post-ICH only (termed "new"). Using multivariable modeling, associations were sought between pre-ICH SSRI use and ICH risk in the case-control set, and associations between post-ICH SSRI use and 3-month outcome were analyzed in the ICH case set. Exploratory analyses sought to assess influence of race/ethnicity in models. Results- The final study cohort consisted of 2287 ICH cases and 2895 controls. Pre-ICH SSRI use was not associated with ICH risk (odds ratio, 0.824 [95% CI, 0.632-1.074]) nor potentiation of ICH risk with anticoagulant or antiplatelet use. New post-ICH SSRI use was associated with unfavorable modified Rankin Scale score at 3 months after ICH (odds ratio, 1.673 [95% CI, 1.162-2.408]; P=0.006) in multivariable analyses. Additional propensity score analysis indicated a similar trend but did not reach statistical significance (P=0.107). When stratified by race/ethnicity, multivariable modeling demonstrated reduced ICH risk with pre-ICH SSRI use in Hispanics (odds ratio, 0.513 [95% CI, 0.301-0.875]; P=0.014), but not non-Hispanic whites or blacks, and no associations between post-ICH SSRI use and 3-month outcome in any racial/ethnic group. Conclusions- In a large multiethnic cohort, pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcome after ICH. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01202864.
| S-EPMC7147963 | biostudies-literature
Project description:Major depressive disorder (MDD) is the most prevalent mental illness contributing to global disease burden. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the first-line treatment for MDD, but are only fully effective in 30% of patients and require weeks before improvement may be seen. About 30% of SSRI-resistant patients may respond to augmentation or switching to another antidepressant, often selected by trial and error. Hence a better understanding of the causes of SSRI resistance is needed to provide models for optimizing treatment. Since SSRIs enhance 5-HT, in this review we discuss new findings on the circuitry, development and function of the 5-HT system in modulating behavior, and on how 5-HT neuronal activity is regulated. We focus on the 5-HT1A autoreceptor, which controls 5-HT activity, and the 5-HT1A heteroreceptor that mediates 5-HT actions. A series of mice models now implicate increased levels of 5-HT1A autoreceptors in SSRI resistance, and the requirement of hippocampal 5-HT1A heteroreceptor for neurogenic and behavioral response to SSRIs. We also present clinical data that show promise for identifying biomarkers of 5-HT activity, 5-HT1A regulation and regional changes in brain activity in MDD patients that may provide biomarkers for tailored interventions to overcome or bypass resistance to SSRI treatment. We identify a series of potential strategies including inhibiting 5-HT auto-inhibition, stimulating 5-HT1A heteroreceptors, other monoamine systems, or cortical stimulation to overcome SSRI resistance.
| S-EPMC6502905 | biostudies-literature
Project description:BackgroundAnxiety, obsessive-compulsive, and stress-related disorders frequently co-occur, and patients often present symptoms of several domains. Treatment involves the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), but data on comparative efficacy and acceptability are lacking. We aimed to compare the efficacy of SSRIs, SNRIs, and placebo in multiple symptom domains in patients with these diagnoses over the lifespan through a 3-level network meta-analysis.Methods and findingsWe searched for published and unpublished randomized controlled trials that aimed to assess the efficacy of SSRIs or SNRIs in participants (adults and children) with diagnosis of any anxiety, obsessive-compulsive, or stress-related disorder in MEDLINE, PsycINFO, Embase, and Cochrane Library from inception to 23 April 2015, with an update on 11 November 2020. We supplemented electronic database searches with manual searches for published and unpublished randomized controlled trials registered in publicly accessible clinical trial registries and pharmaceutical companies' databases. No restriction was made regarding comorbidities with any other mental disorder, participants' age and sex, blinding of participants and researchers, date of publication, or study language. The primary outcome was the aggregate measure of internalizing symptoms of these disorders. Secondary outcomes included specific symptom domains and treatment discontinuation rate. We estimated standardized mean differences (SMDs) with 3-level network meta-analysis with random slopes by study for medication and assessment instrument. Risk of bias appraisal was performed using the Cochrane Collaboration's risk of bias tool. This study was registered in PROSPERO (CRD42017069090). We analyzed 469 outcome measures from 135 studies (n = 30,245). All medications were more effective than placebo for the aggregate measure of internalizing symptoms (SMD -0.56, 95% CI -0.62 to -0.51, p < 0.001), for all symptom domains, and in patients from all diagnostic categories. We also found significant results when restricting to the most used assessment instrument for each diagnosis; nevertheless, this restriction led to exclusion of 72.71% of outcome measures. Pairwise comparisons revealed only small differences between medications in efficacy and acceptability. Limitations include the moderate heterogeneity found in most outcomes and the moderate risk of bias identified in most of the trials.ConclusionsIn this study, we observed that all SSRIs and SNRIs were effective for multiple symptom domains, and in patients from all included diagnostic categories. We found minimal differences between medications concerning efficacy and acceptability. This three-level network meta-analysis contributes to an ongoing discussion about the true benefit of antidepressants with robust evidence, considering the significantly larger quantity of data and higher statistical power when compared to previous studies. The 3-level approach allowed us to properly assess the efficacy of these medications on internalizing psychopathology, avoiding potential biases related to the exclusion of information due to distinct assessment instruments, and to explore the multilevel structure of transdiagnostic efficacy.
| S-EPMC8224914 | biostudies-literature
Project description:To examine the independent contribution of major depressive disorder (MDD), generalized anxiety disorder (GAD), and selective serotonin reuptake inhibitors (SSRIs) to changes in body composition in older adolescents.Medically healthy 15- to 20-year-olds who were unmedicated or within 1 month of starting an SSRI were prospectively followed. Psychiatric functioning and medication treatment were assessed monthly. Body Mass Index (BMI) was measured every 4 months. Every 8 months, a whole-body dual-energy radiograph absorptiometry scan was obtained to determine lean BMI, fat mass index, and visceral fat mass. Linear mixed effects regression analysis examined associations between MDD, GAD, and SSRI use variables and body composition measures.Over 1.51 ± 0.76 years of follow-up, 264 participants contributed 805 observations. After adjusting for age, sex, physical activity, dietary intake, and time in the study, MDD severity was inversely associated, prospectively, with BMI, fat mass index, and lean BMI z scores, whereas cumulative SSRI treatment duration and dose were positively associated with these outcomes. GAD severity and diagnosis were not significantly associated with any body composition outcome. Moreover, citalopram and escitalopram were most strongly associated with the increase in all body composition measures, including visceral fat mass, whereas the associations with fluoxetine were somewhat weaker. Sertraline was not different from no SSRI treatment.Depression severity was associated with a decrease in measures of body composition in older adolescents over a mean of 1.5 years, whereas SSRI treatment was positively associated with these outcomes, with differential effects across treatment groups.
| S-EPMC5495528 | biostudies-literature