Trials Of Selective Serotonin Reuptake Inhibitors Research Articles

The Impact of Development on Antidepressant and Placebo Response in Anxiety Disorders: A Bayesian Hierarchical Meta-Analytic Examination of Randomized Controlled Trials in Children, Adolescents, and Adults.

Background: Understanding how development influences medication and placebo responses in anxiety disorders could inform treatment decisions, including age-specific first- versus second-line psychopharmacological interventions. Objective: To meta-analytically compare the trajectory of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and placebo response in youth and adults with anxiety disorders. Methods: Weekly symptom severity data were extracted from prospective, randomized, parallel-group, placebo-controlled trials of SSRIs and SNRIs in children, adolescents, and adults with anxiety disorders (generalized, separation, and social anxiety disorders as well as panic disorder). Treatment response was modeled for the standardized change in continuous measures of anxiety using a Bayesian hierarchical model. Change in symptom severity was evaluated as a function of time, and post hoc analyses were conducted to determine the sensitivity of these results across sample heterogeneity and alternative functional forms. Results: Data were included from 11 trials of youth (SSRI, κ = 7; SNRI, κ = 4) and 71 studies of adults (SSRI, κ = 46; SNRI, κ = 25). In total, 1067 youth participated in SSRI trials and 1024 in SNRI trials. In total, 10,826 adults participated in SSRI trials (placebo, n = 5367; SSRI n = 5,459) and 6232 in SNRI trials (placebo, n = 3,128; SNRI n = 3,094). A logarithmic model best described the response. Placebo response was similar in youth and adults (mean difference = -1.98 ± 6.21, 95% credible interval [CrI]: -10.2 to 14.2, p = 0.750), and statistically significant improvement from baseline emerged by week 2 in both adults (mean difference: -18.34 + 1.017, 95% CrI: -20.3 to 16.3, p < 0.001) and youth (mean difference: -23.74 + 3.736, 95% CrI: -31.1 to -16.4, p < 0.001). SSRIs produced similar improvements for youth and adults (p = 0.129), but SNRIs produced slower improvement in youth than adults (p = 0.018). Conclusions: Antidepressant-related improvement occurs early in youth and adults with anxiety disorders. SSRI response is similar in adults and youth; however, SNRIs produce greater responses in adults than youth, potentially representing a developmental effect.

Supra-Therapeutic Selective Serotonin Reuptake Inhibitor (Ssri) Dosesfor Refractory Obsessive-Compulsive Disorder: A Case Report

Supra-Therapeutic Selective Serotonin Reuptake Inhibitor (Ssri) Dosesfor Refractory Obsessive-Compulsive Disorder: A Case Report

Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration.

We believe there are serious problems with a recently published and highly publicized paper entitled "Serotonin reduction in post-acute sequelae of viral infection." The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the "Discussion" section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, "Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment", it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs' effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.

Trajectory and magnitude of response in adults with anxiety disorders: a Bayesian hierarchical modeling meta-analysis of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and benzodiazepines.

How the trajectory of response to medication (and placebo response) varies among selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and across anxiety disorders is unknown. We performed a meta-analysis using weekly symptom severity data from randomized, parallel-group, placebo-controlled trials of SSRIs, SNRIs, and benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in anxiety using Bayesian hierarchical models. Across 122 trials (N=15,760), SSRIs, SNRIs, and benzodiazepines produced significant improvement in anxiety compared to placebo. Benzodiazepines produced faster improvement by the first week of treatment (p<0.001). By week 8, the response for benzodiazepines and SSRIs (p=0.103) and SNRIs (p=0.911) did not differ nor did SSRIs and SNRIs differ (p=0.057), although for patients with generalized anxiety disorder (GAD), the benzodiazepines produced greater improvement than SNRIs at week 8 (difference-12.42, CrI: -25.05 to -0.78, p=0.037). Medication response was similar across anxiety disorders except for benzodiazepines, which produced greater improvement over the first 4weeks compared to SSRIs and SNRIs in panic disorder. For SSRIs and SNRIs, women improved more than men, and for benzodiazepines, older patients improved more compared to younger patients. Finally, placebo response plateaued by week 4 of treatment, and, at week 8, social anxiety disorder trials had lower placebo response compared to other anxiety disorders. Benzodiazepines show early improvement compared to SSRIs and SNRIs. However, by week 8, all treatments yield similar results. Patient characteristics influence the improvement trajectory and magnitude, suggesting potential for personalized medication selection.

What Is the Added Benefit of Combining Cognitive Behavioral Therapy and Selective Serotonin Reuptake Inhibitors in Youth with Obsessive Compulsive Disorder? A Bayesian Hierarchical Modeling Meta-Analysis.

Background: Treatment of obsessive-compulsive disorder (OCD) in children and adolescents frequently involves cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), or their combination. However, how adding CBT to SSRIs affects the trajectory and magnitude of improvement has not been evaluated meta-analytically. Methods: We performed a meta-analysis using weekly data from prospective randomized parallel group trials of CBT and SSRIs in pediatric patients with OCD. Response was modeled for the change in the Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) using a Bayesian hierarchical model over 12 weeks. Results: Fourteen studies included pharmacotherapy arms, 4 studies included combined pharmacotherapy and psychotherapy, and 10 studies included a placebo or control arm. The studies included 1146 patients (mean age 12.7 ± 1.3 years, mean 42.1% female). In the logarithmic model of response, statistically significant differences in treatment effects for CBT+SSRI and SSRI monotherapy were observed compared with placebo (SSRI β = -3.59, credible interval [95% CrI]: -4.13 to -3.02, p < 0.001; SSRI+CBT β = -4.07, 95% CrI: -5.05 to -3.04, p < 0.001). Adding CBT to an SSRI produced numerically (but not statistically significantly) greater improvement over 12 weeks. Greater improvement was observed in studies with more boys (p < 0.001), younger patients (p < 0.001), and in studies with greater baseline symptom severity (p < 0.001). Conclusions: In children and adolescents with OCD, compared with placebo, both SSRIs and SSRI+CBT produced early and sustained improvement over 12 weeks, although the improvement was also related to sample characteristics. Longer term studies are needed to determine when the additive benefit of CBT emerges relative to SSRI monotherapy.

Placebo response in trials with patients with anxiety, obsessive-compulsive and stress disorders across the lifespan: a three-level meta-analysis

QuestionRandomised controlled trials assessing treatments for anxiety, obsessive-compulsive and stress-related disorders often present high placebo response rates in placebo groups. Understanding the placebo response is essential in accurately estimating the...

Repetitive transcranial magnetic stimulation (r-TMS) and selective serotonin reuptake inhibitor-resistance in obsessive-compulsive disorder: A meta-analysis and clinical implications

IntroductionDespite promising results from several randomized controlled trials (RCTs) and meta-analyses, the efficacy of r-TMS as a treatment for OCD remains controversial, at least in part owing to inconsistency in the trial methodologies and heterogeneity in the trial outcomes. This meta-analysis attempts to explain some of this heterogeneity by comparing the efficacy of r-TMS in patients with or without resistance to treatment with selective serotonin reuptake inhibitors (SSRI), defined using standardized criteria. MethodsWe conducted a pre-registered (PROSPERO ID: 241381) systematic review and meta-analysis. English language articles reporting blinded RCTs were retrieved from searches using MEDLINE, PsycINFO, and Cochrane Library databases. Studies were subjected to subgroup analysis based on four stages of treatment resistance, defined using an adaptation of published criteria (1 = not treatment resistant, 2 = one SSRI trial failed, 3 = two SSRI trials failed, 4 = two SSRI trials failed plus one or more CBT trial failed). Meta-regression analyses investigated patient and methodological factors (age, duration of OCD, illness severity, stage of treatment-resistance, or researcher allegiance) as possible moderators of effect size. ResultsTwenty-five independent comparisons (23 studies) were included. Overall, r-TMS showed a medium-sized reduction of Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores (Hedge's g: -0.47; 95%CI: - 0.67 to −0.27) with moderate heterogeneity (I2 = 39.8%). Assessment of publication bias using Trim and Fill analysis suggested a reduced effect size that remained significant (g: -0.29; 95%CI: −0.51 to −0.07). Subgroup analysis found that those studies including patients non-resistant to SSRI (stage 1) (g: -0.65; 95%CI: −1.05 to −0.25, k = 7) or with low SSRI-resistance (stage 2) (g:-0.47; 95%CI: −0.86 to −0.09, k = 6) produced statistically significant results with low heterogeneity, while studies including more highly resistant patients at stage 3 (g: −0.39; 95%CI: −0.90 to 0.11, k = 4) and stage 4 (g: -0.36; 95%CI: −0.75 to 0.03, k = 8) did not. Intriguingly, the only significant moderator of the effect size found by meta-regression was the severity of baseline depressive symptoms. All trials showed evidence of researcher allegiance in favour of the intervention and therefore caution is required in interpreting the reported effect sizes. ConclusionThis meta-analysis shows that r-TMS is an effective treatment for OCD, but largely for those not resistant to SSRI or failing to respond to only one SSRI trial. As a consequence, r-TMS may be best implemented earlier in the care pathway. These findings would have major implications for clinical service development, but further well-powered RCTs, which eliminate bias from researcher allegiance, are needed before definitive conclusions can be drawn.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Adjuvant Priming Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Obsessive-Compulsive Disorder: In Search of a New Paradigm!

Repetitive transcranial magnetic stimulation (rTMS) is used as a therapeutic option for obsessive-compulsive disorder (OCD) in both clinical and research settings. There has been no consensus with regard to target area and other parameters, although 1-Hz rTMS over the supplementary motor area (SMA) is found to be promising. Priming stimulation, which involves high-frequency followed by low-frequency rTMS, has been shown to enhance neural response to low-frequency rTMS. Hence, this study was conducted to investigate the effect of adjunctive priming rTMS over the SMA in treatment-resistant OCD. Thirty patients with OCD who were symptomatic after an adequate selective serotonin reuptake inhibitor trial were randomized into 2 groups: one group receiving active priming stimulation (6-Hz rTMS at 80% resting motor threshold) followed by 1-Hz rTMS (priming rTMS group) and the other receiving sham stimulation followed by 1-Hz rTMS (rTMS-only group). Both groups received 10 sessions of such interventions for 2 weeks. Both the rater and patients were blind to the treatment allocation. Assessments were done using the Yale-Brown Obsessive Compulsive Scale, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Clinical Global Impression-Improvement scale at baseline, 2 weeks, and 4 weeks. Both groups showed a significant improvement in all domains of psychopathology over time. The priming rTMS group was better than the rTMS-only group in reducing the Yale-Brown Obsessive Compulsive Scale compulsion score (P < 0.023) as well as scores of the Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Clinical Global Impression-Improvement scale. None developed any adverse effects requiring medical attention. Priming rTMS over the SMA is safe and has favorable effects in OCD. It seems to have a predominant effect on the reduction of compulsions, presumably rectifying the impaired response inhibition in patients with OCD.

Self-Stigma and Treatment Effectiveness in Patients with SSRI Non-Responsive Obsessive-Compulsive Disorder.

PurposeObsessive compulsive disorder (OCD) is a debilitating mental disorder that often takes a chronic course. One of the factors influencing the treatment effectiveness in anxiety and depressive disorders is the self-stigma. This study focused on the relationship between the self-stigma, symptomatology, and therapeutic outcomes in patients with OCD.Patients and MethodsNinety-four inpatients with OCD, who did not sufficiently respond to at least one selective serotonin reuptake inhibitor trial, participated in the study. They attended a six-week therapeutic program consisting of exposure and response prevention, transdiagnostic group cognitive behavioral therapy, individual sessions, mental imagery, relaxation, sport, and ergotherapy. The participants completed several scales: the Internalized Stigma of Mental Illness Scale (ISMI), the self-report Yale-Brown Obsessive Compulsive Scale (Y-BOCS-SR), Beck Anxiety Scale (BAI), Beck Depression Scale-II (BDI-II), and Dissociative Experiences Scale (DES). A senior psychiatrist filled in the Clinical Global Impression (CGI-S).ResultsThe average scales’ scores considerably declined in all measurements except for DES. The self-stigma positively correlated with all psychopathology scales. It was also higher in patients with a comorbid personality disorder (PD). The higher self-stigma predicted a lower change in compulsion, anxiety, and depressive symptoms but not the change of obsessions or the overall psychopathology.ConclusionThe self-stigma presents an important factor connected to higher severity of OCD. It is also a minor predictor of a lower change in symptomatology after combined treatment.

Abstract WP196: Selective Serotonin Reuptake Inhibitors (SSRI) for Depression and Functional Recovery After Stroke: A Meta-Analysis

Background: Post-stroke depression is common and it impedes rehabilitation and function recovery after stroke, and numerous trials evaluated SSRI’s for depression prophylaxis. The objective of this study is to assess the use of SSRI for prevention of poststroke depression and the potential effect on functional recovery after stroke. Methods: We searched electronic databases up to July 2019 for randomized controlled trials of SSRI’s for patients with stroke versus placebo. We calculated pooled odds ratios and 95% CIs by using random-effects models. The primary end points were depression and good functional outcome (modified Rankin Scale score of 0-2) at 90 days post-randomization. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Twelve randomized control trials assessing 4,887 patients have been included in the meta-analysis. SSRI treatment after stroke decreased the odds of depression compared to control group (OR = 0.48, 95% CI - 0.30 to 0.78, p=0.003). There was no heterogeneity between the trials (Cochran’s Q statistic 4.623, df 5; P = .337, I 2 =5.626%). The proportion of subjects who achieved mRS 0-2 at 90 days was similar between SSRI and control groups (OR= 3.471, 95% CI - 0.59 to 20.38, p=0.168). Conclusion: SSRI treatment for the stroke patients reduces the incidence of depression but it does not increase the odds of good functional recovery.

Selective Serotonin Reuptake Inhibitor Monotherapy for Anxiety Disorders in Children and Adolescents with Autism Spectrum Disorder: A Chart Review.

Objective: Anxiety disorders are one of the most commonly co-occurring psychiatric diagnoses in youth with autism spectrum disorder (ASD), with a frequency ranging from 22% to 84%. Methods: We conducted a chart review of 29 children and adolescents with ASD who had been treated with selective serotonin reuptake inhibitor (SSRI) monotherapy for an anxiety disorder for at least 2 months. Subsequent chart reviews were conducted for the first follow-up visit within 2-6 months (M = 4.2 months) and the visit closest to 9 months posttreatment (ranging from 7 to 12 months; M = 10.5 months). The presence of adverse events (AEs) was examined, and a consensus Clinical Global Impressions Improvement (CGI-I) score was determined. Results: Fifty-five percent of patients were given a CGI-I of "improved" or "very much improved" at the 9-month follow-up. Four patients discontinued treatment owing to AEs. Other reported AEs not leading to discontinuation included vivid dreaming, increased emotional lability, and irritability. Responders included a number of patients who had failed previous SSRI trials. Conclusions: This study suggests that SSRI treatment should be considered for individuals with ASD and anxiety disorders, even if prior SSRI trials have been unsuccessful.

Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents

ImportanceDepressive disorders (DDs), anxiety disorders (ADs), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are common mental disorders in children and adolescents.ObjectiveTo examine the relative efficacy and safety of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and placebo for the treatment of DD, AD, OCD, and PTSD in children and adolescents.Data SourcesPubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Database from inception through August 7, 2016.Study SelectionPublished and unpublished randomized clinical trials of SSRIs or SNRIs in youths with DD, AD, OCD, or PTSD were included. Trials using other antidepressants (eg, tricyclic antidepressants, monoamine oxidase inhibitors) were excluded.Data Extraction and SynthesisEffect sizes, calculated as standardized mean differences (Hedges g) and risk ratios (RRs) for adverse events, were assessed in a random-effects model.Main Outcomes and MeasuresPrimary outcomes, as defined by authors on preintervention and postintervention data, mean change data, and adverse event data, were extracted independently by multiple observers following PRISMA guidelines.ResultsThirty-six trials were eligible, including 6778 participants (3484 [51.4%] female; mean [SD] age, 12.9 [5.1] years); 17 studies for DD, 10 for AD, 8 for OCD, and 1 for PTSD. Analysis showed that SSRIs and SNRIs were significantly more beneficial compared with placebo, yielding a small effect size (g = 0.32; 95% CI, 0.25-0.40; P < .001). Anxiety disorder (g = 0.56; 95% CI, 0.40-0.72; P < .001) showed significantly larger between-group effect sizes than DD (g = 0.20; 95% CI, 0.13-0.27; P < .001). This difference was driven primarily by the placebo response: patients with DD exhibited significantly larger placebo responses (g = 1.57; 95% CI, 1.36-1.78; P < .001) compared with those with AD (g = 1.03; 95% CI, 0.84-1.21; P < .001). The SSRIs produced a relatively large effect size for ADs (g = 0.71; 95% CI, 0.45-0.97; P < .001). Compared with participants receiving placebo, patients receiving an antidepressant reported significantly more treatment-emergent adverse events (RR, 1.07; 95% CI, 1.01-1.12; P = .01 or RR, 1.49; 95% CI, 1.22-1.82; P < .001, depending on the reporting method), severe adverse events (RR, 1.76; 95% CI, 1.34-2.32; P < .001), and study discontinuation due to adverse events (RR, 1.79; 95% CI, 1.38-2.32; P < .001).Conclusions and RelevanceCompared with placebo, SSRIs and SNRIs are more beneficial than placebo in children and adolescents; however, the benefit is small and disorder specific, yielding a larger drug-placebo difference for AD than for other conditions. Response to placebo is large, especially in DD. Severe adverse events are significantly more common with SSRIs and SNRIs than placebo.

Direct comparison of tricyclic and serotonin-reuptake inhibitor antidepressants in randomized head-to-head trials in acute major depression: Systematic review and meta-analysis.

A comparison across trials conducted over several decades suggested superior efficacy of tricyclic antidepressants (TCAs) over selective serotonin-reuptake inhibitors (SSRIs). However, this outcome may reflect a selective secular decline of responses after randomization to placebo. Remaining uncertainty encouraged direct comparison of the drug-types in trials involving randomized, head-to-head comparisons. We systematically identified reports of randomized trials of TCAs versus SSRIs for major depression in several digital databases, and applied standard meta-analytic and multiple-factor regression methods to analyze and pool the findings. In 89 head-to-head trials, there was no detectable overall difference in responder rates or percent-improvement between TCAs and SSRIs. In addition to non-difference between drug-types, outcomes were unrelated to reporting-year, trial-size or nominal duration, proportion of women participants, initial depression ratings, rating scales, subjects/arm, imipramine-equivalent mg/day drug dose, or dropout rate. Trial size and duration increased significantly over the years 1980-2016. Previous evidence suggesting superior benefits of TCAs over SSRIs for the treatment of acute major depression is probably an artifact of a selective secular decline in responses to placebo, as no difference was found in a large series of direct comparisons of these antidepressant-types.

Depression in dialysis patients.

Depression is the most common psychiatric illness in patients with end-stage renal disease (ESRD). The reported prevalence of depression in dialysis population varied from 22.8% (interview-based diagnosis) to 39.3% (self- or clinician-administered rating scales). Such differences were attributed to the overlapping symptoms of uraemia and depression. Systemic review and meta-analysis of observational studies showed that depression was a significant predictor of mortality in dialysis population. The optimal screening tool for depression in dialysis patients remains uncertain. The Beck Depression Inventory (BDI), Patient Health Questionnaire (PHQ) and Center for Epidemiologic Studies Depression Scale (CESD) have been validated for screening purposes. Patients who scored ≥14 using BDI should be referred to a psychiatrist for early evaluation. Structured Clinical Interview for DSM disorders (SCID) remains the gold standard for diagnosis. Non-pharmacological treatment options include cognitive behavioural therapy and exercise training programs. Although frequent haemodialysis may have beneficial effects on patients' physical and mental well-being, it cannot and should not be viewed as a treatment of depression. Selective serotonin reuptake inhibitors (SSRIs) are generally effective and safe in ESRD patients, but most studies were small, non-randomized and uncontrolled. The European Renal Best Practice (ERBP) guideline suggests a trial of SSRI for 8 to 12 weeks in dialysis patients who have moderate-major depression. The treatment effect should be re-evaluated after 12 weeks to avoid prolonging ineffective medication. This review will discuss the current understanding in the diagnosis and management of depression in dialysis patients.

Early onset of response with selective serotonin reuptake inhibitors in obsessive-compulsive disorder: a meta-analysis.

Selective serotonin reuptake inhibitors (SSRIs) are recommended as the first-line pharmacologic treatment for obsessive-compulsive disorder (OCD). SSRI response is thought to be delayed in OCD, even more so than in major depression. We conducted a meta-analysis to examine the trajectory of treatment response to SSRIs and how this trajectory is modulated by dosage. PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched on May 22, 2013, for randomized, placebo-controlled SSRI trials in OCD with the search terms "serotonin uptake inhibitors" [MeSH] OR "serotonin uptake inhibitors" [Pharmacologic Action] AND "obsessive-compulsive disorder" [MeSH]. There were no language limitations on the search. Randomized, placebo-controlled trials that examined the efficacy of SSRIs in the treatment of adults with OCD and utilized the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as an outcome were selected. We extracted weekly symptom data from randomized, placebo-controlled trials of SSRIs for the treatment of adults with OCD in order to characterize the trajectory of pharmacologic response. Our primary outcome was weighted mean difference on the Y-BOCS of SSRI treatment compared to placebo. We used the PROC MIXED procedure in SAS to examine 6 possible models of SSRI response. Interaction terms were utilized to examine the effect of dose, individual agent, and year of publication on SSRI response. The meta-analysis included 17 trials of SSRIs including 3,276 subjects. A statistically significant benefit of SSRIs compared to placebo was seen within 2 weeks after the start of treatment (weighted mean difference = -0.91 [95% CI, -0.54 to -1.28], P < .001). A logarithmic response curve, indicating decreasing symptom improvement over time, provided the best fit for the trajectory of OCD symptom improvement. A significantly greater response was associated with using higher doses of SSRIs (P < .0001). These results suggest that the greatest incremental treatment gains in OCD are seen early on in SSRI treatment. This is consistent with a previous meta-analysis examining time course of SSRI action in major depressive disorder and contrasts with the widely held belief that SSRI response in OCD is delayed.

Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials.

It has been suggested that the efficacy of antidepressants has been overestimated in clinical trials owing to unblinding of drug treatments by adverse events. To investigate the association between adverse events and the efficacy of selective serotonin reuptake inhibitors (SSRIs). The literature was searched to identify randomised, double-blind, placebo-controlled trials of SSRIs in the treatment of major depression. Efficacy outcomes were response to treatment and change in depressive symptoms. Reporting of adverse events was used as an indicator of tolerability. Random effects meta-analyses were used to calculate pooled estimates. Meta-regression analyses were performed to investigate the association between adverse events and efficacy. Potential mediation was investigated with the Baron & Kenny approach. A total of 68 trials (n = 17 646) were included in the analyses. In meta-analysis SSRIs were superior to placebo in terms of efficacy (odds ratio, OR = 1.62, 95% CI 1.51-1.72). More patients allocated to SSRIs reported adverse events than did patients receiving placebo (OR = 1.73, 95% CI 1.58-1.89). Meta-regression analyses did not find an association between adverse events and efficacy (P = 0.439). There was no indication of adverse events mediating the effect of SSRI treatment. Our results do not support, but also do not unequivocally disprove, the hypothesis that adverse events lead to an overestimation of the effect of SSRIs over placebo.

Prevalence and impact of obsessive-compulsive symptoms in depression: a STAR*D report.

Obsessive-compulsive symptoms (OCS) may be underrecognized in patients suffering from major depressive disorder. These patients may not receive optimal psychopharmacologic or psychological treatment if their OCS are not attended to. We performed a secondary analysis of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial database, the largest effectiveness study of "real-world" depression ever conducted, to determine the frequency of OCS and their effects on depression outcome. 3,984 adult subjects without a previous selective serotonin reuptake inhibitor trial for their current major depressive episode, per DSM-IV diagnostic criteria, had data for rating scales of interest at entry into Level 1 of the STAR*D trial, a 12-week open trial of citalopram at a dose of 20-60 mg/d to assess rates of depression remission. Our primary interest was the OCD subscale of the Psychiatric Diagnostic Screening Questionnaire. At study entry, 53% of the STAR*D sample (which excluded patients with primary obsessive-compulsive disorder) endorsed ≥ 1 OCS, and 14% endorsed ≥ 4 OCS. Subjects endorsing ≥ 4 OCS had significantly lower corrected odds of depression remission on both the 17-item Hamilton Depression Rating Scale (HDRS-17) (OR = 0.61) and the Quick Inventory of Depressive Symptomatology (odds ratio [OR] = 0.51). Number of OCS endorsed was positively correlated with HDRS-17 score (r = 0.26, P < .0001). Consistent with findings from the Dunedin, New Zealand Community Study, the most common obsessions were doubts of having inadvertently caused harm and violent obsessions. OCS are common in depressed outpatients and are often not attended to. They impact clinical recovery from depression and should be screened for since sufferers are often reluctant to disclose these symptoms. ClinicalTrials.gov identifier: NCT00021528.

Selective serotonin reuptake inhibitors for fibromyalgia syndrome.

Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. To assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional beneficial outcome (NNTB) 10, 95% CI 5 to 100; and in global improvement (proportion of patients who reported to be much or very much improved: 50/168 (29.8%) of patients with SSRIs and 26/162 (16.0%) of patients with placebo) RD 0.14, 95% CI 0.06 to 0.23; NNTB 7, 95% CI 4 to 17. SSRIs did not statistically, or clinically, significantly reduce fatigue: standard mean difference (SMD) -0.26, 95% CI -0.55 to 0.03; 7.0% absolute improvement on a 0 to 10 scale, 95% CI 14.6% relative improvement to 0.8% relative deterioration; nor sleep problems: SMD 0.03, 95 % CI -0.26 to 0.31; 0.8 % absolute deterioration on a 0 to 100 scale, 95% CI 8.3% relative deterioration to 6.9% relative improvement. SSRIs were superior to placebo in the reduction of depression: SMD -0.39, 95% CI -0.65 to -0.14; 7.6% absolute improvement on a 0 to 10 scale, 95% CI 2.7% to 13.8% relative improvement; NNTB 13, 95% CI 7 to 37. The dropout rate due to adverse events was not higher with SSRI use than with placebo use (23/146 (15.8%) of patients with SSRIs and 14/138 (10.1%) of patients with placebo) RD 0.04, 95% CI -0.06 to 0.14. There was no statistically or clinically significant difference in serious adverse events with SSRI use and placebo use (3/84 (3.6%) in patients with SSRIs and 4/84 (4.8%) and patients with placebo) RD -0.01, 95% CI -0.07 to 0.05. There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia. The black box warning for increased suicidal tendency in young adults aged 18 to 24, with major depressive disorder, who have taken SSRIs, should be considered when appropriate.

SSRI antidepressants are not associated with cerebral microbleeds or ischaemic vascular lesions

ABSTRACT FROM: Aarts N, Akoudad S, Noordam R, et al . Inhibition of serotonin reuptake by antidepressants and cerebral microbleeds in the general population. Stroke 2014; 45:1951–7. In observational cohort...