Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability.

OBJECTIVE--To examine the evidence for using selective serotonin reuptake inhibitors instead of tricyclic antidepressants in the first line treatment of depression. DESIGN--Meta-analysis of 63 randomised controlled trials comparing the efficacy and acceptability of selective serotonin reuptake inhibitors with those of tricyclic and related antidepressants. MAIN OUTCOME MEASURES--Improvement in mean scores on Hamilton depression rating scale for 53 randomised controlled trials. Pooled drop out rates from the 58 trials which reported drop out by treatment group. RESULTS--Among the 20 studies reporting standard deviation for the Hamilton score no difference was found in efficacy between serotonin reuptake inhibitors and tricyclic and related antidepressants (standardised mean difference 0.004, 95% confidence interval -0.096 to 0.105). The difference remained insignificant when the remaining 33 studies that used the 17 item and 21 item Hamilton score were included by ascribing weighted standard deviations. The odds ratio for drop out rate in patients receiving serotonin reuptake inhibitors compared with those receiving tricyclic antidepressants was 0.95 (0.86 to 1.07). Similar proportions in both groups cited lack of efficacy as the reason for dropping out but slightly more patients in the tricyclic group cited side effects (18.8% v 15.4% in serotonin reuptake group). CONCLUSIONS--Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit.     

Selective serotonin reuptake inhibitors and gastrointestinal bleeding: a case-control study

Background

Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal (GI) bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding.

Methods

We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months) and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day).

Results

581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57–1.96) or for whichever other grouping of antidepressants.

Conclusions

The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2.     

Selective serotonin reuptake inhibitors,and serotonin and norepinephrine reuptake inhibitors for anxiety,obsessive-compulsive,and stress disorders: A 3-level network meta-analysis

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.

In a meta-analysis of randomized trials, Natan Pereira Gosmann and colleagues study efficacy of SSRIs and SNRIs for symptoms of anxiety, obsessive-compulsive, and stress-related disorders.     

Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies

Background

It 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.

Methods

We 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.

Results

Eight 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).

Interpretation

Based 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.There is uncertainty about the safety of selective serotonin reuptake inhibitors (SSRIs), which may cause worsening of suicidal thoughts in vulnerable people.^1,2 In 2005, a systematic review of published randomized controlled trials comparing SSRIs with another active treatment or placebo found an almost 2-fold increase in the odds of fatal and nonfatal suicide attempts among those exposed to SSRIs.³ No increase in risk was observed, however, when only fatal suicide attempts were included. Another systematic review,⁴ which included both published and unpublished randomized controlled trials submitted by pharmaceutical companies to the safety review of the Medicine and Healthcare products Regulatory Agency compared the use of SSRIs and placebo in adults with depression and other clinical conditions.⁴ This review showed no evidence of increased risk of completed suicide and only weak evidence of increased risk of self-harm.More recently, the US Food and Drug Administration (FDA) performed a meta-analysis of individual patient data from 372 randomized placebo-controlled trials of antidepressants with a total of nearly 100 000 patients.⁵ This study reported that the incidence of reported suicidal behaviour was strongly related to age.⁵ The risk associated with antidepressant use relative to placebo was increased among patients aged 25 or fewer years, and it was reduced among patients aged 65 or more years.⁵ The risk among patients aged 25–64 years was neutral; however, risk was reduced when suicidal behaviour and ideation were considered together.⁵ Based on these findings, in May 2007 the FDA ordered that all antidepressant drugs carry an expanded black-box warning on their label that included information about increased risk of suicidal behaviour in young adults aged 18–24 years.^6,7A controversial point of the FDA analysis is that the included trials were not primarily designed to measure suicidality (a composite outcome that includes suicide ideas, preparatory acts, suicide attempts and deaths by suicide).⁵ Of all suicidality events, less than 30% were serious suicide attempts or deaths. Additionally, considering that suicidality was self-reported rather than observed by others in most clinical trials, it is possible that antidepressant treatment, particularly in younger individuals, enhanced communication about suicidality, which may have allowed them to become more articulate and open about their thoughts and actions. Alternatively, antidepressant treatment might have enhanced communication about suicidality in all age groups, but increased attention to adverse effects might have led to enhanced detection of suicidality in younger individuals.⁵It is unlikely that individual randomized trials will be designed to primarily investigate the effect of antidepressant use on suicidality, and future systematic reviews of clinical trial data will not be able to overcome the limitations of the FDA analysis. Therefore, we sought to further explore the association between SSRI exposure and risk of completed or attempted suicide by conducting a systematic review and meta-analysis of observational studies. By including a large, broad spectrum of individuals followed under naturalistic circumstances, systematic reviews of observational studies may offer an added dimension in the evaluation of drug safety that is complementary to that provided by clinical trials.^8,9 Additionally, observational studies may allow researchers to move from the controversial concept of suicidality to hard outcomes such as suicide attempt and completion. Specifically, we set out to quantify the risk of completed or attempted suicide among people in different age groups with depression after exposure to SSRIs.     

Selective serotonin reuptake inhibitors attenuate the antigen presentation from dendritic cells to effector T lymphocytes

Fluoxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been found to possess immune modulation effects, in addition to its antidepressant effects. However, it remains unclear whether SSRIs can suppress the antigen-presenting function of dendritic cells (DCs). Therefore, Fluoxetine was applied to a co-culture of Aggregatibacter actinomycetemcomitans (Aa)-reactive T cells (×Aa-T) isolated from Aa-immunized mice and DCs. This resulted in the suppressed proliferation of ×Aa-T stimulated with Aa-antigen presentation by DCs. Specifically, Fluoxetine increased the extracellular 5-hydroxytryptamine (5-HT) in the ×Aa-T/DC co-culture, whereas exogenously applied 5-HT promoted T-cell proliferation in the ×Aa-T/DC co-culture, indicating that Fluoxetine-mediated suppression of ×Aa-T/DC responses cannot be attributed to extracellular 5-HT. Instead, Fluoxetine remarkably suppressed the expression of costimulatory molecule ICOS-L on DCs. Fluoxetine also promoted a greater proportion of CD86(Low) immature DCs than CD86(High) mature DCs, while maintaining the expression levels of CD80, MHC-class-II and PD-L1. These results suggested that Fluoxetine suppressed the ability of DCs to present bacterial antigens to T cells, and the resulting T-cell proliferation, in a SERT/5-HT-independent manner and that diminished expression of ICOS-L on DCs and increase of CD86(Low) immature DCs caused by Fluoxetine might be partially associated with Fluoxetine-mediated suppression of DC/T-cell responses.     

Selective serotonin reuptake inhibitors and raft inhibitors shorten the period of Period1-driven circadian bioluminescence rhythms in rat-1 fibroblasts

Alterations in circadian rhythm generation may be related to the development of mood disorders. Although it has been reported that the most popular antidepressant, selective serotonin reuptake inhibitors (SSRIs) affect circadian phase, no data are available that describe the effects of SSRIs on other circadian parameters (period, amplitude and damping rate) in dissociated cells. In the present study we used real-time monitoring of bioluminescence in rat-1 fibroblasts expressing the Period1-luciferase transgene, and that in Period1-luciferase transgenic mouse suprachiasmatic nucleus (SCN) explants, in order to characterize the effects of SSRI on circadian oscillator function in vitro. We found that mRNA of the serotonin transporter (SERT), a target of SSRIs, was expressed in rat-1 fibroblasts. Sertraline, fluoxetine, fluvoxamine, citalopram and paroxetine all significantly shortened the period of Period1-bioluminescence rhythms in rat-1 fibroblasts. The amplitude was reduced by sertraline, and the damping rate was decreased by sertraline, fluoxetine, flvoxamine and paroxetine. The effect of sertraline was dose-dependent, and it also shortened the circadian period in the SCN. SERT is associated with lipid microdomains, which are required for efficient SERT activity. Indeed, cholesterol chelating reagent methyl-beta-cyclodextrin significantly reduced the period and the amplitude in rat-1 fibroblasts. Furthermore, lipid binding reagent xylazine significantly reduced the period. In summary our data present evidence that SSRIs affect circadian rhythmicity. The action of SSRIs is likely mediated by suppression of SERT activity. A better understanding of the relationship between mental illness and biological timing may yield new insight into disease etiology and avenues for treatment.     

Prescribing selective serotonin reuptake inhibitors as strategy for prevention of suicide.

OBJECTIVE--To evaluate a policy to reduce the incidence of suicide by means of changing the prescribing of antidepressants from the older tricyclic antidepressants to the routine first line use of selective serotonin reuptake inhibitors or newer tricyclic and related antidepressants. DESIGN--Cost effectiveness analysis with sensitivity analyses using observational data on costs, volume of prescribing, deaths, and toxicity. SETTING--United Kingdom primary care. INTERVENTIONS--Selective serotonin reuptake inhibitors or newer tricyclic and related antidepressants compared with the use of older tricyclics. MAIN OUTCOME MEASURES--Cost per life saved and cost per life year saved. RESULTS--The potential number of lives which may be saved from a switch to the routine first line use of selective serotonin reuptake inhibitors is between 300 and 450 each year. The cost per life year gained ranges from 19,000 pounds to 173,000 pounds, depending on the assumptions used. The cost per life year gained through the use of the newer tricyclic and related antidepressants is considerably lower. CONCLUSIONS--The cost per life year gained through avoiding suicides by the routine first line use of serotonin reuptake inhibitors is likely to be high. The new tricyclics and related drugs are of similar toxicity to the serotonin reuptake inhibitors but are considerably cheaper and so are most cost effective for this purpose. Further research is required on such prescribing. Because of the great uncertainties the shift to considerably more expensive options must be further investigated.     

Inhibition of serotonin reuptake.

An uptake system on the serotonin neuronal membrane apparently functions to inactivate serotonin that has been released into the synaptic cleft. Various inhibitors of this active transport system on serotonin neurons are known, and some are specific in the sense that they do not inhibit the active uptake system on norepinephrine neurons. The most widely studied specific inhibitor of the serotonin neuron pump is fluoxetine, 3-(p-trifluoromethylphenoxy-N-methyl-3-phenyl propylamine (Lilly 110140). When fluoxetine or other effective but less specific serotonin uptake inhibitors are given, a rapid decrease in serotonin turnover occurs and the rate of firing of single neural units in the serotonin rich raphe area of brain is reduced. This decrease in serotonin turnover and release may be a compensatroy mechanism in response to an enhanced action of serotonin on synaptic receptors. Through the use of fluoxetine and other serotonin uptake inhibitors, the role of serotonin neurons in various brain functions--behavior, sleep, regulation of pituitary hormone release, thermoregulation, pain responsiveness, and so on--can be studied.     

Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials

Background

Selective serotonin reuptake inhibitors are increasingly used in the long-term treatment of depression. Much of the supporting evidence about the effects of these drugs comes from discontinuation trials, a variant of randomized controlled trials whose design is problematic to interpret. We conducted a systematic review to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of unipolar depression.

Methods

We identified placebo-controlled randomized trials with a treatment duration of at least 6 months by searching MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to update a recently published systematic review. Efficacy was defined in terms of response to treatment (50% improvement in depression score relative to baseline) and remission (score of 7 or below on the Hamilton rating scale for depression). Key secondary outcomes included quality of life, return to work, need for additional treatment and self-harm. Overall acceptability was defined in terms of dropouts for any reason over a course of treatment.

Results

Of the 2693 records identified initially, we included 6 randomized controlled trials that met our eligibility criteria. These studies had a moderate risk of bias, had assigned a total of 1299 participants with depression to either treatment or placebo and had followed both groups for 6–8 months. We observed statistically significant improvements in response to treatment (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.12–2.48), but not in remission (OR 1.46, 95% CI 0.92–2.32) or acceptability (OR 0.87, 95% CI 0.67–1.14). The effects appeared greater among patients without comorbidities.

Interpretation

There is a lack of classic randomized controlled trials of serotonin reuptake inhibitors lasting more than 1 year for the treatment of depression. The results of our systematic review support current recommendations for 6–8 months of antidepressant treatment following initial recovery but provide no guidance for longer treatment.Over the past decade, the use of selective serotonin reuptake inhibitors for the management of depression has increased dramatically, and preliminary evidence suggests that long-term use, for more than 1 or 2 years, accounts for much of this rise.^1–3 Clinical practice guidelines generally recommend a 6- to 9-month course following initial recovery after a first episode of depression and longer, sometimes indefinite, therapy after subsequent episodes, to prevent relapse.^4–10Long-term randomized controlled trials of antidepressants have typically used 1 of 2 possible designs, each answering different questions (Figure 1).¹¹ The most widely used design is called the “discontinuation trial,” a 2-phase study in which all participants are initially treated with an open (unblinded) course of drug therapy. Participants attaining a certain response during the open-treatment phase enter the second phase, during which they are randomly assigned to continue active drug treatment or to receive placebo.^12–14 Discontinuation trials are believed to minimize the number of participants with depression who must be exposed to placebo. This advantage comes at a cost, since the results apply only to patients with a response to the medication, not to those who experience spontaneous recovery; furthermore, withdrawal symptoms may lead to an overestimate of the true effect of the medication. When this design is used to test long-term therapy with selective serotonin reuptake inhibitors for the treatment of depression, the results are difficult to interpret with confidence because rates of spontaneous recovery in depression are potentially high and because withdrawal effects can mimic depression.^13–15Open in a separate windowFigure 1: Two designs of randomized controlled trials used to investigate long-term antidepressant therapy.The second type of randomized trial used to test long-term therapy with selective serotonin reuptake inhibitors is a 2-arm parallel randomized controlled trial, hereafter referred to as a classic randomized controlled trial (Figure 1).¹⁶ In this type of trial, participants with acute depression are assigned to receive either placebo or active drug, and all those achieving a certain response, either to the drug or to the placebo, are followed. The advantage of classic randomized controlled trials is that data from all participants contribute to our understanding of the drug''s real-world effectiveness. Their main drawback is that a greater number of acutely ill people may have to receive placebo than in a discontinuation trial.¹³ Most classic trials of antidepressants are short-term studies. Fergusson and colleagues,¹⁷ in a systematic review examining selective serotonin reuptake inhibitors and suicide, identified 702 classic trials involving a total of 18 413 participants, the majority of which (93%) lasted less than 6 months.A recent systematic review based mainly on studies with discontinuation designs showed that, in a subgroup of patients who experienced recovery while taking medications, long-term therapy with selective serotonin reuptake inhibitors reduced the chances of relapse by up to 70% for up to 36 months, relative to patients whose therapy was discontinued earlier.⁶ However, there has been no systematic review of classic randomized trials of long-term therapy with this drug class to determine the potential benefits in all patients with depression, including those with spontaneous recovery.We sought to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of moderate to severe depression, including subgroups of patients with major chronic health conditions. We also examined a number of key indicators of the quality of evidence and its clinical importance.     

Benzylamine histamine H(3) antagonists and serotonin reuptake inhibitors

The design, synthesis, and in vitro activity of a series of novel 5-ethynyl-2-aryloxybenzylamine-based histamine H(3) ligands that are also serotonin reuptake transporters is described.     

Conformationally restricted homotryptamines 3. Indole tetrahydropyridines and cyclohexenylamines as selective serotonin reuptake inhibitors

A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.