The efficacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants

A meta-analysis of the efficacy of five selective serotonin re-uptake inhibitors (SSRIs) against non-selective and noradrenergic re-uptake inhibitors (mainly tricyclic antidepressants, TCAs) is presented. Fifty five double- blind studies were identified after excluding those multiply reported or with methodological problems likely to bias the outcome in favour of SSRIs. Standardised effect sizes and 95% confidence intervals were calculated based on the difference in the reduction in mean Hamilton depression rating scale (HDRS) scores for the two antidepressants. For studies not reporting standard deviations, the pooled variance from complete studies was used and a variance-weighted mean effect size calculated. There were no differences in efficacy between SSRIs and comparator antidepressants for SSRIs taken together or individually. If studies were classified into high and low depression scores based on a median split of initial HDRS scores, there was a slight advantage to TCAs in the high HDRS group. In addition, SSRIs were slightly less effective than TCAs in in-patients and against combined serotonin and noradrenaline re-uptake inhibitors (clomipramine and amitriptyline). These findings were accounted for by a clinically significant lower efficacy of paroxetine in these subgroups. In contrast, SSRIs as a group were marginally more effective than noradrenergic antidepressants, a finding accounted for by two studies with sertraline. Fluvoxamine was the only SSRI to have been tested adequately in in-patients, where it displayed equal efficacy to TCAs. This meta-analysis confirms that SSRIs and TCAs are in general equally effective, but suggests that paroxetine's efficacy in in-patients and against clomipramine and amitriptyline is not proven.     

Discontinuation rates for selective serotonin reuptake inhibitors and other second-generation antidepressants in outpatients with major depressive disorder: a systematic review and meta-analysis

The present study aimed to systematically compare overall loss to follow-up, discontinuation rates because of adverse events and discontinuation rates because of a lack of efficacy in published studies assessing the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) compared to other second-generation antidepressants in treating outpatients with major depressive disorder (MDD). We searched MEDLINE, Embase, The Cochrane Library, PsychLit and the International Pharmaceutical Abstracts from 1980 to 2004 (April). Twenty double-blinded, randomized controlled trials met our eligibility criteria and compared SSRIs to other second-generation antidepressants in adult outpatients with MDD. Pooled relative risks of discontinuation rates because of (i) any reason (overall loss to follow-up), (ii) adverse events and (iii) a lack of efficacy did not differ substantially between SSRIs as a class and other second-generation antidepressants. Taking the similar efficacy of second-generation antidepressant into account, our findings suggest that clinicians can focus on other practically or clinically relevant considerations such as costs, differences in side-effect profiles, onset of action or aspects of health-related quality of life to tailor a treatment to an individual patient's needs.     

Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression

Background: In asthma small airways inflammation often persists despite inhaled corticosteroids therapy. Objective: To discuss the effects of ciclesonide, a newer inhaled corticosteroid on small airways inflammation and the reliability of some biomarkers of small airways inflammation in asthma. Methods and results: Evaluation of a study assessing the short-term effects of ciclesonide on small airways inflammation in patients with mild to moderate asthma. Conclusions: Ciclesonide could have beneficial effects on small airways inflammation and some of the outcome measures used as efficacy endpoints could represent possible biomarkers of small airways involvement in obstructive chronic respiratory diseases.     

Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression

Selective serotonin reuptake inhibitors (SSRIs) are now generally regarded as effective and better tolerated alternatives to tricyclic antidepressants (TCAs) for the treatment of depression. SSRIs also seem to be as well tolerated as moclobemide, mirtazapine, venlafaxine, reboxetine and nefazodone and show comparable efficacy. Minor differences have been observed between some SSRIs and some of the newer antidepressants but these findings are far from conclusive. Widespread use of the SSRIs has highlighted some unforseen adverse effects associated with SSRIs, namely hyponatraemia, EPSE and sexual dysfunction. Overall, differences in efficacy and tolerability between individual SSRIs are small and clinically insignificant.     

The use of tricyclic antidepressants and selective serotonin reuptake inhibitors in women who are breastfeeding

Postpartum depression is a well-recognized psychiatric condition that has gained increased attention over the past decade due to several nationally publicized tragedies. Medical management of this condition in women who are breastfeeding provides a unique challenge to health care professionals who may seek to maintain a fine balance between limiting the infant's exposure to hormone-altering drugs and maintaining the benefits of breastfeeding. No controlled trials have examined antidepressant therapy in nursing women; however, numerous case reports and case series have been published. Relatively few serious adverse effects have been reported. Although tricyclic antidepressants have been the treatment of choice in the past, selective serotonin reuptake inhibitors are gaining popularity due to their superior safety profiles. Of all the agents reviewed in the literature, sertraline was the most prescribed, and no adverse effects were reported. Therefore, this agent would be a good first choice for treatment-naive women. For treatment of postpartum depression in women with a history of successfully treated depression, the most practical approach may be to continue therapy with the previously effective agent. Treatment should be maintained at the lowest effective dosage to minimize infant exposure. Both mother and child should be closely monitored; in addition, collaboration between the prescribing physician and the child's pediatrician is essential.     

Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are used to treat depression. Whereas cardiovascular effects have occasionally been reported during controlled studies with SSRIs, TCA treatment poses a well-known problem in this respect. To investigate the putative correlation between antidepressant dose or serum levels and adverse effects, the authors devised a naturalistic study to evaluate the tricyclic antidepressants' and SSRIs' effect on the cardiovascular system. The authors also compared antidepressant serum levels to adverse effects. Inpatients treated with TCAs or SSRIs were included; an electrocardiogram (ECG) and a Schellong test were carried out on the day patients entered the hospital and during steady-state treatment with antidepressant drugs when blood was drawn for therapeutic drug monitoring. The patient population consisted of 114 acutely depressed patients; 81 patients were treated with TCAs and 33 with SSRIs. The TCAs comprised amitriptyline (n = 43), clomipramine (n = 11), doxepin (n = 19) and imipramine (n = 8); the SSRIs comprised fluvoxamine (n = 14) and paroxetine (n = 19). In TCA-treated patients, the authors observed the same type of abnormalities in conduction and orthostatic hypotension as had been observed earlier. The authors also observed cases of first-degree atrioventricular block, prolonged QTc interval, and orthostatic hypotension in SSRI-treated patients. Thus SSRIs also appear to affect the cardiovascular system, which might pose a problem for patients with preexisting conduction disease. The authors observed a strong correlation between the decrease in systolic pressure and antidepressant serum concentration (except for clomipramine and paroxetine), suggesting that antidepressant serum level is a better correlate than dose.     

Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: a systematic review and meta-analysis.

To evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with depressive disorder, the main electronic databases and the reference lists of retrieved articles and reviews were searched up to January 2007. Randomized controlled studies (RCT) were assessed for methodological quality, taking into consideration the specific diagnostic and severity evaluation tools used, and a meta-analysis on the efficacy of SSRIs compared placebo was undertaken. In all, 13 studies were included, covering a total of 2530 children and adolescents. Eleven studies met the criteria for inclusion in the meta-analysis. The pooled odds ratio was 1.57 (95% C.I. 1.29-1.91). Only fluoxetine appeared to offer a moderately significant benefit profile (OR=2.39). All studies differed in diagnostic tools and primary efficacy measures. SSRI treatment, especially with fluoxetine, may be effective on child and adolescent depression. Nevertheless, additional RCTs with sound methodological designs, validated diagnostic instruments, large sample sizes, and consistent outcomes are necessary to determine the role of SSRIs, alone or in combination with psychological interventions in the treatment of depression in children and adolescents.     

The economics of selective serotonin reuptake inhibitors in depression: a critical review

The prevalence of depression and the high costs associated with its treatment have increased interest in pharmacoeconomic evaluations of drug treatment, particularly in the 1990s as the use of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) expanded substantially. This review presents results from specific studies representing the key study designs used to address the pharmacoeconomics of SSRI use: retrospective administrative database analyses, clinical decision analysis models, and randomised clinical trials. Methodological considerations in interpreting results are highlighted. In retrospective administrative database analyses, most comparisons have been made between SSRIs and tricyclic antidepressants (TCAs). A few studies have addressed differences between SSRIs. The studies focused on healthcare cost (to payer) and cost-related outcomes (e.g. treatment duration, drug switching). Although SSRIs are generally associated with higher drug acquisition costs than are TCAs, total healthcare costs are at least offset, if not decreased, by reductions in costs associated with use of SSRIs. Although studies from the early 1990s show some advantage for fluoxetine, the results are limited by use of data from shortly after the introduction of paroxetine and sertraline; studies from the mid- 1990s on that compare drugs within the SSRI class show general equivalence in terms of cost. Important methodological advances are occurring in retrospective studies, with selection bias and other design limitations being addressed statistically. Clinical decision analysis models permit flexibility in terms of ability to specify different alternative treatment scenarios and varying durations. Sensitivity analysis aids interpretability, although model inputs are limited by data availability. Results from short term (1 year duration or less) studies comparing SSRIs and TCAs suggest that SSRIs are more cost effective or that there is no difference. Longer term studies (lifetime Markov models) focus more on the impact of maintenance antidepressant therapy and show more mixed results, generally favouring SSRIs over TCAs. The results indicate that the effect of SSRIs is mainly through prevention of relapse. Important assumptions of these models include fewer serious adverse effects and lower treatment discontinuation rates with SSRIs. Naturalistic clinical trials provide greater generalisability than traditional randomised clinical trials. One naturalistic trial found that nearly half of TCA-treated patients switched to another antidepressant within 6 months; only 20% of SSRI-treated patients switched. Cost differences between groups were minimal. These studies indicate few differences in medical costs, depression outcomes and health-related quality of life between TCAs and fluoxetine, although fewer fluoxetine-treated patients switched treatment.     

Efficacy of venlafaxine compared with tricyclic antidepressants in depressive disorder: a meta-analysis

With respect to the pharmacological characteristic, venlafaxine is comparable with tricyclic antidepressants (TCAs), and venlafaxine might be comparable in efficacy. We performed a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with TCAs (imipramine, clomipramine, amitriptyline, nortriptyline and desipramine). Relevant double-blind randomised trials were identified from systematic searches of electronic databases. An exact analysis of the estimated odds ratios of response of the TCA relative to venlafaxine showed no overall significance of treatment effect (P = 0.38). The odds ratios were not homogenous across studies (P = 0.0213). The average dose of venlafaxine was 103.5 mg/day and for the TCA 106.1 mg/day. An exact analysis of the estimated odds ratios of the withdrawals and side effects in the trials with a TCA relative to venlafaxine showed no overall significance of withdrawal. From our review, no significant difference in treatment effect between low dose of both venlafaxine and the TCAs could be found. In our opinion, because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.     

Efficacy and tolerability of milnacipran in the treatment of major depression in comparison with other antidepressants : a systematic review and meta-analysis

BACKGROUND: Milnacipran, a dual serotonin-noradrenaline reuptake inhibitor, is one of the newer antidepressants that clinicians use for the routine care of patients with major depression. We undertook a systematic review and meta-analysis of randomized controlled trials that compared the efficacy and tolerability of milnacipran with other antidepressants. OBJECTIVE: To assess the efficacy and tolerability of milnacipran in comparison with TCAs, SSRIs and other drugs in the acute phase of treatment for major depression. METHODS: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials registers, journals, conference proceedings, trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished randomized controlled trials that compared the efficacy and adverse events of milnacipran versus any other antidepressant. The search was conducted in December 2006 and updated in May 2007. No language restrictions were applied. All relevant authors were contacted to supplement any incomplete reporting in the original papers. Randomized controlled trials comparing milnacipran with any other active antidepressants as monotherapy in the acute phase of treatment for major depression were selected. Participants were aged > or =18 years, of both sexes and with a primary diagnosis of unipolar major depression. Studies were excluded when the participants had specific psychiatric and medical co-morbidities.Two independent reviewers assessed the quality of trials for inclusion, and subsequently extracted data. Disagreements were resolved by consensus. Meta-analyses were conducted for efficacy and tolerability outcomes. Sixteen randomized controlled trials (n = 2277) were included in the meta-analyses. RESULTS: No differences were found in achieving clinical improvement, remission or overall tolerability when comparing milnacipran with other antidepressants. However, compared with the TCAs, fewer patients taking milnacipran were early treatment withdrawals due to adverse events (number needed to harm (NNH) = 15; 95% CI 10, 48). Significantly more patients taking TCAs experienced adverse events compared with milnacipran (NNH = 4; 95% CI 3, 7). CONCLUSIONS: The overall effectiveness and tolerability of milnacipran versus other antidepressants does not seem to differ in the acute phase of treatment for major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due to adverse events and the rates of patients experiencing adverse events. Milnacipran may benefit some patient populations who experience adverse effects from other antidepressants in the acute phase of treatment for major depression.     

The impact of tricyclic antidepressants and selective serotonin re-uptake inhibitors on handwriting movements of patients with depression

RATIONALE: Psychomotor retardation is a common symptom of patients with major depressive disorder. While a variety of clinical examinations using different techniques have been undertaken to assess the motor component of psychomotor retardation in depression, the effects of antidepressants on psychomotor functions have been examined less extensively. OBJECTIVE: The aim of the present study was to examine the effect of various pharmacological treatments on handwriting movements of patients with depression. METHODS: Kinematic data of automated handwriting movements of 18 depressed patients receiving tricyclic antidepressants (TCAs), 18 patients on selective serotonin re-uptake inhibitors (SSRIs) and 18 healthy subjects was recorded and analysed. Groups were matched according to age, sex, handedness and education level. For the assessment of fine motor movements, a digitising tablet was used. Subjects were asked to perform a simple writing task. Movement time, velocity and acceleration of the handwriting movements were measured. RESULTS: Statistical analysis of writing movements revealed motor slowing in patients receiving TCAs. In comparison with both healthy subjects and patients receiving SSRIs, the TCA group displayed an increased movement time, reduced automation of handwriting, lower maximum velocities and reduced acceleration of descending strokes. CONCLUSIONS: The results suggest either that TCAs have adverse effects on motor functioning or that they are less effective in the treatment of motor retardation than SSRIs.     

Effect on sexual function of long-term treatment with selective serotonin reuptake inhibitors in depressed patients treated in primary care

The purpose of this study was to prospectively examine the occurrence and severity of sexual dysfunction symptoms in depressed patients before and after 6 months of treatment with selective serotonin reuptake inhibitors. The study was part of a randomized, double-blind, controlled trial of sertraline or citalopram in patients with a DSM-III-R major depressive disorder treated by general practitioners. Three hundred eight patients (221 women and 87 men) were assessed at baseline and after 6 months of treatment by means of the Montgomery-Asberg Depression Rating Scale and five items from the Utvalg for Kliniske Undersogelser (UKU) Side Effect Scale covering different aspects of sexual functioning. As measured by the UKU Side Effect Scale, sexual desire and mean total score significantly improved in women, and sexual desire improved in men. Men reported no change in orgasmic dysfunction, erectile dysfunction, or mean total score, but there was a trend toward worsening of ejaculatory dysfunction. However, in the subgroup of women who reported no sexual problems at baseline, 11.8% reported decreased sexual desire, and 14.3% reported orgasmic dysfunction at week 24. The corresponding figures in the same subgroup of men were 16.7% and 18.9%, respectively, and as many as 25% experienced ejaculatory dysfunction after 24 weeks. There were no statistically significant differences between sertraline and citalopram in the magnitude or frequency of adverse sexual side effects.     

Treatment of depression in acute coronary syndromes with selective serotonin reuptake inhibitors

Depression in patients with acute coronary syndromes (ACS) is common and associated with impaired cardiovascular prognosis in terms of cardiac mortality and new cardiovascular events. It remains unclear whether antidepressant treatment may reverse these effects. In this review, the literature is evaluated on (i) the antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with ACS; (ii) the pleiomorphic effects of SSRIs that may be associated with cardiovascular prognosis; and (iii) the effects of SSRIs on cardiovascular prognosis.SSRIs provide modest relief of depressive symptoms in selected subgroups of depressed patients with ACS. With respect to the pleiomorphic effects of SSRIs, three mechanisms of how SSRIs may improve cardiovascular prognosis are discussed: via platelet function, via the autonomic nervous system (ANS) and via vasomotor tone. Some studies show that SSRIs may reduce platelet activity and sympathetic nervous system activation, but results are inconclusive. SSRIs are associated with vasodilation but this needs to be confirmed with in vivo experiments. Some non-experimental studies describe favourable effects of SSRIs on cardiovascular prognosis. Despite recent developments, much of the effect of SSRIs on cardiovascular prognosis remains unclear. Although some studies suggest effects of SSRIs on platelet function, ANS and vasomotor tone, which may lead to improved cardiovascular prognosis, results are largely inconclusive. More well designed studies addressing these questions are needed. Moreover, since the effects of SSRIs on depression itself are limited, efforts should be dedicated to study the diagnostic validity and homogeneity of depression in the context of ACS and the presence of clinically relevant subtypes.     

Orphan comparisons and indirect meta-analysis: a case study on antidepressant efficacy in dysthymia comparing tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors by using general linear models

Direct comparisons of the efficacy of competing interventions are not always available in the literature. This situation leads to the presence of clinically relevant "orphan comparisons" of therapeutic interventions which have never been compared head-to-head. To overcome this limitation, simple methods for indirect meta-analysis have been suggested. Nevertheless, their results are prone to bias when more than 1 indirect comparison is tested because of the likely duplication of data for some comparisons. In contrast, general linear models can be used to extend simple indirect meta-analysis beyond 1 indirect comparison by fitting to incomplete data using maximum likelihood within the framework of multitreatment comparisons. This study presents a tutorial application of general linear models to the comparative efficacy of several antidepressants in dysthymia (tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors. Working with previously published data comparing the efficacy of antidepressants with placebo, it is shown that tricyclic antidepressants and selective serotonin reuptake inhibitors present similar efficacy (odds ratio = 1.19, P = 0.37; relative risk = 1.10, P = 0.24; risk difference = 0.03, P = 0.53), whereas monoamine oxidase inhibitors outperform both tricyclic antidepressants and selective serotonin reuptake inhibitors, at least for some effect scales (odds ratio = 1.57, P = 0.05; relative risk = 1.25, P = 0.05; risk difference = 0.09, P = 0.08). This finding, which is an instance of a relevant orphan comparison and could not be obtained otherwise, could motivate the conduct of clinical trials or focused systematic reviews to support or refute its importance through appropriate head-to-head comparisons.     

Selective serotonin reuptake inhibitors for late-life depression: a comparative review

Late-life depression is a serious health problem that is challenging to manage but generally responds well to pharmacotherapy. Selective serotonin (5-hydroxytryptamine: 5-HT) reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants, are usually used as first-line agents for elderly patients with depression. Like most drugs, SSRIs have not been widely tested in clinical trials that approximate 'real-life' geriatric situations. However, studies completed to date provide valuable information about the efficacy, safety and tolerability of this class of antidepressants among older patients with depression, including those with depression secondary to stroke or dementia and those with other comorbid physical disorders. Although one SSRI may be more efficacious or better tolerated by elderly patients than another, existing data do not support such claims. However, other distinguishing features may influence the choice of agent. For example, fluoxetine, fluvoxamine and paroxetine are more likely to be involved in significant drug-drug interactions than are citalopram or sertraline. In contrast to the other SSRIs, fluoxetine has a half-life well in excess of 1 day, which can be an advantage when weaning the patient off therapy in that it may reduce the incidence of discontinuation symptoms, but a significant disadvantage if the patient cannot tolerate the drug or experiences an adverse drug-drug interaction.