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Ann Fam Med. 2005 Sep-Oct;3(5):449-56. Related Articles, Links
Click here to read
Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression
in primary care: a meta-analysis.
Arroll B, Macgillivray S, Ogston S, Reid I, Sullivan F, Williams B, Crombie I.
Department of General Practice and Primary Health Care, University of Auckland, NZ. b.arroll@auckland.ac.nz
PURPOSE: Depression is common in primary care. There are no systematic reviews of depression treatment comparing antidepressants
with placebo; hence, we do not know whether these medications are effective in primary care. METHODS: We searched the Cochrane
Collaboration Depression, Anxiety and Neurosis Group register of controlled trials, MEDLINE, International Pharmaceutical
abstracts, PsycINFO, and EMBASE. Abstracts of potential studies were reviewed independently by 2 authors. Studies needed to
include randomized controlled trials of either a tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor
(SSRI), or both, and placebo in a primary care setting. The data and quality of the studies were extracted and assessed by
2 authors blind to the other's choice. Disagreements were resolved by discussion. The main outcome measures were the standardized
mean difference and weighted mean difference of the final mean depression scores, the relative risk of improvement, and the
number withdrawing because of side effects. Pooling of results was done using Review Manager 4.2.2. RESULTS: There were 10
studies in which TCAs were compared with placebo, 3 in which SSRIs were compared with placebo, and 2 with both compared with
placebo. One half of the studies were of low methodological quality, and nearly all studies were of short duration, typically
6 to 8 weeks. Pooled estimates of efficacy data showed a relative risk of 1.26 (95% CI, 1.12-1.42) for improvement with TCAs
compared with placebo; For SSRIs, relative risk was 1.37 (95% CI, 1.21-1.55). Most patients, 56% to 60%, responded well to
active treatment compared with 42% to 47% for placebo. The number needed to treat for TCAs was about 4, and for SSRIs it was
6. The numbers needed to harm (for withdrawal caused by side effects) ranged from 5 to 11 for TCAs and 21 to 94 for SSRIs.
Low-dose (100 mg or 75 mg) as well as high-dose TCAs were effective. CONCLUSION: This systematic review is the first comparing
antidepressants with placebo for treatment of depression in primary care. Both TCAs and SSRIs are effective. This review is
also the first to show that low-dose TCAs are effective in primary care. Prescribing antidepressants in primary care is a
more effective clinical activity than prescribing placebo.
Publication Types:
* Meta-Analysis
PMID: 16189062 [PubMed - indexed for MEDLINE]
Ann Intern Med. 2005 Sep 20;143(6):415-26. Related Articles, Links
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Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder.
Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS.
Division of Pharmaceutical Policy and Evaluative Sciences, University of North Carolina, Chapel Hill, North Carolina
27599, USA. rahansen@unc.edu
BACKGROUND: Reviews have compared the efficacy and tolerability of newer second-generation antidepressants with those
of placebo or older treatments, but comparative evidence for use of second-generation antidepressants to treat major depressive
disorder has not been evaluated. PURPOSE: To systematically evaluate comparative data on the efficacy, effectiveness, and
tolerability of commonly prescribed second-generation antidepressants (selective serotonin reuptake inhibitors, bupropion,
duloxetine, mirtazapine, and venlafaxine) in the treatment of major depressive disorder. DATA SOURCES: MEDLINE, EMBASE, and
PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts were searched from January 1980 through February
2005 for reviews; randomized, controlled trials; meta-analyses; and observational studies. STUDY SELECTION: The authors reviewed
46 head-to-head randomized, controlled trials comparing one second-generation antidepressant with another. Twenty-four observational
studies and placebo-controlled trials were also included for assessment of safety and tolerability. DATA EXTRACTION: Two researchers
independently reviewed titles and abstracts. Trained reviewers abstracted data from each study and assigned an initial quality
rating. A second reviewer verified the data extraction and quality rating. DATA SYNTHESIS: According to fair to good evidence,
the second-generation antidepressants that were compared had only minimal differences in efficacy, and 88% of comparative
efficacy studies reported no statistically significant difference in any outcome measure at the end of the study. One effectiveness
trial rated good and 2 effectiveness trials rated fair reported no statistically significant differences in primary outcome
measures for compared drugs. Meta-analyses showed a modest but statistically significant additional treatment effect for sertraline
and venlafaxine compared with fluoxetine. About 96% of comparative trials were sponsored by or had at least 1 author affiliated
with a pharmaceutical company; the remaining trials did not report funding sources. Adverse event profiles differed among
drugs; however, the degree and quality of adverse event assessment varied and only 13% of trials used a standardized scale
to assess adverse events. LIMITATIONS: Quantitative analyses could not be done for many drug comparisons because the quantity
and quality of the evidence were inadequate. Most published evidence was from trials sponsored by pharmaceutical companies,
and publication bias may have occurred. CONCLUSIONS: Overall, second-generation antidepressants probably do not differ substantially
for treatment of major depressive disorder. Choosing the agent that is most appropriate for a given patient is difficult.
Publication Types:
* Meta-Analysis
* Review
PMID: 16172440 [PubMed - indexed for MEDLINE]
Curr Med Res Opin. 2004 Apr;20(4):477-84. Related Articles, Links
Quality assessment of meta-analyses of RCTs of pharmacotherapy in major depressive disorder.
Hemels ME, Vicente C, Sadri H, Masson MJ, Einarson TR.
Faculty of Pharmacology, University of Toronto, Canada. MEHH@Lundbeck.com
BACKGROUND: Meta-analyses (MAs) of randomized controlled trials (RCTs) have the potential to provide the highest level
of evidence, but the quality of published MAs has not been systematically assessed. Therefore, we determined reliability was
significant (kappa = 0.89; p < 0.05). the quality of reporting in MAs of RCTs of pharmacotherapy for major depressive disorder
(MDD) in adults (18-65 years) without comorbidities and examine trends over time. METHODS: MEDLINE, EMBASE, Healthstar, Psychlit
and Cochrane databases were searched (1980-2002) by 4 independent reviewers for MAs of RCTs.Articles meeting inclusion criteria
were blinded. Inter-rater reliability (kappa) was evaluated using a test-retest strategy on 4 articles. Quality was (p = 0.74)
did not detect a difference in quality of assessed using the QUOROM checklist. Time trends were evaluated by calculating Spearman's
rho. RESULTS: One hundred articles were identified, 68 were excluded [co-morbidities (9), inappropriate comparator (13), inappropriate
outcome (15), article not available (5), inappropriate patient population (15), and inappropriate study design (11)]; 32 were
included. Initial kappa was 0.81 (p < 0.05). After resolution of disagreements, the test-retest The mean overall quality
score was 50.2% (SD 15.8%, range = 16.7-88.9%). The overall score for Titles was very poor (22%), Abstracts (40%) and Methods
(49%) were poor, while overall Results score was minimally acceptable (54%). Good quality scores were found for Introduction
(91%) and Discussion (97%). No time trends were identified using Spearman's correlation analysis (rho 0.05; p = 0.79). The
Mann-Whitney U test articles published before and after the QUOROM. CONCLUSION: Despite quality guidelines, the average quality
of published MAs of antidepressants is barely acceptable (50.2%). A need exists for adherence to standardized reporting and
quality guidelines.
PMID: 15119985 [PubMed - indexed for MEDLINE]
Cochrane Database Syst Rev. 2004;(1):CD003012. Related Articles, Links
Update of:
Cochrane Database Syst Rev. 2001;(2):CD003012.
Active placebos versus antidepressants for depression.
Moncrieff J, Wessely S, Hardy R.
Psychiatry, University College London, Warley hospital, Mascalls Lane, Brentwood, Essex, UK, CM14 4TU.
BACKGROUND: Although there is a consensus that antidepressants are effective in depression, placebo effects are also thought
to be substantial. Side effects of antidepressants may reveal the identity of medication to participants or investigators
and thus may bias the results of conventional trials using inert placebos. Using an 'active' placebo which mimics some of
the side effects of antidepressants may help to counteract this potential bias. OBJECTIVES: To investigate the efficacy of
antidepressants when compared with 'active' placebos. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and
Neurosis review groups's search strategy was used to search MEDLINE (1966-2000), PsychLIT (1980-2000) and EMBASE (1974-2000)
and this was last done in July 2000. Reference lists from relevant articles and textbooks were searched and 12 specialist
journals were handsearched up to 1996. SELECTION CRITERIA: Randomised and quasi randomised controlled trials comparing antidepressants
with active placebos in people with depression. DATA COLLECTION AND ANALYSIS: Since many different outcome measures were used
a standard measure of effect was calculated for each trial. A subgroup analysis of inpatient and outpatient trials was conducted.
Two reviewers independently assessed whether each trial met inclusion criteria. MAIN RESULTS: Nine studies involving 751 participants
were included. Two of them produced effect sizes which showed a consistent and statistically significant difference in favour
of the active drug. Combining all studies produced a pooled estimate of effect of 0.39 standard deviations (confidence interval,
0.24 to 0.54) in favour of the antidepressant measured by improvement in mood. There was high heterogeneity due to one strongly
positive trial. Sensitivity analysis omitting this trial reduced the pooled effect to 0.17 (0.00 to 0.34). The pooled effect
for inpatient and outpatient trials was highly sensitive to decisions about which combination of data was included but inpatient
trials produced the lowest effects. REVIEWER'S CONCLUSIONS: The more conservative estimates from the present analysis found
that differences between antidepressants and active placebos were small. This suggests that unblinding effects may inflate
the efficacy of antidepressants in trials using inert placebos. Further research into unblinding is warranted.
Publication Types:
Meta-Analysis
Review
Review, Academic
PMID: 14974002 [PubMed - indexed for MEDLINE]
Ann Pharmacother. 2003 Dec;37(12):1891-9. Related Articles, Links
Meta-analysis of placebo rates in major depressive disorder trials.
Stolk P, Ten Berg MJ, Hemels ME, Einarson TR.
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht, Netherlands.
BACKGROUND: Placebo effects in major depressive disorder (MDD) have received much interest in the medical literature.
However, few quantitative analyses have been done in homogeneous populations.OBJECTIVE: To determine efficacy rates for placebo
in patients with MDD; to quantify the correlation between efficacy and publication year, as well as between placebo and drug
response rates.DESIGN: Searching MEDLINE (1966-December 2000), EMBASE (1998-February 2001), HealthSTAR (1975-December 2000),
and Cochrane (1980-December 2000) databases, randomized, placebo-controlled trials were retrieved including patients with
MDD as defined by Diagnostic and Statistical Manual of Mental Disorders, 3rd and 4th editions criteria, Hamilton Rating Scale
for Depression score >/=18 or Montgomery-Asberg Depression Rating Scale score >/=16, reporting successes as 50% decreases
in scores after 6-8 weeks of treatment. Response rates were summarized using a random effects meta-analysis for per protocol
(PP) and intent-to-treat (ITT) results.RESULTS: We included 24 of 134 potential studies examining 4459 patients, 1786 on placebo
and 2673 on an antidepressant. Placebo response rates were 45.5% (PP) and 26.9% (ITT). Correlations were significant between
year and rates (PP rho 0.448, p = 0.042; ITT rho 0.557; p = 0.006), but not for active drugs. Placebo and drug rates were
correlated (PP r 0.397, p = 0.020; ITT r 0.539; p = 0.002).CONCLUSIONS: These placebo rates confirm those reported previously,
but were from a homogeneous population. Although statistically significant, the correlation between drug and placebo rates
was lower than others reported. During the study period, placebo rates increased linearly; active drugs did not. Correlations
between placebo and drug response rates reflected moderate to strong effect sizes. We suggest that current methodology has
been unsuccessful in achieving unbiased double-blind conditions not influenced by extra-trial factors, including time.
Publication Types:
Meta-Analysis
PMID: 14632596 [PubMed - indexed for MEDLINE]
J Psychopharmacol. 2004 Jun;18(2):251-6. Related Articles, Links
Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials.
Taylor MJ, Carney SM, Goodwin GM, Geddes JR.
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
The objective of this review was to determine the effectiveness, adverse effects and acceptability of folate in the treatment
of depression. Electronic databases (Cochrane Controlled Trials Register and the Cochrane Collaboration Depression, Anxiety
and Neurosis Controlled Trials Register) and reference lists were searched, and authors, experts and pharmaceutical companies
contacted to identify randomized controlled trials that compared treatment with folic acid or 5'-methyltetrahydrofolic acid
to an alternative treatment, for patients with a diagnosis of depressive disorder. Three randomized trials (247 participants)
were included. Two studies assessed the use of folate in addition to other treatment, and found that adding folate reduced
Hamilton Depression Rating Scale (HDRS) scores on average by a further 2.65 points [95% confidence interval (CI) 0.38-4.93].
Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at 10 weeks (relative risk
0.47, 95% CI 0.24-0.92). The remaining study found no statistically significant difference when folate alone was compared
with trazodone. The identified trials did not find evidence of any problems with the acceptability or safety of folate. The
limited available evidence suggests folate may have a potential role as a supplement to other treatment for depression. It
is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency.
PMID: 15260915 [PubMed - in process]
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