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The International Journal of... Feb 2014We examined whether noradrenergic and specific serotonergic antidepressants (NaSSAs: mirtazapine and mianserin), as augmentation therapy, have therapeutic potential for... (Meta-Analysis)
Meta-Analysis Review
We examined whether noradrenergic and specific serotonergic antidepressants (NaSSAs: mirtazapine and mianserin), as augmentation therapy, have therapeutic potential for schizophrenia treatment. A systematic review was conducted of PubMed, Cochrane Library and PsycINFO in December 2012 and meta-analyses of double-blind, randomized placebo-controlled trials were performed. Standardized mean difference (SMD), risk ratio (RR), number-needed-to-treat (NNT), number-needed-to-harm (NNH) and 95% confidence intervals (CI) were calculated. Results were across 12 studies and 362 patients were included (mirtazapine: seven trials and 221 patients; mianserin: five trials and 141 patients). NaSSA augmentation therapy was superior to placebo in overall symptoms (S.M.D. = -0.75, CI -1.24 to -0.26, p = 0.003, N = 11, n = 301), negative symptoms (S.M.D. = -0.88, CI -1.41 to -0.34, p = 0.001, N = 9, n = 240) and response rate (RR = 0.71, CI 0.57-0.88, p = 0.002, NNT = 4, p<0.00001, N = 6, n = 163). There was no significant difference in positive symptoms, depressive symptoms or discontinuation rate between NaSSAs and placebo treatments. In addition, no patients who received NaSSAs developed worsening psychosis during the study. For individual NaSSAs, mirtazapine was superior to placebo in overall symptoms (S.M.D. = 0.98, CI = -1.74 to -0.22, p = 0.01, N = 7, n = 194), negative symptoms (S.M.D. = -1.25, CI -1.88 to -0.62, p = 0.0001, N = 6, n = 172) and response rate (RR = 0.70, p = 0.04, NNT = 4, p = 0.0004, N = 4, n = 119). Moreover, NaSSAs were associated with reduced akathisia score (p < 0.00001) and extrapyramidal symptom scales (p = 0.01). However, NaSSAs caused drowsiness/sedation/somnolence compared with placebo (RR = 3.52, p = 0.002, NNT = 6, p = 0.01, N = 8, n = 209). Our results indicate that NaSSA (especially mirtazapine) augmentation therapy improved overall and negative symptoms in patients with schizophrenia. Because the included studies were small, the results should be treated with caution.
Topics: Adrenergic alpha-Antagonists; Antidepressive Agents; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin Antagonists
PubMed: 23823741
DOI: 10.1017/S1461145713000667 -
The Journal of Clinical Psychiatry Dec 2007To compare paroxetine with placebo and other antidepressants across multiple efficacy and tolerability outcomes. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To compare paroxetine with placebo and other antidepressants across multiple efficacy and tolerability outcomes.
DATA SOURCES
Searches were conducted in MEDLINE (1966-2004), EMBASE (1980-2004), CINAHL (1982-2004), all Evidence-Based Medicine Reviews (1991-2004), HealthSTAR (1975-2004), BIOSIS (1980-2004), and PsycINFO (1840-2004). Medical Subject Headings (MeSH) included "paroxetine" OR "Paxil" exploded. The searches were not restricted by language, publication type, or study design.
STUDY SELECTION
A study report was included if it described a randomized trial of paroxetine versus placebo or other antidepressants for patients with depressive disorders. Records were screened independently by 2 reviewers under the supervision of another reviewer.
DATA EXTRACTION
Three investigators abstracted data, including study design, trial characteristics, and psychiatric assessment tools, using a prespecified form. Two investigators assessed quality of reporting using Jadad's scale.
DATA SYNTHESIS
We included 62 unique randomized controlled trials. Paroxetine yielded consistently and significantly better remission (rate difference [RD]: 10% [95% CI = 6 to 14]), clinical response (RD: 17% [95% CI = 7 to 27]), and symptom reduction (effect size: 0.2 [95% CI = 0.1 to 0.3]) than placebo. Such consistency in the evidence base was not observed between paroxetine and other antidepressants. Pairwise comparisons of paroxetine and venlafaxine, mirtazapine, mianserin, or fluoxetine yielded inconsistent results across efficacy outcomes. Controlled-release paroxetine was the only antidepressant with significantly fewer dropouts due to adverse events than immediate-release paroxetine (RD: 5% [95% CI = 0.1 to 11]).
CONCLUSIONS
There were no significant and valid differences between paroxetine and other antidepressants to suggest that multiple modes of action improve clinical outcomes.
Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder; Female; Humans; Male; Middle Aged; Paroxetine; Placebos; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 18162015
DOI: 10.4088/jcp.v68n1204 -
Journal of Oral Rehabilitation Jul 2018The purpose of this study was to systematically review the literature for studies that investigated the association between use of psychotropic medications and presence...
The purpose of this study was to systematically review the literature for studies that investigated the association between use of psychotropic medications and presence of sleep bruxism (SB). Observational studies were selected in a two-phase process. Searches were performed on six electronic databases, and a grey literature search was conducted on three databases. SB diagnosis was based on questionnaires or clinical examinations; no polysomnography examinations were performed. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Analytical Cross-Sectional Studies. Overall quality of evidence was evaluated according to the Grading of Recommendations Assessment, Development and Evaluation criteria. Five analytical cross-sectional studies were included, evaluating antidepressants, anticonvulsants and psychostimulants. One study was judged as low risk of bias, three as moderate risk and one high risk. Antidepressants were evaluated in adult populations only; duloxetine (Odds Ratio [OR] = 2.16; 95% Confidence Interval [95% CI] = 1.12-4.17), paroxetine (OR = 3.63; 95% CI = 2.15-6.13) and venlafaxine (OR = 2.28; 95% CI = 1.34-3.86) were positively associated with SB risk. No increased odds of SB were observed considering use of citalopram, escitalopram, fluoxetine, mirtazapine and sertraline. With regard to anticonvulsants, only barbiturates were associated with SB in children (OR = 14.70; 95% CI = 1.85-116.90), while no increased odds were observed for benzodiazepine, carbamazepine and valproate. The only psychostimulant evaluated was methylphenidate, and an association with SB was observed in adolescents (OR = 1.67; 95% CI = 1.03-2.68). Findings from this SR suggested that medications such as duloxetine, paroxetine, venlafaxine, barbiturates and methylphenidate might be associated with SB; however, overall quality of evidence was considered very low, and therefore, caution is recommended.
Topics: Cross-Sectional Studies; Humans; Mental Disorders; Observational Studies as Topic; Polysomnography; Psychotropic Drugs; Sleep Bruxism
PubMed: 29663484
DOI: 10.1111/joor.12633 -
Journal of the American Geriatrics... Aug 2019To assess adverse effects of pharmacologic antidepressants for treatment of major depressive disorder (MDD) in adults 65 years of age or older. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To assess adverse effects of pharmacologic antidepressants for treatment of major depressive disorder (MDD) in adults 65 years of age or older.
DESIGN
Systematic review and meta-analysis.
SETTING
Specialist or generalist outpatient setting, rehabilitation facility, and nursing facilities.
PARTICIPANTS
Persons 65 years and older with MDD.
INTERVENTION
Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine compared with another antidepressant, placebo, or nonpharmacologic therapy.
MEASUREMENTS
Adverse events, arrhythmias, cognitive impairment, falls, fractures, hospitalization, mortality, QTc prolongation, serious adverse events, and withdrawals due to adverse events.
RESULTS
Nineteen randomized controlled trials and two observational studies were included. Most studies evaluated treatment of the acute phase (<12 wk) of MDD of moderate severity. SSRIs led to a statistically similar frequency of overall adverse events vs placebo (moderate strength of evidence [SOE]), but SNRIs caused more overall adverse events vs placebo (high SOE) during the acute treatment phase. Both SSRIs and SNRIs led to more study withdrawals due to adverse events vs placebo (SSRIs low SOE; SNRIs moderate SOE). Duloxetine led to a more falls vs placebo (moderate SOE) during 24 weeks of acute and continuation treatment of MDD.
CONCLUSION
In patients 65 years of age or older with MDD, treatment of the acute phase of MDD with SNRIs, but not SSRIs, was associated with a statistically greater number of overall adverse events vs placebo. SSRIs and SNRIs led to a greater number of study withdrawals due to adverse events vs placebo. Duloxetine increased the risk of falls that as an outcome was underreported in the literature. Few studies examined head-to-head comparisons, most trials were not powered to evaluate adverse events, and results of observational studies may be confounded. Comparative long-term studies reporting specific adverse events are needed to inform clinical decision making regarding choice of antidepressants in this population. J Am Geriatr Soc 67:1571-1581, 2019.
Topics: Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Major; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Observational Studies as Topic; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 31140587
DOI: 10.1111/jgs.15966 -
Frontiers in Neurology 2017Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of...
BACKGROUND
Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain.
METHODS
Systematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis.
RESULTS
Out of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects.
CONCLUSION
Our synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients' comorbidities and co-medication.
PubMed: 28769859
DOI: 10.3389/fneur.2017.00307 -
The Journal of Clinical Psychiatry Oct 2008Antidepressant-associated manic and hypomanic episodes have been reported in bipolar I disorder but are rare in major depressive disorder (MDD). Several lines of... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
Antidepressant-associated manic and hypomanic episodes have been reported in bipolar I disorder but are rare in major depressive disorder (MDD). Several lines of evidence suggest that bipolar II disorder is a distinct illness from bipolar I disorder and MDD. The risk of antidepressant-associated mood elevations (AAME) in bipolar II disorder relative to bipolar I disorder and MDD is unknown.
DATA SOURCES
We conducted a computer-aided MEDLINE search encompassing the dates 1949 to February 2008, using the keywords antidepressant and mania, antidepressant and hypomania, antidepressant and bipolar, fluoxetine and bipolar, fluvoxamine and bipolar, sertraline and bipolar, paroxetine and bipolar, citalopram and bipolar, escitalopram and bipolar, venlafaxine and bipolar, mirtazapine and bipolar, bupropion and bipolar, monoamine oxidase inhibitor and bipolar, phenelzine and bipolar, tranylcypromine and bipolar, tricyclic and bipolar, imipramine and bipolar, amitriptyline and bipolar, nortriptyline and bipolar, and desipramine and bipolar.
STUDY SELECTION
All prospective English-language studies, including randomized, controlled trials (RCTs), open-label studies, and naturalistic treatment reports, were eligible for inclusion. We located 13 studies, including 7 RCTs, that reported rates of antidepressant-associated mood elevations in bipolar I disorder versus bipolar II disorder, and 5, including 4 RCTs, that reported rates in bipolar II disorder versus MDD.
DATA EXTRACTION
Data were combined to estimate mean switch rates and subjected to meta-analysis to determine the relative risks of antidepressant-associated mood elevations in bipolar I disorder versus bipolar II disorder and in bipolar II disorder versus MDD.
DATA SYNTHESIS
The mean rates of antidepressant-associated mood elevations in studies comparing bipolar I disorder and bipolar II disorder were 14.2% and 7.1%, respectively, in acute trials (less than 16 weeks), and 23.4% and 13.9%, respectively, in maintenance studies. The mean rates in reports comparing bipolar II disorder and MDD were 8.1% and 1.5%, respectively, in acute trials, and 16.5% and 6.0%, respectively, in maintenance studies. The relative risk (RR) of antidepressant-associated mood elevations was greater in bipolar I disorder than bipolar II disorder (RR = 1.78, 95% CI = 1.24 to 2.58, p = .002), and higher in bipolar II disorder than MDD (RR = 2.77, 95% CI = 1.26 to 6.09, p = .01). Mood elevations occurred almost exclusively into hypomania in MDD and bipolar II disorder, while patients with bipolar I disorder experienced manias and hypomanias with similar frequencies.
CONCLUSIONS
The risk of antidepressant-associated mood elevations in bipolar II disorder is intermediate between that in bipolar I disorder and MDD.
Topics: Affective Symptoms; Antidepressive Agents; Bipolar Disorder; Depressive Disorder, Major; Humans; Risk
PubMed: 19192442
DOI: 10.4088/jcp.v69n1009 -
Human Psychopharmacology Dec 2005Given the relationship between sleep and depression, there is inevitably going to be an effect of antidepressants on sleep. Current evidence suggests that this effect... (Meta-Analysis)
Meta-Analysis Review
Given the relationship between sleep and depression, there is inevitably going to be an effect of antidepressants on sleep. Current evidence suggests that this effect depends on the class of antidepressant used and the dosage. The extent of variation between the effects of antidepressants and sleep may relate to their mechanism of action. This systematic review examines randomised-controlled trials (RCTs) that have reported the effect that antidepressants appear to have on sleep. RCTs are not restricted to depressed populations, since several studies provide useful information about the effects on sleep in other groups. Nevertheless, the distinction is made between those studies because the participant's health may influence the baseline sleep profiles and the effect of the antidepressant. Insomnia is often seen with monoamine oxidase inhibitors (MAOIs), with all tricyclic antidepressants (TCAs) except amitriptyline, and all selective serotonin reuptake inhibitors (SSRIs) with venlafaxine and moclobemide as well. Sedation has been reported with all TCAs except desipramine, with mirtazapine and nefazodone, the TCA-related maprotiline, trazodone and mianserin, and with all MAOIs. REM sleep suppression has been observed with all TCAs except trimipramine, but especially clomipramine, with all MAOIs and SSRIs and with venlafaxine, trazodone and bupropion. However, the effect on sleep varies between compounds within antidepressant classes, differences relating to the amount of sedative or alerting (insomnia) effects, changes to baseline sleep parameters, differences relating to REM sleep, and the degree of sleep-related side effects.
Topics: Antidepressive Agents; Humans; Sleep
PubMed: 16229049
DOI: 10.1002/hup.726 -
Journal of Clinical Psychopharmacology Apr 2012The objective was to perform a systematic review and meta-analysis of studies that assessed the effect of the combination of antidepressants from the beginning of the... (Comparative Study)
Comparative Study Meta-Analysis Review
The objective was to perform a systematic review and meta-analysis of studies that assessed the effect of the combination of antidepressants from the beginning of the treatment of major depressive disorder. Studies were retrieved from PubMed (1966 to August 2010), Cochrane Library (August 2010), Embase (1980 to August 2010), PsycINFO (1980 to August 2010), Lilacs (1982 to August 2010), clinical trials registry, thesis database (www.capes.gov.br), and secondary references. All randomized controlled trials that compared a combination of antidepressants with a single antidepressant from the beginning of the treatment of major depressive disorder in adults were included. Data analysis was performed using the Review Manager 5.0. Of 3492 studies retrieved, five satisfied the inclusion criteria. In one study, only data about dropouts were included. Antidepressant combination was shown to be better than a single antidepressant considering remission (relative risk [RR], 2.71; 95% confidence interval [CI], 1.69-4.35) and response (RR, 1.55; 95% CI, 1.21-1.97). Mirtazapine plus selective serotonin reuptake inhibitor (SSRI) was superior to an isolated SSRI for remission (RR, 1.88; 95% CI, 1.06-3.33). Tricyclic antidepressant plus SSRI was superior to SSRI for remission and response (RR, 8.58; 95% CI, 1.70-43.32 and RR, 1.78; 95% CI, 1.07-2.93, respectively). There was no difference between combined and monotherapy groups in dropouts owing to adverse effects. The results suggest that antidepressant combination is more efficient than a single antidepressant without a significant decrease in tolerability. However, the small number of clinical trials and methodological problems precludes definitive conclusions.
Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Remission Induction; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 22367652
DOI: 10.1097/JCP.0b013e318248581b -
The Cochrane Database of Systematic... Jan 2010The National Institute for Health and Clinical Excellence clinical practice guideline on the treatment of depressive disorder recommended that selective serotonin... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The National Institute for Health and Clinical Excellence clinical practice guideline on the treatment of depressive disorder recommended that selective serotonin reuptake inhibitors should be the first-line option when drug therapy is indicated for a depressive episode. Preliminary evidence suggested that sertraline might be slightly superior in terms of effectiveness.
OBJECTIVES
To assess the evidence for the efficacy, acceptability and tolerability of sertraline in comparison with tricyclics (TCAs), heterocyclics, other SSRIs and newer agents in the acute-phase treatment of major depression.
SEARCH STRATEGY
MEDLINE (1966 to 2008), EMBASE (1974 to 2008), the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials up to July 2008. No language restriction was applied. Reference lists of relevant papers and previous systematic reviews were hand-searched. Pharmaceutical companies and experts in this field were contacted for supplemental data.
SELECTION CRITERIA
Randomised controlled trials allocating patients with major depression to sertraline versus any other antidepressive agent.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data. Discrepancies were resolved with another member of the team. A double-entry procedure was employed by two reviewers. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy (the number of patients who responded or remitted), acceptability (the number of patients who failed to complete the study) and tolerability (side-effects).
MAIN RESULTS
A total of 59 studies, mostly of low quality, were included in the review, involving multiple treatment comparisons between sertraline and other antidepressant agents. Evidence favouring sertraline over some other antidepressants for the acute phase treatment of major depression was found, either in terms of efficacy (fluoxetine) or acceptability/tolerability (amitriptyline, imipramine, paroxetine and mirtazapine). However, some differences favouring newer antidepressants in terms of efficacy (mirtazapine) and acceptability (bupropion) were also found. In terms of individual side effects, sertraline was generally associated with a higher rate of participants experiencing diarrhoea.
AUTHORS' CONCLUSIONS
This systematic review and meta-analysis highlighted a trend in favour of sertraline over other antidepressive agents both in terms of efficacy and acceptability, using 95% confidence intervals and a conservative approach, with a random effects analysis. However, the included studies did not report on all the outcomes that were pre-specified in the protocol of this review. Outcomes of clear relevance to patients and clinicians were not reported in any of the included studies.
Topics: Antidepressive Agents; Depression; Humans; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome
PubMed: 20091586
DOI: 10.1002/14651858.CD006117 -
The Cochrane Database of Systematic... Dec 2011Mirtazapine has a unique mechanism of antidepressive action and is one of the commonly used antidepressants in clinical practice. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Mirtazapine has a unique mechanism of antidepressive action and is one of the commonly used antidepressants in clinical practice.
OBJECTIVES
The aim of the present review was to assess the evidence on the efficacy and acceptability of mirtazapine compared with other antidepressive agents in the acute-phase treatment of major depression in adults.
SEARCH METHODS
We searched the Cochrane Collaboration Depression, Anxiety and Neurosis review group's specialised register (CCDANCTR), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years to April 2011), EMBASE, (1980 to July 2011) MEDLINE (1950 to July 2011) and PsycINFO (1974 to July 2011). Reference lists of the reports of relevant studies were checked and experts in the field contacted. The review was not limited to English-language articles.
SELECTION CRITERIA
Randomised controlled trials (RCTs) allocating participants with major depression to mirtazapine versus any other antidepressive agent.
DATA COLLECTION AND ANALYSIS
Two authors independently checked eligibility and extracted data on an intention-to-treat basis. The primary outcome was response to treatment. The secondary outcomes included dropouts and individual adverse events.Meta-analyses were conducted using the random-effects model.
MAIN RESULTS
A total of 29 RCTs (n = 4974), mostly following up the participants for six weeks in outpatient clinics and inadequately reporting the risk of bias, were included. In comparison with tricyclic antidepressants (10 trials, n = 1553) there was no robust evidence to detect a difference between mirtazapine and tricyclics in terms of response at two weeks (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.64 to 1.13) or at the end of acute-phase treatment (at 6 to 12 weeks) (OR 0.89, 95% CI 0.72 to 1.10). In comparison with selective serotonin reuptake inhibitors (SSRIs) (12 trials, n = 2626) mirtazapine was significantly more effective at two weeks (OR 1.57, 95% CI 1.30 to 1.88) and at the end of acute-phase treatment (OR 1.19, 95% CI 1.01 to 1.39). Mirtazapine was significantly more effective than a serotonin-noradrenaline reuptake inhibitor (venlafaxine only, two trials, n = 415) at two weeks (OR 2.29, 95% CI 1.45 to 3.59) and at the end of acute-phase treatment (OR 1.53, 95% CI 1.03 to 2.25).In terms of dropouts, there was no robust evidence to detect a difference between mirtazapine and other antidepressants. Mirtazapine was more likely to cause weight gain or increased appetite and somnolence than SSRIs but less likely to cause nausea or vomiting and sexual dysfunction.
AUTHORS' CONCLUSIONS
Some statistically significant and possibly clinically meaningful differences between mirtazapine and other antidepressive agents were found for the acute-phase treatment of major depression. Mirtazapine is likely to have a faster onset of action than SSRIs during the acute-phase treatment. Dropouts occur similarly in participants treated with mirtazapine and those treated with other antidepressants, although the adverse event profile of mirtazapine is unique.
Topics: Adult; Antidepressive Agents; Antidepressive Agents, Tricyclic; Cyclohexanols; Depression; Humans; Mianserin; Mirtazapine; Randomized Controlled Trials as Topic; Venlafaxine Hydrochloride
PubMed: 22161405
DOI: 10.1002/14651858.CD006528.pub2