Table 21Intervention, numbers of patients, and quality ratings of studies assessing adverse events

Author, YearInterventionsNResultsQuality rating
Tolerability and Discontinuation
Brambilla et al. 2005231Fluoxetine compared with SSRIs (SR)NRNo difference in discontinuation rates because of adverse eventsGood
Cipriani et al., 200530Fluoxetine compared with SSRIs (SR)14,391No differences in overall discontinuation ratesGood
Cipriani et al., 201032Sertraline compared with SSRIs (SR)NRHigher rates of diarrhea for sertralineGood
Cipriani et al., 200929Escitalopram compared with SSRIs (SR)NRSimilar rates of adverse eventsGood
Gartlehner et al. 2008225Venlafaxine compared with SSRIs3,416Higher rates of nausea and vomiting for venlafaxineGood
Girardi et al. 200928Duloxetine compared with escitalopram, fluoxetine, paroxetine, venlafaxineNRHigher rates of overall discontinuation and discontinuation due to adverse events for duloxetineGood
Greist et al., 2004226Pooled analysis: Duloxetine compared with Paroxetine compared with Fluoxetine2,345No differences in nausea between duloxetine and paroxetine, and duloxetine and fluoxetineN/A
Haffmans et al, 1996229Fluvoxamine compared with Paroxetine217Significantly more diarrhea and nausea with fluvoxamineFair
Kiev et al., 199780Fluvoxamine compared with Paroxetine60Significantly more sweating with paroxetineFair
Mackay et al., 1997, 1999227, 228Prescription
Event Monitoring
≥ 60,000Venlafaxine had highest rate of nausea and vomiting; paroxetine highest rate of sexual side effects; among SSRIs, most overall adverse events with fluvoxamineN/A
Meijer et al., 2002230Sertraline compared with SSRIs (OS)1251Significantly more diarrhea with sertralineFair
Pigott et al., 2007289Duloxetine compared with Escitalopram296Over 8 months higher discontinuation rates for duloxetine than for escitalopramFair
Rapaport et al., 199667Fluvoxamine compared with fluoxetine100Significantly more nausea with fluoxetineFair
Vanderkooy et al., 2002252Bupropion compared with paroxetine compared with sertraline compared with venlafaxine193Higher rates of sexual adverse events for paroxetine. Higher rates of gastrointestinal disorders for sertralineFair
Cardiovascular Events
Chen et al.,2008233Nested case- control study1086 casesIncreased risk of ischemic stroke for SSRIs

No excess risk for hemorrhagic stroke
Jick et al., 2008236Nested case-control study782 casesNo increased risk of idiopathic venous thromboembolism for SSRIsFair
Kharofa et al., 2007235Case-control study916 casesNo increased risk for hemorrhagic stroke for SSRIsFair
Martinez et al., 2010232Nested case- control study568 casesNo difference in sudden cardiac death or near death of venlafaxine compared with fluoxetine or citalopramFair
Trifirò et al., 2010234Nested case- control study996 casesCurrent use of SSRIs associated with increased risk of ischemic stroke compared with non-useGood
Changes in Weight
Benkert et al., 200090Mirtazapine compared with Paroxetine275Significant weight gain with mirtazapineFair
Fava et al., 200073Fluoxetine compared with Paroxetine compared with Sertraline284Highest weight gain with paroxetineFair
Kasper et al., 2009238Escitalopram vs. paroxetine (pooled data)777No differences in weight gain between escitalopram and paroxetineN/A
Maina et al. 2004237Open-label SSRIs149Highest weight gain with paroxetine, fluvoxamine, and citalopramFair
Schatzberg et al., 200289Mirtazapine compared with Paroxetine255Significant weight gain with mirtazapineFair
Vestergaard et al., 2008243SSRIs Case-control study124,655 casesIncreased risk of fracture for citalopram, fluoxetine, sertralineGood
Ziere et al., 2008244SSRIs Prospective cohort study7983SSRIs increased the risk for nonvertebral fracturesFair
Gastrointestinal Bleeding
Barbui et al., 2009240SSRIs Case-control study35,869No increased risk for gastrointestinal bleeding with SSRIsGood
de Abajo et al., 2008242SSRIs Case-control study11,321Increased risk of gastrointestinal tract bleeding with SSRIsFair
Targownik et al., 2009241SSRIs Case-control study70,142Increased risk of gastrointestinal tract bleeding with SSRIsFair
Sexual Dysfunction
Clayton et al., 2002255Cross-sectional survey6,297Highest risk for paroxetine and mirtazapine; lowest risk for bupropionN/A
Clayton et al., 2007256Duloxetine compared with Escitalopram114Significantly more sexual adverse events with escitalopramFair
Coleman et al., 1999115Bupropion compared with Sertraline364Significantly more sexual adverse events with sertralineFair
Coleman et al., 2001110Bupropion compared with Fluoxetine456Significantly more sexual adverse events with fluoxetineFair
Croft et al., 1999114Bupropion compared with Sertraline360No differencesFair
Ekselius et al., 2001250Citalopram compared with Sertraline308No differencesFair
Kennedy et al., 2006253Bupropion compared with Paroxetine141Significantly more sexual adverse events with paroxetineFair
Landen et al. 2005251Citalopram compared with Paroxetine119No differencesGood
Montejo et al., 2001254Prospective cohort study1,022Highest incidence of sexual dysfunction for citalopram, paroxetine and venlafaxine; lowest for mirtazapine and nefazodoneFair
Nieuwstraten et al, 2001108Bupropion compared with SSRIs (SR)1,332Significantly higher rate of sexual satisfaction in bupropion groupGood
Segraves et al., 2000128Bupropion compared with Sertraline248Significantly more sexual adverse events with sertralineFair
Acharya et al., 2006271Duloxetine compared with placebo (pooled data)2,996No difference in suicide riskFair
Aursnes et al., 2005263Paroxetine compared with placebo (pooled data)1,466Higher risk of suicides in patients on paroxetineFair
Barbui et al., 2009274SSRIs (SR of observational studies)➢ 200,000SSRIs increase risk of suicides in adolescents but decrease risk in adultsGood
Bridge et al., 2007283SSRIs (SR)5,310Higher risk of suicidality for SSRI-treated patientsGood
Didham et al. 2005280SSRIs57,000No difference in suicides or self-harm among citalopram, fluoxetine, and paroxetineFair
Fergusson et al., 2005278SSRIs compared with placebo (SR)87,650Higher risk of suicide attempts for SSRI-treated patientsGood
Gibbons et al., 2007260SSRIs (retrospective cohort study)226,866SSRIs have a protective effectFair
Gunnell et al., 20052582nd gen. AD compared with placebo (SR)40,000No differences in adultsGood
Hammad et al., 2006282SSRIs (SR)4,582Higher risk of suicidality for SSRI-treated patientsGood
Isacsson et al., 2005264SSRIs (Case-control)l41,279No increased riskFair
Jick et al., 2004267SSRIs (Case-control; database review)159,810No differencesN/A
Jick et al., 1995266Antidepressants (database review)172,598Significantly higher risk of suicide with fluoxetine and mianserin compared to dothiepinN/A
Khan et al., 2003268Antidepressants (database review)NRNo differencesN/A
Lopez-Ibor, 1993269Antidepressants (database review)4,686No differencesN/A
Martinez et al., 2005259Antidepressants (database review)146,095No differencesN/A
Nelson et al., 2007262Sertraline compared with placebo (secondary analysis of RCT data)752No difference in suicidal thoughts between sertraline and placeboFair
Olfson and Marcus, 2008273Anidepressants compared with no antidepressants1,368Antidepressants increase risk of suicides in adolescents but decrease risk in adultsGood
Pedersen et al., 2005270Escitalopram compared with placebo (retrospective cohort study)4,091Higher rate of self-harm in escitalopram than in placeboFair
Rahme et al., 2008275SSRIs (retrospective cohort study)128,229No increase of suicide death with SSRI useFair
Schneeweiss et al., 2010281Antidepressants (retrospective cohort study)20,906No differences in risks of suicidality among antidepressants in childrenGood
Schneeweiss et al., 2010277Antidepressants (retrospective cohort study)287,543No differences in risks of suicidality among antidepressants in adultsGood
Tiihonen et al., 2006265Antidepressants (retrospective cohort study)15,390Use of antidepressants was associated with an increased risk of attempted suicideFair
Tourian et al., 2010276Desvenlafaxine compared with placebo (pooled data analysis)2,950No difference in risk of suicidalityN/A
Valuck et al., 2004285Antidepressants (retrospective cohort study)24,119No difference in risk of suicide attemptsFair
Vanderburg et al., 2009272Sertraline compared with placebo (pooled analysis)19,923No increase in suicidality riskN/A
Vitiello et al., 2009152Fluoxetine compared with placebo(RCT)439Risk of suicidality in adolescents does not decrease over timeGood
Other Adverse Events
Alper et al., 2007248Analysis of FDA trials data33,885Seizures more common in bupropion than in other antidepressantsGood
Andersohn et al. 2009288Case control study11,206Long-term use of antidepressants in moderate or high daily doses was associated with an increased risk of diabetesFair
Buckley et al., 2002287Database analysis47,329Highest rate of fatal toxicity for venlafaxineN/A
Coogan et al., 2005290Case-control4,996No association between breast cancer and SSRIsFair
Dunner et al., 1998291Prospective observational3,100Rate of seizures for bupropion within range of other antidepressantsFair
Johnston et al., 1991292Prospective observational3,341Rate of seizures for bupropion within range of other antidepressantsFair
Strombom et al., 2008246Duloxetine compared with venlafaxine (Prescription Event Monitoring)60,052No difference in risk for hepatic injury between duloxetine and venlafaxineN/A
Whyte et al., 2003249Prospective observational538Seizures more common in venlafaxine overdose than TCA or SSRI overdoseGood

Abbreviations: SR, Systematic review

From: Results

Cover of Drug Class Review: Second-Generation Antidepressants
Drug Class Review: Second-Generation Antidepressants: Final Update 5 Report [Internet].
Gartlehner G, Hansen RA, Reichenpfader U, et al.
Portland (OR): Oregon Health & Science University; 2011 Mar.
Copyright © 2011 Oregon Health & Science University.

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