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Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An
Update of the 2007 Comparative Effectiveness Review
First Last, Credentials
Accreditation StatementPhysician Credit Designation StatementPRIME Education, Inc. (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. PRIME® designates this live activity for a maximum of .50 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity.Physician Assistant Accreditation StatementAAPA accepts AMA Category 1 CME Credit™ for the PRA from organizations accredited by ACCME.Nurse Practitioner Accreditation StatementPRIME Education, Inc. (PRIME®) is accredited by the American Academy of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 060815. This program is accredited for .50 contact hour. Program ID# CER38.This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standards.Nurse Accreditation StatementPRIME Education, Inc. (PRIME®) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. PRIME® designates this activity for .50 contact hour.California Nurse Accreditation StatementPRIME® designates this educational activity for .50 contact hour for California nurses. PRIME® is accredited as an approver of continuing education in nursing by the California Board of Registered Nursing.
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Disclosure Information
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Bradley N Gaynes, MD, MPH Planner None None None None None None None
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Merck for unbranded presentations re:
federally supported research about
approaches to reduce hospital readmissions
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Pamela Feinberg-Rivkin, RN, BSN, CCM, CRRN, ABDA, QRP Reviewer
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Learning Objectives
Upon completion of this activity, the participant is expected to be able to:– Compare the effectiveness and efficacy of
antidepressants in treating depressive symptoms in adults
– Assess the benefits and harms of antidepressants among certain adult patient subgroups
– Apply the findings of the systematic review to improve outcomes for adult patients through patient-centered care
Background: Depression
• Depressive disorders:• Major depressive disorder
(MDD)• Dysthymia• Subsyndromal depression
(including minor depression)
• Most prevalent: MDD• Affecting 16% (lifetime) of
US adults• Economic burden (2000):
$83.1 billion – 30% of cost is direct medical expenses
Egan BM, et al. JAMA. 2010;303:2043-2050. Law, MR et al. BMJ. 2003;326:1427-1431.
• Pharmacotherapy management• 1st generation antidepressants
• Tricyclic antidepressants• Monoamine oxidase inhibitors
• 2nd generation antidepressants• Selective serotonin reuptake
inhibitors• Selective serotonin and
norepinephrine reuptake inhibitors
• Other 2nd-generation antidepressants
Pharmacotherapy
• Efficacy of 1st and 2nd generation antidepressant mediations is similar, however:
• 1st generation antidepressants often• Produce multiple side effects patients find intolerable• Have risk for harm when taken in overdose or in
combination with certain other meds
• 2nd generation antidepressants are the focus of this review because they• Have relatively favorable side-effect profile• Play a prominent role in management of patients with MDD
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Phases of Treatment for Clinical Depression
Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52 Suppl:28-34.
TIME
Episode of Depression
Baseline
ClinicalDepression
TreatmentBegins
SOMESYMPTOMS
OFDEPRESSION
Response
Remission Sustained Remission
Relapse Recurrence
UnresolvedSymptoms
Acutephase
Continuationphase
Maintenancephase
INC
RE
AS
ED
SE
VE
RIT
Y
6-12 weeks 4-9 months ≥ 1 year
2nd Generation Antidepressants in U.S.Generic Name Trade Name* Class Labeled Uses Generic $† Brand $†
Bupropion‡ Wellbutrin, Wellbutrin SR, Wellbutrin XL
Other MDD, SAD 53-166 235-499
Citalopram‡ Celexa SSRI MDD 31-38 127-143
Desvenlafaxine Pristiq SSRI MDD - 157
Duloxetine Cymbalta SSRI MDD, GAD, neuropathic pain, fibromyalgia - 166-181
Escitalopram Lexapro SSRI MDD, GAD - 121-125
Fluoxetine‡ Prozac, Prozac Weekly SSRI MDD, OCD, PMDD, panic d/o, bulimia nervosa 22-136 176-449
Mirtazapine‡ Remeron, Remeron Soltab
Other MDD 44-77 124-190
Nefazodone‡ Serzone Other MDD - 65-70
Paroxetine‡ Paxil, Paxil CR SSRI MDD, OCD, panic d/o, social anxiety d/o, GAD, PTSD, PMDD§
20-115 130-163
Sertraline‡ Zoloft SSRI MDD, OCD, panic d/o, PTSD, PMDD, social anxiety d/o
28-29 146-152
Trazodone‡ Desyrel Other MDD NR NR
Venlafaxine‡ Effexor, Effexor XR SSRI MDD, GAD, panic d/o, social anxiety d/o II 88-129 168-193
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Key Questions: KQ1a – KQ2b• Do commonly used medications for depression differ in efficacy or
effectiveness in treating depressive symptoms? (KQ1a)• If a patient has responded to one agent in the past, is that agent better
than current alternatives at treating depressive symptoms? (KQ1b)• Are there any differences in efficacy or effectiveness between immediate-
release and extended-release formulations of second-generation antidepressants? (KQ1c)
• For responders to antidepressant treatment, do 2nd-generation antidepressants differ in efficacy or effectiveness for preventing relapse (i.e., continuation phase) or recurrence (i.e., maintenance phase) when a patient continues the drug they initially responded to or switches to a different antidepressant? (KQ2a)
• For adults with a depressive syndrome that has not responded to acute antidepressant treatment or has relapsed (continuation phase) or recurred (maintenance phase), do alternative second-generation antidepressants differ in their efficacy or effectiveness? (KQ2b)
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
.
Key Questions: KQ3-KQ5• With accompanying symptoms such as anxiety, insomnia, and
neurovegetative symptoms, do medications or combinations of medications differ in efficacy or effectiveness for treating the depressive episode or for treating the accompanying symptoms? (KQ3)
• For adults with a depressive syndrome, do commonly used antidepressants differ in safety, adverse events, or adherence? (KQ4a)
• Are there any differences in safety, adverse events, or adherence between immediate-release and extended-release formulations of second-generation antidepressants? (KQ4b)
• How do the efficacy, effectiveness, or harms of treatment with antidepressants for a depressive syndrome differ for the following subpopulations?– Elderly or very elderly patients– Other demographic groups (defined by
age, ethnic or racial group, and sex)– Patients with medical comorbidities (e.g.,
IHD, cancer)
– Patients with psychiatric and behavioral comorbidities (e.g., substance abuse disorders)
– Patients taking other medications
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
.
Framework for the Comparative Effectiveness Update of Second-Generation Antidepressants
KQ1, KQ3Acute Phase
• Response• Remission
Final Health Outcomes
• Quality of Life• Functional
Capacity
KQ2, KQ3Continuation
Phase• Maintenance
of response• Maintenance
of remission
Adverse effects of treatment
Second-Generation Antidepressants
Treatment for MDD, dysthymia, orsubsyndromaldepressivedisorders
KQ4
KQ1, KQ2, KQ3, KQ5Intermediate Outcomes
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Grading the Strength of Evidence• Ratings based on GRADE(Grading of Recommendations
Assessment, Development, and Evaluation) framework• Considerations: number of studies, the size of the studies,
strength of study design, and the quality of individual studies• Strength of evidence classified into 4 categories:
e
High High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
Low Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient Evidence is either unavailable or does not permit estimation of an effect.
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Study DesignId
entifi
catio
nSc
reen
ing
Elig
ibili
tyIn
clud
ed
6,353 identified (3,722 records remaining after eliminating duplicates)
3,722 abstracts screened
6,186 records from database search
167 records from other sources
2,265 excluded
1,457 full-text articles assessed for eligibility
228 studies (267 articles) included in qualitative synthesis
92 studies included in quantitative synthesis
• Strength of evidence grades (high, moderate, low, or insufficient) based on methods guidance for the EPC program; outcomes for which we have no studies are designated no evidence.
• Good, fair, or poor designations relate to quality grades given to each study; see Methods chapter of main report. We provide the designations only for good (or poor) studies; the remaining studies are all of fair quality.
1,190* full-text articles excluded:• 7 Foreign languages • 10 Too short of duration• 84 Wrong population• 142 Wrong drug• 197 Wrong outcome• 260 Wrong publication• 279 Does not address
outcomes of interest • 464 Wrong design• 79 Poor quality* Multiple exclusion reasons are possible for each article
Overview of Findings of 2nd-Generation Antidepressants• Generally, 2nd-generation antidepressants have
similar effectiveness– 37% of patients with no improvement– 53% had only partial improvement– 25% - 33% improved with addition or substitution of a
different drug if the first drug = no improvement
• These medications worked at different rates – 7 studies funded by the manufacturer of mirtazapine
suggested that it worked faster than citalopram, fluoxetine, paroxetine, or sertraline
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Overview of Findings of 2nd- Generation Antidepressants• Average of 63% experienced ≥ 1 side effect
– Most common are nausea and vomiting, constipation, diarrhea, dizziness, headache, and sleeplessness
• Venlafaxine, an SNRI, associated with a higher incidence of nausea and vomiting than SSRIs.
• Venlafaxine more likely than SSRIs to be discontinued due to adverse events, but less likely to be discontinued because of lack of efficacy
• Sertraline more likely to cause diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, or venlafaxine
SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Overview of Findings of 2nd- Generation Antidepressants• Mirtazapine led to higher weight gains than fluoxetine,
paroxetine, venlafaxine, or trazodone. • Trazodone showed higher rates of sleepiness than bupropion,
fluoxetine, mirtazapine, paroxetine, or venlafaxine.• Paroxetine and venlafaxine had the highest rates of
discontinuation syndrome—a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRIs or SNRIs. Fluoxetine produced the lowest rates of the syndrome.
• Bupropion less likely to cause sexual dysfunction than fluoxetine, paroxetine, or sertraline.
• Paroxetine had higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline.
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Overview of Findings of 2nd-Generation Antidepressants• Efficacy among all of the 2nd-generation medications did not
differ substantially for treatment of depression in patients with accompanying anxiety
• Efficacy among all of the medications did not differ between people older than 55 years or those with type 2 diabetes.
• No evidence addressed how 2nd-generation antidepressants compare when a patient responds to one agent and then is required to switch to a different agent (e.g., because of changes in health insurance benefits).
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ 1a: Major Depressive Disorder
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy Moderate 61 head-to head trials and 31 placebo-controlled trials indicate no substantial differences in efficacy exist among 2nd-generation antidepressants
Comparative effectiveness
Moderate 3 effectiveness trials (1 good) and indirect evidence from efficacy trials indicate no substantial differences in effectiveness among 2nd-generation antidepressants
Quality of life Moderate 18 trials indicate efficacy with respect to quality of life does not differ among 2nd –generation antidepressants
Onset of action Moderate • 7 trials suggest mirtazapine has significantly faster onset of action than citalopram, fluoxetine, paroxetine, and sertraline. Whether this difference can be extrapolated to other 2nd-generation antidepressants is unclear.
• Most other trials do not indicate a faster onset of action of one 2nd-generation antidepressant compared with another
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ 1a: Dysthymia
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy Insufficient • No head-to-head evidence exists • 5 placebo- controlled trials were insufficient to draw
conclusions about comparative efficacyComparative effectiveness
Insufficient No head-to-head evidence exists. • One effectiveness trial provides mixed evidence about
paroxetine versus placebo• patients older than 60 showed greater improvement
on paroxetine• those younger than 50 did not show any difference
Quality of life Insufficient No Evidence
Onset of action Insufficient No Evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ 1a: Subsyndromal Depression
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy Low • 1 nonrandomized, open-label trial did not detect any difference between citalopram and sertraline
• Results from 2 placebo-controlled trials were insufficient to draw conclusions
Comparative effectiveness Insufficient No Evidence
Quality of life Insufficient No Evidence
Onset of action Insufficient No Evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ 1b: Greater Efficacy/Effectiveness with Previously Effective Medications
Outcome of Interest Strength of Evidence
Findings
Major depressive disorder Insufficient No Evidence
Dysthymia Insufficient No Evidence
Subsyndromal depression Insufficient No Evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ1c: Efficacy/Effectiveness - IR vs. XR
Disorder, and Outcome of Interest
Strength of Evidence
Findings
Major depressive disorder
Moderate
• 2 trials indicate no differences in response to treatment exist between paroxetine IR & paroxetine CR
• 2 trials did not detect significant differences in maintenance of response and remission between fluoxetine daily and fluoxetine weekly
Low 1 trial reported higher response rates for venlafaxine XR than venlafaxine IR
Dysthymia Insufficient No Evidence
Subsyndromal depression
Insufficient No Evidence
CR = controlled release; IR = immediate release; XR = extended release
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ2a: Maintenance of Response or Remission
Disorder, and Outcome of Interest
Strength of Evidence
Findings
Continuing initial medications -----------------------------------------------------------------------
Comparative efficacy Moderate 6 efficacy trials and one naturalistic study; no significant differences exist between escitalopram and desvenlafaxine, escitalopram and paroxetine, fluoxetine and sertraline, fluoxetine and venlafaxine, fluvoxamine and sertraline, and trazodone and venlafaxine for preventing relapse or recurrence.
Comparative effectiveness
Insufficient No Evidence
Switching medications --------------------------------------------------------------------------------Comparative efficacy Insufficient No Evidence
Comparative effectiveness
Insufficient No Evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ2b: Achieving Response in Unresponsive or Recurrent Disease
Disorder, and Outcome of Interest
Strength of Evidence
Findings
Comparative efficacy Low 4 trials suggest no differences or only modest differences between SSRIs and venlafaxine• Numerical trends favored venlafaxine over comparator
drugs in three of these trials• Differences were statistically significant in only one
trial, which compared venlafaxine with paroxetineComparative effectiveness
Low 2 effectiveness studies are conflicting • 1 trial rated good; no significant differences in
effectiveness exist among bupropion SR, sertraline, and venlafaxine XR
• 1 effectiveness trial found venlafaxine to be modestly superior to citalopram, fluoxetine, mirtazapine, paroxetine, and sertraline
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Anxiety
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy for depression
Moderate 5 head-to-head trials suggest that efficacy does not differ substantially for treatment of depression in patients with accompanying anxiety.
Comparative effectiveness for depression
Insufficient No evidence
Comparative efficacy for anxiety
Moderate 8 head-to-head trials and three placebo-controlled trials suggest that no substantial differences in efficacy exist among 2nd-generation antidepressants for treatment of accompanying anxiety symptoms.
Comparative effectiveness for anxiety
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Insomnia
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy for depression
Insufficient Results from 1 head-to-head study are insufficient to draw conclusions about the comparative efficacy for treating depression in patients with coexisting insomnia
Comparative effectiveness for depression
Insufficient No evidence
Comparative efficacy for insomnia
Low 5 head-to-head trials suggest that no substantial differences in efficacy exist among second-generation antidepressants for treatment of accompanying insomnia. Results are limited by study design; differences in outcomes are of unknown clinical significance
Comparative effectiveness for insomnia
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Low Energy
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy for depression
Insufficient • Results from one placebo-controlled trial of bupropion XL are insufficient to draw conclusions about treating depression in patients with coexisting low energy
• Results from head-to-head trials are not availableComparative effectiveness for depression
Insufficient No evidence
Comparative efficacy for low energy
Insufficient • Results from one placebo-controlled trial of bupropion XL are insufficient to draw conclusions about treating low energy in depressed patients
• Results from head-to-head trials are not availableComparative effectiveness for low energy
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Melancholia
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy for depression
Insufficient • Results from 2 head-to-head trials are insufficient to draw conclusions about treating depression in patients with coexisting melancholia
• Results are inconsistent across studiesComparative effectiveness for depression
Insufficient No evidence
Comparative efficacy for melancholia
Insufficient No evidence
Comparative effectiveness for melancholia
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Pain
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy for depression
Insufficient • 2 placebo-controlled trials are conflicting regarding the superiority of duloxetine over placebo.
• Results from head-to-head trials are not availableComparative effectiveness for depression
Insufficient No evidence
Comparative efficacy for pain
Moderate Evidence from 1 systematic review, 2 head-to-head trials (one poor), and 5 placebo-controlled trials indicate no difference in efficacy between paroxetine and duloxetine.
Comparative effectiveness for pain
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ3: Treatment of Depression in Patients With Psychomotor Change
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy for depression
Insufficient Results from 1 head-to-head trial are insufficient to draw conclusions about the comparative efficacy for treating depression in patients with coexisting psychomotor change
Comparative effectiveness for depression
Insufficient No evidence
Comparative efficacy for psychomotor change
Moderate No evidence
Comparative effectiveness for psychomotor change
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Somatization
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy for depression
Insufficient No evidence
Comparative effectiveness for depression
Insufficient No evidence
Comparative efficacy for somatization
Moderate Results from 1 head-to-head trial • Are insufficient to draw conclusions about
comparative efficacy for treating somatization • Results indicate similar improvement in somatization
Comparative effectiveness for somatization
Insufficient Evidence from 1 open-label head-to-head trial • is insufficient to draw conclusions about comparative
efficacy for treating coexisting somatization in depressed patients
• Results indicate no difference in effectiveness
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ4a: Risk of Harms – General Tolerability
Outcome of Interest Strength of Evidence
Findings
Adverse-events profiles
High 92 efficacy trials and 48 studies of experimental or observational design show results are similar among 2nd- generation antidepressants. The incidence of specific adverse events differs across antidepressants
Comparative risk of nausea and vomiting
High Meta-analysis of 15 studies indicates that venlafaxine has a higher rate of nausea and vomiting than SSRIs as a class.
Comparative risk of weight change
High 7 trials indicate that mirtazapine leads to higher weight gains than citalopram, fluoxetine, paroxetine, & sertraline
Comparative risk of GI adverse events
Moderate • 15 studies indicate that sertraline has a higher incidence of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine
• Results from 1 systematic review confirm some of these findings
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ4a: Risk of Harms – General Tolerability continued
Outcome of Interest Strength of Evidence
Findings
Comparative risk of somnolence
Moderate 6 trials indicate that trazodone has a higher rate of somnolence than bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine
Comparative risk of discontinuation syndrome
Moderate A good systematic review indicates that • paroxetine and venlafaxine have the highest rates of
discontinuation syndrome• fluoxetine has the lowest
Comparative risk of discontinuation of treatment
High Meta-analyses of numerous efficacy trials indicate that overall discontinuation rates are similar. • Duloxetine and venlafaxine have higher rate of
discontinuations due to adverse events than SSRIs as a class
• Venlafaxine has a lower rate of discontinuations because of lack of efficacy than SSRIs as a class
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ4a: Risk of Harms – Severe Adverse Events
Outcome of Interest Strength of Evidence
Findings
Comparative risk of suicidality (suicidal thoughts and behavior)
Insufficient 11 observational studies (2 good quality), 5 meta-analyses or systematic reviews (4 good), and 1 systematic review yield conflicting information about the comparative risk of suicidality
Comparative risk of sexual dysfunction
High 6 trials indicate that bupropion causes significantly less sexual dysfunction than escitalopram, fluoxetine, paroxetine, and sertraline
Moderate Among SSRIs, paroxetine has the highest rates of sexual dysfunction
Comparative risk of seizures
Insufficient 3 studies (1 good observational design) yield conflicting information about the comparative risk of seizures
Cardiovascular events
Insufficient 1 good observational study and 1 pooled analysis yield non-comparative or conflicting information about the comparative risk of CV events
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ4a: Risk of Harms – Severe Adverse Events continued
Outcome of Interest Strength of Evidence
Findings
Comparative risk of hyponatremia
Insufficient • No trials or observational studies assessing hyponatremia met criteria for inclusion in this review
• 1 cohort study not meeting inclusion criteria suggested that hyponatremia was more common in elderly patients treated with various antidepressants than in placebo-treated patients
Comparative risk of hepatotoxicity
Insufficient • Evidence from existing studies is insufficient to draw conclusions about the comparative risk of hepatotoxicity
• Weak evidence indicates that nefazodone might have an increased risk of hepatotoxicity
Comparative risk of serotonin syndrome
Insufficient • No trials or observational studies assessing serotonin syndrome were included in this review
• Numerous case reports of this syndrome exist but were not included in this review
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ4a: Risk of Harms – Adherence
Outcome of Interest Strength of Evidence
Findings
Comparative adherence in efficacy studies
Moderate Efficacy studies indicate no differences in adherence
Comparative adherence in effectiveness studies
Insufficient Evidence from existing studies is insufficient to draw conclusions about adherence in real-world settings
Comparative persistence
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ4b: Differences of Harms – MDD
Outcome of Interest Strength of Evidence
Findings
Comparative risk of harms
Moderate Findings from 1 trial each indicate that no differences in harms exist between fluoxetine daily and fluoxetine weekly or between venlafaxine IR and venlafaxine XR.
Low 1 trial provides evidence that paroxetine IR leads to higher rates of nausea than paroxetine CR
Comparative adherence
Low 1 trial provides evidence that fluoxetine weekly has better adherence rates than fluoxetine daily.
Comparative persistence
Low Evidence from 1 observational study indicates that prescription refills are more common with the extended-release than the immediate-release formulation of bupropion
Dysthymia Insufficient No evidence
Subsyndromal depression
Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ5: Subgroups– Age
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy
Moderate 11 trials indicate efficacy does not differ substantially among 2nd-generation antidepressants for treating MDD in patients age 60 years or older
Insufficient • No head-to-head evidence found for dysthymia or subsyndromal depression
• Results from 1 good placebo-controlled trial showed no difference between fluoxetine and placebo
Comparative effectiveness
Insufficient No evidence in older patients with MDD
Insufficient 1 effectiveness study showed greater improvement with paroxetine vs. placebo in dysthymia patients older than 60 years; insufficient evidence to draw conclusions on comparative effectiveness
Comparative harms
Low 6 studies indicate adverse events may differ somewhat across 2nd-generation antidepressants in older adults.
Insufficient No head-to-head studies were found for dysthymia or subsyndromal depression.
Summary of Findings, KQ5: Subgroups– Sex
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy Insufficient No evidence
Comparative effectiveness
Insufficient No evidence
Comparative harms Low 2 trials suggest differences between men and women in sexual side effects
Subgroups– Race or EthnicityComparative efficacy Insufficient No evidence
Comparative effectiveness
Insufficient No evidence
Comparative harms Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Summary of Findings, KQ5: Subgroups– Comorbidities
Outcome of Interest Strength of Evidence
Findings
Comparative efficacy
Low• A subgroup analysis of 1 trial indicates significantly
greater response with venlafaxine XR than fluoxetine in patients with MDD and comorbid generalized anxiety disorder
Insufficient
• Placebo-controlled trials assessed efficacy in patients with the following comorbidities: alcohol/substance abuse, Alzheimer’s disease/dementia, arthritis, diabetes, HIV/AIDS, multiple sclerosis, stroke, and vascular disease
• No head-to-head evidence exists on comparative efficacy
Comparative effectiveness
Insufficient No evidence
Comparative harms Insufficient No evidence
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Clinical Bottom Line:Limitations• Most trials were conducted in highly selected
populations• Publication bias might affect the estimates of
some comparisons• Mixed-treatment comparisons cannot
conclusively exclude differences in efficacy. • Evidence within subgroups was limited
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
Clinical Bottom Line:Conclusion• Current evidence does not warrant
recommending a particular 2nd-generation antidepressant on the basis of differences in efficacy
• Differences in onset of action and adverse events may be considered when choosing a medication
Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
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