second-generation antidepressants in the pharmacologic treatment of adult depression: an update of...

Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An

Update of the 2007 Comparative Effectiveness Review

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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


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)


.

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


.

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


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.


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


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


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.


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).


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


Summary of Findings, KQ 1a: Dysthymia


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


Summary of Findings, KQ 1a: Subsyndromal Depression


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


Summary of Findings, KQ 1b: Greater Efficacy/Effectiveness with Previously Effective Medications


Findings

Major depressive disorder Insufficient No Evidence

Dysthymia Insufficient No Evidence

Subsyndromal depression Insufficient No Evidence


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


Summary of Findings, KQ2a: Maintenance of Response or Remission



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.



Switching medications --------------------------------------------------------------------------------Comparative efficacy Insufficient No Evidence




Summary of Findings, KQ2b: Achieving Response in Unresponsive or Recurrent Disease



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


Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Anxiety


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



Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Insomnia


Findings


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 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



Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Low Energy


Findings


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


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



Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Melancholia


Findings


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


Comparative efficacy for melancholia


Comparative effectiveness for melancholia



Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Pain


Findings


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


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



Summary of Findings, KQ3: Treatment of Depression in Patients With Psychomotor Change


Findings


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 efficacy for psychomotor change

Moderate No evidence

Comparative effectiveness for psychomotor change



Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Somatization


Findings





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


Summary of Findings, KQ4a: Risk of Harms – General Tolerability


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


Summary of Findings, KQ4a: Risk of Harms – General Tolerability continued


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


Summary of Findings, KQ4a: Risk of Harms – Severe Adverse Events


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


Summary of Findings, KQ4a: Risk of Harms – Severe Adverse Events continued


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


Summary of Findings, KQ4a: Risk of Harms – Adherence


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



Summary of Findings, KQ4b: Differences of Harms – MDD


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



Summary of Findings, KQ5: Subgroups– Age


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


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


Findings

Comparative efficacy 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 harms Insufficient No evidence


Summary of Findings, KQ5: Subgroups– Comorbidities


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 harms Insufficient No evidence


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


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


Thank you for the opportunity to share this information with you

• For CE/CME:– www.ce.effectivehealthcare.ahrq.gov/credit– Use code: CER38

• For electronic copies of the clinician guide, the consumer guide, and the full systematic review– www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports

/?pageaction=displayproduct&productID=862

– For free print copies– AHRQ Publications Clearinghouse (800) 358-9295

We encourage you to visit AHRQ’s continuing education website regularly to participate in future programs.

http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=862

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