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What Works for Depression?
An Evidence-based Comparison of Treatment Options

Slide Presentation - Text Version

Slide 1

What Works for Depression?
An Evidence-based Comparison of Treatment Options
April 29, 2013
Bruce Seeman, Agency for Healthcare Research and Quality
Gerald Gartlehner, MD, MPH, RTI- International

Slide 2

Agenda

  • AHRQ and the Effective Health Care Program
  • Second-Generation Antidepressants for Treating Adult Depression-An Update from Dr. Gartlehner
  • Questions and Answers

Slide 3

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Slide 4

Agency for Healthcare Research and Quality (AHRQ)

  • Mission: To improve the quality, safety, efficiency, and effectiveness of health care for all Americans
  • Research: ~80 percent of AHRQ's budget is invested in grants and contracts focused on improving health care
  • The AHRQ Effective Health Care Program (EHC):
    • Provides current, unbiased evidence on clinical effectiveness of health care interventions
    • Focuses on patient-centered outcomes
    • Helps consumers, providers, and policy-makers make informed choices
    • Does not make treatment recommendations
    • Long-term goal: Improve health care quality and patient health outcomes through informed decision making by patients, providers, and policymakers

Slide 5

What is Comparative Effectiveness Research (CER)?

  • Comparative effectiveness research — a type of patient-centered outcomes research — compares drugs, medical devices, tests, surgeries, or ways to deliver health care, so that patients and their families can make more informed choices.
  • Findings are descriptive, not prescriptive, and are intended as tools for informed decision making, not recommendations.
  • Findings highlight current evidence about effectiveness, risks, and side effects.

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Second-Generation Antidepressants for Treating Adult Depression-An Update

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Funding Support and Disclaimer

  • Funded by the Agency for Healthcare Research and Quality (AHRQ) through Contract No. 290-2007-10056-1 to RTI International
  • This presentation is provided to assist in decisionmaking and should not be construed to represent clinical recommendations or guidelines.
  • Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.

Available at: www.effectivehealthcare.ahrq.gov/secondgenantidep.cfm.

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Outline of Presentation

  • Background
  • Questions addressed in the CER on second-generation antidepressants for adults with depressive disorders:
    • Overall comparative effectiveness of treatments
    • Treating patients with unresponsive or recurrent disease
    • Treating depression with accompanying symptoms
    • Comparative adverse effects
    • Effectiveness and adverse effects in different patient subpopulations
  • Clinical Implications and Conclusions

Slide 9

Background: Burden of Disease

  • Depressive disorders such as major depressive disorder (MDD), dysthymia, and subsyndromal depression are serious, disabling illnesses.
  • MDD affects more than 16 percent of adults at some point during their lifetimes.
  • In any given year, about 7% of the US population suffer from a depressive episode.
  • Women are about twice as likely as men to develop a depressive disorder.
  • In 2000, the economic burden of depressive disorders in the United States was estimated to be $83.1 billion.

Slide 10

Antidepressants Sales in the United States

Table: Total dispensed prescriptions MN in the U.S. market from 2008-20011

Dispensed Prescriptions MN 2011 2010 2009 2008
Total US Market 4,024 3,993 3,949 3,866
  • Antidepressants
264 254 247 241
  • Lipid Regulators
260 260 254 242
  • Narcotic Analgesics
238 244 241 239
  • Antidiabetics
173 172 169 166
  • Ace Inhibitors (Pain & Combo)
164 168 166 163
  • Beta Blockers (Pain & Combo)
161 162 163 164
  • Respiratory Agents
153 153 152 147
  • Anti-Ulcerants
150 147 146 139
  • Diuretics
128 131 132 135
  • Anti-Epileptics
128 122 116 110

Table: Total spending $BN in the U.S. market from 2008-2011

Spending $ BN 2011 2010 2009 2008
Total US Market 319.9 308.6 300.7 285.7
  • Oncologics
23.2 22.3 21.5 19.7
  • Respiratory Agents
21.0 19.3 18.1 16.0
  • Lipid Regulators
20.1 18.8 18.6 18.1
  • Antidiabetes
19.6 17.7 15.8 13.6
  • Antipsychotics
18.2 16.2 14.7 14.3
  • Autoimmune Diseases
12.0 10.6 9.7 8.6
  • Antidepressants
11.0 11.6 11.5 11.7
  • HIV Antivirals
10.3 9.3 8.2 7.1
  • Anti-Ulcerants
10.1 11.9 14.1 14.2
  • Narcotic Analgesics
8.3 8.4 8.0 7.3

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“Me-too” Drugs

  • Drugs that are structurally very similar to already known drugs, with only minor differences.

Image: Timeline showing the increased development of various “me-too” drugs from 1980 to present day.

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Second-generation Antidepressants
Image: Systems network chart of antidepressants and their associated clinical trials, which depicts the difficulty in figuring out whether one specific drug is really more efficacious than another.

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Controversy about Comparative Effectiveness
Image 1: Report Title: Comparative Benefits and Harms of Second-Generation Antidepressants: Background Paper for the American College of Physicians

…no substantial differences in efficacy among second-generation antidepressants

Image 2: Report Title: Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis

….escitalopram and sertraline have a more beneficial efficacy/harms profile than other antidepressants.

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Image 1: Screenshot of AHRQ’s EHC Program Comparative Effectiveness Review Number 46, Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review

Image 2: Screenshot of AHRQ consumer summary, Medicines for Treating Depression: A Review of the Research for Adults

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Population of interest
Adult outpatients with

  • Major depressive disorder
  • Dysthymia
  • Subsyndromal depression

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Phases of Treatment for Major Depression
Image: Assessment of the comparative effectiveness of antidepressants for all phases of the disease including acute, continuation, and maintenance.
Source: Recreated based on Kupfer, 1991

Slide 17

Second-Generation Antidepressants Included in the 2011 Updated Review
Chart: List of available generic second-generation drugs. This table summarizes the second-generation antidepressants that are available in the United States by their mechanism of action; it shows names, therapeutic class, and U.S. Food and Drug Administration–approved (labeled) uses.

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Methods

  • Systematic literature search in multiple electronic databases (1980-2011)
  • Extensive grey literature searches for unpublished studies
  • Dual review of the literature
  • Critical appraisal of the risk of bias of included studies.
  • RCTs for efficacy and effectiveness, observational studies for harms
  • Meta-analyses and network meta-analyses
  • Grading of the strength of evidence with respect to important outcomes

Slide 19

  • The strength of evidence was classified into four broad categories:

Table: Evidence-based Practice Center GRADE approach which is used to assess the quality of the body of evidence for each outcome. The overall strength is graded as high, moderate, low, or insufficient.

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 either is unavailable or does not permit a conclusion.

Slide 20

Outcomes of Interest
Table: List of health outcomes of interest for efficacy and effectiveness, and safety and tolerability of second-generation antidepressants.

Health Outcomes Safety and Tolerability
  • Response
  • Remission
  • Speed of response/remission
  • Relapse
  • Quality of life
  • Functional capacity
  • Hospitalization
  • Overall adverse effects
  • Withdrawals
  • Serious adverse events
  • Specific adverse events including:
    • Hyponatremia
    • Seizures
    • Suicide
    • Hepatotoxicity
    • Weight gain
    • Gastrointestinal symptoms
    • Sexual side effects
    • Others

Slide 21

Results
Flow Chart: Top-level overview of the report’s review process. Researchers reviewed more than 6,000 abstracts and included 228 studies, both randomized control trials as well as observational and non-randomized studies.

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Results: Major Depressive Disorder

  • 37% did not respond during 6 to 12 weeks of treatment; 53% did not achieve remission.
  • The evidence is insufficient to determine factors that can reliably predict response or nonresponse in individual patients.

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Results: Major Depressive Disorder

  • Overall, similar efficacy, effectiveness, and effects on quality of life
    • Statistically significant differences are likely not clinically relevant
    • No differences between IR and XR formulations
      Strength of Evidence: Moderate
  • Mirtazapine has a faster onset of action (1–2 weeks) than  citalopram, fluoxetine, paroxetine, and sertraline; Response rates were similar after 4 weeks of treatment.
    Strength of Evidence: Moderate

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Results: Major Depressive Disorder

  • Overall, similar efficacy between immediate (IR)- and extended- release (XR) formulations
    • Fluoxetine daily vs. fluoxetine weekly

Strength of Evidence: Moderate

  • Paroxetine IR vs. paroxetine CR

Strength of Evidence: Moderate

  • Venlafaxine IR vs. venlafaxine XR

Strength of Evidence: Low

  • Mixed evidence about better adherence and persistence with XR than IR medications

Strength of Evidence: Moderate to Low

Slide 25

Results: Preventing Relapse and Maintaining Remission

  • Maintaining Remission
    • Most second-generation antidepressants effectively maintain remission (prevent relapse and recurrence) with similar efficacy.
      Strength of Evidence: Moderate

Slide 26

Results: Achieving Response in Unresponsive or Recurrent Disease

  • Resistant or Refractory Depression
    • Venlafaxine may be modestly superior to other selective serotonin reuptake inhibitors; however, results on comparative effectiveness are mixed.
      Strength of Evidence: Low

Slide 27

Questions & Answers

Slide 28

Treating Depression with Accompanying Symptoms

  • Anxiety
  • Insomnia
  • Low Energy
  • Melancholia
  • Pain
  • Psychomotor Change
  • Somatization

Slide 29

Results: Treatment of Depression in Patients with Accompanying Symptom

  • Similar efficacy for the treatment of depression in patients with accompanying symptoms

Strength of Evidence: Moderate (anxiety), low (insomnia), insufficient (low energy, melancholia, pain, psychomotor changes, somatization)

Slide 30

Results: Treatment of Accompanying Symptom in Patients with Depression

  • Similar efficacy for the treatment of anxiety, pain, insomnia in patients with depression

Strength of Evidence: Moderate (anxiety, pain), low (insomnia)

  • Insufficient evidence to determine the comparative efficacy of second-generation antidepressants in treating low energy, psychomotor changes, melancholia, or somatization

Slide 31

Comparative Harms of Second-Generation Antidepressants

  • Overall comparative risk of specific adverse events
  • Discontinuation because of adverse events
  • Risk of severe adverse events

Slide 32

Results: Risk of Harms

  • Constipation, diarrhea, dizziness, headache, insomnia, nausea, sexual adverse events, and somnolence were commonly and consistently reported adverse events.
  • 63 percent of patients in efficacy trials experienced at least one adverse event.
  • Nausea and vomiting were the most common reasons for discontinuation in efficacy studies

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Results: Comparative Risk for Harms

  • Overall rates of adverse events were similar among second-generation antidepressants, though incidence of specific adverse effects differed across antidepressants.

Strength of Evidence: High

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Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (1 of 3)
Table: Overall rates of adverse events are similar among second-generation antidepressants, although the incidence of specific adverse events differed across antidepressants (e.g., nausea and vomiting, weight gain, and diarrhea).

Adverse Effects Outcome Strength of Evidence
Nausea and Vomiting Venlafaxine has a 52-percent higher incidence than selective serotonin reuptake inhibitors as a class. High
When used to treat major depressive disorder, paroxetine IR may lead to higher rates of nausea than paroxetine CR. Low
Weight Gain Mirtazapine is associated with more weight gain than citalopram, fluoxetine, paroxetine, and sertraline (0.8–3.0 kg after 6–8 weeks). High
Diarrhea Sertraline was associated with an 8-percent higher incidence of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine. Moderate

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Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (2 of 3)
Table: Overall rates of adverse events are similar among second-generation antidepressants, although the incidence of specific adverse events differed across antidepressants (e.g., somnolence and sexual dysfunction).

Adverse Effects Outcome Strength of Evidence
MDD = major depressive disorder
Somnolence Trazodone was associated with a 16-percent higher incidence of somnolence than bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine. Moderate
Sexual Dysfunction Bupropion had fewer sexual side effects than escitalopram, fluoxetine, paroxetine, and sertraline. High
Paroxetine had the highest rate of sexual side effects when compared with selective serotonin reuptake inhibitors as a class (16% vs. 6%). Moderate
Sexual side effects may occur at different rates between men and women. Low

MDD = major depressive disorder

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Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (3 of 3)
Table: Overall rates of adverse events are similar among second-generation antidepressants, although the incidence of specific adverse events differed across antidepressants (e.g., discontinuation rates and withdrawal symptoms).

Adverse Effects Outcome Strength of Evidence
MDD = major depressive disorder
Discontinuation Rates When compared with most SSRIs, higher discontinuation rates due to adverse effects were seen with duloxetine (67% higher risk) and venlafaxine (40% higher risk). High
Venlafaxine had lower discontinuation rates due to lack of efficacy (35% lower risk). High

 

Withdrawal Symptoms The highest rates of withdrawal symptoms (headache, dizziness, light-headedness, nausea, and anxiety) were reported after discontinuation of paroxetine or venlafaxine. Moderate
Fluoxetine had the lowest rate of withdrawal symptoms. Moderate

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Results: Serious Adverse Events

  • The existing evidence on the comparative risk for rare but severe adverse events such as suicidality, seizures, cardiovascular events, hyponatremia, hepatotoxicity, and serotonin syndrome is insufficient to draw firm conclusions.

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Results: Treating Depression in Subgroups

  • Elderly patients (≥60 years) with MDD had similar efficacy with second-generation antidepressants.
    Strength of Evidence: Moderate
  • Elderly patients (≥60 years) with MDD may experience some differences in adverse events from these drugs.
    Strength of Evidence: Low

Slide 39

Results: Treating Depression in Subgroups

  • Insufficient evidence about differences in efficacy, effectiveness, or risk of harms for subgroups with respect to sex, race or ethnicities, and co-morbidities.

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Results: Dysthymia and Subsyndromal Depression

  • No double-blinded head-to-head evidence is available
  • Evidence is limited to fluoxetine, paroxetine, and sertraline
  • Evidence about the general efficacy of antidepressants for the treatment of dysthymia and subsyndromal depression is mixed.

Strength of Evidence: Insufficient (dysthymia) and low (subsyndromal depression)

Slide 41

Clinical Implications and Conclusions

  • Current evidence does not warrant the choice of one drug over another based on efficacy.
  • Although second-generation antidepressants are similar in efficacy, they cannot be considered identical drugs.
  • Evidence of high and moderate strength supports some differences among individual drugs with respect to onset of action, adverse events, and some measures of health-related quality of life.

Slide 42

Clinical Implications and Conclusions

  • Differences in adverse events or costs might influence the choice of a medication for an individual patient.
  • Given the fact that almost two in five patients do not respond to initial treatment, clinicians need to be familiar with different antidepressants.

Slide 43

Questions & Answers

Slide 44

Many thanks for your attention