Second-Generation Antidepressants for Treating Adult Depression

1
Second-Generation Antidepressants for Treating
AdultDepressionAn Update

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
Outline of Material

• The comparative effectiveness review (CER)
  process
• Background
• Questions addressed in the CER on
  second-generation antidepressants for adults with
  major depressive disorder (MDD)
• Overall comparative effectiveness of treatments
  for MDD
• Treating patients with unresponsive or recurrent
  disease
• Treating symptoms that accompany depression
• Comparative adverse effects
• Evidence available on effectiveness and adverse
  effects in different patient subpopulations
• Conclusions

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Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, the public, and
  others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  Clinician Research Summaries and Consumer
  Research Summaries for use in decisionmaking and
  in discussions with patients. The Research
  Summaries and the full report are available at
  www.effectivehealthcare.ahrq.gov/secondgenantidep.
  cfm.

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/seco
ndgenantidep.cfm.
4
Rating the Strength of Evidence From the
Comparative Effectiveness Review

• The strength of evidence was classified into four
  broad categories

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.
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/seco
ndgenantidep.cfm.
5
Background Prevalence of Depressive Disorders

• Depressive disorders such as major depressive
  disorder (MDD), dysthymia, and subsyndromal
  depression may be serious, disabling illnesses.
• MDD affects more than 16 percent of adults at
  some point during their lifetimes.
• In 2000, the economic burden of depressive
  disorders in the United States was estimated to
  be 83.1 billion. Likely, this number has
  increased during the past 10 years. More than 30
  percent of these costs are attributable to direct
  medical expenses.

American Psychiatric Association. Diagnostic and
statistical manual of mental disorders. 4th ed.
Text rev. 2000. Birnbaum HG, Ben-Hamadi R,
Greenberg PE, et al. Pharmacoeconomics
200927(6)507-17. PMID 19640013. Greenberg PE,
Kessler RC, Birnbaum HG, et al. J Clin Psychiatry
2003 Dec64(12)1465-75. PMID 14728109. Kessler
RC, Berglund P, Demler O, et al. JAMA
2003289(23)3095-105. PMID 12813115.
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Background Treatment for Depression

• Pharmacotherapy dominates the medical management
  of depressive disorders, including
  first-generation and the more recently developed
  second-generation antidepressants.
• First-generation antidepressants include
• Tricyclic antidepressants
• Monoamine oxidase inhibitors
• Second-generation antidepressants dominate the
  medical management of depressive disorders and
  include
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin and norepinephrine reuptake inhibitors
  (SNRIs)
• Selective serotonin and norepinephrine reuptake
  inhibitors (SSNRIs)
• Other drugs with related mechanisms of action
  that selectively target neurotransmitters
• The mechanism of action of most of these agents
  is poorly understood, but they most likely work
  through their effects on neurotransmitters such
  as serotonin, norepinephrine, or dopamine in the
  central nervous system.

Olfson M, Marcus SC. Arch Gen Psychiatry 2009
Aug66(8)848-56. PMID 19652124.
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Background Antidepressant Medications

• In general, the efficacies of first- and
  second-generation antidepressant medications are
  similar.
• However, first-generation antidepressants often
  produce multiple side effects that many patients
  find intolerable, and the risk for harm when
  taken in overdose or in combination with certain
  medications is high.
• Because of their relatively favorable side-effect
  profile, the second-generation antidepressants
  play a prominent role in managing patients with
  major depressive disorder and are the focus of
  this presentation.

Geddes JR, Freemantle N, Mason J, et al. Cochrane
Database Syst Rev 2007 Jul 18(3)CD001851. PMID
17636689. Williams JW, Mulrow CD, Chiquette E, et
al. Ann Intern Med 2000 May 2132(9)743-56.
PMID 10787370.
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Comparative Effectiveness Review on
Second-Generation Antidepressants for Adults With
Depression

• A systematic review of 248 clinical studies
  published between January 1980 and January 2011
  sought to determine the effectiveness, benefits,
  and adverse effects of second-generation
  antidepressants for adults with depression.
• This presentation is provided to assist in
  decisionmaking and should not be construed to
  represent clinical recommendations or guidelines.
  The full report is available at
  www.effectivehealthcare. ahrq.gov/secondgenantidep
  .cfm.

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/seco
ndgenantidep.cfm.
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Second-Generation Antidepressants Included in the
2011 Updated Review
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/seco
ndgenantidep.cfm.
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Outcomes of Interest in Studies on
Second-Generation Antidepressants for Depression
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
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
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Overall Comparative Effectiveness of
Second-Generation Antidepressants for Treating
Major Depressive Disorder

• Overall Comparative Effectiveness
• Immediate-Release and Extended-Release
  Formulations
• Treatment Adherence and Persistence

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
12
Overall Comparative Effectiveness of
Second-Generation Antidepressants for Treating
Adults With MDD

• Overall, second-generation antidepressants have
  similar efficacy, effectiveness, and effects on
  quality of life (37 did not respond during 6 to
  12 weeks of treatment 53 did not achieve
  remission).Strength of Evidence Moderate
• Mirtazapine has a faster onset of action (12
  weeks) than do citalopram, fluoxetine,
  paroxetine, and sertraline however, response
  rates were similar after 4 weeks of treatment.
  Strength of Evidence Moderate
• Elderly patients (60 years) with major
  depressive disorder (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

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
13
Immediate-Release Versus Extended-Release
Formulations of Second-Generation Antidepressants
for Adults With MDD

• Fluoxetine daily and fluoxetine weekly have
  similar response and remission rates.Strength of
  Evidence Moderate
• Paroxetine IR (immediate release) and paroxetine
  CR (controlled release) have similar response
  rates.Strength of Evidence Moderate
• One trial reported higher response rates for
  venlafaxine XR (extended release) than
  venlafaxine IR.Strength of Evidence Low

MDD major depressive disorder
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
14
Adherence and Persistence in Second-Generation
Antidepressants for Adults With MDD

• Adherence rates were similar (strength of
  evidence moderate) for the following
  comparisons
• Citalopram versus sertraline
• Bupropion SR versus fluoxetine, paroxetine, or
  sertraline
• Bupropion versus trazodone
• Paroxetine IR versus paroxetine CR
• Adherence rates in patients with major depressive
  disorder (MDD) were higher for fluoxetine weekly
  versus daily.
• Strength of Evidence Low
• Adherence rates were similar in patients treated
  with paroxetine IR and those receiving paroxetine
  CR.
• Strength of Evidence Moderate
• Patients with MDD refilled prescriptions for
  bupropion XL more frequently than for bupropion
  SR.
• Strength of Evidence Low

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
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Comparative Effectiveness of Second-Generation
Antidepressants in Continuation and Maintenance
Phases

• Preventing Relapse
• Maintaining Remission
• Treating Resistant or Refractory Depression

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
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Comparative Effectiveness of Second-Generation
Antidepressants in Continuation and Maintenance
Phases

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

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
17
Effectiveness of Second-Generation
Antidepressants in Treating Symptoms That May
Accompany Depression

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

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
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Effectiveness in Treating Symptoms That May
Accompany Depression

• Second-generation antidepressants have similar
  efficacy for treating depression in patients who
  also have anxiety. Strength of Evidence
  Moderate
• Improvements in anxiety scores were similar among
  second-generation antidepressants for patients
  with depression.Strength of Evidence Moderate
• Paroxetine and duloxetine showed similar
  improvements in pain scores in patients with
  depression.Strength of Evidence Moderate
• Several second-generation antidepressants are
  equally effective in treating insomnia symptoms
  in patients with depression.Strength of
  Evidence Low
• There was insufficient evidence to determine the
  comparative efficacy of second-generation
  antidepressants in treating low energy,
  psychomotor changes, melancholia, or
  somatization.

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
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Comparative Harms of Second-Generation
Antidepressants

• Overall Comparative Harms
• Specific Adverse Events by Drug
• Risk of Severe Adverse Events

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
20
Overall Comparative Harms of Second-Generation
Antidepressants for Adults With Major Depressive
Disorder

• Overall rates of adverse events were similar
  among second-generation antidepressants, though
  incidence of specific adverse effects differed
  across antidepressants.
• Strength of Evidence High
• Overall differences in formulations
• No differences in harms were found between
  fluoxetine daily and fluoxetine weekly or between
  venlafaxine IR and venlafaxine XR.Strength of
  Evidence Moderate

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
21
Specific Comparative Harms of Second-Generation
Antidepressants for Adults With MDD (1 of 3)
Adverse Effects Outcome Strength of Evidence
Nausea andVomiting Venlafaxine has a 52-percent higher incidence than selective serotonin reuptake inhibitors as a class. When used to treat major depressive disorder, paroxetine IR may lead to higher rates of nausea than paroxetine CR. High Low
Weight Gain Mirtazapine is associated with more weight gain than citalopram, fluoxetine, paroxetine, and sertraline (0.83.0 kg after 68 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
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
22
Specific Comparative Harms of Second-Generation
Antidepressants for Adults With MDD (2 of 3)
Adverse Effects Outcome Strength of Evidence
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. Paroxetine had the highest rate of sexual side effects when compared with selective serotonin reuptake inhibitors as a class (16 vs. 6). Sexual side effects may occur at different rates between men and women. High Moderate Low
MDD major depressive disorder
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
23
Specific Comparative Harms of Second-Generation
Antidepressants for Adults With MDD (3 of 3)
Adverse Effects Outcomes Strength of Evidence
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). Venlafaxine had lower discontinuation rates due to lack of efficacy (35 lower risk). High High
Withdrawal Symptoms The highest rates of withdrawal symptoms (headache, dizziness, light-headedness, nausea, and anxiety) were reported after discontinuation of paroxetine or venlafaxine. Fluoxetine had the lowest rate of withdrawal symptoms. Moderate Moderate
MDD major depressive disorder SSRI selective
serotonin reuptake inhibitor
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
24
Risks of Severe Adverse Events From
Second-Generation Antidepressants for Adults With
MDD
Severe Adverse Effects Outcomes Strength of Evidence
Suicidality Evidence is insufficient to evaluate the comparative risk of suicidal thoughts and behavior. Insufficient
Others Evidence is insufficient to evaluate the comparative risk for rare but severe adverse effects such as seizures, cardiovascular events, hyponatremia, hepatotoxicity, and serotonin syndrome. Insufficient
MDD major depressive disorder
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
25
Noncomparative Evidence on Adverse Effects
Diabetes, Fractures, and Bleeding

• Unrated evidence on second-generation
  antidepressants shows
• An increased risk for diabetes in patients on
  recent long-term use (gt24 months) of moderate to
  high doses of fluvoxamine, paroxetine, or
  venlafaxine.
• An increased risk for fractures (hip and other
  fractures, except fractures of the forearms or
  spine) for patients on high-dose citalopram,
  fluoxetine, paroxetine, and sertraline.
• An increased risk for upper gastrointestinal
  tract bleeding during treatment with selective
  serotonin reuptake inhibitors.

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Gaps in Knowledge (1 of 2)

• The general efficacy of second-generation
  antidepressants for treating dysthymia and
  subsyndromal depression.
• Differences in benefits and harms in subgroups
  such as the very elderly or patients with common
  comorbidities.
• The most appropriate duration of antidepressant
  treatment for maintaining remission.
• The effect of drug dosage on the risk of relapse
  or recurrence.

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
27
Gaps in Knowledge (2 of 2)

• The most effective second-generation
  antidepressant in patients who either did not
  respond or could not tolerate a first-line
  treatment.
• How combinations of antidepressants compare with
  monotherapy in treatment-resistant depression.
• How outcomes of second-generation antidepressants
  differ in populations with accompanying symptoms
  such as anxiety, insomnia, pain, or fatigue.
• The comparative risks of second-generation
  antidepressants with respect to rare but serious
  adverse effects such as suicidality,
  hyponatremia, hepatotoxicity, seizures,
  cardiovascular adverse events, and serotonin
  syndrome.

Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ
Comparative Effectiveness Review No. 46.
Available at www.effectivehealthcare.ahrq.gov/sec
ondgenantidep.cfm.
28
What To Discuss With Your Patients About
Second-Generation Antidepressants

• The benefits of the different second-generation
  antidepressants for treating their specific
  symptoms.
• How they will know if their medication is
  working.
• How to identify the potential adverse effects of
  the medications and how to handle them.
• How long they may need to take their current
  antidepressant.
• The importance of adhering to their treatment
  regimens and what to expect if they stop taking
  their medications such as withdrawal or
  discontinuation syndrome.
• To always consult their health care provider
  before discontinuing any medication.
• How their medications will affect the symptoms
  that may be accompanying their depression such as
  anxiety, insomnia, or chronic pain.
• Their comorbidities and the medications they may
  be taking for them and how these may influence
  their depression-related outcomes.