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NATIONAL CLINICAL PRACTICE GUIDELINE

Adult Depression

Clinical Practice Guideline

Approved by the

National Guideline Directors

February 2012

This guideline is informational only. It is not intended or designed as a substitute for the reasonable exercise of independent clinical judgment by practitioners, considering each patient’s needs on an individual basis.

Guideline recommendations apply to populations of patients. Clinical judgment is necessary to design treatment plans for individual patients.

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Table of Contents

Introduction... 1

Guideline Summary ... 5

Rationale Statements ... 12

1. First-Line Treatment of Major Depressive Disorder (MDD) ... 12

2. Hypericum (St. John’s Wort) for MDD... 38

3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, Or Plan ... 44

4. Second-Line Treatment Of MDD ... 48

5. Length Of Treatment With Antidepressants In Patients With MDD... 63

6. Follow-Up For Patients In The Acute Phase of Treatment For MDD... 70

7. Follow-Up For Patients In The Continuation Phase of Treatment of MDD... 72

8. Follow-Up For Patients In Maintenance Phase of Treatment of MDD ... 74

9. Discontinuation of Antidepressants in Patients with MDD... 75

10. Treatment Preferences For MDD In Different Ethnic Groups ... 77

11. Patient Self-Management Strategies for Improving Symptoms of MDD... 80

12. Behavioral Health Education Classes For Adults With MDD... 95

13. Antidepressants To Avoid During Pregnancy or Breastfeeding... 98

Appendix A: Criteria for Grading the Evidence ... 108

Appendix B: Supporting Documentation ... 110

1. First-Line Treatment of Major Depressive Disorder (MDD) ... 110

Problem Formulation 1 ... 110

Search Strategy ... 111

Evidence Tables ... 114

2. Hypericum (St. John’s Wort) For Treatment of MDD ... 196

Problem Formulation 2 ... 196

Search Strategy ... 197

Evidence Tables ... 200

3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, or Plan... 207

Problem Formulation 3 ... 207 Search Strategy ... 208 Evidence Tables ... 210 4. Second-Line Treatement of MDD ... 214 Problem Formulation 4 ... 214 Search Strategy ... 215 Evidence Tables ... 218

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5. Length of Treatment With Antidepressants In Patients With MDD... 228

Problem Formulation 5 ... 228

Search Strategy ... 229

Evidence Tables ... 232

6. Follow-Up For Patients In The Acute Phase of Treatment For MDD... 239

Problem Formulation 6 ... 239

Search Strategy ... 240

Evidence Table... 242

7. Follow-Up For Patients In The Continuation Phase of Treatment For MDD ... 243

Problem Formulation 7 ... 243

Search Strategy ... 244

Evidence Table... 246

8. Follow-Up For Patients In Maintenance Phase Treatment Of MDD ... 247

Problem Formulation 8 ... 247

Search Strategy ... 248

Evidence Table... 249

9. Discontinuation of Antidepressants In Patients With MDD... 250

Problem Formulation 9 ... 250

Search Strategy ... 251

Evidence Tables ... 253

10. Treatment Preferences For MDD In Different Ethnic Groups ... 255

Problem Formulation 10 ... 255

Search Strategy ... 256

Evidence Table... 258

11. Patient Self-Management Strategies For Improving Symptoms of MDD... 259

Problem Formulation 11 ... 259

Search Strategy ... 260

Evidence Tables ... 262

12. Behavioral Health Education Classes For Adults With MDD... 276

Problem Formulation 12 ... 276

Search Strategy ... 277

Evidence Tables ... 279

13. Antidepressants To Avoid During Pregnancy or Breastfeeding... 283

Problem Formulation 13 ... 283

Search Strategy ... 284

Evidence Tables ... 285

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Introduction

Kaiser Permanente’s National Guideline Program

The National Guideline Program (NGP) supports the development of a core set of explicit, scientifically-based clinical practice guidelines, practice resources, and evidence synopses to assist Kaiser Permanente (KP) physicians, administrators, and other health care professionals in determining the most effective medical practices.

This core set of evidence-based resources will:

 Create Programwide economies of scale,

 Support ongoing performance improvement activities,

 Consistently provide high quality resources for use in care delivery tools and systems, and

 Increase KP regions’ abilities to leverage clinical guidelines to improve clinical outcomes.

Clinical practice guidance, based on scientific evidence, is essential for providing high quality care and continuously improving on it. Such guidance needs to be integrated into the electronic medical record and other decision support tools to be accessible to clinicians at the point of care. In addition, engaging our members in collaborative, shared decision-making conversations regarding their personal preferences is an essential component of patient-centered quality care. Furthermore, cost-effectiveness of various evidence-based interventions and resource limitations are important considerations. This involves addressing health problems in ways that maximize the health of the population given the available resources.

Who are the National Guideline Directors’?

The National Guideline Directors (NGD) are a group of experts and advocates of evidence-based medicine who provide direction and oversight to the National Guideline Program (NGP). In this role, the NGD selects and approves topics for evidence-based knowledge products, owns Kaiser Permanente’s Common Methodology, and is responsible for quality assurance review. This group is composed of representatives from the Care Management Institute (CMI) and all eight regions.

What Is the Guideline Quality Committee?

The Guideline Quality (GQ) Committee is a subcommittee of the NGD consisting of a group of evidence experts from various KP regions and CMI who review and approve all the National Guidelines. This review ensures that the processes used to develop guideline content have adhered to KP evidence-based methods and that the labels applied to clinical recommendations therein are accurate (e.g., “evidence-based” or “consensus-based”).

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How Are Guidelines Developed?

Guidelines are developed with the use of an “evidence-based methodology” and involve a systematic literature search, critical appraisal of the research design and statistical results of relevant studies, and grading of the sufficiency (quantity, quality, consistency, and relevancy) of the evidence for drawing conclusions. An evidence search includes literature published in peer-reviewed scientific journals, existing evidence-based guidelines, consensus-based statements from external professional societies and government health organizations, and clinical expert opinion of KP regional specialty groups. For additional information on evidence grading, see Table 1 in Appendix A.

To develop a or revise a guideline, CMI consultants work with a multidisciplinary Guideline Development Team (GDT). Each GDT consists of a core group of physicians, representing primary care and the specialties most affected by the guideline topic, and, as appropriate, other content experts from disciplines such as pharmacy, nursing, and health education. The members of a GDT are nominated by the respective National Guideline Directors to represent their regions. The GDT reviews the appraisal of the evidence and develops or revises clinical

recommendations based on the current evidence. Each regional representative then presents the draft guideline recommendations to key experts and champions in their regions for critical review and support to improve the likelihood of implementation once the guideline is published.

How Often Are Guidelines Reviewed and Revised?

To keep current with changing medical practices, all guidelines are reviewed, and, if appropriate, revised at least every two years. To develop the Adult Depression Guideline, released in

February 2010, a multidisciplinary, interregional GDT first met in November 2009 to define the scope of the guideline. The Project Management Team then performed systematic reviews of the medical literature on each of the clinical questions identified by the GDT, assembled the

evidence, and developed draft recommendations for review by the GDT. All of the

recommendations and supporting evidence were reviewed in depth by the GDT in a series of meetings from November through January 2010. The GQ Committee reviewed and approved the guidelines in February 2010. All recommendations included in the guideline were approved by the NGD.

What Does It Mean for a Guideline to Be Evidence-Based?

Each clinical recommendation within a guideline is labeled as “evidence-based” or “consensus-based.” A recommendation is considered “evidence-based” if there has been a systematic review of the evidence, the evidence is sufficient, and the recommendation is consistent with the

evidence. A recommendation can also be considered “evidence-based” if there is insufficient evidence but either no particular intervention is recommended or options are recommended without favoring one of the options over others. A recommendation is considered “consensus-based” if there has been a systematic review of the evidence, the evidence is insufficient to support an evidence-based recommendation, and the GDT decides to make a consensus recommendation.

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What Does It Mean for a Guideline to Be Approved and National?

A recommendation that is consistent with the above policies is labeled as “National Guideline Directors Approved.” A recommendation that fails to satisfy those criteria is not approved and will be noted as such. A National Guideline Directors Approved guideline for which at least 90% of the recommendations are approved by at least six of the eight KP regions is a "National

Guideline." On the topics for which they exist, National Guidelines are the preferred evidence source for KP HealthConnect content.

Contact information: David Price, MD

Adult Depression Clinical Lead Care Management Institute E-mail: david.price@kp.org

Devon McCabe, MA

Care Management Consultant Care Management Institute E-mail: devon.d.mccabe@kp.org

Acknowledgments

The Kaiser Permanente (KP) Adult Depression Clinical Practice Guideline is the result of the extensive clinical expertise, collaborative efforts, and outstanding personal contributions of the following participants:

KP Adult Depression Guideline Project Management Team

David Price, MD Clinical Lead Care Management Institute

Devon McCabe, MA Project Manager Care Management Institute

Christy N. Pham, MPH Lead Analyst KP-Southern California

Erin G. Stone, MD, FACP EBM Methodologist Care Management Institute

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KP Adult Depression Guideline Development Team

There were no conflict of interests for any member of the Guideline Development Team (GDT).

Colorado Jean E Milofsky MD – Regional Department Chair, Psychiatry Kerri Gaughan, PharmD, BCPP – Clinical Pharmacy Specialist, Mental Health David Price, MD – Director of Medical Education, CPMG;

CMI Depression Guideline & Education Lead;

Medical Director, KP National CME Program

Georgia Sam W. Moss, MD, MS – Lead Physician, Adult Medicine;

Assistant to the Chief of Medicine for

Asthma/Depression

Hawai’i John Draeger, MD – Chief, Behavioral Health Service Samuel V Gadam – Geriatric psychiatrist

Mid-Atlantic States Timothy M Sitts, MD – Psychiatrist

Northern California Mason Turner, MD – Chief, Department of Psychiatry;

Assistant Director, Regional Mental Health

and Chemical Dependency

Joyce O. Arango, DrPH – Sr. Managerial Consultant, Northern California

Guidelines Director

John Guzman, PhD – Subchief, SSF Behavioral Medicine, Regional

Chair; Behavioral Medicine Subchiefs

Gabrielle Beaubrun, MD – Psychiatrist Assistant Chief of Psychiatry Steve Olson, MD – Family Physician, Depression Champion;

Co-Manager Behavior Medicine Services

Northwest Jonathan Ebbing, MD – Psychiatrist Ohio William S. Schwab, MD PhD AGSF – Chief of Geriatrics

Horia Craciun, MD – Psychiatrist

Larissa Elgudin, MD – Regional Chief of Behavioral Health Services,

Parma

Program Offices Andrew Bertagnolli, PhD – Senior Consultant,

Behavioral Medicine & Pain Mgmt

Care Management Institute

Southern California Christy N. Pham, MPH – Consultant, Technology Assessment &

Guidelines Unit

Erin G. Stone, MD, FACP – Physician Lead,

Clinical Content and Decision Support

Debbie R Kubota, PharmD – Pharmacist Evidence Analyst & Strategist

Misha Askren, MD – Family Medicine

Mark Dreskin, MD – Regional Depression Co-Lead;

Physician in Charge;

Same Day Acute Medical Services

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Guideline Summary

1.

First-Line Treatment of Major Depressive Disorder (MDD)

1A For patients with mild to moderate Major Depressive Disorder (MDD), use either

antidepressant medication or psychotherapy* as first-line treatment. Evidence-based: B

1B Given the lack of evidence on a clearly superior approach for mild to moderate MDD,

base treatment decisions on patient and clinician preference, potential side effects, and

cost. Consensus-based

1C For patients with severe or chronic MDD, combine antidepressant use and

psychotherapy* as first-line treatment. Evidence-based: B

1D If antidepressants are used, any class of antidepressant (SSRI, TCA, SNRI, NRI, or DA)

may be prescribed as first-line treatment of MDD. Evidence-based: B

1E Given the equivalence of therapeutic effect, base the choice of antidepressant on

patient’s prior response, patient and clinician preference, potential side effects, and cost.

Consensus-based

* (Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy)

This guideline is informational only. It is not intended or designed as a substitute for the reasonable exercise of independent clinical judgment by practitioners, considering each patient’s needs on an individual basis.

Guideline recommendations apply to populations of patients. Clinical judgment is necessary to design treatment plans for individual patients.

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2.

Hypericum (St. John’s Wort) For Treatment of MDD

2A The GDT makes no recommendation for or against providing hypericum

(St. John’s wort) in patients with mild to moderate Major Depression.

There is fair evidence of effectiveness of hypericum in this population. However, due to lack of consistency of preparation oversight and dosage across trials, and concerns about lack of FDA oversight and consistency of hypericum preparations, the balance of

benefits, harms, and costs compared with other treatments cannot be determined.

Evidence-based: C*

2B The GDT recommends against providing hypericum (St. John’s wort) to patients with

severe Major Depression. Evidence-based

3.

Antidepressants In Patients With MDD Expressing Suicidal

Ideation, Intent, or Plan

3A For patients with Major Depression expressing suicidal intent or plan, the GDT

recommends consultation with specialty behavioral health. Consensus-based

3B For patients with suicidal ideation or who have made previous suicide attempts, the GDT

recommends consultation or collaboration with a psychiatrist before prescribing TCAs or

venlafaxine. Consensus-based

* Please note that only recommendations approved since the adoption in 2006 of evidence grading will use letters (A, B, C, etc.) to specify the grade of the evidence. Recommendations approved prior to 2006 will not include a letter grade following the statement “evidence-based.” For additional information on evidence grading, see Appendix A.

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4.

Second-Line Treatment of MDD

4A For patients with MDD whose symptoms fail to remit after first-line treatment, the GDT

recommends an assessment of the adherence to the initial treatment regimen.

Consensus-based

4B For patients with MDD whose symptoms fail to remit after adherence to first-line

treatment, the GDT recommends that treatment options include:

 Combining antidepressants and psychotherapy. Evidence-based

 Increasing the dose of the initial antidepressant. Consensus-based

 Switching to a different antidepressant of the same or different class.

Consensus-based

 Switching from psychotherapy to antidepressants or antidepressants to psychotherapy.

Consensus-based

 Combined pharmacologic treatment (monitoring for toxicity, side effects and drug

interactions) with SSRIs and:

 low-dose TCAs, or  bupropion, or  buspirone, or  mirtazepine, or  lithium, or  liothyronine (T3).

Consensus-based (all in this list)

4C The GDT makes no recommendation for or against providing folate or inositol to patients

whose MDD symptoms fail to remit after adhering to first-line treatment.

Evidence-based: I

4D The GDT makes no recommendation for or against providing atypical an antipsychotics

to primary care patients with (nonpsychotic, nonbipolar) MDD whose symptoms fail to remit after adherence to first-line treatment.

There is fair evidence of short-term effectiveness for use of atypical antipsychotic agents to augment antidepressants in patients with nonpsychotic, nonbipolar MDD who fail to remit after initial treatment. However, due to lack of longer-term data, known

cardiometabolic risks of treatment with these medications, and lack of comparison data against other strategies, the balance of benefits, harms and costs compared with other

treatments cannot be determined. Evidence-based: I

4E The GDT recommends against providing augmentation with pindolol for patients with

MDD whose symptoms fail to remit after adherence to first-line treatment.

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5.

Length of Treatment With Antidepressants In Patients With MDD

Patients Who Achieve Symptom Remission

5A The GDT recommends that patients with MDD who achieve symptom remission

with antidepressants should continue antidepressants at the same dose for at least an

additional six to 12 months. Evidence-based

Patients With One Lifetime Episode of MDD

5B Based on patient and provider preference, the GDT recommends that a trial of

antidepressant discontinuation is optional for patients in their first lifetime episode of MDD, who are being treated with antidepressants, achieve remission, and remain

asymptomatic for six to 12 months after acute phase treatment. Consensus-based

Patients With Two or More Lifetime Episodes of MDD

5C The GDT recommends that patients with two or more lifetime episodes of MDD, who are

being treated with antidepressants and remain asymptomatic after acute phase treatment, should be maintained on the medication and dose with which they achieved remission for at least an additional 15 months to five years after acute phase treatment.

Consensus-based

Patients With Chronic MDD or MDD With Concurrent Dysthymia

5D The GDT recommends that patients with chronic MDD (continual symptoms for

more than two years) or Double Depression (MDD and dysthymia) who improve with antidepressants during acute phase treatment should continue antidepressants for at least

an additional 15 to 28 months after acute phase treatment. Evidence-based

6.

Follow-Up For Patients In The Acute Phase

(First Three Months) of Treatment For MDD

6 For patients who are starting treatment with antidepressants for Major Depression, the

GDT recommends that the minimum recommended follow-up frequency is one patient contact* within the first month, and at least one additional patient contact four to eight weeks after the first contact.

Assess for adherence, side effects, suicidal ideation, and patient response during both

these visits. Consensus-based

* Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone calls/email between patient and a care manager. The use of email between patients and providers is relatively new, and has not been a widely utilized means of communication to date. However, it is being increasingly advocated as part of a patient-centered, more efficient (“less visit dependent”) model of care. At least one member of the GDT uses this modality regularly and deems it effective for follow-up contacts.

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7.

Follow-Up For Patients In The Continuation Phase

(Months Four To 12) of Treatment For MDD

7 After achieving symptom remission, the GDT recommends at least one follow-up

contact* during the fifth or sixth month of treatment in patients with Major Depression.

Assess for continuing symptom remission and dosage/treatment adjustment during this contact.

The GDT recommends additional patient follow-up to consider either continuing treatment beyond the continuation phase, or attempting a trial of treatment

discontinuation. Consensus-based

8.

Follow-Up For Patients In The Maintenance Phase

(Beyond 12 Months) of Treatment For MDD

8A For asymptomatic patients with Major Depression who are continuing on antidepressants

beyond 12 months, the GDT recommends at least one annual follow-up contact* is

recommended to assess for continuing symptom remission, the need for ongoing

treatment, and dosage/treatment adjustment. Consensus-based

8B The GDT recommends that additional follow-up for asymptomatic patients with Major

Depression who are continuing on antidepressants beyond 12 months should be based on

patient preference and response. Consensus-based

9.

Discontinuation of Antidepressants In Patients With MDD

9A Fluoxetine may be discontinued, without tapering, with a relatively low risk of adverse

effects. Evidence-based

9B The GDT recommends tapering other antidepressants (other SSRIs, TCAs, SNRIs, NRIs,

and DAs) over a two to four week period. Consensus-based

10. Treatment Preferences For MDD In Different Ethnic Groups

10 Because patient preferences for treatment may vary based on their ethnicity and culture,

the GDT recommends asking patients from different ethnic groups about treatment

preference when discussing treatment options for MDD. Evidence-based

* Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone calls/email between patient and a care manager. The use of email between patients and providers is relatively new, and has not been a widely utilized means of communication to date. However, it is being increasingly advocated as part of a patient-centered, more efficient (“less visit dependent”) model of care. At least one member of the GDT uses this modality regularly and deems it effective for follow-up contacts.

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11. Patient

Self-Management

Strategies For Improving Symptoms of MDD

Exercise

11A Exercise is an adjunctive strategy (in addition to antidepressants or psychotherapy)

for treating MDD. Evidence-based :B

Internet Resources

11B Selected internet-based patient self-help materials may be used as an optional adjunct strategy (in addition to antidepressants or psychotherapy) for treating MDD.

Consensus-based

Bibliotherapy

11C Selected bibliotherapy* may be used as an optional adjunct strategy (in addition to

antidepressants or psychotherapy) for treating MDD. Consensus-based

Befriending

11D Befriending† is an optional adjunct to antidepressants or psychotherapy for treating

MDD. Consensus-based

Patient-Initiated Combined Phone/Computer Programs

11E There is insufficient evidence for or against using patient-initiated combined

phone/computerprograms in the treatment of MDD. Evidence-based: I

Light Therapy

11F There is insufficient evidence for or against using light therapy as a primary or

adjunctive treatment for nonseasonal forms of MDD. Evidence-based: I

Music Therapy

11G There is insufficient evidence for or against using music therapy in the treatment of

MDD. Evidence-based: I

Life Review Therapy

11H There is insufficient evidence for or against using life review therapy in the treatment of

MDD. Evidence-based: I

12. Behavioral Health Education Classes For Adults With MDD

(Cognitive Behavioral Skills or Problem-Solving Classes)

12 For patients with mild to moderate MDD, the GDT recommends behavioral health

education classes as an adjunctive treatment option. However, these classes should not

be used in lieu of either antidepressant medication or psychotherapy. Evidence-based

*

Bibliotherapy: Advising people to read specific written material based on cognitive-behavioral approaches to depression treatment.

Befriending: Consists of a designated befriender who meets the depressed person to talk and socialize with for at least one hour per week.

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13. Antidepressants To Avoid During Pregnancy or Breastfeeding

Pregnancy

13A Do not start paroxetine in women who are pregnant. Evidence-based: D

13B Use caution in starting other selective serotonin re-uptake inhibitors (SSRIs) in women

who are pregnant. Consensus-based

 Discuss risks to the mother and fetus of untreated maternal depression, as well as the

risk of fetal adverse effects from antidepressants.

13C If drug therapy is a consideration for treatment of maternal MDD during pregnancy and/or breastfeeding, then:

 Individualize according to patient history and need for medication, and

 Discuss the benefits and harms of the various treatment options with the patient.

Consensus-based

13D If MDD is in remission and a woman becomes pregnant while taking antidepressants during the continuation or maintenance phase of treatment, then:

 Discuss the risks to the mother and fetus of untreated maternal depression or

depression relapse after antidepressant discontinuation, as well as the risk of fetal adverse effects from continuing antidepressants, and

 Monitor for first trimester fetal malformations if taking paroxetine.

Consult OB/GYN for considerations on fetal malformation screening.

Consensus-based

Breastfeeding

13E Do not start fluoxetine and/or citalopram in breastfeeding women in most circumstances.

If used, they should be used with caution, and only in patients who had good results with

these medications during pregnancy or a previous depression episode. Consensus-based.

13F In women taking antidepressants during pregnancy whose depression is in remission and

who desire to breastfeed:

 Discuss the risks to the mother and fetus of untreated maternal depression or

depression relapse after antidepressant discontinuation and the risk of adverse effects in the nursing newborn of mothers continuing antidepressants, and

 Consider changing treatment for depression if the newborn shows potential

antidepressant-related adverse effects (withdrawal symptoms) during the first few hours after birth.

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Rationale Statements

1.

First-Line Treatment of Major Depressive Disorder (MDD)

1A For patients with mild to moderate Major Depressive Disorder (MDD), use either

antidepressant medication or psychotherapy* as first-line treatment. Evidence-based: B

1B Given the lack of evidence on a clearly superior approach for mild to moderate MDD,

base treatment decisions on patient and clinician preference, potential side effects, and

cost. Consensus-based

1C For patients with severe or chronic MDD, combine antidepressant use and

psychotherapy* as first-line treatment. Evidence-based: B

1D If antidepressants are used, any class of antidepressant (SSRI, TCA, SNRI, NRI, or DA)

may be prescribed as first-line treatment of MDD. Evidence-based: B

1E Given the equivalence of therapeutic effect, base the choice of antidepressant on

patient’s prior response, patient and clinician preference, potential side effects, and cost.

Consensus-based

Evidence Grade†

Evidence for Recommendation 1A: Fair. Evidence for Recommendation 1C, D: Good.

Rationale:

2010 Update

New evidence was found, the recommendation remains unchanged.

*

(Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy)

The criteria for grading the strength of the evidence as either “good,” “fair,” or “insufficient” adheres to the KP National Guideline Program’s “Policies and Procedures” documents entitled “Label and Language of

Recommendations” and “KP System for Grading the Strength of a Body of Evidence,” which are located in Appendix A.

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Search Strategy

Some studies found and used in this guideline did not appear in PubMed search results due to the

way studies are indexed in PubMed. Casacalenda(1) study was indexed as a review article in

PubMed and did not show up in the search results due to the way PubMed indexing is done. Another information source was the AHRQ Evidence report on the Treatment of

Depression-Newer Pharmacotherapies.(2) See Appendix B for more information on the search strategy.

The GDT determined that a limited review of the clinical question focusing on first-line medication treatment for MDD was most appropriate for the current 2010 update. Systematic reviews and meta-analyses were included in the current update. Original studies that

demonstrated selective reporting using non-systematic searches or were industry-sponsored were excluded.

Note: There is no universally used definition of mild, moderate, and severe Major Depression.

To determine severity, clinicians can use either the depression score from a standardized, validated depression rating scale (such as the PHQ-9, Beck Depression Inventory, Zung Depression Scale, and others that are often used in Major Depression studies) or use the following commonly used clinical consensus rating system as a guide to determining symptom severity.

Severity of Major Depression SYMPTOM

SEVERITY NUMBER OF MDD SYMPTOMS (DSM-IV CRITERIA) OR OCCUPATIONAL IMPAIRMENT PATIENT FAMILY, SOCIAL,

Mild 5 to 6 Minor

Moderate 6 to 7 Moderate

Severe 8 to 9 Severe; including suicidal intention or plan

After reviewing this new evidence, the overall recommendation for first-line antidepressant treatment remains unchanged. The included studies are summarized below (please refer to Evidence Table 1.1 for study details). A limited review focusing on first-line medication choice for treatment of MDD was conducted. Systematic reviews and meta-analyses were included. Analyses using non-systematic searches and single antidepressant vs. placebo trials of

established (previously reviewed) antidepressants were excluded. Eighteen relevant systematic reviews and meta-analyses were identified. Efficacy outcomes were measured by response rates, defined as a reduction of 50% of baseline Hamilton Depression Rating Scale (HAM-D) or the Montgomery-Asberg Depression Rating Scale (MADRS) or a score of ‘much improved’ on the Clinical Global Impression score(CGI); and/or remission, defined frequently in studies by a preset cut-point of

≤ 7 to 9 on the HAM-D score. Tolerability or acceptability was measured by overall dropout

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Three studies (Mukai 2009,(3) Gartlehner 2008a,(4) Gartlehner 2008b(5)) compared the efficacy and tolerability of different drug classes (e.g., TCA, SSRI, SNRI, other antidepressants) to each other; nine studies (Cipriani 2009b,(6) Cipriani 2009c,(7) Cipriani 2009a,(8) Nakagawa 2009,(9)

Omori 2009,(10) Cipriani 2008,(11) Van den Broek 2009,(12) Weinmann 2008,(13) Watanabe

2008(14)) compared individual antidepressants to other antidepressants; and six studies (Arroll

2009,(15) Hansen 2008,(16) Barbui 2009,(17) Barbui 2008,(18) Deshauer 2008,(19) Nelson 2008(20)) evaluated antidepressants, individually or as a class, relative to placebo. The majority of the studies focused on the 12 newer, second-generation antidepressants that included bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone and venlafaxine.

Head-to-Head Comparisons of Antidepressants

*

 Mukai et al. (2009)(21) reviewed 18 RCTs examining the efficacy of single- versus

dual-action Antidepressants for the treatment of depression among patients ≥ 59 years. In this narrative review, authors conducted a systematic search of published studies; however, data were scarce and insufficient to conduct a meta-analysis of head-to-head comparisons. In addition, publication bias assessment was not reported. Overall, limited data suggest that dual-action agents such as TCAs and SNRIs do not appear to confer any additional efficacy benefits over single-action agents such as SSRIs in the treatment of depression in the elderly. Two trials found no significant difference in efficacy between TCAs vs. SSRIs; three studies found no significant difference between venlafaxine vs. SSRIs; one study of duloxetine vs. placebo (funding source not reported) found significant improvement in depression (p < 0.001), pain (p < 0.001), and cognition (p = 0.013) in favor of duloxetine; and five studies suggested no additional efficacy benefit for the SNRI venlafaxine compared with SSRIs or TCAs.

 Gartlehner et al. (2008a)(4) conducted a meta-analysis of 203 studies (including

head-to-head RCTs; observational studies; placebo trials; systematic reviews, meta-analyses, and studies with pooled data) on the comparative benefits and harms of second-generation

antidepressants. Overall, no substantial differences in comparative efficacy and effectiveness of second-generation antidepressants for treatment of MDD were detected; the evidence did not support the choice of one second-generation antidepressant over another. Nevertheless, authors noted some differences in adverse events. Some statistical differences in onset of action were noted, however these differences may not be clinically significant since most response rates were similar after four weeks of treatment and all seven studies that examined speed of response were funded by manufacturer.

*

The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

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 In a separate sub-analysis, Gartlehner et al. (2008b)(5) assessed the comparative harms

of second-generation Antidepressants for MDD by reviewing 104 studies (83 head-to-head RCTs (N > 17,000) and 21 observational studies (N > 740.000)). Outcome measures were rates of adverse effects, specific adverse effect reported, and overall rate of adverse effect. Adverse effects profiles of second-generation antidepressants were similar; nausea, vomiting, diarrhea, dry mouth, sweating, headache, dizziness, sexual dysfunction and weight gain were commonly reported adverse effect. However, individual drugs differed in frequencies of specific adverse effects, which might be clinically relevant and influence the choice of treatment for individual patients (on a case-by-case basis).

 Roughly 63% of patients in efficacy trials experienced at least one adverse effect.

No significant difference was detected between second-generation antidepressants and SSRIs, except for venlafaxine, which had higher discontinuation from adverse effects and higher rate of nausea and vomiting than SSRIs [(Relative Risk (RR) discontinuation from adverse effects: 1.42 (95% CI: 1.15 to 1.75); RR = from nausea and vomiting: RR = 1.53 (95% CI: 1.26 to 1.86); NNH = 9 (95% CI: 6 to 23)].

 Compared with other second-generation antidepressants, paroxetine frequently was

associated with higher rates of sexual dysfunction and bupropion with lower rates of sexual dysfunction; mirtazapine and paroxetine were associated with more weight gain (up to 3 kg, although not always specified); and sertraline was associated with higher rates of diarrhea. However, differences did not lead to significantly different discontinuation rates.

 Cipriani et al. (2009a)(8) evaluated the efficacy and acceptability of 12 second-generation antidepressants in a meta-analysis of 117 RCTs (N = 25,928). Only seven of these trials were in primary care settings. Included studies were of short duration. Fifteen unpublished studies from industry were included, it was not specified how many of these favored the funder’s antidepressant (no funnel plots or assessment of publication bias was noted, and it was not clear how many of these studies were also included in the FDA trial database). Authors noted a small number included in each pair-wise comparison. Mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious treatments for depression response (remission was not assessed). Escitalopram, sertraline, bupropion, and citalopram were better tolerated than other antidepressants. Reboxetine, fluvoxamine, paroxetine, and duloxetine tended to have lower efficacy and tolerability than other antidepressants. Numbers needed to treat or harm were not calculated, making it difficult to assess the absolute differences in each analysis. Additionally, statistical significance (defined as p < 0.05 in this analysis) was not adjusted for multiple comparisons, so many differences could have been due to chance.

(19)

Escitalopram vs. Other Antidepressants

 Cipriani et al. (2009b)(6) examined the efficacy and tolerability of escitalopram compared to

other Antidepressants in 22 RCTs. Patients with medical comorbidity were excluded, limiting the potential applicability to primary care settings. In terms of efficacy,

escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR = 0.67, 95% CI: 0.50 to 0.87) and remission (OR = 0.53, 95% CI: 0.30 to 0.93). In terms of tolerability, fewer patients allocated to escitalopram withdrew from trials due to any cause compared to duloxetine (OR = 0.62, 95% CI: 0.38 to 0.99). This analysis is limited by potential publication and sponsorship biases and potential selective reporting of results.

Milnacipran vs. Other Antidepressants

 Nakagawa et al. (2009)(9) examined milnacipran versus other antidepressants in a

meta-analysis of 16 RCTs (N = 2777). When compared to TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse events (OR 0.55; 95% CI: 0.35 to 0.85) and there was a trend that suggested fewer adverse events of sleepiness/ drowsiness, dry mouth or constipation. No other significant differences in efficacy, acceptability and tolerability were detected when comparing milnacipran with other antidepressive agents. However, authors noted that there remained “inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression.” Milnacipran is not currently available in the United States.

Fluvoxamine vs. Other Antidepressants

 Omori et al. (2009)(10) reviewed the efficacy and tolerability of fluvoxamine and other

antidepressants in 53 RCTs (N = 8,244 for efficacy; N = 6,440 for tolerability). In terms of efficacy, no significant differences were detected in response and remission rates between fluvoxamine and other antidepressants as a class (TCAs, heterocyclics, SNRIs, SSRIs) in early or end of acute phase of treatment. In addition, dropouts for any reason or for adverse effects were not significantly different between fluvoxamine and other antidepressants as a class or individually. Nausea or vomiting and weight loss or anorexia were more frequent with fluvoxamine than with TCAs and some other antidepressants (mianserin, milnacipran, and newer antidepressants); constipation and dry mouth were more common with TCAs than with fluvoxamine. The authors concluded that “the initial selection of an antidepressant medication will and should largely be based on the anticipated side effect profile and patient’s preference.”

(20)

Sertraline vs. Other Antidepressants

 Cipriani et al. (2009c)(22) assessed the efficacy and tolerability of sertraline compared to

other antidepressants in 59 RCTs (N = 9,950). Evidence favoring sertraline over some individual antidepressants for the acute phase treatment of major depression was found, either in terms of treatment response (fluoxetine) or acceptability/tolerability (amitriptyline, imipramine, paroxetine, and mirtazapine). No statistically significant difference in remission between fluoxetine and sertraline was noted. However, some differences favoring other antidepressants over sertraline in terms of response (mirtazapine, amitriptyline) and

acceptability (bupropion) were also noted. Sertraline was generally associated with a higher rate of participants experiencing diarrhea. Overall, the quality of included studies was low, not all pre-specified outcomes were reported in included studies, and outcomes of clear relevance to patients and clinicians were not reported in any of the included studies. No analysis of publication bias was conducted. Few studies reported remission rates, those that did were underpowered to detect clinical significance. Analysis of sertraline vs. other antidepressants as a class was not conducted.

 Cipriani et al. (2008)(11) evaluated sertraline compared to other antidepressants in a

meta-analysis of 56 RCTs (N = 8,507 for efficacy; N = 8,387 for tolerability). There was substantial overlap of studies in this analysis and the analysis conducted in Cipriani et al. (2009a)(8), thus many of the same limitations (short duration of included trials, few trials conducted in primary care settings) apply. Trials including patients with medical disorders were excluded from this analysis, also limiting applicability to the primary care setting. FDA trial databases and similar European trial databases were searched for study inclusion in this analysis; most included studies were funded by the maker of sertraline. This analysis also did adjust the level of significance to p < 0.01 to account for multiple comparisons. Included studies used different dosing schedules, making it difficult to determine differences (or lack thereof) between equivalent effective doses of antidepressants. Sertraline was more

efficacious than other SSRIs [RR = 0.88 (99% CI: 0.78 to 0.99), p = 0.009; NNT = 17], particularly fluoxetine [RR = 0.85 (99% CI: 0.74 to 0.98); p = 0.004; NNT = 12]. But sertraline’s efficacy was not significantly different from TCAs [RR = 0.95 (99% CI: 0.83 to 1.09)] or any other antidepressants, For acceptability, no significant differences were detected between sertraline and TCAs [RR = 0.83 (99% CI: 0.66 to 1.04)], SSRI [RR = 0.9 (99% CI: 0.68 to 1.18)], or any other antidepressants. In the conclusions section, the authors site “cardiovascular physicians’ belief and clinical care practices” in treating depression in patients with cardiovascular disease as observational evidence

supporting their conclusion of sertraline “as a candidate for initial choice of antidepressant.”

Venlafaxine vs. Other Antidepressants

 Van den Broek et al. (2009)(12) compared the effectiveness of venlafaxine to TCAs in seven

RCTs (N = 947). There were no significant differences for response [OR = 0.88 (95% CI: 0.66-1.16)] or withdrawal [OR = 1.21 (95% CI: 0.89-1.64)] of TCA vs.

venlafaxine. However, authors noted that “because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.”

(21)

 Weinmann et al. (2008)(13) evaluated the efficacy and tolerability of venlafaxine compared

with SSRI in 17 RCTs (N = 3,523 for response analysis; N = 3,142 for remission analysis). There were no statistically significant differences between venlafaxine and the SSRI group with respect to response [random-effect RR = 1.05, (95% CI: 1.00 to 1.10); NNT = 27] and remission [random-effect RR = 1.04, (95% CI: 0.96 to 1.13); NNT = 34]. Total rate of treatment discontinuation did not differ between venlafaxine and SSRIs (RR = 1.05,

95% CI: 0.93 to 1.2, NNH = 100), but there were significantly more dropouts due to adverse effects in the venlafaxine vs. SSRIs group [RR = 1.38, 95% CI: 1.08 to 1.77, NNH = 32].

Mirtazapine vs. Other Antidepressants

 Watanabe et al. (2008)(14) conducted a systematic review on 25 RCTs (N = 4,842) on the

effectiveness and tolerability of mirtazapine compared with other antidepressants (TCAs, SSRIs, SNRIs, and other). Results were stratified according to treatment duration, including early phase (2 weeks), end of acute-phase (6 to 12 weeks), and end of continuation phase (4 to 6 months).

 Analysis of efficacy at early phase of treatment found no significant differences between

mirtazapine and TCAs in response [RR = 0.9 (99% CI: 0.69 to 1.18)] and remission [RR = 0.87 (99% CI: 0.52 to1.47)]; mirtazpine was superior to SSRIs in both response [RR = 1.36 (99% CI: 1.13 to 1.64); NNT = 11] and remission [RR = 1.68

(99% CI: 1.2 to 2.36); NNT = 25], particularly, significantly better than paroxetine in response [RR = 2.02 (99% CI: 1.09 to 3.75); NNT = 8] and sertraline in remission

[RR = 1.73 (99% CI: 1.01 to 2.98); NNT = 12]; and mirtazapine was significantly superior to SNRI in terms of response [RR = 1.77 (99% CI: 1.08 to 2.89); NNT = 6] but not in remission [RR = 2.21(99% CI: 0.93 to5.26)].

 At the end of the acute phase (6 weeks), no statistical significant differences were detected,

except for superior remission outcome in comparison of mirtazapine with paroxetine [RR = 1.34 (99% CI: 1.04 to 1.73); NNT = 10)].

 At the end of the continuation phase (24 weeks), one study examined mirtazapine with

paroxetine and no significant differences were detected.

 No significant differences in tolerability were identified between patients treated with

mirtazapine and TCAs (RR = 0.87 (95% CI: 0.7 to 1.08)], SSRIs (RR = 1.07

(95% CI: 0.92 to 1.26)], SNRI (venlafaxine) [RR = 0.82 (95% CI: 0.58 to 1.16)], or other antidepressants (trazodone) [RR = 0.93 (95% CI: 0.58 to 1.5)].

 Mirtazapine dropouts due to adverse effects were similar to SSRI [RR = 1.22 (95% CI:

0.87 to 1.73)], SNRI [RR = 0.59 (95% CI: 0.27 to 1.29)], and trazodone [RR = 0.66 (95% CI: 0.3 to 1.46)]. Subgroup analysis found mirtazapine had lower withdrawals due to adverse effects compared with sertraline [RR = 2.58 (95% CI: 1.28-5.24); NNH = 11].

 Based on findings authors concluded that “although mirtazapine is highly likely to have

better efficacy profile than paroxetine or venlafaxine in terms of early response, in view of similar efficacy of mirtazapine and other antidepressants, results suggest that clinicians should also focus on other practically or clinically relevant considerations such as

differences in the side effect profiles, to tailor treatment to best fit an individual patient’s needs.”

(22)

Antidepressants vs. Placebo

*

 Arroll et al. (2009)(15) reviewed 14 RCTs examining the effectiveness of TCAs and/or SSRIs

compared to placebo. Both TCAs and SSRIs were significantly more effective than placebo for depression reduction and symptoms [RR = 1.24 (95% CI: 1.11 to 1.38) and

NNT = 7 to 16; and RR = 1.28 (95% CI: 1.15 to 1.43) and NNT = 7 to 8, respectively]. More adverse effects were associated with TCAs than with SSRIs [NNH = 4 to 30 vs. 20 to 90, respectively].

 Hansen et al. (2008)(16)compared MDD relapse and recurrence rates during continuation

and maintenance phase treatment with second-generation antidepressant compared with placebo in 27 RCTs. Results were stratified by duration (those <1 year were categorized as relapse prevention and trials ≥ 1 year were categorized as recurrence prevention). NNTs for relapse prevention over a (mean of eight months) and recurrence (mean of 16 months) were each five [RR = of relapse: 0.54 (95% CI: 0.46 to 0.62), RR = of recurrence: 0.56

(95% CI: 0.48 to 0.66)]. In addition, loss to follow-up because of adverse events was not significantly different between active treatment and placebo (RR = 1.42,

95% CI: 0.92 to 2.20).

 Nelson et al. (2008)(20) reviewed 10 RCTs (N = 2377) on the efficacy of second-generation

antidepressants for depression in late-life (> 60 years) with respect to treatment response, remission, and tolerability. Those assigned to active drug treatment had significantly greater response [OR = 1.4 (95% CI: 1.24 to 1.57); NNT = 13] and remission [OR = 1.27

(95% CI: 1.12-1.44); NNT = 20] compared with placebo. Response rates were higher in the longer trials compared to the shorter trials [10 to 12 weeks OR = 1.73 (95% CI: 1.42 to 2.09) vs. 6 to 8 weeks OR = 1.22 (95% CI: 1.05 to 1.42)]. However, compared with placebo, there were increased odds of overall medication discontinuation [OR = 1.22 (95% CI: 1.06 to 1.4); I2 = 48.2%] and discontinuation due to medication adverse effects [OR = 1.84 (95% CI: 1.51 to 2.24)]. Evidence did not suggest superiority of one class of medication over another. Authors concluded that “for every 100 patients treated, eight would show a response and five a remission in excess of placebo and for every two patients who responded, one discontinued prematurely because of adverse effects.”

 Deshauer et al. (2008)(23) pooled 6 RCTs (N = 1299) to evaluate SSRIs versus placebo

for MDD. Treatment response at sic to eight months showed SSRIs to be superior to placebo [OR = 1.66 (95% CI: 1.12 to 2.48)], particularly in depressed patients without other

comorbidities [OR = 2.13 (95% CI: 1.11 to 4.08)]. There were no statistically significant differences in remission [OR = 1.46 (95% CI: 0.92 to 2.32)] or drop-out rates [OR = 0.87 (95% CI: 0.67 to 1.14)] between SSRI and placebo.

*

The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

(23)

Paroxetine vs. Placebo

 Barbui et al. (2008)(18) compared paroxetine with placebo in a meta-analysis of 40 RCTs

(N = 6391). The primary outcome was discontinuation and the secondary outcome was response. Significantly more patients assigned to receive paroxetine left the study because of side effects [random effect RR = 1.77 (95% CI: 1.44 to2.18); NNH = 17], reported any adverse effects [OR = 1.27, 95% CI: 0.88 to 1.83, NNH = 9], and experienced suicidal tendencies compared with patients given placebo OR = 2.55 (95% CI: 1.17 to 5.54); NNH = 142]. Patients who received paroxetine were more likely to experience an improvement in depressive symptoms compared to patients receiving placebo [random effect RR = 0.83 (99% CI: 0.77 to 0.90); NNT = 9].

Suicide Risk – Antidepresants vs. Placebo

 Barbui et al. (2009)(17) conducted a meta-analysis of eight observational studies

(> 200,000 patients) to assess the risk of suicide based on SSRI exposure. Overall, there

wasan increased risk of attempted or completed suicide among adolescents exposed to

SSRIs[random-effect OR = 1.92 (95% CI: 1.51 to 2.44)]. In subgroup analysis, paroxetine

and venlafaxine were associated with increased risk. However there was a decreased risk of attempted or completed suicide among adults and elderly individuals exposed to SSRIs (≥ 65 years) [OR = 0.57 (95% CI: 0.47 to 0.70); OR = 0.46 (95% CI: 0.27 to 0.79)]. No individual antidepressant was significantly associated with completed or attempted suicide in adults. Patients may have had additional comorbidities that may have influenced selection of treatment and have unaccounted for effects on suicide risk. Funnel plot suggested that small negative studies may not have been published and included in the analysis.

Discussion:

In aggregate, updated evidence suggests no significant differences in efficacy among the

different classes of antidepressants (TCAs, SSRIs, SNRIs; N = 4 new studies(21), (4), (5), (24)). Five newly identified meta-analyses/systematic reviews ((20), (16), (17), (25), (23)) support the proposition that antidepressant treatment for MDD is more efficacious than placebo, especially among

patients without other comorbidities.(23) One study (Nelson 2008(20)) found that response to

treatment is greater in longer trials (10 to 12 weeks) compared with shorter trials (6 to 8 weeks), supporting findings of the STAR*D trial (reviewed previously). Three studies ((21), (4), (5)) did not detect significant differences among antidepressant drug classes in discontinuation for any

reason and/or from side effects. However, one study (Arroll 2009(15)) suggested that more

adverse events were associated with TCAs than SSRIs and another study (Nelson 2008(20)) noted

increased odds for discontinuation of medication treatment compared to placebo. One study

(Barbui 2009(17)) reported a decreased risk of suicide attempts or completion in depressed adults

treated with SSRIs, but supported previously found associations between antidepressant exposure and suicide risk in adolescents. Although significant differences in tolerability were not detected in several studies, there was some evidence that showed marginal differences in the adverse event profiles among individual antidpressants ((4), (5), (13)).

(24)

A variety of results were reported among studies that assessed the effectiveness and tolerability of individual antidepressants relative to other antidepressants or placebo. In a head-to-head

comparison study of 12 new second-generation antidepressants, Cipriani et al. (2009a)(8) reported

that mirtazapine, escitalopram, venlafaxine and sertraline were among the most efficacious while reboxetine, fluvoxamine, and duloxetine were the least efficacious. One study (Watanabe

2008(14)) found that mirtazapine was equivalent to TCAs and more efficacious than SSRIs,

(particularly paroxetine); no significant differences in tolerability were detected between

mirtazapine and other antidepressants. Cipriani 2009b(6) showed statistically better response for

escitalopram compared with citalopram and better escitalopram tolerability compared with duloxetine. Two studies demonstrated no significant differences in efficacy between venlafaxine

and SSRI(13) or TCAs,(12) although one study found more dropouts due to adverse events in

venlafaxine treated patients compared with SSRI patients(13). Cipriani (2009c(7)) found better response for sertraline compared with fluoxetine, and a trend in favor of mirtazapine for efficacy

and bupropion for tolerability over sertraline. Another Cipriani analysis (2008(11)) reported no

differences in efficacy and tolerability between sertraline, TCAs, and other antidepressants while sertraline was superior to SSRI, especially fluoxetine, in efficacy. There were significant

overlaps in the studies included in these two Ciprani analyses. One study(9) found better

tolerability of milnacipran compared with TCAs; however, the authors noted that there was insufficient evidence to establish the overall effectiveness and acceptability of milnacipran compared to other antidepressants (milnacipran is not available in the United States). One

study(10) reported no significant differences in tolerability between fluvoxamine and other classes

of antidepressants. Finally, one study (18) concluded that paroxetine was superior to placebo in

response, but more withdrawals due to adverse events were observed in patients allocated to paraoxetine than placebo.

Altogether, the NNT for antidepressant treatment, either as a class or individually, ranged from 4 to 34 and the NNH ranged from 9 to 90. As a result, the benefits of antidepressant treatment for MDD appear to outweigh the identified harms.

Several important limitations were present in most of the included systematic review and meta-analyses that warrant cautious interpretation of the reported results. The majority of included studies were funded by the pharmaceutical industry, which tends to favor the funded medication. Unpublished results were likely missing from many of the analyses. The same small group of researchers published many of the studies included, and in some cases, separate analyses were presented that included several common trials, making it appear that there is stronger evidence to support a conclusion than really exists. Only a minority of studies in some analyses was

conducted in primary care settings, and several studies excluded patients with comorbidities, making generalization to primary care difficult. Data was unavailable for many head-to-head comparison studies of individual antidepressants, and selective reporting of results may have occurred in several of the included trials. Selective participation of symptomatic volunteers was observed in most included trials, which may potentially overstate the true effectiveness in real world settings. Most studies reported on symptom response rather than symptom remission.

(25)

Many trials included multiple comparisons, increasing the risk of finding a statistically

significant result that is truly a chance finding. Data on tolerability based on dropout rates due to adverse events were also difficult to interpret due to the variability among individual drug adverse effects profiles. Methodological concerns such as inadequate blinding and analytical methods (e.g., completer analyses and last observation carried forward methods of imputing missing data) may bias studies in favor of active treatment). Variability in dosing strategies can lead to higher effective doses of one medication being compared with lower effective doses of another. Although some studies found statistically significant results, whether these findings translate to significant clinical relevance is questionable.

Conclusion:

New evidence from systematic reviews of mostly lower quality studies did not suggest the need to change the previous guideline recommendation regarding antidepressants for treatment of severe MDD. Although individual studies suggest marginal benefit for specific antidepressants, in aggregate there is no consistent “directionality” amongst the studies. Furthermore, the

absolute clinically important difference between antidepressants is uncertain, due to the limited quantity of the comparison studies.

Therefore, the GDT continues to find that the balance of evidence supports the use of

antidepressant medication as a first-line treatment for MDD. The GDT continues to recommend, consistent with the previous guideline recommendations, that any class of antidepressant (SSRI, TCA, SNRI, NRI, or DA) may be prescribed as first-line treatment of MDD. Similarly, the GDT maintains that clinicians base the choice of antidepressant on a patient’s prior response, patient and clinician preference, potential side effects, and cost.

2008 Guideline

(26)

2006 Guideline

New evidence was found that did not change the existing recommendation.

Antidepressants Alone or vs. Placebo*

 Montgomery, et al. (2003)(26) reviewed four RCTs examining the effectiveness of reboxetine

in the treatment of severe depression. In three of the four trials, the reboxetine group had a significantly greater decrease in Hamilton Depression Scale (HAMD) score when compared with placebo. In three of the four trials, antidepressant efficacy occurred significantly faster (at two weeks) in the reboxetine group when compared with the placebo group. In three of the four trials, the responder rate (50% improvement from baseline HAM-D score) was significantly higher in the reboxetine group (56 to 74%) compared with placebo (20 to 52%). Patients unresponsive to previous antidepressant treatment were excluded. Remission rates were not reported. Limitations of this analysis include: small number of studies, all studies included were funded by Pharmacia, the manufacturer of reboxetine, and a systematic review was not performed (unpublished studies may not have been included), the four studies were not similar in terms of duration or number of subjects, and one of the four studies had a higher baseline mean HAMD score than the rest (35.4 vs. 26.4, 27.0, and 27.2).

 One systematic review(27) found in the Cochrane Database found that TCAs, SSRIs, and

MAOIs are all effective in treating older adult patients with depression and a severe medical illness. The results, using a fixed effects model, for the three groups respectively were: TCAs: OR = 0.32 (95% CI: 0.21 to 0.47); SSRIs: OR = 0.51 (95% CI: 0.36 to 0.72); MAOIs: OR = 0.17 (95% CI: 0.07 to 0.39).

 Another Cochrane review(28) analyzed the effectiveness of antidepressants compared with

“active placebos”, based on growing concerns that differential rates of side effects between active antidepressant drugs and inactive (inert) placebos in RCTs may lead to “unblinding” of patients and clinicians to their treatment group and may potentially bias results in favor of active medication.

 All the studies in the review produced a pooled estimate of effect of 0.39 standard deviations

(95% CI: 0.24 to 0.54) in favor of antidepressants. When one strongly positive trial was omitted, sensitivity analysis reduced the pooled effect size to 0.17 (95% CI: 0.00 to 0.34). The review concludes that differences between antidepressants and active placebos are small.

 In their analysis of five systematic reviews and seven subsequent RCTs, Clinical Evidence

(Issue 14, January 2006) found a positive treatment effect of antidepressants over placebo for adults in primary and secondary care with MDD. They note, however, that there is relatively little information given about severe side effects when compared with placebo, and that publication bias has been found in RCTs of selective serotonin reuptake inhibitors.

 On average, 69% of people taking placebo had worse outcomes over a mean of six weeks

than the average person taking antidepressant drugs (mean effect size = 0.5 for change in

score with antidepressant drugs versus placebo).(29)

*

The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

(27)

 Low-dose TCAs significantly increased the proportion of people who responded at four weeks and at three to 12 months (RR = 1.65, 95% CI: 1.36 to 2.00) compared with placebo

(RR = 2.14, 95% CI: 1.41 to 3.26).(30)

 Newer antidepressants significantly increased the proportion of people who responded

compared with placebo (51% vs. 31% respectively; RR = 1.6, 95% CI: 1.5 to 1.7).(31)

 Antidepressants significantly increased the proportion of people who responded to treatment

over four to 12 weeks compared with placebo (RR = 1.9, 95% CI: 1.6 to 2.3).(32)

 Reboxetine significantly increased the proportion of people who responded at six weeks

compared with placebo (74% vs. 20% respectively, p < 0.001).(33)

 Reboxetine at any dose significantly increased the proportion of people who responded over

four weeks compared with placebo (60% vs. 35% respectively; p < 0.05).(34)

 Reboxetine significantly improved mean Social Adaptation Self-Evaluation Scale score at

eight weeks compared with placebo (35.3 vs. 27.2 respectively, p < 0.05).(35)

 Escitalopram significantly improved depressive symptoms compared with placebo at eight

weeks (change in MARDS score: -15 with escitalopram, -12 with placebo, p = 0.002).(36)

 Escitalopram 10 mg daily, escitalopram 20 mg daily, and citalopram 40 mg daily all

significantly improved depressive symptoms compared with placebo at eight weeks (change

in MADRS score from baseline: -12.8, -13.9, -12.0, -9.4 respectively; p ≤ 0.05 for all

treatments versus placebo).(37)

 Duloxetine significantly improved depressive symptoms compared with placebo (change in

HAM-D score from baseline: -10.9 vs. -6.1 respectively, p < 0.001).(38)

 In a meta-analysis (nonindustry funded) examining the efficacy and tolerability of tricyclic

antidepressants and SSRIs compared with placebo in primary care, Arroll, et al. (2005)(39)

extracted pooled data showing that both classes of antidepressant were significantly more effective than placebo. Most studies were of short duration (less than eight weeks) and of lower methodologic quality. For TCAs, the pooled NNT for improvement was about four; the NNH for withdrawal due to side effects was 5 to 11. Low doses of tricyclic

antidepressants (75 to 100 mg of amitriptyline or equivalent) were as effective as higher doses. For SSRIs, the NNT for improvement was six, the NNH for withdrawal due to side effects ranged from 21 to 94. This meta-analysis included many more studies comparing TCAs with placebo than those comparing SSRIs with placebo, and patients’ severity of depression was heterogeneous across studies. The authors conclude that “prescribing antidepressants in primary care is a more effective clinical strategy than prescribing placebo.”

(28)

Head-to-Head Comparisons of Antidepressants*

 At the end of an eight week randomized trial with no placebo control subjects, Moore, et al.

(2005)(40) found that patients treated with escitalopram had significantly greater adjusted

(2.1 points, p < 0.05) decrease in MADRS (Montgomery-Asberg Depression Rating Scale) scores from baseline and higher responder (76.1% vs. 61.3%, p < 0.01) and remitter rates (56.1% vs. 46.3%, p < 0.05) compared with patients treated with citalopram. Adverse effects and treatment withdrawals were not significantly different between groups. Both the

difference in mean score changes from baseline, and the calculated difference between mean MADRS scores at endpoint (13.9 vs. 15.4 points) are of marginal clinical significance.

 In a small Japanese study examining the efficacy and safety of fluvoxamine and nortriptyline,

Otsubo, et al. (2005)(41) found no significant differences in total HAMD score change

(-9 vs. -12, p = 0.14), CGI (Clinician rating of Global Improvement) scores (figures not reported, p = 0.055), responder rates (55.6% vs. 57.9% on HAMD, 52.8% vs. 44.7% on CGI) or HAMD remission rates (38.9% vs. 26.3%). The authors state that the incidence of adverse events was generally higher in nortriptyline-treated patients, but no statistical analysis of significance was reported.

 In a six week study with small sample sizes (n = 41 patients), Wehmeier, et al. (2005)(42)

found that geriatric patients taking fluoxetine had the same HAMD treatment response (57.1% vs. 60.0%) and improvement in HAMD scores (11.9 vs. 15.8 points) as those taking trimipramine. The fluoxetine group reported fewer adverse events than the trimipramine group (54.5% vs. 66.7%) but no statistical analysis of significance was performed. The authors conclude that the two drugs are similar in terms of effectiveness and tolerability.

 In a two-phase study (eight week acute phase and six month continuation phase) Detke,

et al. (2004)(43) tested the effectiveness of duloxetine (both 80 mg and 120 mg doses) and

paroxetine against a placebo control. In the acute phase, the authors found both doses of duloxetine and paroxetine to be statistically significantly different from placebo on all of the following outcomes: HAMD score reduction (range -11 to -12.1 points), response rates (70 to 82%), and remission rates (47 to 58%). In the continuation phase, of all the treatment groups, the higher dose of duloxetine had the longest time to loss of response when compared with placebo (p = 0.023). The adverse events ranged from 4 to 11.4%, statistical significance was not reported). Despite the implication of superiority of duloxetine, it should be noted that there was no statistical analysis comparing duloxetine with paroxetine, and duloxetine was used at doses higher than currently recommended by the manufacturer.

 Sechter, et al. (2004)(44) compared milnacipran and paroxetine and found no significant

differences between the two drugs on any of the following measures: HAMD score reduction from baseline (-11.8 vs. -12 points), MADRS score reduction (-16.2 vs. -16.8 points), response rate (58.1 vs. 60.3%), and remission rate (33.1% vs. 35.1%). The paroxetine group had significantly greater post-treatment discontinuation symptoms

(31.8% vs. 13.0%) (p = 0.032). The study was funded by the manufacturer of milnacipran.

*

The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

(29)

 In a multicenter, 22 week study of 151 geriatric outpatients, Allard, et al. (2004)(45) examined the efficacy and tolerability of venlafaxine compared with citalopram, and found that both treatment groups showed comparable improvements in MADRS score (-18 vs. -17.4 points) over time. The incidence of spontaneously reported side effects/adverse effects was higher in the venlafaxine group than in the citalopram group (62% vs. 43% respectively), but no

statistical analysis was performed to evaluate this difference. Treatment discontinuation due to side effects was rare (less than 10% in each group).

 In an eight week trial, Montgomery, Huusom, & Bothmer (2004)(46) compared escitalopram

and venlafaxine and found no significant differences between groups on MADRS (-20.7 vs. -20.4 points) or HAMD (-14.4 vs. -14 points) scores. The escitalopram group achieved response and remission significantly faster than the venlafaxine group (4.6 days p < 0.05 and 6.6 days p < 0.001 respectively). These authors found greater incidences of side effects in the venlafaxine group, specifically nausea, constipation and sweating (p < 0.05), but overall treatment discontinuation rates were similar (14.4% vs. 13.3%).

 Rapaport (2003)(47) studied the efficacy of paroxetine controlled release (CR) compared with

paroxetine immediate release (IR) and placebo. A statistically significant adjusted difference compared with placebo was found for both active treatments in HAMD total score change (-12.1 and -12.3 points vs. -9.5 points), CGI response rate (43% and 44% vs. 26%) and HAMD remission rate (72% and 65% vs. 52%) at 12 weeks. Post-hoc analysis noted that patients with chronic depression (duration of more than two years) responded as well as those with short-term depression. Statistical comparisons between active treatments were not reported. Withdrawal due to adverse events was highest in the paroxetine IR group, (16% vs. 12.5% vs. 8.3% for placebo) but statistical significance was not evaluated. Two authors were either employees or major stockholders of the company funding the study.

 Sauer, Uppertz-Helmhold & Dierkes (2003)(48) found noninferiority of venlafaxine ER

compared with amitriptyline ER, based on equivalent changes in HAMD to

References

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