Adult Depression Clinical Practice Guideline

Transcription

1 NATIONAL CLINICAL PRACTICE GUIDELINE Adult Depression Clinical Practice Guideline 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. Approved by the National Guideline Directors February 2012

2 Table of Contents Introduction... 1 Guideline Summary... 5 Rationale Statements First-Line Treatment of Major Depressive Disorder (MDD) Hypericum (St. John s Wort) for MDD Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, Or Plan Second-Line Treatment Of MDD Length Of Treatment With Antidepressants In Patients With MDD Follow-Up For Patients In The Acute Phase of Treatment For MDD Follow-Up For Patients In The Continuation Phase of Treatment of MDD Follow-Up For Patients In Maintenance Phase of Treatment of MDD Discontinuation of Antidepressants in Patients with MDD Treatment Preferences For MDD In Different Ethnic Groups Patient Self-Management Strategies for Improving Symptoms of MDD Behavioral Health Education Classes For Adults With MDD Antidepressants To Avoid During Pregnancy or Breastfeeding Appendix A: Criteria for Grading the Evidence Appendix B: Supporting Documentation First-Line Treatment of Major Depressive Disorder (MDD) Problem Formulation Search Strategy Evidence Tables Hypericum (St. John s Wort) For Treatment of MDD Problem Formulation Search Strategy Evidence Tables Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, or Plan Problem Formulation Search Strategy Evidence Tables Second-Line Treatement of MDD Problem Formulation Search Strategy Evidence Tables i National Adult Depression Clincial Practice Guideline

3 5. Length of Treatment With Antidepressants In Patients With MDD Problem Formulation Search Strategy Evidence Tables Follow-Up For Patients In The Acute Phase of Treatment For MDD Problem Formulation Search Strategy Evidence Table Follow-Up For Patients In The Continuation Phase of Treatment For MDD Problem Formulation Search Strategy Evidence Table Follow-Up For Patients In Maintenance Phase Treatment Of MDD Problem Formulation Search Strategy Evidence Table Discontinuation of Antidepressants In Patients With MDD Problem Formulation Search Strategy Evidence Tables Treatment Preferences For MDD In Different Ethnic Groups Problem Formulation Search Strategy Evidence Table Patient Self-Management Strategies For Improving Symptoms of MDD Problem Formulation Search Strategy Evidence Tables Behavioral Health Education Classes For Adults With MDD Problem Formulation Search Strategy Evidence Tables Antidepressants To Avoid During Pregnancy or Breastfeeding Problem Formulation Search Strategy Evidence Tables References ii National Adult Depression Clincial Practice Guideline

4 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 ). 1 National Adult Depression Clincial Practice Guideline

5 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 peerreviewed 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 The GQ Committee reviewed and approved the guidelines in February 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 consensusbased. 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 consensusbased 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. 2 National Adult Depression Clincial Practice Guideline

6 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 david.price@kp.org Devon McCabe, MA Care Management Consultant Care Management Institute 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 Tabitha Pousson Staff Assistant Care Management Institute 3 National Adult Depression Clincial Practice Guideline

7 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 Kerri Gaughan, PharmD, BCPP Clinical Pharmacy Specialist, Mental Health 4 National Adult Depression Clincial Practice Guideline

8 Guideline Summary 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. 1. First-Line Treatment of Major Depressive Disorder (MDD) 1A 1B 1C 1D 1E For patients with mild to moderate Major Depressive Disorder (MDD), use either antidepressant medication or psychotherapy * as first-line treatment. Evidence-based: B 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 For patients with severe or chronic MDD, combine antidepressant use and psychotherapy * as first-line treatment. Evidence-based: B 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 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) 5 National Adult Depression Clincial Practice Guideline

9 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. 2B 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 * 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 3B For patients with Major Depression expressing suicidal intent or plan, the GDT recommends consultation with specialty behavioral health. Consensus-based 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. 6 National Adult Depression Clincial Practice Guideline

10 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. 4E 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 The GDT recommends against providing augmentation with pindolol for patients with MDD whose symptoms fail to remit after adherence to first-line treatment. Evidence-based 7 National Adult Depression Clincial Practice Guideline

11 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 between patient and clinician, or phone calls/ between patient and a care manager. The use of 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. 8 National Adult Depression Clincial Practice Guideline

12 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 8B 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 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 9B Fluoxetine may be discontinued, without tapering, with a relatively low risk of adverse effects. Evidence-based 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 between patient and clinician, or phone calls/ between patient and a care manager. The use of 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. 9 National Adult Depression Clincial Practice Guideline

13 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/computer programs 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. 10 National Adult Depression Clincial Practice Guideline

14 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. Consensus-based 11 National Adult Depression Clincial Practice Guideline

15 Rationale Statements 1. First-Line Treatment of Major Depressive Disorder (MDD) 1A 1B 1C 1D 1E For patients with mild to moderate Major Depressive Disorder (MDD), use either antidepressant medication or psychotherapy * as first-line treatment. Evidence-based: B 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 For patients with severe or chronic MDD, combine antidepressant use and psychotherapy * as first-line treatment. Evidence-based: B 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 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. 12 National Adult Depression Clincial Practice Guideline

16 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) PATIENT FAMILY, SOCIAL, OR OCCUPATIONAL IMPAIRMENT 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 rates, discontinuation rates due to adverse events, or rates of adverse events. 13 National Adult Depression Clincial Practice Guideline

17 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 dualaction 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-tohead 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. 14 National Adult Depression Clincial Practice Guideline

18 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 > )). 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. 15 National Adult Depression Clincial Practice Guideline

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 metaanalysis 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. 16 National Adult Depression Clincial Practice Guideline

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 metaanalysis 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: )] or withdrawal [OR = 1.21 (95% CI: )] 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. 17 National Adult Depression Clincial Practice Guideline

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: ); 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. 18 National Adult Depression Clincial Practice Guideline

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: ); 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. 19 National Adult Depression Clincial Practice Guideline

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 was an 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) ). 20 National Adult Depression Clincial Practice Guideline