Research report
Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults.: III. Pharmacotherapy

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Abstract

Background

In 2001, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT) partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders. A revision of these guidelines was undertaken by CANMAT in 2008–2009 to reflect advances in the field.

Methods

The CANMAT guidelines are based on a question–answer format to enhance accessibility to clinicians. An evidence-based format was used with updated systematic reviews of the literature and recommendations were graded according to Level of Evidence using pre-defined criteria. Lines of Treatment were identified based on criteria that included Levels of Evidence and expert clinical support. This section on “Pharmacotherapy” is one of 5 guideline articles.

Results

Despite emerging data on efficacy and tolerability differences amongst newer antidepressants, variability in patient response precludes identification of specific first choice medications for all patients. All second-generation antidepressants have Level 1 evidence to support efficacy and tolerability and most are considered first-line treatments for MDD. First-generation tricyclic and monoamine oxidase inhibitor antidepressants are not the focus of these guidelines but generally are considered second- or third-line treatments. For inadequate or incomplete response, there is Level 1 evidence for switching strategies and for add-on strategies including lithium and atypical antipsychotics.

Limitations

Most of the evidence is based on trials for registration and may not reflect real-world effectiveness.

Conclusions

Second-generation antidepressants are safe, effective and well tolerated treatments for MDD in adults. Evidence-based switching and add-on strategies can be used to optimize response in MDD that is inadequately responsive to monotherapy.

Introduction

The Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT), a not-for-profit scientific and educational organization, collaborated on the publication in 2001 of evidence-based clinical guidelines for the treatment of depressive disorders (Kennedy and Lam, 2001). A revision of these guidelines was undertaken by CANMAT in 2008–2009 to update the recommendations based on new evidence. The scope of these guidelines encompasses the management of adults with unipolar major depressive disorder (MDD). This section on Pharmacotherapy is one of 5 guideline articles. There are separate CANMAT guidelines for bipolar disorder (Yatham et al., 2009).

Pharmacotherapy remains the most studied and best evidenced treatment for MDD. Since 2000, at least 225 RCTs, 145 meta-analyses and 3 major systematic reports have been published on antidepressant medications for MDD. Despite this proliferation of data, it is widely recognized that the methodology of RCTs for antidepressants (including strict inclusion/exclusion criteria, intensive and frequent contact, short study duration, etc.), which are primarily conducted by pharmaceutical companies for registration of new medications, may not reflect real world clinical practice (Kennedy and Lam, 2001). While the past few years have also seen the emergence of larger scale effectiveness trials to address real-world generalizability, such as the U.S. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (Rush et al., 2004), these trials are still limited by many methodological deficiencies and some of the most important clinical questions remain unanswered. Hence, the recommendations are presented as guidance for clinicians who should consider them in the context of individual patients, and not as standards of care.

Section snippets

Methods

The full methods have been described elsewhere (Kennedy et al., 2009b) but, in summary, relevant English language studies published from January 1, 2000 to December 31, 2008 were identified using computerized searches of electronic databases (PubMed, PsychInfo, Cochrane Register of Clinical Trials), inspection of bibliographies, and review of other guidelines and major reports. The question–answer format of the previous guidelines has been retained based on feedback from clinicians.

What are the principles of pharmacotherapy management?

General principles of treatment with pharmacotherapy are similar to those for other treatment modalities for depression (Patten et al., 2009). Table 2 summarizes these principles, as adapted for pharmacotherapy. Adherence deserves special attention because early discontinuation rates of antidepressants are high. Although clinical practice guidelines recommend that the minimum duration of antidepressant treatment for MDD should be 6–12 months, about 30% of patients discontinue medications within

How long do you wait for a clinical response?

Most clinical trials define “clinical response” as ≥50% reduction in the score on a depression rating scale and “clinical remission” as a score within the “normal range” of the scale. Clinical lore states that the lag time for antidepressant therapeutic effects may be 2–4 weeks or longer. However, recent studies have shown an earlier onset of action, especially in those patients who eventually respond. Several recent meta-analyses concluded that onset of antidepressant effect can occur within 1–2

Which antidepressants can be used during pregnancy?

Since the previous guidelines in 2001, there have been no RCTs evaluating the safety and efficacy of antidepressants during pregnancy. The evidence remains limited to small studies or case control/cohort designs, often with many confounding variables and conflicting results. For example, comparison groups usually include women who are not using antidepressants but who are not necessarily depressed, so potential adverse effects associated with depression itself are not taken into account (Table

Role of funding source

These guidelines were entirely funded with internal funding from the Canadian Network for Mood and Anxiety Treatments; no external funds were sought or received.

Conflict of interest

RWL is on Speaker/Advisory Boards for, or has received research funds from: Advanced Neuromodulation Systems Inc., AstraZeneca, BrainCells Inc., Biovail, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Research Foundation, Eli Lilly, Janssen, Litebook Company Ltd., Lundbeck, Lundbeck Institute, Mathematics of Information Technology and Advanced Computing Systems, Michael Smith Foundation for Health Research, Servier, Takeda, UBC

Acknowledgments

CANMAT thanks the external reviewers: Murray W. Enns, MD, FRCPC (University of Manitoba), Glenda M. MacQueen, MD, PhD, FRCPC (University of Calgary) and Allan H. Young, MBChB, MPhil, PhD, FRCPsych (UK) (University of British Columbia).

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