Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition

This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition' . The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.

# Introduction
Depression is a highly prevalent mental disease that is prone to recurrence and chronicity, and the WHO forecasted that this disease would be second only to heart disease as a cause of loss of healthy years by 2020. Nevertheless, due to its pathological features, the treatment of depression has not been systematized, but is dependent on the experience of individual pathologists. As an attempt to overcome such circumstances, ceaseless efforts have been made worldwide for the development of an evidence-based clinical practice guideline that would suggest therapeutic recommendations systematically [bib_ref] Kasper S; the Executive Committee for the Korean Medication Algorithm Project for..., Lee [/bib_ref].
The treatment guideline development team judged that the Republic of Korea currently has, at least, the minimum infrastructure needed for producing an evidencebased clinical practice guideline. This decision was based on the improved national environment, in which rapidly growing information and communication networks now provide up-to-date knowledge on treatment, which can be accessed and applied efficiently. In 2005, the Republic of Korea Government began to take note of the seriousness of major depressive disorder (MDD) and realized that a guideline would be essential for the improv ed and systematic treatment of depression, and at last decided to build a national depression clinical research center as a national health and medical treatment technology infrastructure development project. Our research team developed the "Evidence-based, Pharmacological Treatment Guideline for Depression in Korea" in 2008, and developed the "Evidence-based, Non-pharmacological Treatment Guideline for Depression in Korea" in 2010 [bib_ref] Evidence-based, non-pharmacological treatment guideline for depression in Korea, Park [/bib_ref]. Due to the limitations of the initial pharmacological treatment guideline, the accumulation of new clinical information with time, and the emphasis on the importance of a guideline reflecting the current local clinical situation, the "Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition" was released in 2012. In an attempt to inform Korean practitioners of the recommendations made in the revised edition, tients, such as the initiation of antidepressant treatment, efficacy and side effects of treatment, increase in drug dosage, and augmentation, combination, and switching of medication.

## Adaptation process
The clinical practice guideline adaptation manual (version 1.0), which was originally developed by the ADAPTE Collaboration, translated under the official approval of the original Bureau of Clinical Research Support Center, and modified to fit the current clinical environment of Korea, was used for the adaptation and revision of this new guideline. The guideline went through most of the processes proposed in the modified manual.

## Search of treatment guidelines
A comprehensive search of the National Guideline Clearinghouse, NHS Evidence, Guidelines International Network, and PubMed was conducted. 2,526 articles were identified, and among them, only the guidelines prepared by governments, states, or learned societies were selected from the search list. Based on these inclusion criteria, 21 depression treatment guidelines were selected.

## Evaluation of treatment guidelines
The 21 studies on treatment guidelines for depression were selected and evaluated by a working group composed of a psychiatrist, a specialist on preventive medicine, and a clinical psychologist, using the AGREE II Tool. The selected studies were assessed for all of the 6 domains of AGREE II, that is, the scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. The total score was converted to a percentile, and depending on the converted scores, weighted values were assigned as follows: 3 points for a score 60 and above, 2 points for 40 and above but less than 60, 1 point for a score below 40. The points were then summed (with the total of 18 points). Among the studies, 12 articles were found to be of good quality and were finally selected as shown in [fig_ref] Table 1: Twelve clinical practice guidelines for depression Formal title, Development group, Year of... [/fig_ref]. The consistency of the evidence itself, the interpretation of evidence, and the recommendations in each treatment guideline were reviewed. The scientific feasibility of the treatment guidelines was also reviewed and integrated by examining the validity, the standard level and the consistency of the evidence, and the concordance with other treatment guidelines.

## Recommendation grades
Expert panel meetings were held for the selection of recommendation statements. A total of 12 experts participated in the evaluation, scoring each statement on a scale of 1 to 9 (1, most inappropriate and 9, most appropriate). Panel meetings were held face to face after preliminary evaluation, results and problems were reviewed and the recommendations were amended, with a second evaluation taking place [bib_ref] Going from evidence to recommendations, Guyatt [/bib_ref].

## Treatment guideline preparation
Once the content of the adapted treatment guideline was decided upon, all past processes were recorded in the guideline draft in detail. The main principles of the drafting process are as follows: The process is transparent and accurate, the content of reference studies is reflected accurately and the studies are appropriately referenced, and it is acknowledged that the original treatment guideline developers have made great contribution. This guideline was prepared based on these principles.

## External expert review and approval
The guideline draft was reviewed by five experts (peer review), and the results of the reviews were also reflected in this guideline. A public hearing was held to collect the stakeholders' opinions. Finally the approval of the Korean Neuropsychiatric Association was obtained on April 13, 2011.

## Key questions and recommendations
Key question 1. What is the first-line treatment agent among antidepressants?

## Evidence
In order to be considered a first-line antidepressant, the antidepressant must have the same efficacy as tricyclic antidepressants (TCAs), a favorable tolerance level, and a high safety level even when taken in large doses. As there is sufficient evidence that selective serotonin reuptake inhibitors (SSRIs) satisfy these qualifications, the New Zealand guidelines group, National Institute for Health and Clinical Excellence (NICE), British Association for Psychopharmacology (BAP), and the Clinical Research Center for Depression guidelines have strongly recommended SS-RIs as a first-line treatment agent [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. Furthermore, the Canadian Network for Mood and Anxiety Treatments (CAN-MAT), American Psychiatric Association (APA), and Northern Sydney Central Coast Mental Health Drug & Alcohol (NSCC-MHDA) and University of Sydney CADE Clinic guidelines have recommended serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs) and norepinephrine and specific serotonergic antidepressants (NaSSAs) as first-line antidepressants [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. TCAs are as effective as SSRIs; however, TCAs have many adverse effects, poor tolerability, and high discontinuation rates. Therefore, TCAs are not recommended as first-line treatment agents [bib_ref] A meta-analysis of the efficacy and tolerability of paroxetine versus tricyclic antidepressants..., Montgomery [/bib_ref] [bib_ref] Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its..., Puech [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref]. However, patients with melancholic depression or patients who have responded well to TCAs previously are recommended to use TCAs as first-line treatment agents.

## Recommendations
SSRIs, SNRIs, NDRIs, and NaSSAs are strongly recommended as first-line treatment agents. However, TCAs are weakly recommended as first-line agents, depending on patient factors and medication costs. The APA guideline described SSRIs as superior in their safety profile and tolerability. The BAP and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines described SSRIs as having better tolerability than TCAs, and having a lower discontinuation rate [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Initial antidepressant choice in primary care: effectiveness and cost of fluoxetine vs..., Simon [/bib_ref] [bib_ref] Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review, Vaswani [/bib_ref]. In addition, the New Zealand guidelines group reviewed 13 studies on the effects of antidepressants and concluded that SSRIs were superior in tolerability to other antidepressants such as TCAs and venlafaxine.

## Recommendations
In patients with low tolerability to antidepressant medication, SSRIs are weakly recommended as a treatment agent.

## Key question 3. what factors influence the choice of antidepressant medication?

## Evidence
The NICE, CANMAT, BAP, Hong Kong, ACP, NSCCMHDA and University of Sydney CADE Clinic, and WFSBP guidelines have recommended considering the potential side effects of the medication and previous history of side effects when on that medication [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The APA, BAP, Hong Kong, ACP, and WFSBP guidelines have recommended considering the preference of and acceptability to the patient [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The CANMAT, APA, Hong Kong, ACP, and WFSBP guidelines have also recommended considering the cost of treatment [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. Furthermore, the CANMAT guideline has also recommended considering the age, sex, severity of the illness, availability of medication, and discontinuation symptoms [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] , while the BAP, NSCCMHDA and University of Sydney CADE Clinic, and WFSBP guidelines have recommended considering adherence to medication and family history of medication [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. Finally, the WFSBP guideline has also recommended considering the physician's experience with a given drug [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref].

## Recommendations
It is strongly recommended that the potential side effects of the medication, patient history of having side effects when taking medication, drug interaction, previous treatment response, preference of and acceptability to the patient, cost of treatment, and co-existing diseases all be considered when selecting antidepressants.

## Recommendations
It is strongly recommended that antidepressants be augmented with antipsychotic medication in psychotic depression.

## Key question 4-3.
Which antidepressant is most efficacious in the treatment of seasonal depression?

## Evidence
The NICE, CANMAT, APA, and BAP guidelines noted that taking bupropion may prevent major depressive episodes in the winter [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. The BAP and WFSBP guidelines have recommended sertraline (28) and fluoxetine [bib_ref] Multicenter, placebo-controlled study of fluoxetine in seasonal affective disorder, Lam [/bib_ref] for the treatment of seasonal depression [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The NICE guideline maintained that evidence on antidepressants being effective in treating seasonal depression is insufficient; however, the evidence supports that antidepressants are effective in preventing depression.
The WFSBP guideline described SSRIs as having efficacy in treating seasonal depression; however, SSRIs take longer to treat symptoms than light therapy and have more side effects [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Multicenter, placebo-controlled study of fluoxetine in seasonal affective disorder, Lam [/bib_ref] [bib_ref] Effects of fluoxetine versus bright light in the treatment of seasonal affective..., Ruhrmann [/bib_ref].

## Recommendations
Although there is not much evidence on the efficacy of antidepressants in the treatment of seasonal depression, SSRIs and bupropion may be weakly recommended as a treatment modality.
The NICE and APA guidelines have described moclobemide as more efficacious than placebo. The NICE guideline reported that an HRSD score improvement of over 50% was superior to placebo. The APA guideline reported that 6 mg per day of transdermal selegiline for 6 weeks was shown to be more efficacious in 177 MDD patients compared to placebo [bib_ref] A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal..., Amsterdam [/bib_ref] [bib_ref] Selegiline transdermal system for the treatment of major depressive disorder: an 8-week,..., Feiger [/bib_ref]. The NICE guideline noted that evidence of tolerability is not sufficient.

## Recommendations
It is strongly recommended that MAOIs are more efficacious than placebo in the treatment of depression.
Key question 5-3. Are SSRIs (including escitalopram) more efficacious than placebo in the treatment of depression?

## Evidence
The New Zealand guidelines group, NICE, APA, BAP, Hong Kong, WFSBP, and Clinical Research Center for Depression guidelines have all described SSRIs to be superior to placebo in treating depression . In particular, the NICE guideline described SSRIs as having greater efficacy than placebo with HDRS improvement of more than 50%, with similar effects in moderate, severe, and extremely severe depression. The BAP guidelines described SSRIs as having a 61% response rate, whereas placebos had a 50% response rate [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. The WFSBP guideline also suggested as evidence, double-blind studies reporting SSRIs as being more efficacious than placebos [bib_ref] Symptom reduction and suicide risk in patients treated with placebo in antidepressant..., Khan [/bib_ref] [bib_ref] Tollefson GD. Meta-analysis of randomised controlled trials of fluoxetine v. placebo and..., Bech [/bib_ref]. However, the NICE guideline described the difference in remission rate to be non-significant, and although a significant difference was shown in moderate and extremely severe depression, the effect was not clinically relevant.

## Recommendations
It is strongly recommended that SSRIs are more efficacious than placebo in the treatment of depression.

## Key question 5-4.
Are SNRIs (venlafaxine, duloxetine) more efficacious than placebo in the treatment of depression?

## Evidence
The NICE and APA guidelines have described duloxetine and venlafaxine as being more efficacious than placebo. Three studies that compared the efficacy of duloxetine and placebo reported duloxetine to be superior, and the effect size was also statistically superior. At the end of treatment, duloxetine seemed to be efficacious in the improvement of HDRS compared to placebo. However, pain associated with depression showed no significant difference. The discontinuation rate at the early stages of treatment was twice as high for duloxetine compared to placebo, but the discontinuation due to ineffectiveness was twice as high for placebo.

## Recommendations
It is strongly recommended that duloxetine and venlafaxine are more efficacious than placebo in the treatment of depression.

## Key question 5-5.
Are NaSSAs (mirtazapine) more efficacious than placebo in the treatment of depression?

## Evidence
The APA and Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines have described mirtazapine as having superior efficacy compared to placebo. A meta-analysis comparing 6 studies reported that when mirtazapine was taken for 6-8 weeks, superior treatment efficacy was observed compared to placebo [bib_ref] Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the..., Bech [/bib_ref]. Furthermore, the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guideline identified mirtazapine as having superior antidepressant effects compared to placebo, based on many doubleblind studies and meta-analyses (level 1).

## Recommendations
It is strongly recommended that mirtazapine is more efficacious than placebo in the treatment of depression.
Key question 5-6. Are NDRIs (bupropion) more efficacious than placebo in the treatment of depression?

## Evidence
The APA and the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines reported bupropion to be more efficacious than placebo. Bupropion showed superior efficacy in the treatment of depression in the acute phase compared to placebo [bib_ref] Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL, Modell [/bib_ref] , and all three forms of bupropion are more efficacious than placebo [bib_ref] 15 years of clinical experience with bupropion HCl: from bupropion to bupropion..., Fava [/bib_ref]. In addition, the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guideline found bupropion to be more efficacious than placebo, based on many double-blind studies (level I).

## Recommendations
It is strongly recommended that bupropion is more efficacious than placebo in the treatment of depression.

## Key question 5-7.
Are serotonin antagonist and reuptake inhibitors (SARIs, trazodone) more efficacious than placebo in the treatment of depression?

## Evidence
The APA and Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines described trazodone as having a superior antidepressant effect over placebo. Trazodone is still widely used, and shows better antidepressant effects compared to placebo [bib_ref] Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the..., Bech [/bib_ref] [bib_ref] Bupropion in depression: a tri-center placebo-controlled study, Pitts [/bib_ref]. Therefore, trazodone is recommended as more efficacious than placebo.

## Recommendations
It is strongly recommended that trazodone is more efficacious than placebo in the treatment of depression.
Key question 6. Is there a difference among the efficacies of antidepressants?
Key question 6-1. When compared to other antidepressants, do TCAs have a different antidepressant efficacy?

## Evidence
The NICE, APA, and BAP guidelines have described amitriptyline to be equal or slightly more effective than other antidepressants (SSRIs, SNRIs, MAOIs) [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. Especially in the case of inpatients, amitriptyline showed a slightly higher efficacy than other TCAs or SSRIs [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref] [bib_ref] Amitriptyline v. the rest: still the leading antidepressant after 40 years of..., Barbui [/bib_ref] [bib_ref] Amitriptyline versus other types of pharmacotherapy for depression, Guaiana [/bib_ref]. In addition, in melancholic depression and severe depression, its efficacy was superior to SSRIs [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref]. However, many side effects have been reported, and treatment can also be terminated due to the side effects.

## Recommendations
It is strongly recommended that TCAs show a similar efficacy to other antidepressants. [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref]. A meta-analysis on 12 reversible inhibitor of MAOA studies reported that moclobemide did not show a difference in efficacy compared to imipramine and clomipramine in admitted patients with severe depression or psychotic depression [bib_ref] Moclobemide and tricyclic antidepressants in severe depression: meta-analysis and prospective studies, Angst [/bib_ref].

## Recommendations
It is strongly recommended that MAOIs show equal efficacy to other antidepressants and moclobemide also shows equal efficacy.
Key question 6-3. When compared to other antidepressants, do SSRIs have a different antidepressive efficacy?

## Evidence
The New Zealand guidelines group, NICE, CANMAT, APA, Hong Kong, and ACP guidelines described SSRIs as having similar antidepressant effects to other agents but better tolerability [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. More than ten meta-analyses have reported SSRIs to be as effective as TCAs [bib_ref] A meta-analysis of the efficacy and tolerability of paroxetine versus tricyclic antidepressants..., Montgomery [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref] [bib_ref] Fluoxetine versus other types of pharmacotherapy for depression, Cipriani [/bib_ref] [bib_ref] Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants..., Macgillivray [/bib_ref] [bib_ref] Antidepressants versus placebo for depression in primary care, Arroll [/bib_ref] , and many studies have reported that there is not much evidence that other antidepressants are more effective than SSRIs [bib_ref] Fluoxetine versus other types of pharmacotherapy for depression, Cipriani [/bib_ref] [bib_ref] Are SSRIs really more effective for anxious depression?, Panzer [/bib_ref] [bib_ref] SSRIs versus other antidepressants for depressive disorder, Geddes [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic and heterocyclic antidepressants: comparison of drug..., Barbui [/bib_ref] [bib_ref] Efficacy of escitalopram in the treatment of major depressive disorder compared with..., Kennedy [/bib_ref] [bib_ref] Comparative benefits and harms of second-generation antidepressants: background paper for the American..., Gartlehner [/bib_ref]. Furthermore, the New Zealand guidelines group reported that escitalopram is superior to other SSRIs and venlafaxine [bib_ref] Efficacy of escitalopram in the treatment of major depressive disorder compared with..., Kennedy [/bib_ref]. SSRIs are also relatively safe when taken in large amounts, so they are recommended as a first-line treatment and also to patients with a risk of suicide. However, some studies have reported that SN-RIs are superior to SSRIs in the remission of symptoms [bib_ref] The effect of venlafaxine compared with other antidepressants and placebo in the..., Bauer [/bib_ref].

## Recommendations
It is strongly recommended that SSRIs show similar efficacy to other antidepressants. . The CANMAT guideline described venlafaxine to be superior to duloxetine, fluoxetine, and pooled SSRIs, and duloxetine to be superior to paroxetine and pooled SSRIs [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. The APA guideline reported venlafaxine and duloxetine to be as effective as SSRIs [bib_ref] A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of..., Perahia [/bib_ref] [bib_ref] Efficacy of duloxetine and selective serotonin reuptake inhibitors: comparisons as assessed by..., Thase [/bib_ref]. A few studies have recommended SNRIs as more beneficial than SSRIs [bib_ref] The effect of venlafaxine compared with other antidepressants and placebo in the..., Bauer [/bib_ref]. However, there is evidence that patients taking venlafaxine discontinue the drug due to its side effects. In addition, whereas venlafaxine has proven to have an efficacy equal to TCA, there are not yet systematic studies comparing the efficacy of duloxetine and TCAs [bib_ref] The effect of venlafaxine compared with other antidepressants and placebo in the..., Bauer [/bib_ref] [bib_ref] Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and..., Smith [/bib_ref].
A meta-analysis comparing 105 studies on the difference in efficacy among antidepressants reported that no specific difference exists among the agents.

## Recommendations
It is strongly recommended that SNRIs have a similar antidepressive efficacy compared to other antidepressants.
Key question 6-5. When compared to other antidepressants, do NaSSAs (mirtazapine) have a different antidepressive efficacy?

## Evidence
The NICE, CANMAT, APA, BAP, ACP, WFSBP, Clinical Research Center for Depression, and the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines have described mirtazapine as having equal treatment efficacy to other antidepressants [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The NICE guideline described the possibility of reaching remission and decreasing depressive symptoms was greater compared to SSRIs, but no clinical significance was observed. However, mirtazapine was described to be less prone to early discontinuation compared to other antidepressants. The APA and Clinical Research Center for Depression guidelines described mirtazapine as having earlier onset of treatment efficacy compared to fluoxetine, paroxetine, and sertraline [bib_ref] Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the..., Bech [/bib_ref] [bib_ref] Mirtazapine compared with paroxetine in major depression, Benkert [/bib_ref] , but no significant difference was observed in the response rate. The APA guideline described mirtazapine as having equal efficacy to SSRIs.

## Recommendations
It is strongly recommended that mirtazapine has a similar anti-depressive efficacy as other antidepressants.
Key question 6-6. When compared to other antidepressants, do NDRIs (bupropion) have a different antidepressive efficacy?

## Evidence
The APA guideline described SSRIs to be more effective in patients diagnosed with depression and anxiety compared to bupropion [bib_ref] Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment..., Papakostas [/bib_ref]. However bupropion is effective for symptoms of fatigue and drowsiness and is FDA approved for cessation of smoking, and does not cause too much weight gain.

## Recommendations
Bupropion may be weakly recommended to be effective as other antidepressants.
Key question 6-7. When compared to other antidepressants, do SARIs (trazodone) have a different antidepressive efficacy?

## Evidence
The APA and Clinical Research Center for Depression guidelines reported trazodone to have an efficacy equal to that of TCAs and other antidepressants. However, the CANMAT guideline described trazodone as not having a superior antidepressive efficacy compared to mirtazapine [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] Which antidepressants have demonstrated superior efficacy? a review of the evidence, Montgomery [/bib_ref] , and the APA guideline described trazodone as showing inferior efficacy when treating severe depression or depression with severe psychomotor retardation compared to other antidepressants [bib_ref] Effectiveness of antidepressants: meta-analysis of dose-effect relationships in randomised clinical trials, Bollini [/bib_ref] [bib_ref] A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and..., Rudolph [/bib_ref].

## Recommendations
Trazodone may be weakly recommended to show similar antidepressive efficacy compared to other antidepressants.

## Key question 7.
When is the appropriate time to assess treatment efficacy if symptoms do not improve with antidepressant treatment?

## Evidence
The NICE, CANMAT, and WFSBP guidelines have recommended 2-4 weeks as the appropriate time for assessment, and the BAP, Hong Kong, and Clinical Research Center for Depression guidelines have recommended at least 4 weeks before assessment [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The New Zealand guidelines group and TDMHMR in collaboration with Texas universities guidelines recommended 4-6 weeks, the APA guideline recommended 4-8 weeks, and the ACP guideline recommended 6-8 weeks [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref].

## Recommendations
When there is no improvement or only mild improvement of symptoms (25%), it is strongly recommended that treatment ef- (62). Phenelzine was reported to show an increased treatment response with an increase in dosage in the moderate-to high-dose range [bib_ref] High dose tranylcypromine therapy for refractory depression, Amsterdam [/bib_ref].

## Recommendations
It is strongly recommended that when there is no response to first-line treatment with MAOIs, increasing the dose may help treatment.
Key question 9-3. When treatment with SSRIs (including escitalopram) does not result in a treatment response, does increasing the dosage help achieve treatment response?

## Evidence
The APA guideline reported that a higher dosage of SSRIs is more effective. MDD patients were assigned randomly to 0, 10, 20, 40, or 60 mg/day, and it was reported that the groups taking 10-20 mg showed more improvement than the placebo-treated group, but less improvement than the group taking 40-60 mg [bib_ref] Moclobemide twice daily in the treatment of major depressive episode: a double-blind,..., Gagiano [/bib_ref]. However, the groups taking 20, 30, and 40 mg showed more side effects than the placebo group. The BAP guideline reported 20 mg of escitalopram as having better efficacy than 10 mg (13). On the other hand, the Clinical Research Center for Depression guideline indicated that increasing the dosage of fluoxetine and sertraline in treatment-resistant MDD patients did not significantly improve symptoms compared to maintaining the same dosage in such patients [bib_ref] Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients, Burke [/bib_ref] [bib_ref] Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects..., Bech [/bib_ref]. Furthermore, a previous study reported that an increase in the dosage of paroxetine did not significantly improve symptoms [bib_ref] What constitutes an adequate antidepressant trial for fluoxetine?, Schweizer [/bib_ref].

## Recommendations
It is strongly recommended that when there is no response to (3). The CANMANT guideline also referenced a meta-analysis of 8 randomized controlled trials that reported when switching from SSRIs to other antidepressants, significant differences in treatment efficacy were not shown between antidepressants [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref].

## Recommendations
When patients do not respond to SSRIs, it is strongly recommen-ded that switching to a non-SSRI antidepressant will help treatment.

## Key question 11. how efficacious is the combination treatment of two antidepressants?
Key question 11-1. Is the combination treatment of TCAs and another antidepressant efficacious?

## Evidence
The BAP guideline reported that the combination treatment of amitriptyline and moclobemide was more efficacious than amitriptyline therapy alone [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. The APA guideline reported that the combination treatment of TCAs and SSRIs shows a higher remission rate compared to therapy with either TCAs or SSRIs [bib_ref] Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a..., Nelson [/bib_ref].

## Recommendations
There is strong evidence that when treatment response to firstline therapy is not sufficient, combination treatment with TCAs and another antidepressant is helpful.

## Key question 11-2. is the combination treatment of maois and another antidepressant efficacious?

## Evidence
The NICE and BAP guidelines reported that randomized control trials on the combination treatment of MAOIs and another antidepressant have been insufficient [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. In particular, the number of controlled trials on the benefits or potential interactions of the combination treatment of TCAs and MAOIs in treatment-resistant depression is insufficient [bib_ref] Combined use of tricyclic antidepressants and monoamine oxidase inhibitors, Lader [/bib_ref].

## Recommendations
When treatment response to first-line therapy is insufficient, the combination treatment of MAOIs and another antidepressant is strongly not recommended.

## Key question 11-3. is the combination treatment of ssris and another antidepressant efficacious?

## Evidence
The APA, BAP, NSCCMHDA and University of Sydney CADE Clinic, Clinical Research Center for Depression, and Hong Kong guidelines have recommended the combination treatment of SSRIs and another antidepressant [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref]. The efficacy of the combination treatment of mirtazapine and SSRIs was proven in a placebo-controlled study [bib_ref] A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine, Carpenter [/bib_ref]. The BAP guideline reported that the combination of reboxetine, bupropion, and TCAs with SSRIs are the most widely used [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] 

## Recommendations
It is strongly recommended that when treatment response to first-line therapy is insufficient, the combination treatment of SSRIs and another antidepressant is helpful.

## Key question 11-4. is the combination treatment of snris and another antidepressant efficacious?

## Evidence
The APA guideline reported that the combination treatment of venlafaxine and mirtazapine will achieve a remission rate of 13.7% in patients that did not previously respond to 3 different medications [bib_ref] Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for..., Mcgrath [/bib_ref]. On the other hand, the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guideline reported that there is not much evidence on the effectiveness of the combination of venlafaxine and SSRIs. Further, when SSRIs that can suppress the metabolism of venlafaxine by CYP2D6 are taken in combination with venlafaxine, the blood level of venlafaxine can increase, and as a result, increased blood pressure, serotonin syndrome, and severe anticholinergic side effects may occur; hence, the combination of the agents must be performed with caution.

## Recommendations
It is strongly recommended that when the treatment response to first-line therapy is insufficient, the combination treatment of SNRIs and another antidepressant is helpful.

## Key question 11-5.
Is the combination treatment of NASSAs (mirtazapine) and another antidepressant efficacious?

## Evidence
The CANMAT, BAP, and Clinical Research Center for Depression guidelines described the combination treatment of mirtazapine or mianserin and other antidepressants (bupropion, venlafaxine, SSRIs, TCAs) as helpful [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. The CANMAT and APA guidelines have noted that the combination treatment of mirtazapine and SSRIs was shown to be superior in a placebo-controlled study [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine, Carpenter [/bib_ref].

## Recommendations
It is strongly recommended that when the treatment response to first-line therapy is insufficient, the combination treatment of NaSSAs and another antidepressant is helpful.
Key question 11-6. Is the combination treatment of NDRIs (bupropion) and another antidepressant efficacious?

## Evidence
The CANMAT, APA, BAP, WFSBP, and the Clinical Research Center for Depression guidelines all reported that the combination treatment of bupropion and SSRIs is efficacious [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. When unresponsive to citalopram, bupropion was shown to be superior to buspirone in effectiveness and tolerability when used in combination with citalopram [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The combination treatment of SSRIs and bupropion was also shown to have superior efficacy to either agent used as monotherapy [bib_ref] Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression, Lam [/bib_ref]. The CANMAT guideline noted that many open-label studies and cohort studies have reported bupropion to be efficacious, but randomized controlled trials have not reported such efficacy [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] To combine or not to combine? a literature review of antidepressant combination..., Dodd [/bib_ref].
The New Zealand guidelines group, NICE, APA, TDMHMR in collaboration with Texas universities, and WFSBP guidelines have recommended that adult patients who have responded to antidepressant treatment should continue more than 6 months of antidepressant therapy in order to prevent relapse [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The APA guideline recommended that patients who were successfully treated in the acute phase should continue treatment for 4-9 months. The TDMHMR in collaboration with Texas universities guideline recommended continuing therapy for 6-9 months after remission. The WFSBP guideline recommended continuing therapy for more than 9 months, considering the patient's psychiatric history, and if there are persisting symptoms, treatment should be continued until all symptoms resolve [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref].

## Recommendations
It is strongly recommended that treatment be continued for at least 6 months after remission.

## Key question 13-2.
How long should antidepressant treatment be continued in maintenance therapy?

## Evidence
The Hong Kong, NSCCMHDA and University of Sydney CADE Clinic, WFSBP, and Clinical Research Center for Depression guidelines have recommended that patients with recurrent MDD continue treatment for 3 yr [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The APA guideline has recommended maintenance therapy for patients who have experienced 3 or more depressive episodes, while the Hong Kong and NSCCMHDA and University of Sydney CADE Clinic guidelines have recommended maintenance therapy of 3-6 months or 1 yr after the first depressive episode [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref].

## Recommendations
It is strongly recommended that maintenance therapy be continued for at least 3 yr for recurrent MDD.

## Key question 14.
What are the withdrawal symptoms of antidepressants and the management of such symptoms?

## Evidence
The NICE, APA, ACP, and NSCCMHDA and University of Sydney CADE Clinic guidelines have described the withdrawal symptoms of antidepressants to include an increase in mood fluctuation (for example, hypersensitivity), gastrointestinal symptoms (nausea), neuromotor abnormalities (ataxia), vasomotor abnormalities (sweating), neurosensory abnormalities (sensory abnormalities), insomnia and other neurological problems [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The NSCCMHDA and University of Sydney CADE Clinic guideline described general withdrawal symptoms of SS-RIs as flu-like symptoms, a shock-like sensation, dizziness, dreaming excessively, insomnia, and tearing. The general withdrawal symptoms of TCAs were described as flu-like symptoms and insomnia [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref]. The APA and ACP guidelines reported that paroxetine may have a long-term discontinuation syndrome, and venlafaxine may have similar symptoms as well [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. Most of the guidelines have recommended a slow tapering down of antidepressants or retaking the previous antidepressant or switching to an antidepressant that has a long half-life.

## Recommendations
It is strongly recommended that antidepressants be tapered slowly as to prevent withdrawal symptoms. When withdrawal symptoms appear, it is strongly recommended that the previous medication be taken again or that an antidepressant in the same line with a longer half-life be administered.

## Key question 15. do antidepressants influence the suicide of mdd patients?

## Evidence
The CANMAT, APA, BAP, Hong Kong, and WFSBP guidelines have reported that there is no clear evidence on whether antidepressants increase suicide-related behaviors in adults [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. However, suicidal risks may increase in patients under 30 yr old who are receiving initial treatment, and the APA guideline has quoted the results of a meta-analysis reporting that suicidal ideation and rates were statistically 1.5-2.5 times higher in patients 25 yr old and under, compared to control groups. On the other hand, the ACP guideline quoted a meta-analysis reporting no evidence that antidepressants increase suicide risks, but the risk of suicide attempts that are not fatal may increase [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug..., Gunnell [/bib_ref].

## Recommendations
Although the evidence that antidepressants increase the suicide rate is insufficient, it is strongly recommended that clinicians show caution in light of the suicide risk of patients 25 yr old and under. [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. It was also recommended to switch to bupropion when sexual side effects arise from other antidepressants [bib_ref] Strategies for managing antidepressantinduced sexual dysfunction: systematic review of randomised controlled trials, Taylor [/bib_ref]. Furthermore, mirtazapine was reported to cause sexual side effects at a similarly low rate to bupropion. The ACP guideline described paroxetine as causing sexual side effects; however, the exact rate has not yet been reported [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref].

## Recommendations
It is strongly recommended that bupropion be prescribed to patients who complain of sexual side effects, and mirtazapine can also be weakly recommended.

# Discussion
A clinical practice guideline can be defined as a systematic description that helps clinicians and patients choose their health management program in a specific clinical situation. The present guideline was developed to reduce the discrepancies in clinical treatment, inappropriate levels of treatment, and treatment costs by improving the quality of treatment in Korea. Not only the USA and UK, but also Canada, New Zealand, and Singapore are developing their own evidence-based guidelines. Guidelines that have been developed by evidence-based methods are becoming the mainstream treatment modality worldwide for the following reasons: First, given the huge amount of published research these days, no one individual can keep up with the rate of development of medical knowledge; second, treatment recommendations may be contradictory among experts, and if clinical practice is only based on the judgment of the practitioner, different recommendations may be made in the same clinical situation.
In summary, our evidence-based treatment guideline has made certain recommendations considered appropriate to the current clinical situation of Korea [fig_ref] Table 2: http [/fig_ref]. The revised edition of the treatment guideline is considered to comprise new clinical information, and to reflect the current clinical situation of Korea, when compared to the previous version. Furthermore, the Evidence-based, Non-pharmacological Treatment Guideline for Depression in Korea (4) has also been developed, which strengthens the holistic approach of the guidelines to the treatment of depression when used together. The next step for the treatment guideline development team to take may be harmonizing the pharmacological and non-pharmacological treatment guidelines to a single comprehensive guideline, in order to complete the holistic approach to treating depression. Until further development of specific methodologies for the pharmacological treatment of depression is achieved in Korea, we recommend the wide distribution of the Evidence-based Pharmacological Treatment Guideline for Depression in Korea, Revised Edition, so that it is available to all clinical practitioners. The guideline is considered to be helpful when selecting the appropriate pharmacological treatment for MDD patients in Korea.
[table] Table 1: Twelve clinical practice guidelines for depression Formal title, Development group, Year of publication, (Reference number) Abbreviation [/table]