The Korean Medication Algorithm Project for Depressive Disorder 2021: Comparisons with Other Treatment Guidelines
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Review
https://doi.org/10.9758/cpn.2022.20.1.37 pISSN 1738-1088 / eISSN 2093-4327
Clinical Psychopharmacology and Neuroscience 2022;20(1):37-50 Copyrightⓒ 2022, Korean College of Neuropsychopharmacology
The Korean Medication Algorithm Project for Depressive Disorder
2021: Comparisons with Other Treatment Guidelines
Young Sup Woo1, Won-Myong Bahk1, Jeong Seok Seo2, Young-Min Park3, Won Kim4, Jong-Hyun Jeong1,
5 6 7 7 1 8
Se-Hoon Shim , Jung Goo Lee , Seung-Ho Jang , Chan-Mo Yang , Sheng-Min Wang , Myung Hun Jung ,
Hyung Mo Sung9, Il Han Choo10, Bo-Hyun Yoon11, Sang-Yeol Lee7, Duk-In Jon8, Kyung Joon Min2
1 2
Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Department of Psychiatry, College of Medicine,
Chung-Ang University, Seoul, 3Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, 4Department of
5
Psychiatry, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Department of Psychiatry, Soonchunhyang University Cheonan
6
Hospital, College of Medicine, Soonchunhyang University, Cheonan, Department of Psychiatry, Haeundae Paik Hospital, College of Medicine,
7
Inje University, Busan, Department of Psychiatry, Wonkwang University Hospital, School of Medicine, Wonkwang University, Iksan,
8
Department of Psychiatry, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 9Department of Psychiatry,
10
Soonchunhyang University Gumi Hospital, College of Medicine, Soonchunhyang University, Gumi, Department of Neuropsychiatry, College
11
of Medicine, Chosun University, Department of Psychiatry, Chosun University Hospital, Gwangju, Department of Psychiatry, Naju National
Hospital, Naju, Korea
The Korean Medication Algorithm Project for Depressive Disorder (KMAP-DD) first was published in 2002, and has
been revised four times, in 2006, 2012, 2017, and 2021. In this review, we compared recommendations from the
recently revised KMAP-DD 2021 to four global clinical practice guidelines (CPGs) for depression published after 2010.
The recommendations from the KMAP-DD 2021 were similar to those from other CPGs, although there were some
differences. The KMAP-DD 2021 reflected social culture and the healthcare system in Korea and recent evidence about
pharmacotherapy for depression, as did other recently published evidence-based guidelines. Despite some intrinsic limi-
tations as an expert consensus-based guideline, the KMAP-DD 2021 can be helpful for Korean psychiatrists making
decisions in clinical settings by complementing previously published evidence-based guidelines, especially for some
clinical situations lacking evidence from rigorously designed clinical trials.
KEY WORDS: Depressive disorder; Pharmacotherapy; Consensus; Guideline; KMAP-DD 2021.
INTRODUCTION quate response to standard AD therapy, and burden from
“trial-and-error” is one of the barriers to fast and effective
Depression is a prevalent and debilitating psychiatric AD treatment in clinical practice [3,4]. Many trials have
disorder characterized by frequent recurrence and sig- investigated treatment strategies for people who showed
nificant morbidity and mortality [1]. Pharmacotherapy insufficient treatment response, and many studies have in-
has been a mainstream treatment strategy for depression vestigated predictors of treatment outcomes, such as early
since the introduction of antidepressants (ADs) in the late treatment improvement, depressive episode character-
50s [2]. Despite substantial progress in psychopharma- istics, and patient characteristics [5-9]. However, it is diffi-
cology during the past several decades, a significant por- cult for clinicians to be acquainted with and consider al
tion of patients with depression experiences an inade- rapidly accumulating evidence when choosing the best
treatment strategy for various scenarios, which increases
Received: September 24, 2021 / Accepted: October 13, 2021
the need for new treatment guidelines.
Address for correspondence: Won-Myong Bahk
Department of Psychiatry, Yeouido St. Mary’s Hospital, Many clinical practice guidelines (CPGs) for depression
College of Medicine, The Catholic University of Korea, have been published [10-17]. The majority of these CPGs
10 63-ro, Yeongdeungpo-gu, Seoul 07345, Korea
E-mail: wmbahk@catholic.ac.kr primarily is based on evidence obtained from well-de-
ORCID: https://orcid.org/0000-0002-0156-2510
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
3738 Y.S. Woo, et al.
signed controlled clinical trials and has great benefits. balances systematic reviews with consensus expert opin-
However, they might not be suitable for actual clinical ion [41].
practice because of various culture-specific characteris-
tics such as depression, patient-related factors, and clinical Royal Australian and New Zealand College of
environment, such as health care policy and prevailing Psychiatrists’ Clinical Practice Guidelines for
medical insurance system. Thus, the Korean Medication Mood Disorders: Major Depression
Algorithm Project for Depressive Disorder (KMAP-DD) The Royal Australian and New Zealand College of
was developed in 2002, based on an expert consensus Psychiatrists (RANZCP) developed the Mood Disorders
from Korean psychiatrists with experience treating de- Clinical Practice Guidelines for clinical management of
pression [18]. Thereafter, the KMAP-DD was revised four mood disorders in 2015 [46], and revised them in 2020
times in 2006 [19], 2012 [20], 2017 [21], and 2021 [22]. (RANZCP 2020) [14]. The RANZCP 2020 encompasses
To identify similarities and differences between KMAP-DD both evidence-based and expert consensus-based recom-
and other global CPGs, we compared the recommenda- mendations (CBRs) to provide advice and guidance re-
tions of the KMAP-DD with those of other CPGs starting in garding management of mood disorder, derived from sci-
2012 [23,24]. Thus, we aimed to compare the recom- entific evidence and supplemented by expert clinical
mendations of the updated KMAP-DD 2021 with those of consensus. When sufficient evidence exists, the Mood
relatively recently published CPGs to supplement any Disorder Committee formulates evidence-based recom-
KMAP-DD 2021 weaknesses and to direct future revisions mendations according to the Australian National Health
of the Korean Medication Algorithm Project. and Medical Research Council Levels of Evidence for
Intervention Studies. Where this is not possible; for exam-
TREATMENT GUIDELINES ple, because of insufficient evidence, they develop CBRs
FOR COMPARISON [14].
British Association for Psychopharmacology Guidelines World Federation of Societies of Biological Psychiatry
The British Association for Psychopharmacology (BAP) Guidelines for Biological Treatment of Unipolar
has published a series of evidence-based guidelines for Depressive Disorders
the use of drugs in psychiatric disorders, with an emphasis The World Federation of Societies of Biological Psychiatry
on producing comprehensive but concise and useable (WFSBP) published an evidence-based guideline in 2002
guidelines based on a review of current evidence [17]. [47,48]. The second edition was revised and published in
BAP published their first guidelines in 1993 [25], and re- 2007 [49], and an updated version was published in 2013
vised them in 2000 [26] and 2008 [27]. The most recent (WFSBP 2013) [16], on acute and continuation treatment,
revision of the BAP guidelines (BAP 2015) [17] updates and an update on maintenance treatment was added in
the guidelines in light of new evidence and to make a 2015 [11]. The recommendations in the WFSBP guide-
strong effort toward evidence-based recommendations lines were based on an initial comprehensive review of all
only. available evidence by a systematic literature search and
appraisal. The guidelines were intended for use by all
Canadian Network for Mood and Anxiety Treatments physicians seeing and treating patients with these con-
Clinical Guidelines for the Management of Major ditions [16].
Depressive Disorders
The Canadian Network for Mood and Anxiety Treatments Korean Medication Algorithm Project for Depressive
(CANMAT) and the Canadian Psychiatric Association col- Disorder 2021
laborated to publish evidence-based guidelines for de- The KMAP-DD 2021 [22] is a set of expert consensus-
pression in 2001 [28-34]. These guidelines were revised based guidelines. The detailed methods regarding the
in 2009 [35-40], and the most recent revised version was composition of the review committee, questionnaire pre-
published in 2016 (CANMAT 2016) [1,12,41-45]. The paration, data analyses, and development of treatment guide-
CANMAT 2016 applied a clinically useful method that lines and algorithms for this fourth revision were similar toKMAP-DD 2021 Comparisons 39
those for previous KMAP-DD studies [18,20,21]. The de-
Evidence-based and expert
tailed full methods have been described [22]; the ques-
tionnaire used in the KMAP-DD 2021, is similar to that
Methodology
consensus-based
questions used to develop the KMAP-DD 2017 [21], with
Expert consensus
Evidence-based
Evidence-based
Evidence-based
some modifications. The survey consists of 40 main ques-
tions with 7 parts. A 9-point scale from the RAND Corporation
[50] was applied to assess the adequacy of each treatment
option. Each treatment option was classified into three
categories based on the lowest 95% confidence interval
All doctors (usually primary care
of the scores: ≥ 6.5 for first-line treatment, 3.5−6.5 for
second-line, and ＜ 3.5 for third-line. The first-line treat-
and primary-care physicians
Psychiatrists, psychologists,
ment options rated as 9 by 50% or more experts were de-
Primary-care physicians
Audience
fined as the treatments of choice (TOCs). The character-
istics of the above-mentioned four treatment guidelines
Psychiatrists,
physicians)
Psychiatrists
Psychiatrists
are summarized in Table 1.
COMPARISONS OF
TREATMENT OPTIONS ACROSS
TREATMENT GUIDELINES
2013 (acute and continuation treatment)
2015 (maintenance treatment)
Initial Treatment for Depressive Episode
In the KMAP-DD 2021, AD monotherapy was recom-
Publication year
mended as the TOC for a mild to moderate episode and
2016
2015
2020
2021
the first-line treatment for severe nonpsychotic episodes
(Table 2). The combination of an AD and an atypical anti-
psychotic (AAP) was recommended as the first-line treat-
ment for severe nonpsychotic episodes and the TOC for
psychotic major depressive episodes (MDE). Among ADs,
Table 1. Characteristics of global treatment guidelines for depressive disorder
escitalopram was the TOC, and other selective serotonin
reuptake inhibitors (SSRIs), serotonin-norepinephrine re-
Korean Medication Algorithm Project for Depressive Disorder 2021
Royal Australian and New Zealand College of Psychiatrists Clinical
uptake inhibitors (SNRIs) excluding milnacipran, and mir-
World Federation of Societies of Biological Psychiatry Guidelines
Guidelines for the Management of Major Depressive Disorders
tazapine were recommended as first-line ADs for depres-
Canadian Network for Mood and Anxiety Treatments Clinical
Practice Guidelines for Mood Disorders: Major Depression
for Biological Treatment of Unipolar Depressive Disorders
sion of all severity levels. Vortioxetine also was included
British Association for Psychopharmacology Guidelines
in the first-line medications for nonpsychotic MDE.
Among AAPs, aripiprazole was selected as the first-line
treatment for nonpsychotic MD and as the TOC for psy-
Organization
chotic depression. Quetiapine and olanzapine were rec-
ommended as first-line treatments for psychotic depression.
For mild episodes, most CPGs recommend non-phar-
macological interventions such as psychoeducation, psy-
chological treatment, or self-management as the first-line
treatment except in situations where pharmacological
treatment might be considered, including patient prefer-
ence, previous response to pharmacotherapy, recurrent
depression, and lack of response to non-pharmacological
interventions (Table 2) [12,17]. Moreover, most CPGs40 Y.S. Woo, et al.
recommend AD monotherapy for moderate-to-severe de-
AAP, atypical antipsychotics; AD, antidepressant; BAP, British Association for Psychopharmacology Guidelines; CANMAT, Canadian Network for Mood and Anxiety Treatments Clinical Guidelines
WFSBP, World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Unipolar Depressive Disorders (WFSBP); KMAP-DD, Korean Medication Algorithm Project for
for the Management of Major Depressive Disorders; RANZCP, Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines for Mood Disorders: Major Depression;
Combined psychological
intervention and AD pressive episodes without psychotic features [12,14,16,17],
RANZCP 2020
and augmentation with AAP is recommended for psy-
chotic depression (Table 2). The discrepancies between
medication
KMAP-DD 2021, and other CPGs might reflect a rela-
tively higher preference by Korean psychiatrists for AAPs
for treating severe depression without psychotic features.
Pharmacotherapy in some situations (patient pre-
response to nonpharmacological interventions)
ference, previous response to AD, or lack of
Second-Step Treatment in Cases of Inadequate
Response to Initial Treatment
Psychoeducation, self-management,
In the KMAP-DD 2021, for cases that showed no re-
AD monotherapy
CANMAT 2016
sponse to initial AD monotherapy, augmenting with an
AD + AAP
AAP or adding or switching to another AD was recom-
psychological treatment
mended as the first-line treatment (Table 3). In cases of
partial response to initial AD monotherapy, adding anoth-
er AD or augmenting with an AAP was recommended. In
cases of no response to combination AD and AAP, switch-
ing the AD or AAP or adding another AD was recom-
Table 2. Comparisons of recommendations for initial treatment of major depressive disorder across practice guidelines
mended. When switching AD, another AD from a differ-
persists for more than 2–3 months
Short duration of AD monotherapy
ent pharmacological class among SSRIs, SNRIs, mirtaza-
moderate-to-severe recurrent
depression or the depression
pine, or vortioxetine was preferred. The one exception of
if there is prior history of
AD monotherapy
an out of class switch was that switching to another SNRI
AD + AAP
BAP 2015
from an initial SNRI was recommended as a first-line
treatment. When adding another AD, one from a different
pharmacological class among SSRIs, SNRIs, mirtazapine,
bupropion, vortioxetine, or agomelatine was preferred.
When augmenting with AAP for psychotic depression,
aripiprazole was chosen as the TOC, and quetiapine or
olanzapine was recommended as first-line treatment.
AD monotherapy
Aripiprazole or quetiapine was preferred as the first-line
WFSBP 2013
augmenting agent for non-psychotic depression.
In the WFSBP 2013 [16], a combination of two ADs (an
SSRI with a presynaptic autoreceptor inhibitor) and aug-
mentation with lithium, quetiapine, or aripiprazole were
recommended when initial treatment shows an in-
AD monotherapy
AD monotherapy
adequate response (Table 3). In cases of intolerance to ini-
KMAP-DD 2021
AD + AAP
AD + AAP
tial AD monotherapy, switching to a new AD with evi-
dence of better tolerance was recommended. The BAP
2015, recommended considering both within- and be-
tween-class switching of ADs when there has been no re-
sponse or intolerance and adding augmenting agents
Severe with psychotic
when there is a partial response (Table 3) [17]; The BAP
Depressive Disorder.
psychotic features
recommends adjunctive use of quetiapine, aripiprazole,
Severity
Severe without
and lithium. The CANMAT 2016, recommended switch-
Moderate
features
ing AD when intolerance or no response to initial treat-
Mild
ment is an issue and to add an adjunctive medication inTable 3. Comparisons of recommendations for treatment of major depressive disorder with poor response to initial treatment across practice guidelines
Treatment step Response KMAP-DD 2021 WFSBP 2013 BAP 2015 CANMAT 2016 RANZCP 2020
MDE, insufficient Non-response Switching AD, adding AD/AAP, Switching AD (to different Switching AD (either within Switching AD Augmentation (lithium,
response to switching AAP (if applied in or same class when intole- or between AD class) aripiprazole)
initial treatment previous step) rance); AD combination;
Partial Adding AD/AAP, switching AAP augmentation with lithium, Adding quetiapine, aripipra- Adding AAP
response (if applied in previous step) quetiapine, aripiprazole zole, or lithium
Third step or For MDE without psychotic Augmentation (lithium, Consider a different AD class After failure of 1 or more ADs, Switching (after aug-
treatment features: combination of 2 quetiapine, aripiprazole), after more than one failure consider switch to a second- mentation) within
resistance ADs, augmentation with AAP, switching AD with the with a specific class; Consider line or third-line Ads; For classes: intolerability
combination of 2 ADs and 1 potential for superior venlafaxine after more than early treatment resistance, ofdifferent classes: lack
AAP, augmentation with both efficacy (venlafaxine, one SSRI failure and addition consider adjunctive use of of efficacy
AAP and other augmenting escitalopram, of AD, AAP, or augmenting psychological and neuro-
agents (lithium, valproate, tranylcypromine) agent (tri-iodothyronine, stimulation treatments
lamotrigine, carbamazepine, lithium) when AD switching
buspirone, thyroid hormone, has been unsuccessful
or psychostimulants)
AAP, atypical antipsychotics; AD, antidepressant; BAP, British Association for Psychopharmacology Guidelines; CANMAT, Canadian Network for Mood and Anxiety Treatments Clinical Guidelines
for the Management of Major Depressive Disorders; MDE, major depressive episode; RANZCP, Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines for Mood
Disorders: Major Depression; WFSBP, World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Unipolar Depressive Disorders (WFSBP); KMAP-DD, Korean
Medication Algorithm Project for Depressive Disorder.
KMAP-DD 2021 Comparisons 4142 Y.S. Woo, et al.
cases of partial response (Table 3) [12]. Aripiprazole, que- hibitor such as mirtazapine. The first-choice augmenting
tiapine, and risperidone were recommended as first-line agents were lithium, quetiapine, and aripiprazole. If aug-
adjunctive medications and brexpiprazole, lithium, mod- mentation strategies were used as the second-step treat-
afinil, olanzapine, and triiodothyronine as second-line ment, switching to a different AD with the potential of su-
adjunctive medications [12]. Interestingly, RANZCP 2020, perior efficacy (e.g., venlafaxine, escitalopram, and tra-
recommended only an augmenting strategy, especially nylcypromine) was recommended (Table 3). The BAP
with lithium or aripiprazole, as the first-line treatment 2015 [17], recommended a different AD class after more
where there has been insufficient response (Table 3); it than one failure with a specific class and change to ven-
stated that switching is the next alternative after augmen- lafaxine after more than one SSRI failure (Table 3). They
tation [2]. recommended to addition of quetiapine, aripiprazole,
These results are consistent with KMAP-DD 2021 and and lithium as first-line treatments and risperidone, olan-
other guidelines in that adding augmenting agents (aripi- zapine, tri-iodothyronine, and mirtazapine as second-line
prazole, quetiapine, and lithium) is preferred when initial treatments. BAP 2015, also suggested adding bupropion,
treatments fail [2,12,16,17]. buspirone, lamotrigine, tryptophan, modafinil, and other
stimulants. Moreover, these guidelines noted that it was
Third-Step Treatment in Cases of Inadequate appropriate to consider multiple combinations concurrently
Response to Second-Step Treatment or to use other approaches with limited evidence in se-
The KMAP-DD 2021, recommends a third-step treat- verely treatment-resistant patients. In CANMAT 2016
ment for cases of inadequate response to second-step [12], considering a switch to second-line or third-line ADs
treatment (Table 3). For nonpsychotic depression, adding including tricyclic antidepressants (TCAs), monoamine
an AAP was the TOC, and addition of another AD was oxidase inhibitors (MAOIs), and quetiapine or vilazodone
recommended as a first option when second-step treat- was recommended after one or more AD failures (Table
ment with AD monotherapy failed. For cases of non- 3). RANZCP 2020 [2] recommended switching as the
psychotic depression that showed inadequate response to third-step strategy once augmentation was trialed (Table
combination of two ADs, adding an AAP or switching an 3). They also stated that switching AD should involve
AD to an AAP were recommended. Switching to another change to another class, although switching within class
AAP or AD, adding another AD, or adding other augment- is acceptable if the main reason for doing so is that the ini-
ing agents including lithium, valproate, lamotrigine, car- tial medication was not taken as prescribed (e.g., because
bamazepine, buspirone, thyroid hormone, or psychosti- of side effects or poor adherence). In general, the recom-
mulants was recommended for cases of nonpsychotic de- mendations from other guidelines are in line with those of
pression that failed to respond to combinations of AD and KMAP-DD 2021; switching or adding various augment-
AAP. For psychotic depression, switching an AD or AAP ing agents or ADs in different class, with superior efficacy
into another AD or AAP and adding other augmenting but inferior safety, or with limited evidence.
agents were preferred as the first treatment in this step,
and triple combinations (e.g., two ADs and one AAP, one Pharmacological Treatment for Persistent Depressive
AD and two AAPs, or combination of AD, AAP, and other Disorder and Each Subtype of Depression
augmenting agents) were considered for third-line In the KMAP-DD 2021, AD monotherapy with escitalo-
treatment. Among other augmenting agents, lithium was pram was the TOC for persistent depressive disorder
the first option in the third step. (PDD). Other SSRIs including sertraline, fluoxetine, and
Most guidelines did not recommend separately a sec- paroxetine; and SNRIs including desvenlafaxine, ven-
ond or third step; rather, they recommended strategies for lafaxine, duloxetine, and milnacipran, vortioxetine, and
cases that failed to respond adequately to initial treatment. mirtazapine were recommended as first-line treatments as
However, some recommendations corresponded to the well. For PDD, BAP 2015 [17], presented the results from
third step. In the WFSBP 2013 [16], augmentation strat- a meta-analysis [51] that found a higher response rate
egies recommended for second-step treatment were com- than that of placebo for fluoxetine, paroxetine, sertraline,
binations of an SSRI with a presynaptic autoreceptor in- moclobemide, imipramine, ritanserin, amisulpride, andKMAP-DD 2021 Comparisons 43 acetyl-l-carnitine. They also noted that moclobemide and ond line for MDE with melancholic features. Milnacipran amisulpride showed superiority over fluoxetine in pair- can be used as the first-line treatment for melancholic or wise comparisons. CANMAT 2016 [12], presented results atypical depression but is considered a second-line treat- from the same meta-analysis by Kriston et al. [51], and ment for seasonal depression. Agomelatine was the first- noted that SSRIs were similar in efficacy but superior in line AD for MDE with atypical features and second-line tolerability to TCAs in another meta-analysis of chronic AD for melancholic or seasonal depression. depression [52]. While RANZCP 2020 [2], recommended use of ami- For MDE with mixed features, KMAP-DD 2021, recom- triptyline or venlafaxine for melancholia, other CPGs did mended a combination of AD with AAP or mood stabil- not provide clear recommendations for pharmacological izer (MS) as the first-line treatment. Among AAPs, aripi- treatment of melancholic depression. CANMAT 2016 prazole, quetiapine, and olanzapine were included in the [12], noted that no specific ADs have demonstrated su- first line, and lithium and valproate were preferred as the periority. BAP 2015 [17], concluded that it is insufficient first-line MS. Among ADs, SSRIs, venlafaxine, desvenla- to guide first-line AD choices, although a few retro- faxine, bupropion, and mirtazapine were recommended spective studies suggested that TCAs are more effective as first-line treatments. CANMAT 2016 [12], reported that than SSRIs for melancholic depression. WFSBP 2013 [16], there were no trials that used the Diagnostic and Statistical presented conflicting results and did not offer any recom- Manual of Mental Disorders 5th edition criteria for mixed mendations: paroxetine [53], venlafaxine [54], and mo- features; however, monotherapy with lurasidone or zipra- clobemide [55] were more effective than placebo and as sidone was efficacious for major depressive episodes with effective as TCAs in some studies, but TCAs and SNRIs mixed symptoms. were more effective than SSRIs in other studies [56,57]. For MDE with anxious distress, AD monotherapy or For atypical features, the KMAP-DD 2021, recom- combination of AD and AAP was recommended as the mends various SSRIs and SNRIs as first-line treatments, first-line strategy. SSRIs and SNRIs except milnacipran or which is different from other CPGs. While CANMAT 2016 mirtazapine and vortioxetine were the first-line ADs. [12] stated that no specific ADs have shown superiority, These results are consistent with the recommendations WFSBP 2013 [16], suggested that irreversible MAOIs from RANZCP 2020 [2], which suggest escitalopram or such as phenelzine and tranylcypromine could be more venlafaxine when anxiety is the key or prominent MDD beneficial for patients with atypical features. BAP 2015 symptom. In recommendations from WFSBP 2013 [16], [17], also suggested an advantage of MAOIs over TCAs in depressed patients with prominent anxiety symptoms or atypical depression. Moreover, BAP 2015 [17], noted that with co-morbid anxiety disorders can be treated effec- MAOIs (e.g., moclobemide) could be effective for seasonal tively with an SSRI, venlafaxine, TCA, or MAOI. It also depression, as could sertraline, fluoxetine, and bupropion. stated that clinicians should start patients at lower doses However, MAOIs were excluded from the choices in the and increase the dose slowly for those with prominent KMAP-DD 2021, survey because preference for MAOIs anxiety symptoms. CANMAT 2016 [12], recommended had been low in previous KMAP-DDs, and MAOI use has use of an AD with efficacy in generalized anxiety disorder declined due to side effects, drug−drug interactions, and but also noted no differences in efficacy between SSRIs, difficulty of following a low-tyramine diet [58]. SNRIs, and bupropion. For MDE with melancholic features, atypical features, Pharmacological Treatment for Child and Adolescent or with seasonal pattern, KMAP-DD 2021, recommended Depression SSRIs and SNRIs except milnacipran or vortioxetine as a The KMAP-DD 2021, does not suggest a first-line treat- first-line AD. Escitalopram was the TOC for MDE with ment for disruptive mood dysregulation disorder (DMDD). melancholic features. Mirtazapine was the first line for Monotherapy with AD or AAP, or combination of AAP melancholic and seasonal depression and the second line and AD was recommended as second-line strategy. for atypical depression. Bupropion was included in the KMAP-DD 2021, recommended escitalopram, fluoxetine, recommended first-line ADs for MDE with atypical fea- aripiprazole, or risperidone for DMDD. Valproate also tures and seasonal pattern but is recommended as the sec- was recommended for male patients. There are no guide-
44 Y.S. Woo, et al. lines for recommendations for DMDD; thus, we cannot where depression is severe, or when there is a history of compare directly the KMAP-DD 2021, recommendations moderate-to-severe recurrent depression. In recent CPGs with those of other CPGs. In clinical trials for DMDD, lith- for depression in children and young people [64], psy- ium was not beneficial compared with placebo for pa- chological therapy including CBT, non-directive suppor- tients with severe mood dysregulation [59], but treatment tive therapy, and IPT was recommended for mild depres- with a psychostimulant alone [60] or combined with ari- sion in children and adolescents. For moderate-to-severe piprazole [61] could be effective for DMDD. Given the depression, the NICE guidelines [64] recommended psy- dearth of evidence regarding treatment strategies for DMDD, chological therapy initially; combined treatment of fluox- the CBRs in the KMAP-DD 2021, could be valuable. etine and psychological therapy could be considered as However, they should be further tested for applicability in initial treatment for moderate-to-severe depression in clinical practice. young people (12−18 years). Sertraline and citalopram KMAP-DD 2021 recommended AD monotherapy as were limited to situations when patients and parents/care- the TOC for mild-to-moderate depression in children, and givers have been informed fully, the depression is suffi- it was the first-line treatment strategy for mild-to-moderate ciently severe, and there has been a reasonable effort to depression in adolescents. AD monotherapy and combi- try combination treatment of fluoxetine and psycho- nation with AAP were the first-line strategies for children logical therapy [64]. and adolescents with severe non-psychotic depression, Caution should be paid to AD use in children and ado- and combination of AD with AAP was the TOC for severe lescents, because ADs can be associated with increased psychotic depression. Among ADs, escitalopram was the risk of suicide and mood swings in young people [65,66]. TOC and fluoxetine was the first-line treatment for chil- Although psychological intervention should be the first dren and adolescents with mild-to-moderate depression. step for mild depressive episodes in pediatric depression Sertraline was the first-line AD for adolescents with patients based on risk-benefit evaluation, cautious phar- mild-to-moderate depression. For children and adoles- macotherapy could be considered for more severe epi- cents with psychotic or severe non-psychotic depression, sodes or when initial psychosocial intervention for mild escitalopram, fluoxetine, and sertraline were preferred. depressive episodes failed. Among AAPs, aripiprazole was the TOC for children and adolescents with psychotic depression, and risperidone Pharmacological Treatment for Geriatric Depression and quetiapine were the first-line treatment for children Monotherapy with AD was the TOC for mild-to-moder- with psychotic depression. These guidelines, which mainly ate geriatric depression in KMAP-DD 2021. The combi- recommend monotherapy with escitalopram, fluoxetine, nation of AD and AAP and monotherapy with AD were or sertraline, were similar those from CANMAT 2016 the first-line treatments for severe non-psychotic depres- [45], which recommended fluoxetine, escitalopram, ser- sion, and the combination of AD and AAP was recom- traline, and citalopram as the best second-line ADs. The mended as first-line treatment for patients with severe psy- preference for escitalopram over fluoxetine in KMAP-DD chotic episodes. Among ADs, escitalopram was preferred, 2021, reflects recent evidence of the superior efficacy of and SSRIs, SNRIs, vortioxetine, and mirtazapine were rec- escitalopram for improving children and adolescent func- ommended as first-line treatments; paroxetine was in- tion and symptoms compared with placebo [62] and its cluded in the first line only for severe episodes. These rec- relative safety and tolerability [62,63]. ommendations are similar to those from WFSBP 2013 However, CANMAT 2016 [45], recommended cogni- [16], which recommended SSRIs and other newer ADs tive-behavioral therapy (CBT) or interpersonal therapy due to the higher risk of adverse effects with TCAs, such as (IPT) as first-line treatment for major depression among cardiovascular and anticholinergic effects. They also rec- children and youth. Furthermore, BAP 2015 [17], recom- ommended that old age not limit full use of the whole mended that ADs are not a first-line treatment for major spectrum of AD options. However, CANMAT 2016 [45], depression in children and adolescents, and AD treatment recommended escitalopram, which was recommended should be considered only when there has been a partial as the TOC by KMAP-DD 2021, based on level-2 evi- or no response to other treatments such as CBT or IPT, dence, along with bupropion, desvenlafaxine, sertraline,
KMAP-DD 2021 Comparisons 45
venlafaxine, and vortioxetine, although they were in- [16], SSRIs were superior to general supportive care.
cluded as first-line ADs. CANMAT 2016 [45], recom- Based on level-1 evidence, CANMAT 2016 [45], recom-
mended duloxetine, mirtazapine, and nortriptyline as mended CBT and IPT as first-line treatment for mild-to-
first-line treatments with level-1 evidence. Nevertheless, moderate postpartum depression during breastfeeding.
CANMAT 2016 [45], also noted that escitalopram and cit- CANMAT 2016, also recommended citalopram, escitalo-
alopram generally are considered by clinicians to be pram, sertraline, and a combination of SSRI and CBT or
first-line treatments for late-life depression due to their tol- IPT as second-line treatments with level-2 evidence.
erability and fewer drug interactions, although none of the Pharmacotherapy with citalopram, escitalopram, and ser-
RCTs involving these drugs demonstrated superiority over traline was the first-line option for severe postpartum de-
placebo in the elderly. Thus, CANMAT 2016 [45], sug- pression in CANMAT 2016 [45], which also concluded
gested that treatment recommendations for late-life de- that ECT could be considered as a first-line treatment for
pression must be evidence-informed rather than evi- severe depression, especially among patients with psychosis.
dence-based.
Choosing Antidepressants for Specific Situations
Pharmacological Treatment for Depression in Women KMAP-DD 2021, recommended choice of AD based
KMAP-DD 2021 recommended AD monotherapy with on frequent adverse effects and tolerability issues, where-
fluoxetine, escitalopram, sertraline, paroxetine, desvenla- in bupropion, mirtazapine, and vortioxetine were recom-
faxine, or venlafaxine as the first-line treatment strategy mended for sexual dysfunction, and bupropion, fluox-
for premenstrual dysphoric disorder. etine, and tianeptine were recommended for sedation/
For MDD in pregnant women, AD monotherapy was somnolence. When patients were concerned about weight
recommended as the first-line treatment for mild-to-mod- gain, bupropion, fluoxetine, and vortioxetine were re-
erate and severe non-psychotic depression in KMAP-DD commended. Mirtazapine, paroxetine, and TCAs were
2021. For severe psychotic depression during pregnancy, preferred for concerns about sleep disturbance/insomnia.
combination of AD and AAP or electroconvulsive therapy For gastrointestinal trouble such as nausea/vomiting, mir-
(ECT) was recommended. In the WFSBP 2013 [16], ECT tazapine, tianeptine, and bupropion were recommended.
was recommended as the first-line strategy, particularly Escitalopram, agomelatine, and vortioxetine were recom-
during the first trimester. RANZCP 2020 [2], also sug- mended for those concerned about anticholinergic side
gested that ECT is safe during pregnancy and can, in some effects. For patients with orthostatic hypotension, bupro-
instances, be the preferred option. CANMAT 2016 [45], pion, escitalopram, and mirtazapine were recommended
recommended CBT and IPT as the first-line therapy for by KMAP-DD 2021. These recommendations were not
mild-to-moderate depression and ADs including cit- discordant with those of other CPGs. BAP 2015 [17], rec-
alopram, escitalopram, and sertraline as the second-line ommended sildenafil or tadalafil for use in cases of erec-
treatment option. For severe depression during preg- tile dysfunction and bupropion for sexual dysfunction in
nancy, CANMAT 2016 [45], recommended pharmaco- men and bupropion or sildenafil for sexual dysfunction in
therapy with citalopram, escitalopram, and sertraline as women. CANMAT 2016 [12], also reported that agomela-
the first-line treatment, either alone or in combination tine, bupropion, mirtazapine, vilazodone, and vortiox-
with CBT or IPT. The remaining SSRIs except paroxetine, etine had lower risk of sexual side effects, and that escita-
newer-generation ADs, and TCAs were recommended as lopram and paroxetine had higher risk compared with
second-line treatments for severe depression; and ECT al- other ADs. WFSBP 2013 [16] and RANCP 2020 [2] also
so could be considered. reported that the risk of sexual dysfunction was lower with
For postpartum depression, KMAP-DD 2021, recom- bupropion, agomelatine, and mirtazapine. Similar to
mended AD monotherapy and combination of AD with KMAP-DD 2021, RANZCP 2020 [2], and BAP 2015 [17],
AAP as first-line strategies for mild-to-moderate episodes. recommended SSRIs, SNRIs, bupropion, and vortioxetine
Combination of AD with AAP was recommended as when sedation or somnolence was a concern. SSRIs,
first-line treatment for severe non-psychotic episodes and SNRIs, bupropion, agomelatine, and vortioxetine were re-
as TOC for severe psychotic episodes. In WFSBP 2013 commended by RANZCP 2020 [2], and BAP 2015 [17],46 Y.S. Woo, et al. when weight gain was the main concern. For sleep dis- pram and citalopram. However, they also noted that con- turbance, RANZCP 2020, and CANMAT 2016 [2], rec- cerns about QTc alone should not prevent effective use of ommended agomelatine and mirtazapine [12]. SSRIs, citalopram and escitalopram in patients for whom these SNRIs, bupropion, mirtazapine, agomelatine, or vortiox- drugs are indicated. In addition, other ADs can increase etine was suggested by BAP 2015 [17], when anti- the QTc interval, and this issue is not unique to cit- cholinergic adverse effects or orthostatic hypotension was alopram/escitalopram. a concern. Use of ADs for suicidal depressed patients has been a Non-pharmacological Biological Treatments significant and controversial issue for two decades. WFSBP 2013 [16], noted that most ADs have not demon- Electroconvulsive therapy strated efficacy in suicidal patients, and a meta-analysis KMAP-DD 2021, recommended ECT as the first-line showed an increase in suicidal thoughts and attempts in treatment for patients with urgent suicidal risk, pregnant children and adolescents. Thus, WFSBP 2013, recom- patients with severe episodes, and pregnant patients with mended that physicians prescribe a limited supply of po- moderate episodes who were non-responsive to pharma- tentially lethal ADs such as TCA or irreversible MAOIs, cotherapy. These results were consistent with recom- and that the chosen AD is relatively safe in case of an mendations from WFSBP 2013 [16], which recommended overdose. ECT as the first-line treatment for severe major depression Regarding comorbid conditions, KMAP-DD 2021 rec- with psychotic features or psychomotor retardation, treat- ommended escitalopram, sertraline, and bupropion for ment-resistant major depression, and situations when rap- patients with diabetes mellitus; escitalopram, sertraline, id depression relief is required (e.g., severe suicidality or and fluoxetine for patients with thyroid disease; escitalo- medication contraindications such as pregnancy). BAP pram, sertraline, and tianeptine for liver disease; escitalo- 2015 [17], reported that ECT is more effective than AD pram, sertraline, and tianeptine for patients with renal dis- treatment, particularly in severe depression (including ease; escitalopram, sertraline, and tianeptine for patients psychotic depression) cases and treatment-resistant pa- with hypertension; escitalopram, sertraline, and tianeptine tients. CANMAT 2016 [43], recommended ECT as a sec- for patients with cardiovascular illness; escitalopram, ser- ond-line treatment, but as the first-line treatment for pa- traline, and tianeptine for patients with seizure disorders; tients with acute suicidal ideation, psychotic features, escitalopram, sertraline, and bupropion for patients with treatment-resistant depression with level-1 evidence, re- parkinsonism; sertraline, escitalopram, and fluoxetine for peat medication intolerance, catatonic features, prior fa- patients with arrhythmia; and duloxetine, milnacipran, vorable response to ECT, rapidly deteriorating physical and venlafaxine for patients with chronic pain. There are status, and during pregnancy with level-3 evidence. not many discrepancies between KMAP-DD 2021, rec- RANZCP 2020 [2], concluded that bifrontal or bitemporal ommendations and other CPGs. WFSBP 2013, and BAP ECT is necessary in some instances, including clear fea- 2015 [16,17], reported that agomelatine is contraindi- tures of melancholic depression such as psychomotor re- cated for patients with hepatic impairment, and caution is tardation and psychotic features, mood-congruent delu- recommended for venlafaxine in hypertensive patients. sions, and hallucinations. ECT also was recommended as For patients with cardiovascular disease, RANZCP 2020 first-line treatment for catatonia in the context of a mood [2], recommended fluoxetine, sertraline, vortioxetine, disorder and can be administered as the preferred option agomelatine, and escitalopram, and WFSBP 2013 [16] in pregnancy and with urgency including inanition and recommended SSRIs, which cause fewer cardiovascular dehydration. toxicities. For patients with arrhythmia, WFSBP 2013 [16], recommended not using tianeptine or TCAs includ- Repetitive transcranial magnetic stimulation ing amitriptyline, clomipramine, imipramine, and nor- WFSBP 2013 [16], and BAP 2015 [17], did not recom- triptyline due to the risk of conduction delays. BAP 2015 mend repetitive transcranial magnetic stimulation (rTMS) [17], noted that recent evidence suggests the risk of dose- use in depression due to insufficient evidence and un- dependent prolongation of the QT interval with escitalo- certainty regarding the optimum treatment parameters for
KMAP-DD 2021 Comparisons 47
clinical efficacy. However, KMAP-DD 2021, recom-
mended rTMS as a first-line treatment for pregnant pa- ■ Author Contributions
tients with severe MDD. This recommendation was in line Conceptualization: Young Sup Woo, Won-Myong
with recent evidence that non-invasive neurostimulation Bahk. Study design and data collection: Young Sup Woo,
including rTMS could be an effective and feasible alter- Won-Myong Bahk, Jeong Seok Seo, Young-Min Park,
native treatment for antenatal depression [67,68] and Won Kim, Jong-Hyun Jeong, Se-Hoon Shim, Jung Goo
MDD patients with specific psychiatric comorbidities Lee, Seung-Ho Jang, Chan-Mo Yang, Sheng-Min Wang,
[69]. Moreover, CANMAT 2016, considers rTMS a Myung Hun Jung, Hyung Mo Sung, IL Han Choo,
first-line treatment for MDD patients who have failed at Bo-Hyun Yoon, Sang-Yeol Lee, Duk-In Jon, Kyung Joon
least one AD treatment [43], while KMAP-DD 2021, rec- Min. Guideline review: Young Sup Woo, Jeong Seok Seo,
ommended rTMS as the second-line treatment. Won-Myong Bahk, Young-Min Park, Won Kim, Jong-Hyun
Jeong, Se-Hoon Shim, Jung Goo Lee, Seung-Ho Jang.
CONCLUSION Data analysis and interpretation: Jeong Seok Seo,
Won-Myong Bahk, Young Sup Woo, Young-Min Park,
In this review, we compared the recommendations Won Kim, Jong-Hyun Jeong, Se-Hoon Shim, Jung Goo
from KMAP-DD 2021, to those of other CPGs. KMAP-DD Lee, Seung-Ho Jang. Funding acquisition: Won-Myong
2021, is an expert-consensus guideline, while other CPGs Bahk, Jeong Seok Seo. Draft manuscript preparation:
are evidence-based. Hence, although the KMAP-DD 2021 Young Sup Woo. All authors reviewed the results and ap-
recommendations were similar across guidelines, there proved the final version of the manuscript.
were some differences in details. Korean experts needed
rapid antidepressant effects, which may be due to cultural ■ ORCID
or ethnic differences, and this was reflected in the prefer- Young Sup Woo https://orcid.org/0000-0002-0961-838X
ence for AAPs for non-psychotic depression and for com- Won-Myong Bahk https://orcid.org/0000-0002-0156-2510
bination and augmentation in relatively early-stage treat- Jeong Seok Seo https://orcid.org/0000-0002-4880-3684
ments. Although KMAP-DD 2021, has some limitations as Young-Min Park https://orcid.org/0000-0002-4993-1426
a set of expert-consensus guidelines, its strengths are its Won Kim https://orcid.org/0000-0002-5478-7350
recommendations for various situations, such as PDD, Jong-Hyun Jeong https://orcid.org/0000-0003-3570-7607
MDE with mixed features, melancholic depression with Se-Hoon Shim https://orcid.org/0000-0002-3137-6591
atypical features, depression with seasonal pattern, and Jung Goo Lee https://orcid.org/0000-0003-3393-2667
non-psychological medical illness, for which strictly de- Seung-Ho Jang https://orcid.org/0000-0002-3479-0552
signed clinical trials cannot draw evidence or were not Chan-Mo Yang https://orcid.org/0000-0002-4959-7595
performed sufficiently. Considering these advantages, Sheng-Min Wang https://orcid.org/0000-0003-2521-1413
KMAP-DD 2021, provides valuable information to Korean Myung Hun Jung https://orcid.org/0000-0003-2393-3930
clinicians for making decisions in various clinical sit- Hyung Mo Sung https://orcid.org/0000-0002-2396-3358
uations by complementing other evidence-based guidelines. IL Han Choo https://orcid.org/0000-0001-6547-9735
Bo-Hyun Yoon https://orcid.org/0000-0002-3882-7930
■ Funding Sang-Yeol Lee https://orcid.org/0000-0003-1828-9992
This study was supported by the Korean Society for Duk-In Jon https://orcid.org/0000-0002-1565-7940
Affective Disorders and the Korean College of Neuro- Kyung Joon Min https://orcid.org/0000-0001-7037-8904
psychopharmacology. This research did not receive any
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