Japanese Society of Anxiety and Related Disorders/Japanese Society of Neuropsychopharmacology: Clinical practice guideline for social anxiety disorder (2021)

Abstract The development of clinical practice guidelines for social anxiety disorder began in March 2018 when the Joint Clinical Practice Guideline Development Committee for Anxiety and Obsessive–Compulsive Disorders was formed by the Japanese Society of Anxiety and Related Disorders and Japanese Society of Neuropsychopharmacology to jointly develop guidelines for anxiety and obsessive–compulsive disorders. Based on the universal concept of evidence‐based medicine, three clinical questions (CQs) about pharmacotherapy and psychotherapy were developed for clinical guidelines for social anxiety disorder, panic disorders, and obsessive–compulsive disorder in accordance with the Minds “Manual for Guidelines Development 2017 by the Japan Council for Quality Health Care: CQ1—“What is the recommended pharmacotherapy for social anxiety disorder in adults?”; CQ2—“What is the recommended psychotherapy (psychological intervention) for social anxiety disorder in adults?”; and CQ3—“What are the recommendations regarding monotherapy and combination therapy for social anxiety disorder in adults in terms of pharmacotherapy and psychotherapy (psychological interventions)?” Summarized recommendations for social anxiety disorder in adults are selective serotonin reuptake inhibitors and serotonin‐norepinephrine reuptake inhibitor for CQ1, cognitive behavioral therapy for CQ2, and there are no recommendations regarding monotherapy and combination therapy for CQ3. These were answered by considering the balance between benefits and harms based on systematic reviews of each. The aim of this brief guideline for the standard‐of‐care (i.e., medical treatment) for social anxiety disorder in adults (18 years and older) was to help “shared decision making,” in which medical professionals, including physicians, and patients share scientific evidence to decide on a course of treatment.

Network meta-analysis: Statistical analysis for the simultaneous meta-analysis of three or more intervention groups.
Randomized controlled trial (RCT): A research method that aims to avoid evaluation bias and objectively evaluates treatment effects.
Participants are randomly assigned to the intervention group and comparison group for implementation and evaluation.
Selective serotonin reuptake inhibitor (SSRI): Drug that inhibits serotonin reuptake in the brain and enhances serotonin function.
Serotonin-norepinephrine reuptake inhibitor (SNRI): Drug that inhibits the reuptake of serotonin and norepinephrine in the brain and enhances serotonin and norepinephrine function.
Systematic review: A systematic and comprehensive review of the literature and data analysis of high-quality studies, such as RCTs, removing as much data bias, such as publication bias, as possible. and pharmacotherapy that were conducted in Japan and overseas and conduct a systematic review. It was also decided that if a latest national or international systematic review is available, then this systematic review could be used to develop recommendations. Because clinical practice for the treatment of anxiety and obsessive-compulsive disorders involves a combination of medical assessment, diagnosis, psychotherapy, pharmacotherapy, psychoeducation, and other non-pharmacological treatments, including psychiatric rehabilitation, in an integrated manner, we aimed to develop guidelines for clinical practice rather than just a treatment guideline.
The purpose of the clinical practice guideline for social anxiety disorder was to provide recommendations for the treatment of adults (18 years of age and older) with social anxiety disorder, balancing beneficial outcomes (e.g., responsiveness to treatment and symptom improvement) and harmful outcomes (e.g., dropout from treatment) of pharmacotherapy and psychotherapy.

Precautions for use
This guideline was developed with the aim of assisting clinical practice and not dictating treatment. Physicians will need to devise treatment plans at their own discretion without being bound by this guideline. Therefore, mere compliance with this guideline during treatment does not exempt a physician from liability for negligence, and deviations from this guideline cannot be regarded as negligence.
In other words, the content of this guideline is not a basis for medical litigation.

Conflicts of interest (for the past 3 years)
Both individual and organizational conflicts of interest were reported according to the items reported and standard amounts disclosed (financial categories I, II, and III), based on the Japanese Association of Medical Sciences COI Management Guidance on Eligibility Criteria for Clinical Practice Guideline Formulation (released in March 2009). The committee discussed eligibility conditions for appointment of the Chair and Vice-Chair of the committee and the appointment of committee members and whether or not the right to vote should be granted. It was decided that committee members who fall into financial category III would not have voting rights in the committee and that committee members who fall into financial category II would not be able to assume the office of Chair or Vice-Chair. Conflicts of interest include the following over the last 3 years: (1) directorships or advisory positions in companies or for-profit organizations and amounts of their compensation, (2) shareholdings and profits derived from such shares, (3) compensation paid as royalties for patent rights by companies or for-profit organizations, (4) compensation, such as per diem and lecture fees, paid by companies and commercial organizations for time and effort spent by the researcher in attending meetings (e.g., presentations, advice, etc.), (5) compensation paid by companies or commercial organizations for writing manuscripts, pamphlets, etc., (6) research funding provided under contract by companies and commercial organizations, (7) scholarship (support) endowments provided by a company or a for-profit organization, (8) endowment courses provided by a company or for-profit organization, and (9) other compensation (e.g., travel not directly related to research, gifts, etc.). Declarations were reported in writing for the declarant and his/her spouse, first-degree relatives, and persons with whom the declarant shared income or property interests. Organizational structure The following organizational structure was used to determine recommendations and develop the guideline ( Figure 2).

Intended users and facilities for this guideline
Medical professionals who are involved in the treatment of social anxiety disorder (physicians, certified public psychologists, nurses, mental health social workers, occupational therapists, pharmacists, etc.) and patients with social anxiety disorder and their families and caretakers.

Potentially indicated clinical settings
• Primary care (including general internal medicine, psychiatry, and psychosomatic medicine).

How to use the guideline
• Standard-of-care (treatment) recommendations.

Basic characteristics of social anxiety disorder
Clinical characteristics Overall flow of treatment for social anxiety disorder Pharmacotherapy and psychotherapy (i.e., psychological interventions) have been shown to be effective treatments for social anxiety disorder in adults. Antidepressants, mainly SSRIs, are effective in the former, and CBT is considered effective in the latter. However, it has not been established which pharmacotherapy or psychotherapy is optimal. The superiority of both treatment modalities or the efficacy of combination therapy has also not been determined.
In this guideline, we examine which pharmacotherapy and psy- is not absolute or permanent and should be considered a guide. The guideline is not intended to be a legal standard.

Matters related to content covered by the clinical practice guideline
Those covered by the guideline (target population, age, and gender): • Patients with social anxiety disorder (aged over 18 years: adults) of any gender.
Those not covered by the guideline (including excluded populations, clinical conditions, severity of illness, and comorbidities): • Children and young patients (under 18 years of age) with social anxiety disorder.
• Patients with clinically problematic and unstable concomitant physical illness.
• Women who are pregnant or may become pregnant.
• Patients with organic brain diseases and neurodegenerative diseases.
• Patients at obvious risk of self-harm/suicide or other harm.
• Patients with obvious intellectual disabilities.

Matters related to systematic review
Searching for evidence Japanese-language literature, we used Ichu-shi web.

Basic search policy:
The Patient/Population, Intervention, Comparison, and Outcomes (PICO) format was used to search for interventions.
The basic combination is P and I; occasionally C is also specified; O is not specified. Search terms are presented in the Appendix A.

Search period:
For all databases, the search period for CQ1 covers all articles included in the databases up to April 30, 2018, and the search period for CQ2 and CQ3 covers all articles included in the databases up to August 10, 2018.

Criteria for selection and exclusion of literature:
The selection criteria for evidence were the following: the target population was adults (aged 18 years or older) with social anxiety disorder, the study design favored RCTs, the comparison groups included a sham group and a waitlist group, the outcome was defined in terms of benefit (improvement in treatment response and social anxiety symptoms) and harm (dropout from treatment due to side effects, adverse events, etc.), and the language of the studies was either English or Japanese.
A CPG or systematic review paper that met the conditions for adoption is given first priority.
If there are no CPG or systematic review papers that meet the conditions for adoption, then a de novo systematic review is conducted of individual research papers.
In the de novo systematic review, all RCTs that meet the recruitment criteria are prioritized.
If there are no RCTs that meet the recruitment criteria, then observational studies are included.
If there are no observational studies that meet the recruitment criteria, then the systematic review is not conducted. In determining a recommendation and its strength, the "strength of the evidence" and "balance of benefits and harms" that are required in the evaluation and synthesis of evidence and the "diversity of patient values" and "economic perspective" should be considered.

Finalization:
Conduct an external evaluation.

CQ1: What is the recommended pharmacotherapy for social anxiety disorder in adults?
Recommendation: 1. Selective serotonin reuptake inhibitors (SSRIs) are suggested.
Additional information: 1. The drugs covered by national health insurance for social anxiety disorder in Japan are fluvoxamine (Luvox®, Depromel®, and other available generics), paroxetine (Paxil® and other available generics), and escitalopram (Lexapro® and other available generics). These drugs are suggested as first choice.
2. Among drugs that are not covered by national health insurance for social anxiety disorder in Japan, the SSRI sertraline (J Zoloft® and other available generics) and the SNRI venlafaxine (Effexor®) have been reported to be as effective and well tolerated as the above drugs.
However, pharmacotherapy with unapproved drugs in the Japanese market is generally different from ordinary, insured treatment and should be conducted after providing a sufficient explanation of the special benefits and harms of unapproved drugs in Japan, based on ethical considerations for the patient and after obtaining written consent from the patient, which is beyond the scope of responsibility of the guideline.

Background and priority of this issue
Pharmacotherapy has been shown to improve social anxiety symptoms in adults with this condition. However, pharmacotherapy has side effects. It is necessary to identify useful pharmacotherapies that can be used in the current Japanese medical system while considering the benefits and harms.

Explanation
Summary of evidence: Study designs adopted in the body of evidence A PubMed search for existing guidelines or systematic reviews of social anxiety disorder in adults revealed that the most recent systematic review on pharmacotherapy was by Williams et al. 1 Therefore, analyses were conducted with the aim of integrating Based on benefit-harm data, high treatment response rates and low dropout rates were important in making these recommenda- launched in Japan in November 2019, one RCT of social anxiety disorder was conducted after the previous systematic review, which reported its efficacy and acceptability, but the meta-analysis was unavailable. Evidence for other classes of drugs is presented in the Appendix S1.

Panel meeting
What is the quality of the evidence on overall outcomes? (validity of outcomes, consistency of results across studies, directionality of results between studies) A meta-analysis of RCTs showed that for reasonable outcomes of benefit (improvements in treatment response and social anxiety symptoms) and harm (dropout from treatment), there was a risk of bias, inconsistency, and other questions for SSRIs and a risk of bias, inconsistency, imprecision, and other questions for SNRIs.
Therefore, both classes were downgraded two levels, and the final certainty of evidence was determined to be "low."

What is the balance between benefits and harms? (magnitude of benefit vs. magnitude of harm)
SSRIs and SNRIs produced significant improvements in social anxiety compared with placebo, and dropout rates were similar to placebo. Therefore, the overall benefit (improvements in treatment response and social anxiety symptoms) was determined to be higher than harm (dropout from treatment).

What are the patient's values and preferences?
Although side effects of SSRIs and SNRIs were noteworthy, they showed no significant difference in dropout rates from placebo. We concluded that there is no significant uncertainty or diversity in the patients' values and preferences, provided that the effects and side effects are fully explained, and patients consent to the pharmacotherapy of choice. What is the balance between net benefits and costs and resources?
(applicability to actual practice) The cost of treatment is covered by the current national health insurance coverage, with medical remuneration points covering outpatient psychotherapy (540 points for an initial visit of 60 min or more, 330 points for a second visit of less than 30 min, and 400 points for a second visit of 30 min or more) and drug costs (approximately ¥30-¥300 per day, as of April 1, 2019). Medication is available at any psychiatric facility and considered cost-effective because the treatment has been shown to be effective.

Recommendation grading
In the panel meeting discussion, all agreed with the "weak recommendation" label, according to the GRADE assessment.

Descriptions of other relevant clinical guidelines
Existing guidelines include the National Institute for Health and Care Excellence (NICE) in the United Kingdom, 2 S3 in Germany, 3 and Canadian Clinical Practice Guideline (Canadian CPG) in Canada. 4 There are no existing guidelines in Japan.

Randomized controlled trial papers covered in this CQ
There are 26 papers on SSRIs and five papers on SNRIs.
Literature used for meta-analysis of SSRIs: Allgulander C. Paroxetine in social anxiety disorder: a randomized placebo-controlled study. Acta Psychiatr Scand.

CQ2: What is the recommended psychotherapy (psychological intervention) for social anxiety disorder in adults?
Cognitive • Experiential exercises that demonstrate negative effects of selfattention and safety-seeking behavior.
• Video feedback to correct distorted negative self-image.
• Systematic training to pay attention to external stimuli.
• In-session behavioral experiments that examine negative beliefs and homework related to them.
• Discrimination training and rewriting to address traumatic memories of distressing social situations.
• Review and modification of core beliefs.
• Modification of anticipatory anxiety and ruminations related to social situations.
• Gradual exposure to feared social situations (both in-session and as homework).
• Review and modification of core beliefs.
Self-help with support based on CBT Supported self-help for social anxiety disorder consists of the following: • Typically, approximately nine sessions are conducted over 3-4 months using self-help materials based on CBT with support.
• The use of self-help materials is supported by a therapist via faceto-face meetings or telephone for a total of approximately 3 h over the course of a treatment series.

Background and priority of this issue
Social anxiety disorder is a common disorder in Japan, with a reported 12-month prevalence of 0.8%. Considering that the median age of onset in the United States is 13 years and that symptoms persist thereafter, the impact on daily life and quality of life is critical.
Therefore, identifying the recommended psychotherapy is a priority.
Psychotherapy has been shown to improve social anxiety symptoms. In addition to CBT, various other types of psychotherapy are used, including mindfulness cognitive therapy, acceptance and commitment therapy (third-generation behavior therapy), psychodynamic therapy, and Morita therapy. Additionally, guidelines are needed for recommended forms of psychotherapy, such as individual or group sessions, and self-help. Therefore, it is necessary to identify useful psychotherapies that can be provided in the current Japanese medical system.

Summary of evidence
We first searched the NGC and IGL for existing clinical guidelines on social anxiety disorder in adults. The NICE guideline 1 was identified as specific to social anxiety disorder. The P (Patient/ Population) was identified as adults with social anxiety disorder.
The I (Intervention) was CBT, interpersonal therapy, psychodynamic

Recommendation:
1. The administration of cognitive behavioral therapy (CBT), developed specifically for the treatment of social anxiety disorder (based on the Clark and Wells model or the Heimberg model) through individual sessions by a skilled therapist following a series of procedures, is suggested.
(GRADE: None, Strength of recommendation "weak"/ Certainty of evidence "low") Although this therapy can be administered as group therapy (group session), individual therapy is prioritized because of its superiority in terms of clinical-and health-related economic effectiveness.
2. If the patient does not want face-to-face CBT, then self-help with support based on CBT is suggested.
(GRADE: None, Strength of recommendation "weak"/ Certainty of evidence "low") Additional information: 1. In Japan, CBT that is conducted by physicians is covered by national health insurance, but insurance coverage has not yet been approved for CBT that is conducted by certified public psychologists or other professionals besides physicians. 3. The reasons for excluding short-term psychodynamic therapy and other psychotherapies from the recommendations are presented in the Appendix S1.
therapy (psychoanalytic psychotherapy), Morita therapy, and others. included "dropout" and "improvement in social anxiety symptoms" but not "treatment responsiveness." However, because "recovery" was included in the outcome of this CQ as an umbrella concept for "treatment responsiveness," we determined that all PICOs were met (a systematic review using "responsiveness" as the outcome is required in the future Next, data extraction and bias risk assessment were performed for each identified study. Finally, we prepared a descriptive summary of each study. Note that we combined the results of the studies that were identified in this systematic review with those that were included in the network meta-analysis of the NICE guideline and did not re-analyze or re-evaluate the total body of results.

Literature search and screening results
After searching databases and conducting primary and secondary screening, we identified 11 studies that met this CQ. These included CBT-based intervention versus treatment waitlist (n = 7), psychodynamic therapy versus treatment waitlist (n = 1), and other psychotherapy versus treatment waitlist/control (n = 3).
We tracked studies that were published after the NICE guide- A paper 3 that presented the results of the network meta-analysis of the NICE guideline found that psychotherapy (CBT, self-help, exposure therapy/social skills training, and short-term forced psychodynamic therapy) contributed to the improvement in social anxiety symptoms. Of these, individual CBT was the most effective and the only one of the various treatments, including pharmacotherapy, that outperformed both the waitlist and placebo groups. Although dropout from treatment has not been evaluated overall because of the paucity of reported studies, the network meta-analysis that is described above is based on the principle of intention-to-treat, which takes dropout cases into account.

Panel meeting
What is the quality of evidence on overall outcomes?
For this comparison that is included in the NICE guideline, a GRADE assessment could not be made because the required data for individual studies were unavailable. The network meta-analysis as a whole had no serious problems with non-directness, inconsistency, or imprecision, but there were some minor bias risks and some serious issues with publication bias. Therefore, together, they were downgraded by two levels, and the final certainty of evidence was determined to be "low." The results of the NICE guideline systematic review and metaanalysis on which this recommendation was based were mostly from Western countries, with minimal data from Asian countries.
However, because there are findings that outcomes of clinical trials on psychotherapy for social anxiety disorder do not vary significantly across cultures and that minor modifications that consider cultural differences can be expected to be effective, 4,5 the conclusion of this recommendation is unchanged.

What is the balance between benefits and harms?
Individual CBT has produced significant improvements in social anxiety symptoms. Although dropout rates are not addressed in the network meta-analysis, there is no clear evidence from existing research that CBT increases dropout rates. Therefore, the overall benefit (improvement in social anxiety symptoms) was determined to be higher than harm (dropout from treatment).

What are the patient's values and preferences?
In this study, we were unable to search for articles that systematically investigated values and preferences of Japanese patients with social anxiety disorder. However, there have been surveys on psychiatric disorders and anxiety disorders in other countries. [6][7][8][9][10] Overall, patients prefer psychotherapy over pharmacotherapy.
Based on the above, we propose the psychotherapy that is described above because it is assumed to be preferred by patients and because there are fewer side effects than would occur with pharmacotherapy. We propose individual CBT, which is the most clinically effective and cost-effective among various treatments for social anxiety disorder. However, it is necessary to carefully consider the patient's preferences after fully explaining that psychotherapy generally requires more frequent visits and longer sessions than pharmacotherapy and that the patient may need to go to a medical institution that can provide a specific type of psychotherapy and may need to bear the costs.

What is the balance between benefits and costs and resources?
Although treatment costs can be estimated, and the degree of certainty is relatively high, calculation requirements and medical remuneration points fluctuate with revisions to medical fees.
High-frequency individual CBT (e.g., 16 sessions of weekly CBT) is expected to cost more than pharmacotherapy in the short term. However, as shown by the NICE guideline results, it is still cost-effective. Even when modeled for Japan, the costs are likely to be lower than the threshold of willingness to pay (incremental cost-effectiveness ratio = ¥5 million), which is the average amount of money that the Japanese population is willing to pay for treatment. A health economic analysis based on a Japanese clinical trial (see Appendix S1 of Yoshinaga et al. 11 ) showed that the cost-effectiveness of individual CBT was significantly lower than the upper limit of average willingness to pay in the Japanese population. However, from the perspective of a medical facility, the maximum revenue from national health insurance (medical remuneration points) per an individual session of approximately 60-90 min is expected to be 480 points, whereas the salary and other costs of a specialist for 60-90 min would often exceed that amount. This may be a barrier to the widespread use of CBT in insured practices.
If the supply of individual CBT under national health insurance is insufficient because of the above reasons, among others, some patients may be unable to receive psychotherapy unless they pay for it out-of-pocket, which raises the issue of fairness because the out-ofpocket costs will be higher than for insured treatment. Additionally, transportation costs may also be incurred if the medical institution where a particular psychotherapy is provided is not nearby and the patient must travel to a distant location.
Although interventions require specific medical expenses, as mentioned above, some effectiveness can be expected. Additionally, medical expenses are covered by national health insurance, and independent-living medical care for people with disabilities may be available in some cases. A cost-effectiveness analysis that was conducted by the NICE guideline found individual CBT was the most cost-effective, which is thought to be attributable to strong therapeutic effectiveness and the fact that effectiveness is sustained over time.

Recommendation grading
In the panel meeting discussion, all members unanimously agreed to "suggest individual CBT" and "suggest self-help support based on CBT with conditions" because of the lack of a GRADE evaluation and the low overall certainty of evidence.

Descriptions of other relevant clinical guidelines
There are no other treatment guidelines for social anxiety disorder in Japan. Internationally, there is the NICE guideline from the UK that we use here. The conclusions of the NICE guideline are the same as those for the present guideline.

Treatment monitoring and evaluation
Treatment monitoring, evaluation, follow-up, and support for the patient are provided by the therapist. All interventions should be provided by therapists with sufficient knowledge and skills (competencies). For psychotherapy, this should be based on treatment manuals that include guidance on the structure and duration of interventions. Therapists should consider the competency framework (e.g., standards of training) that are set out in relevant treatment manuals and should also consider the following points: • Receiving regular access to quality supervision (guidance from a skilled practitioner) based on information about treatment outcomes.
• Using outcome measures (e.g., Liebowitz Social Anxiety Scale [LSAS] or Social Phobia Inventory [SPIN]) at every session and allowing patients with social anxiety disorder to be involved in reflecting on treatment effects.
• Monitoring and evaluating treatment adherence and therapist competency, such as using video/audio recordings and, where appropriate, external audit and scrutiny.
Potential for future research • There is a need for reanalysis/update of the NICE guideline to include evidence from the network meta-analysis. Systematic reviews/meta-analyses of adverse effects of psychotherapy are also needed.
• Recently, evidence for cross-diagnostic interventions (e.g., unified protocol) for anxiety disorders, including social anxiety disorder, has also been published. Therefore, there is a need to consider whether social anxiety disorder-specific or cross-diagnostic interventions are more effective.

Randomized controlled trial papers covered in this CQ
This CQ is based on the network meta-analysis that was conducted under the following NICE guideline: Background and priority of this issue In Japan, social anxiety disorder is a common disorder with a reported 12-month prevalence of 0.8%. Considering that the median age of onset in the US is 13 years and that symptoms have usually

Recommendation:
There is no recommendation for the use of combined pharmacotherapy and psychotherapy (psychological intervention) for social anxiety disorder in adults.
persisted since adolescence, the impact on daily life and quality of life is significant, and identifying recommended treatments is a priority. Medication and psychotherapy (psychological intervention) are the most common treatment options, but it is also necessary to clarify whether they should be used in combination.

Summary of evidence
We first searched the NGC and IGL for existing clinical guidelines on social anxiety disorder in adults. of this CQ included "dropout" and "improvement in social anxiety symptoms" but not "treatment responsiveness." However, because "recovery" was included as an umbrella concept for "treatment responsiveness," we determined that all PICOs were met (a systematic review using "responsiveness" as the outcome is required in the future

Literature search and screening results
After database searches and primary and secondary screening, no studies that met this CQ were identified. Based on these results, we decided to follow the NICE guideline for evidence regarding CQ3 recommendations. Studies of combination therapy that were included in the network meta-analysis of the NICE guideline were all different combinations (one study each), meaning that certainty was very low and the balance between desirable and undesirable effects could not be determined.

Panel meeting
What is the quality of the evidence on overall outcomes?
A GRADE assessment could not be made for this comparison that is included in the NICE guideline because the required data for individual studies were unavailable. Studies of combination therapies that were included in the network meta-analysis of the NICE guideline were all regarding different combinations, and overall certainty of the evidence was very low.

What is the balance between benefits and harms?
Studies of combination therapies that were included in the network meta-analysis of the NICE guideline were all regarding different combinations (one study each). Therefore, we were unable to determine the balance between desirable and undesirable effects.

What are the patient's values and preferences?
There are patients who do not wish to receive pharmacotherapy or psychotherapy. Combination therapy may also create additional risks and burdens for patients (e.g., side effects of additional SSRIs, hospital visits and costs when there is no nearby medical facility that can provide CBT). It is unclear whether the benefits of combination therapy outweigh these risks and burdens, and there is no clear recommendation for combination therapy. If a patient requests such therapy, then benefits and harms of these therapies should be fully explained to the patient, and the therapies/proposals should be tailored to the patient's preferences.

What is the balance between net benefits and costs and resources?
Cognitive which are certain to be higher than costs of a single treatment alone, is inconclusive. Additionally, pharmacotherapy can be administered at many medical institutions, but CBT can only be provided at a limited number of institutions, which is a significant imbalance in terms of resources.

Recommendation grading
In the panel meeting discussion, all agreed that there were no recommendations about whether or not to implement combined pharmacotherapy and psychotherapy because of the lack of GRADE evaluation and very low overall certainty of the evidence.

Descriptions of other relevant clinical guidelines
No other treatment guidelines for social anxiety disorder exist in Japan. Internationally, there is the UK NICE guideline (2013)  Potential for future research • Because of the lack of evidence for this CQ, the network metaanalysis needs to be reanalyzed and updated to include evidence from the time that the network meta-analysis for the NICE guideline was conducted.
• Comparative studies of treatment response, remission rates, and dropout rates for the three groups of CBT, SSRIs, and CBT plus SSRIs are needed.
• Studies of treatment response, remission rates, and dropout rates for additional SSRIs in the group of partial responders to CBT are needed.
• Studies of treatment response, remission rates, and dropout rates with the addition of CBT to partial responders to SSRIs are needed.

Introduction: Factors that promote and hinder application of the guideline
The guideline has been registered on the Minds Guideline Library website and made available as a downloadable PDF file from the websites of the Japanese Society of Anxiety and Related Disorders and Japanese Society of Neuropsychopharmacology so that it can be widely accessed by medical specialists, non-specialists, patients, and their families. An abridged version of the guideline, educational materials, and a book with detailed explanations will also be prepared to disseminate the guideline.
Factors that promote and hinder application of the guideline, based on feedback from stakeholders, are described below. Factors that promote pharmacotherapy include the fact that SSRIs are covered by national health insurance, and generic drugs also exist and are easy to use. A hindering factor is the fact that benzodiazepines are more likely to be used clinically, which may disincentivize the use of SSRIs. One factor that promotes psychotherapy is that CBT, when conducted by physicians, is also covered by national health insurance. Conversely, factors that hinder psychotherapy include the lack of sufficient medical remuneration points for CBT and the lack of insurance coverage when it is conducted by a certified public psychologist. Although the above factors did not influence guideline development or recommendations, it is necessary to investigate and research in the future the influence of factors that promote and hinder adherence to guideline recommendations in actual clinical practice.

Effectiveness evaluation: Criteria for monitoring (auditing)
We plan to conduct research to examine clinical effects of introducing the guideline using quality indicators and other methods. For members of the Japanese Society of Anxiety and Related Disorders and Japanese Society of Neuropsychopharmacology, a study will be conducted to monitor (audit) and report annually (

Revisions
Every 3 years, or when otherwise necessary (e.g., when a new treatment is introduced), revision of the guideline will be considered.
The Guideline Development Office will convene the Guideline Development Committee to revise the guideline.

AUTH O R CO NTR I B UTI O N S
Conception and design: All authors. Acquisition and analysis of data:

DATA AVA I L A B I L I T Y S TAT E M E N T
Supporting data for this guideline and recommendations are available from the Minds Guideline Library website at https://minds.jcqhc.

E TH I C S S TATEM ENT
N/A. The analysis plan is the following: "The primary endpoint (change in LSAS-J total score [last observation carried forward] at 12 weeks)

O RCI D
will be compared between treatment groups using analysis of covariance (ANCOVA), with treatment group as a factor and baseline LSAS-J total score as a covariate. The 20-mg escitalopram group will be compared with the placebo group only if the superiority of the 10-mg escitalopram group to the placebo group is verified.
The change in LSAS-J total score will be analyzed. The change in LSAS-J total score (at 12 weeks) will be analyzed by observed case and mixed-effect model repeated measure (MMRM) as a sensitivity analysis, and the change in LSAS-J total score (observed case) will be analyzed." As a result, the LSAS-J total score (primary endpoint) did not show a statistically significant difference between the 10-mg escitalopram and placebo groups with regard to change in LSAS-J total score (full analysis set, last observation carried forward) at week 12. Therefore, the 20-mg escitalopram group hypothesis was not tested. However, a non-multiple post hoc analysis showed a statistically significant difference in change in LSAS-J total scores between the placebo and 20-mg escitalopram groups. The MMRM and observed case analyses were performed for sensitivity analysis of the change in LSAS-J total scores at 12 weeks (full analysis set).
The results of the MMRM analysis showed a statistically significant difference in the mean change in LSAS-J total score (at 12 weeks) between the placebo and 10-mg escitalopram groups and between the placebo and 20-mg escitalopram groups. The ANCOVA results of the observed case analysis showed a statistically significant difference in the mean change between the placebo group and 10-and 20-mg escitalopram groups.
In the meta-analysis that was conducted for the guideline, each article was included after a careful examination of whether it met the inclusion criteria, after which the extent of risk of bias was examined for each article, and the data from each article were used to analyze the response rate and reduction of social anxiety symptoms (LSAS reduction). As such, the authors' interpretations of the conclusions of the Asakura et al. 1 paper above were not reflected in the systematic review.

R E FE R E N C E FO R P O S T N OT E
1. Asakura S, Hayano T, Hagino A, Koyama T. A randomized, double-blind, placebo-controlled study of escitalopram in patients with social anxiety disorder in Japan. Curr Med Res Opin. 2016;32 (4):749-57.