Management of unspecified anxiety disorder: Expert consensus

Abstract Aims Treatment guidelines with respect to unspecified anxiety disorder have not been published. The aim of this study was to develop a consensus among field experts on the management of unspecified anxiety disorder. Methods Experts were asked to evaluate treatment choices based on eight clinical questions concerning unspecified anxiety disorder using a nine‐point Likert scale (1 = “disagree” to 9 = “agree”). According to the responses from 119 experts, the choices were categorized into first‐, second‐, and third‐line recommendations. Results Benzodiazepine anxiolytic use was not categorized as a first‐line recommendation for the primary treatment of unspecified anxiety disorder, whereas multiple nonpharmacological treatment strategies, including coping strategies (7.9 ± 1.4), psychoeducation for anxiety (7.9 ± 1.4), lifestyle changes (7.8 ± 1.5), and relaxation techniques (7.4 ± 1.8), were categorized as first‐line recommendations. Various treatment strategies were categorized as first‐line recommendations when a benzodiazepine anxiolytic drug did not improve anxiety symptoms, that is, differential diagnosis (8.2 ± 1.4), psychoeducation for anxiety (8.0 ± 1.5), coping strategies (7.8 ± 1.5), lifestyle changes (7.8 ± 1.5), relaxation techniques (7.2 ± 1.9), and switching to selective serotonin reuptake inhibitors (SSRIs) (7.0 ± 1.8). These strategies were also highly endorsed when tapering the dosage of or discontinuing benzodiazepine anxiolytic drugs. There was no first‐line recommendation regarding excusable reasons for continuing benzodiazepine anxiolytics. Conclusions The field experts recommend that benzodiazepine anxiolytics should not be used as a first‐line option for patients with unspecified anxiety disorder. Instead, several nonpharmacological interventions and switching to SSRIs were endorsed for the primary treatment of unspecified anxiety disorder and as alternatives to benzodiazepine anxiolytics.


| INTRODUC TI ON
Anxiety disorders are frequent and persistent illnesses that is regarded as the ninth most health-related cause of disability. 1 Treatment guidelines based on solid evidence that mainly stems from randomized controlled trials are available in some anxiety disorders including generalized anxiety disorder, panic disorder, and social anxiety disorder. [2][3][4][5] Unspecified anxiety disorder is a diagnosis that is characterized as significant anxiety or phobias without the exact criteria for any other anxiety disorders. According to a cross-sectional study using nationally representative data for physician office-based visits in the United States, unspecified anxiety disorder was the major diagnosis in anxiety disorders, increasing 50% between 1999 and 2002 to 62% between 2007 and 2010. 6 However, to our knowledge, there have been no reports of randomized controlled trials for unspecified anxiety disorder probably because of the heterogeneity of this disease. Thus, treatment guidelines for unspecified anxiety disorder have not been published with the result that clinicians always have difficulty in making treatment decision.
Opinions from field experts reflecting actual clinical experience are useful in providing clear treatment recommendations for issues that are clinically relevant but failed to be addressed in previous studies. Notably, benzodiazepine anxiolytics have been used for the treatment of anxiety disorders due to their efficacy, fast action, and no serious side effects in the short term. 7,8 While maintenance treatment with benzodiazepines has been considered to be associated with several adverse events, including sedation, cognitive impairments, and potential for dependence, 9 recent reports indicated that their efficacy and safety could also be maintained in the long term. 8,[10][11][12][13] The aim of the present study was therefore to develop a consensus among experts on the management of unspecified anxiety disorders, including the use of benzodiazepine anxiolytics.
There was no first-line recommendation regarding excusable reasons for continuing benzodiazepine anxiolytics.

Conclusions:
The field experts recommend that benzodiazepine anxiolytics should not be used as a first-line option for patients with unspecified anxiety disorder. Instead, several nonpharmacological interventions and switching to SSRIs were endorsed for the primary treatment of unspecified anxiety disorder and as alternatives to benzodiazepine anxiolytics.

K E Y W O R D S
anxiolytics, benzodiazepine, expert consensus, unspecified anxiety disorder was used to compare the numbers of these three rating categories for each treatment choice. When the responses were evenly distributed across the three categories with a p-value ≥0.05, the outcome was regarded as "no consensus" for the corresponding clinical question, indicating a controversial strategy. Treatment options with 95% CI values ≥6.5 were regarded as "first-line treatments/strategies," indicating a consensus among the experts for a given situation. Options rated as 9 by more than 50% of the responders were defined as "treatments of choice," indicating a particularly strong first-line recommendation.
Options with 95% CI values ≥3.5 were regarded as "second-line treatments/strategies," indicating reasonable options for patients who do not respond to or cannot tolerate the first-line strategies. Treatment options with 95% CI values <3.5 were considered "third-line treatments/strategies," indicating inappropriate options in general or those used only when other options were ineffective.

| Participant characteristics
The questionnaire was completed by 119 experts, which was con-

| Primary treatment strategy for unspecified anxiety disorder
Benzodiazepine anxiolytic use was not categorized as a first-line recommendation for the primary treatment of unspecified anxiety disorder (Table 1). Lorazepam (4.9 ± 2.4) and ethyl loflazepate (4.8 ± 2.2) were categorized as "no consensus," whereas other benzodiazepine anxiolytics had lower mean values. By contrast, multiple nonpharmacological strategies, including coping strategies (7.9 ± 1.4), psychoeducation for anxiety (7.9 ± 1.4), lifestyle changes (7.8 ± 1.5), and relaxation techniques (7.4 ± 1.8), were categorized as first-line choices for unspecified anxiety disorder. Coping strategies were categorized as the "treatment of choice" as it was rated with 9 by 50.4% of the respondents.

| Treatment strategy when benzodiazepine anxiolytics are ineffective
When benzodiazepine anxiolytic drug use did not improve anxiety symptoms, the only first-line pharmacological treatment was switching to selective serotonin reuptake inhibitors (SSRIs) (7.0 ± 1.8) ( Table 2). Switching to other antidepressants, including serotonin and norepinephrine reuptake inhibitors (5.7 ± 2.0) and mirtazapine (5.5 ± 2.1), was categorized as second-line treatments. However, several treatment strategies were highly recommended in the case of no improvement with benzodiazepine anxiolytics. Differential diagnosis (8.2 ± 1.4, rated with 9 by 63.0% of the respondents) and psychoeducation for anxiety (8.0 ± 1.5, rated with 9 by 51.3% of the respondents) were categorized as "treatments of choice," whereas coping strategies (7.8 ± 1.5), lifestyle changes (7.8 ± 1.5), and relaxation techniques (7.2 ± 1.9) were categorized as first-line recommendations.

| Discontinuation of benzodiazepine anxiolytic drugs
There was no first-line recommendation for the timing of dosage tapering or discontinuation of a benzodiazepine anxiolytic drug after the improvement of anxiety symptoms. Notably, 1-3 month(s) (5.7 ± 2.2) and 3-6 months (5.7 ± 2.1) after the improvement of symptoms were categorized as second-line recommendations.
Moreover, there was also no first-line recommendation concerning excusable reasons for continuing benzodiazepine anxiolytic drugs.
All suggested clinical reasons involving anticipation of physical or mental deterioration (6.7 ± 2.0), history of relapsed anxiety symptoms (6.7 ± 2.1), and no stabilization of physical or mental states or TA B L E 1 Recommended primary treatment strategy for unspecified anxiety disorders.

| DISCUSS ION
In the present study, the practical management of unspecified anxiety disorder was evaluated by the field experts. Benzodiazepine anxiolytic drug use was not considered a first-line strategy for the primary treatment in unspecified anxiety disorder and was only recommended for short-term use after symptom improvement. By contrast, nonpharmacological strategies were highly endorsed for several situations, including primary treatment, subsequent treatment for no improvement with a benzodiazepine anxiolytic drug, and as an alternative to treatment with a benzodiazepine anxiolytic drug.
In addition, switching to SSRIs was strongly recommended when tapering the dosage of or discontinuing benzodiazepine anxiolytic drugs. These recommendations reflect the experts' consensus on reducing the use of benzodiazepine anxiolytic drugs as much as possible in patients with unspecified anxiety disorder.
Benzodiazepine anxiolytics use was not recommended as a firstline strategy for the treatment of unspecified anxiety disorder; however, lorazepam and ethyl loflazepate, which were categorized as "no consensus," were the most commonly endorsed benzodiazepines.
This may reflect physicians' efforts to avoid prescribing benzodiazepine anxiolytic drugs, possibly because of the potential adverse events. In the principle of "above all, do no harm," benzodiazepine anxiolytics should be limited to the treatment of specified anxiety disorders, including generalized anxiety disorder, panic disorder, and social anxiety disorder, for which benzodiazepine anxiolytics are evidenced to be somewhat effective. 3 Abbreviations: CBT, cognitive behavioral therapy; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
a The mean value was lower than that categorized as "no consensus." TA B L E 3 Recommended treatment strategy for tapering the dosage of or discontinuing a benzodiazepine anxiolytic drug for unspecified anxiety disorders.
a The mean value was lower than that categorized as "no consensus." promote positive psychological outcomes. 14-17 Further investigations are needed to clarify the types of coping strategies appropriate for this population.
Similar to the primary treatment of unspecified anxiety disorder, several practical nonpharmacological strategies, including differential diagnosis, psychoeducation for anxiety, coping strategies, lifestyle changes, and relaxation techniques, were categorized as first-line recommendations in cases of nonimprovement with a benzodiazepine anxiolytic drug. It is noteworthy that these nonpharmacological strategies were endorsed more than any other pharmacological strategy. Among them, differential diagnosis and psychoeducation for anxiety were categorized as "treatments of choice." Physicians should thoroughly assess patients' time course and diagnose diseases, including anxiety disorders due to other illnesses or causes (e.g., excessive caffeine intake). 8  There was no first-line recommendation for the timing of dosage tapering or discontinuing benzodiazepine anxiolytic drugs after the improvement of anxiety symptoms. A treatment period of 1-6 months may be reasonable for the prevention of symptom relapse and potential long-term side effects. 9 There was also no first- In conclusion, the field experts recommend not using benzodiazepine anxiolytics as a first-line treatment strategy in unspecified anxiety disorder and only prescribing them in the short term, if needed. Instead, several nonpharmacological interventions, as well as switching to SSRIs, were highly endorsed for primary treatment and as alternatives to benzodiazepine anxiolytics. While these recommendations need to be confirmed in future clinical studies, consensus-based recommendations may be useful to solve clinical questions for which the evidence to date is limited.