Pharmacotherapy and cognitive bias modification for the treatment of anxiety disorders

ABSTRACT

Introduction

Anxiety disorders are characterized by widespread and persistent anxiety or recurrent panic attacks. As a result of their high prevalence, chronicity, and comorbidity, patients’ quality of life and functioning are severely compromised. However, several patients do not receive treatment.

Areas covered

This review discusses the effectiveness, safety, and limitations of major medications and cognitive bias modification (CBM) for treating anxiety disorders. The possibility of combined treatment is also discussed in the literature. Furthermore, drawing on Chinese cultural perspectives, the authors suggest that anxiety can be recognized, measured, and coped with at three levels of skill (技), vision (术), and Tao (道).

Expert opinion

The combination of pharmacotherapy and CBM is possibly more effective in treating anxiety disorders than either treatment alone. However, clinicians and patients should participate in the joint decision-making process and consider comprehensive factors. Moderate anxiety has adaptive significance. In the coming years, by combining the downward analytical system of western culture with the upward integrative system of Chinese culture, a comprehensive understanding of anxiety and anxiety disorders should be established, rather than focusing only on their treatment.

KEYWORDS:

• Anxiety disorders
• cognitive bias modification
• Chinese culture
• pharmacotherapy
• treatment

1. Introduction

Anxiety disorders are a group of common neurotic disorders. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), anxiety disorders are characterized by some typical symptoms, including anxiety and concerns exceeding normal levels, recurrent panic attacks and irritability [1]. These symptoms should present on most days for at least 6 months [2]. Depending on specific symptoms, anxiety disorders can be categorized as follows: generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), agoraphobia, separation anxiety disorder, specific phobia, and selective mutism [1].

Globally, 264 million patients present anxiety disorders (3.6%) [3]. In the USA., the lifetime prevalence of anxiety disorders is 28.8% [4]. Individuals with anxiety disorders experience substantial impairments in their physical, psychological, and social functioning, increasing the overall burden of illness on society [5]. Furthermore, patients with anxiety disorders have comorbidities such as major depression and obsessive – compulsive disorder, among others [5]. Moreover, due to the intensification of interpersonal relationships, life pressures, and several other factors, the incidence of anxiety disorders is potentially increasing. Therefore, owing to high prevalence, chronicity, and comorbidity characteristics of anxiety disorders [6], they rank sixth concerning their contribution to global nonfatal health losses according to the World Health Organization [3].

Despite clinical and social importance of anxiety disorders, estimatingly, up to 41% of individuals with anxiety disorders do not receive treatment [7]. To date, major treatments for anxiety disorders in many countries include pharmacotherapy, psychotherapy, and a combination of both [8]. Pharmacotherapy usually uses antidepressants and anti-anxiety medications (e.g. benzodiazepines) to relieve symptoms. Psychotherapy primarily involves cognitive bias modification (CBM), cognitive behavioral therapy (CBT), and mindfulness-based interventions (MBI), among others. CBM as an emerging and promising therapy may help patients modify irrational cognitive biases, such as attentional and interpretive biases. This article provides an overview of the major medications and CBM used to treat anxiety disorders. In addition to discussing their effectiveness, safety, and limitations, the possibility of their combination is considered.

The recognition systems for anxiety differ between Eastern and Western cultures. A downward analytical system may be applied to recognize anxiety in Western culture, where the problem is broken down into multiple parts that are analyzed independently [9,10]. Thus, Western culture may promote analyzing and addressing separate problems one by one to alleviate anxiety sufferings. In contrast, an upward integrative system might be used to recognize anxiety in Chinese culture, where the object is understood holistically in context [9,10]. Therefore, Chinese culture may encourage ways such as cultivating one’s body and spirit to respond to anxiety disorders. Based on Chinese cultural perspectives, this article proposes that anxiety can be recognized, measured, and coped with at three levels of skill, vision, and Tao.

2. Scope of review

Up to 17 February 2024, we searched Web of Science, PubMed, Scopus, SAGE, including terms ‘anxiety disorder,’ ‘pharmacotherapy,’ ‘medication,’ ‘Cognitive bias modification,’ ‘Psychotherapy’ and ‘Chinese culture.’ Moreover, we made an extra step of including references to the retrieved articles in the relevant sections.

3. Pharmacotherapy

The pathogenesis of anxiety disorders remains inconclusive [11]. It is potentially related to abnormalities in physiological structures in the brain (e.g. abnormal changes in the amygdala, hippocampus, thalamus, and frontal cortex), abnormalities in neurotransmission in the neurotransmitter system, or certain personality traits [12–15]. Amygdala is responsible for processing emotionally relevant information and activating emotional responses in humans, and deficits in the regulation of its activity are considerably critical contributors to the development of anxiety disorders [16]. Given that, currently available medications for treating anxiety disorders primarily act through the amygdala-centered loop and its associated neurotransmitters, aiming at alleviating anxiety symptoms. These medications primarily target serotonin (5-HT), norepinephrine (NE), and gamma-aminobutyric acid (GABA) receptors, among others [17,18]. After considering factors, such as effectiveness, safety, and limitations, commonly used medications for treating anxiety disorders are presented below. However, not all medications mentioned are approved for anxiety disorder indications in all countries.

3.1. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs)

Two classes of antidepressants, SSRIs and SNRIs, are the primary options for treating anxiety disorders. SSRIs and SNRIs are typically used in the initial treatment of anxiety disorders. The primary mechanism of action of SSRIs is to selectively inhibit the reuptake of the neurotransmitter 5-HT, indirectly increasing 5-HT concentration in the synaptic gap [19]. SSRIs primarily include sertraline, paroxetine, fluvoxamine, escitalopram, and fluoxetine [17]. Meanwhile, SNRIs enhance central 5-HT and NE function primarily by selectively inhibiting 5-HT and NE reuptake. The most common SNRIs are venlafaxine and duloxetine.

It typically takes 2–4 weeks to kick in postmedication intake. De Vries et al. [20] demonstrated SSRIs and SNRIs validities through meta-analysis and -regression. They included 56 trials on the treatment of anxiety disorders using SSRIs and SNRIs, all being short term, randomized, double-blind, and placebo-controlled trials. In each trial, baseline severity and change scores were extracted for the drug and placebo groups, aiming to investigate the interaction between baseline severity and antidepressant efficacy (drug – placebo difference). Results showed that compared with the placebo group, an increase in baseline severity did not predict an improvement in efficacy in the drug group. Therefore, antidepressants were effective in patients with varying anxiety levels. Furthermore, Nagata et al. [21] found that the response rates ranged from 43% to 71% after 12 weeks of treatment with SSRIs and SNRIs.

However, before the therapeutic effect is recognized (particularly within the first 2 weeks), SSRIs and SNRIs have some side effects, such as palpitations and jitteriness [22], which can increase the patients’ anxiety and thus potentially reduce the patients’ treatment compliance [8]. Moreover, the discontinuation of antidepressants can be followed by withdrawal syndromes, particularly observed with paroxetine and venlafaxine [8].

However, compared with other medications used to treat anxiety disorders, SSRIs and SNRIs have well-controlled and short-lived side effects that disappear after a few weeks and less frequency and severity of withdrawal syndromes [8]. Therefore, initiating treatment with antidepressants at a relatively low starting dose and stopping them gradually is recommended. During the first few weeks of treatment, SSRIs and SSNIs in combination with benzodiazepines (BZDs) may be considered to minimize side effects [22].

3.2. Benzodiazepines

BZDs are effective for treating anxiety disorders, with their anxiolytic properties being the originally approved indication [23]. BZDs act by binding to benzodiazepine receptors located on GABA_A pentameric complex, promoting the chloride channel openings and enhancing the central inhibitory effect, resulting in anxiolysis and sedation [24]. The prime BZDs currently on the market are diazepam, alprazolam, and lorazepam [23].

For patients with acute-onset anxiety disorders, selectively using BZDs for a short duration is highly effective because they can quickly reduce anxiety symptoms [25]. Furthermore, when only the medications are taken, they are very safe, with relatively low lethality rates, even in cases of overdose [26].

Slee et al. [27] conducted a network meta-analysis involving 89 randomized trials on pharmacotherapy for GAD. The main measures consistent across these trials were efficacy (mean difference [MD] in changes in Hamilton Anxiety Scale [HAM-A] scores) and acceptability (trial discontinuation due to any reason). The results revealed that BZDs demonstrated a positive effect on reducing HAM-A scores (MD = −2.29, 95% confidence interval [CI] = −3.19 to − 1.39); however, patients consuming BZDs were less likely to complete the trial than those taking placebos (odds ratio [OR] = 1.43, 95% CI = 1.12–1.86). In conclusion, compared with placebo, BZDs were effective in reducing the symptoms of GAD, although they were less acceptable.

Gale et al. [28] compared the efficacy of BZDs with placebo in treating GAD. Using meta-analysis methods, 58 placebo-controlled trials were included. Furthermore, the impact of individual variables on efficacy was assessed. In each trial, efficacy (MD between BZDs and placebo) was measured by HAM-A score change. Results demonstrated that HAM-A score change was significantly and positively correlated with the baseline HAM-A scores (for BZDs group: adjusted R2 = 0.407, p < 0.001; for the placebo group: adjusted R2 = 0.1561, p < 0.001) and significantly and negatively correlated with the study duration (adjusted R2 = 0.06781, p = 0.01543). Concisely, the primary BZDs response determinants are the patient’s baseline anxiety severity and treatment duration. The higher the patient’s baseline anxiety level and the shorter the treatment duration, the more effective the BZDs.

However, caution should be exercised while using BZDs. Some typical side effects of BZDs include drowsiness, dizziness, weakness, and slowed breathing [29]. The long-term BZDs usage may cause memory impairment, abuse, dependence, and withdrawal reactions. Furthermore, if individuals use BZDs and opioids in combination, the risk of drug overdose death significantly increases [23]. Moreover, BZDs do not treat depression, even though it is the most common comorbidity of anxiety disorders [8].

Thus, considering these risks, BZDs are considered the second-line therapy for treating anxiety disorders [30]. Furthermore, before initiating BZDs, the US Food and Drug Administration recommends that physicians should thoroughly screen patients for risk factors and consider alternatives whenever possible [29]. Certainly, BZDs effectiveness in treating anxiety disorders should not be underestimated. BZDs should be actively considered a therapeutic option for patients who do not respond to first-line treatment [26]. The usual drug, advantages and drawbacks of first- and second-line medications for the treatment of anxiety disorders are summarized in Table 1.

Table 1. First- and second-line medications for the treatment of anxiety disorders.

Medication	Drug	Advantages	Drawbacks
Selective serotonin reuptake inhibitors (SSRIs)	Sertraline, paroxetine, fluvoxamine, escitalopram, and fluoxetine	Side effects are well-controlled and short-lived. Withdrawal syndromes are less frequent and severe.	Palpitations, jitteriness and withdrawal syndromes may occur.
Selective serotonin norepinephrine reuptake inhibitors (SNRIs)	Venlafaxine and duloxetine
Benzodiazepines (BZDs)	Diazepam, alprazolam and lorazepam	Anxiety symptoms are reduced rapidly. Safe to take alone.	Drowsiness, dizziness, weakness, and slowed breathing may occur. Memory impairment, abuse, dependence, and withdrawal reactions may occur when using BZDs long-term. The risk of drug overdose death may increase when using BZDs and opioids together.

3.3. Other medications

Tricyclic antidepressants (TCAs), including doxepin, amitriptyline, and clomipramine, etc., have been demonstrated to be effective in treating anxiety and anxiety disorders in many studies [31,32]. However, compared with SSRIs and SNRIs, the use of TCAs is associated with a higher incidence of side effects [33]. Moreover, toxicity is very high in cases of overdose [33]. Therefore, TCAs are used less frequently.

Pregabalin has shown consistent effectiveness in treating GAD when used alone or in combination with SSRIs or SNRIs [34–37]. Pregabalin has a more potent sedative effect than SSRIs and SNRIs, making it useful in improving patients’ sleep disturbances [8]. However, if overdose or using incorrect way to take pregabalin, drug abuse and dependence are likely to occur. Furthermore, after the sudden discontinuation of pregabalin, withdrawal syndromes, such as insomnia and nausea, may appear [38].

All the aforementioned drugs could rapidly relieve anxiety symptoms to some degree. However, these drugs usually have only a single target of action. Together with their limitations, such as adverse medication reactions and withdrawal syndromes, it makes the research of new anti-anxiety medications pretty active [39]. Recently, traditional Chinese medicine (TCM) has been gradually developed for the treatment of anxiety disorders because of its unique theories, reliable efficacy, and few side effects [11,40,41]. Under the guidance of the holistic concept of TCM, TCM prescriptions may be used to treat anxiety disorders in a multitargeted approach [40,42]. However, to date, objective assessment tools for TCM diagnosis and treatment are lacking, which hinders further studies.

4. Psychotherapy

4.1. Cognitive bias modification in the treatment anxiety disorders

Cognitive theory suggests that selective information processing plays a key role in the development and maintenance of anxiety disorders [43]. Patients with anxiety disorders tend to have an attentional bias toward threatening stimuli and a negative interpretation of ambiguous information [44]. Various research findings have revealed that cognitive bias toward threatening stimuli (e.g. attention bias, and interpretation bias, etc.) predicts subsequent heightened anxiety responses [45–47]. Given this, researchers have appealed for efforts to directly target the cognitive processes leading to anxiety, treating cognitive biases as the primary target of therapeutic interventions.

At present, CBM training, a computer-based intervention, is one of the psychotherapeutic approaches that has been progressively advanced, with an exponential growth in the related studies [48]. The core idea of CBM is to directly manipulate the target cognitive bias. It provides patients prolonged exposure to task contingencies, favoring a predetermined pattern of processing selectivity [48]. During training, patients are taught to preferentially engage with positive or neutral stimuli while avoiding threatening stimuli, inducing an anticipatory bias subsequently expanded to new situations. In this way, the cognitive processes generating negative thoughts are directly altered from the root cause [49]. Establishing trust is vital for long-term CBM treatment usage, helping in its implementation outside the laboratory.

Depending on the particular type of bias that wanted be changed, CBM has targeted training procedures. Attentional bias modification (ABM) training, for example, targets attentional selectivity. Its design is adapted from the classic point-probe task. However, unlike the dot-probe task where the probe occurs after both stimuli with equal frequency, the probe in ABM procedure occurs after neutral or positive stimuli much more frequently than after negative stimuli (avoid-negative training) [50]. Following prolonged repetition, the patient’s attention to threatening stimuli is suppressed and attentional alertness to neutral or positive stimuli is increased. Linetzky et al. [51] provided direct meta-analysis results of independent ABM treatment for clinical anxiety disorders, including 11 randomized controlled trials. Results based on clinician-rated measures demonstrated that ABM treatment group was associated with a more significant reduction in anxiety symptoms than control group (between-groups effect: d = 0.42, p = 0.001; within-groups effect: Q = 7.25, p < 0.01). Moreover, more patients no longer met DSM diagnostic criteria for anxiety disorders after ABM treatment (d = 0.40, p < 0.05). Therefore, ABM as an emerging approach has great potential for the treatment of anxiety disorders.

Furthermore, cognitive bias modification of interpretation (CBM-I) is a CBM procedure that targets interpretation selectivity. During CBM-I procedure, patients are typically asked to interpret multiple ambiguous situations. Positive feedback will be offered if the patient provides a positive interpretation; otherwise, negative feedback will be offered. Through extensive training, the negative interpretation bias of patients with anxiety disorders is modified. Rozenman et al. [52] provided evidence of CBM-I’s effectiveness by designing a double-blind trial. Twenty-four participants with elevated anxiety symptoms were randomly assigned to CBM-I intervention or interpretation control condition (ICC) group, receiving 12 training sessions. Changes in anxiety symptoms, interpretation bias (including % of threat interpretations endorsed and the interpretation bias index), and stress response (containing electrodermal activity, heart rate, and respiratory sinus arrhythmia) were assessed during pre- and post-intervention periods. The results reported that individuals who received CBM-I intervention experienced better relief in trait anxiety symptoms than those who received ICC (β = −7.92, SE = 2.37, p = 0.002), and the effects remained stable from post-intervention period to 1-month follow-up. Furthermore, CBM-I group presented a high decrease in the percent of threat interpretations endorsed (β = −0.26, SE = 0.10, p = 0.01) and a low interpretation bias index posttraining (MD = −775.55, SE = 326.76, p = 0.02). Moreover, when confronted with the speech stressor task, CBM-I group had a smooth electrical skin activity (p < 0.01) and a low mean heart rate (MD = −11.01, SE = 5.22, p = 0.04). Briefly, relying on multiple measures, such as self-report and physiological measures, this trial has demonstrated that CBM-I is effective in addressing individuals’ interpretation bias and anxiety symptoms.

4.2. Other psychotherapies in the treatment of anxiety disorders

At present, the traditional CBT is recommended as the first-line psychotherapy treatment for anxiety disorders [53]. CBT focuses on changing the way patients respond to anxious thoughts through conscious ‘top – down’ training, involving psychoeducation, cognitive restructuring, and exposure as its primary components [44,54]. In this approach, patients are educated about the maladaptive thoughts and their negative impact on the development of anxiety symptoms; subsequently, they are instructed on how to recognize maladaptive thoughts when they appear out of place as well as how to react to them [55]. CBT efficacy in treating many anxiety disorders has been confirmed in several studies [56,57]. However, its applicability to children and adolescents with anxiety disorders is controversial, and data on its time and cost efficiencies are lacking [53,58]. CBM requires fewer resources for its implementation and can be easily replicated on a larger scale than traditional CBT [44,49]. Therefore, this unconscious ‘bottom – up’ cognitive training has great potential for development [43,46].

Mindfulness refers to consciously non-judgmental awareness of the present moment, guiding individuals to purely pay attention to the physical and mental sensations that are manifested during this moment [59]. In recent years, MBI have also been a nice option for individuals to alleviate their anxiety symptoms. Mindfulness-based Stress Reduction (MBSR) is one such therapy, which includes sitting and walking meditations, yoga asanas, and mindfulness relaxation techniques as its core aspects [60]. Hoge et al. [61] demonstrated that MBSR could effectively alleviate anxiety through a prospective randomized clinical trial. There were 208 adult patients with anxiety disorders recruited and randomly assigned to 8 weeks of the weekly MBSR course or the antidepressant escitalopram. Changes in patients’ Clinical Global Impression-Severity scale (CGI-S) scores were assessed by physicians. The results showed that MBSR had non-inferiority when compared to escitalopram (From baseline to endpoint, the mean difference between groups was −0.07, SE = 0.16, 95% CI = −0.38–0.23, p = 0.65). That means, the effectiveness of MBSR in treating anxiety disorders is comparable to that of first-line medication.

5. Combination treatment of pharmacotherapy and CBM

Pharmacotherapy and CBM treat anxiety disorders with different focuses, with their own advantages and disadvantages.

Pharmacotherapy affords individuals the physical energy to struggle against their problems, enabling them to take control of their bodies, which is an extremely useful external force. It focuses on relieving anxiety symptoms. Some empirical findings demonstrated that the effect sizes of pharmacotherapy are superior to psychotherapy, and the desired effects can be achieved in the short term [31]. If individuals with anxiety disorders have complex conditions, such as severe degrees of illness or comorbid depressive disorders, pharmacotherapy may be prioritized. However, fearing the side effects, patients often resist taking psychotropic drugs [8]. Additionally, patients receiving medications are prone to relapse of anxiety symptoms after medication discontinuation. For example, Taylor et al. [62] found that BZDs using was a strong predictor of symptom relapse (OR = 2.88, 95% CI = 1.36–6.12, p = 0.006). Furthermore, considering the chronic characteristics of anxiety disorders, long-term effects of pharmacotherapy alone are not satisfactory. Some patients with GAD have indicated that they require more than just symptom reduction [63].

Psychotherapy energizes individuals’ mental energy, allowing them to draw support from within. Most individuals with anxiety disorders tend to seek treatment in primary care rather than professional setting [64]. Therefore, the provision of low-intensity, self-directed psychotherapeutic approaches in primary care could greatly improve treatment accessibility for anxiety disorders [65]. According to guidelines on the treatment of anxiety disorders published by the UK National Institute for Health and Clinical Excellence, psychotherapy is considered equal to or even superior to pharmacotherapy [66,67]. By working with access to computer procedures, CBM requires patients to make simple judgments, saving considerable human and material resources and has high acceptability [65,68]. Once patients start treatment, the dropout rate is low. For special groups, such as children, adolescents, and pregnant women, using CBM is safe, with low potential risks. Furthermore, CBM effects are maintained after treatment termination [52]. All of these are benefits of CBM over pharmacotherapy. However, CBM is slower to be effective and more suitable for treating patients with a mild or moderate degree of disease than pharmacotherapy. CBM technology, although constantly growing, remains a young research field [43]. Most published studies have been conducted in laboratory settings and lacked more large sample results from clinical settings [69]. Besides, the effect sizes of CBM intervention are small, and its effectiveness remains controversial, perhaps related to the fact that no optimal way of applying the intervention has been found [49,69–72]. These limitations suggest that CBM may not be ready to be considered a stand-alone treatment [48,72].

In summary, pharmacotherapy and CBM have their benefits and limitations. Considering the possibility of their combination for anxiety disorder treatments would be more realistic, rather than arguing over their use.

In a meta-analysis, Bandelow et al. [31] proved that the combination of pharmacotherapy and psychotherapy works better than psychotherapy alone. They found that the effect size of the combination of CBT and various types of medications (d = 2.12, 95% CI = 1.66–2.59, n = 16) was greater than psychotherapy alone (individual CBT: d = 1.30, 95% CI = 1.19–1.41, n = 93; group CBT: d = 1.22, 95% CI = 0.95–1.49, n = 18; relaxation treatment: d = 1.36, 95% CI = 1.08–1.64, n = 17; etc.). Walkup et al. [68] recruited 488 children with anxiety disorders to compare the effects of sertraline, CBT, and combined treatment on reducing anxiety severity. Results revealed that the combination of sertraline and CBT was superior to medication alone (OR = 3.4, 95% CI = 2.0–5.9, p < 0.001) or CBT alone (OR = 2.8, 95% CI = 1.6–4.8, p < 0.001). It could be seen that in the treatment of anxiety disorders, although studies comparing the effect of combined treatment with treatment alone are few, some published studies conclude that the combination of pharmacotherapy and psychotherapy (e.g. CBT) could produce better effects. Because CBM is a promising psychological treatment, we could speculate that its combination with pharmacotherapy can be more effective in treating anxiety disorders.

Furthermore, findings that the combination of pharmacotherapy and CBM is more effective in treating depressive disorders may provide partial evidence for the possible combination of two modalities being more useful in treating anxiety disorders. Vrijsen et al. [73] recruited 139 patients with depressive disorders who had been taking medications for 2–3 weeks. Following conventional pharmacotherapy, patients were asked to receive CBM training. They were randomly assigned to either the active or control group of CBM Attention Dot-Probe Training (DPT) or CBM Approach-Avoidance Training (AAT). Using Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI-II), improvements in the patients’ depressive symptoms were measured. Results showed that compared with pretraining scores, patients’ HAMD (31% decrease from M = 20.2 to M = 14.0) and BDI-II (30% decrease from M = 30.1 to M = 21.0) scores significantly decreased after CBM training. Furthermore, compared with DPT control group, positive attention bias was significantly increased in DPT experimental group (t(32) = 2.76, p = 0.010). In conclusion, CBM combined with pharmacotherapy may reduce depressive symptoms, indicating that CBM may be an effective additional treatment option for clinical depressive disorders. Given that anxiety disorders and depressive disorders are prone to comorbidity and share a transdiagnostic trait of repetitive negative thoughts, there is a high probability that the conclusion of better effects of the combination of CBM with pharmacotherapy could be applied to anxiety disorders.

Therefore, we suggest that the combination of pharmacotherapy and CBM may generate an effect of one plus one rather than two. However, it is almost inevitable that the choice of anxiety disorder treatment is determined by various factors. Considering variations in efficacy and acceptability of different treatments, together with patient-individualized factors, such as age, sex, illness severity, and current versus previous treatments, the optimal treatment choice may not be standardized among patients [22,27]. Therefore, we cannot firmly draw conclusions about what is the gold standard for the treatment of anxiety disorders. The evidence to date indicates likely that the combination of pharmacotherapy and CBM will be a feasible and effective treatment option in the future, which not only relieves anxiety symptoms, but also modifies the biased cognitive selection patterns that produce anxiety responses.

6. Expert opinion

6.1. The two sides of anxiety

Anxiety is a regular emotion [40], influenced by proximal factors, such as recent life pressures, and distal factors, such as childhood adversity and genetic susceptibility, which could enhance an individual’s sensitivity to threats [74]. Moderate anxiety has adaptive significance in individuals. When an individual is confronted with a real or potential threatening stimulus, potentially disrupting their internal balance, he often uses anxiety as a warning signal. Therefore, various physiological responses (e.g. increased heart rate, blood pressure, and body temperature) and behavioral responses (e.g. inhibition of current behavior and avoidance of threatening stimuli) are manifested [74]. Anxiety motivates individuals to prepare themselves to cope with the external environment, while learning and accumulating experience from it [75]. Its significance is fully reflected in the poem written by Mencius, ‘One prospers in anxiety and hardships while perishes in ease and comfort.’ Anxiety is an emotion we are born to experience and deal with. If we could understand and respond to anxiety properly, it can bring a string of positives. Such non pathological anxiety has often been described as ‘state anxiety,’ implying that the individual experiences anxiety at specific moments, which is worsened by the presence of threatening stimuli [76].

However, if an individual consistently feels widespread and persistent anxiety or recurrent panic attacks, he may develop an anxiety disorder over time. It changes the way a person deals with emotions and behavior and causes somatic symptoms [1]. Such pathological anxiety has often been described as ‘trait anxiety,’ considered an enduring personality trait of individuals that does not change over time [1,74,76]. When confronted with stressors, trait-anxious individuals tend to choose avoidance coping, involving the prevention of unpleasant thoughts and emotions, and the denial or escape from stressful situations [77]. Although it might seem to deal with short-term stressors, it may lead to a destructive cycle of intrusion and avoidance and further maladaptation, such as a tendency to redirect externally imposed pressures toward self-denial, considering the long-term effects [78].

Early diagnosis and comprehensive treatment could help patients improve their quality of life. This review suggests that the combination of pharmacotherapy and CBM may be more effective in treating anxiety disorders than either treatment alone. The former relieves patients’ current symptoms, whereas the latter modifies the cognitive biases that contribute to the symptoms from a long-term perspective. Pharmacotherapy initiation is recommended with first-line antidepressants [79]. If the patient is intolerant to medications or remains unresponsive after 4–6 weeks of treatment while ensuring that medications are appropriate in dosage and patient taking medications adequately and on schedule, switching to different types of antidepressants must be considered (e.g. from one SNRI to another SNRI or SSRI) [8,54]. If the patient appears to show a partial response at this stage, increasing the dosage must be considered [8]. Once first-line antidepressants are found to be ineffective, second-line therapeutic medications or TCM may be considered. CBM is necessary in the pretreatment or prognostic stage and for special groups, such as pregnant women. However, there is a lack of direct evidence, particularly clinical data, to hypothesize that the combination of pharmacotherapy and CBM may be more effective in treating anxiety disorders than either treatment alone. Therefore, relevant clinical trials may be considered to be conducted in the future.

Certainly, the choice of a specific treatment plan should consider several factors, including the patient’s personal preferences, illness severity, somatic and psychiatric comorbidities, current and previous treatment, age, sex, childbearing plans, costs and accessibility of treatment, and other factors [22]. In the next 5 years, personalized treatment strategies for the treatment of anxiety disorders could be the focused on. Moreover, it is encouraged that treatment plans should be decided by clinicians and patients in a joint decision-making process. Patients should be aware of the potential adverse effects and contraindications of different treatment plans, helping improve their compliance and fully develop their initiative [8,22].

In addition, in the next 5 years, current relevant concepts and theories such as holistic health and whole-person development should be refined through the integration of psychiatry, psychology, and other multi-disciplines, establishing better foundations for subsequent research.

6.2. Comprehensive understanding of anxiety and anxiety disorders

Based on Chinese cultural perspective, anxiety can be recognized, measured, and coped with at three levels: skill, vision, and Tao. Their respective meaning and future directions for this are summarized in Table 2. Skill, which means craftsmanship and method, is a kind of micro-level study. It focuses on localization and accumulation of ‘quantity,’ aiming at honing the necessary skills to maturity and completeness. In the field of anxiety disorder treatment, although significant advances have been made in several aspects, many patients fail to respond adequately to existing treatments [80]. More efficient and sophisticated measures are urgently needed. In the next five years, more studies should focus on systematic pharmacology to clarify the pathogenesis of anxiety disorders. In addition, more effective therapies should be developed and the limitations of existing treatments should be addressed. Furthermore, biopsychosocial strategies should be further integrated. Vision, implying behavior and approach, is a kind of meso-level study. It is not limited to enabling the proficiency of skill, but is more concerned with the principles behind how things work. On the basis of skill, technique embodies part of the qualitative leap. For anxiety disorders, not only should we study the pathogenesis and measures, but we also need to focus on the patient. In the next five years, individuals’ methods and behaviors to cope with anxiety from the roots should be explored. Tao, which means natural laws, is a kind of macro-level study, aiming to summarize and generalize the general laws that guide the development of things. Stretching the timeline of life, it can be found that anxiety disorders do not develop overnight. Instead, it develops throughout one’s life and is constantly dynamic in the development process.

Table 2. Chinese cultural perspectives on measuring, coping with, and recognizing Anxiety.

Level	Meaning	Future direction
Micro-level (Skill)	Craftsmanship and method	Drilling down into systems pharmacology; Integrating biopsychosocial strategies further; Developing more effective treatments with fewer limitations.
Meso-level (Vision)	Behavior and approach	Exploring individuals’ approaches and behaviors in coping with anxiety.
Macro-level (Tao)	Natural laws	Training personality traits; Enhancing individual inner strength and integrating the fourfold selves.

The causes of anxiety disorders are complex, with large individual differences, possibly concluded as the influence of personality traits and external environment [12,19,74]. As has been said above, in western culture, anxiety may be recognized by a downward analytical system, in which the problem is broken down into multiple independent analytical parts [9,10]. This approach focuses on deconstructing and analyzing the anxiety problem through rational thinking and scientific processes [81]. When confronted with anxiety disorders, western culture attempt to alleviate suffering by progressively analyzing and resolving separate problems. In contrast, in Chinese culture, anxiety may be recognized using an upward integrative system, in which objects are understood as a whole in context [9,10]. It believes that combining adversity with vision and commitment leads to better management of uncertainty. This cognitive approach assumes that individual problems are closely related to the mind, body, and social environment, with an emphasis on one’s inner cultivation and harmony with nature. When facing anxiety disorders, Chinese culture focuses on the unity of knowledge and action, and propose that one can achieve physical, mental, and spiritual health by cultivating the body and spirit, and practicing to realize the Wisdom of the Tao [9]. In the next five years, the priority in coping with anxiety can be placed on how to train personality traits. Moreover, it should be explored how to enhance individuals’ inner strengths and integrate the four-fold self (egocentric, sociocentric, eco-centric, and cosmocentric selves) so that general external environments may be less likely to cause stress to individuals. Individuals are expected to be organically integrated both internal and external, respecting their talents, interests and abilities so that they are given the opportunity to develop freely. An outstanding advantage is that this form of coping does not sacrifice the integrity of the person.

To date, the world is filled with competition and stress. Instead of waiting for the onset of anxiety disorders to be solved, effectively preventing its development from the roots should be the primary concern. Within the last 5 years, there should be a comprehensive understanding of anxiety and anxiety disorders in the context of Chinese and western cultures, rather than intervention for its own sake. As Wang Guowei said, ‘Enter within and transcend beyond.’

Article highlights

• Anxiety disorders are of great clinical and social importance, but there is an estimate that up to 41% of individuals with anxiety disorders are not treated.

• As a computer-based intervention, cognitive bias modification (CBM) is low-intensity and self-directed, which could broadly improve treatment accessibility, holding great promise.

• There is the possibility that the combination of pharmacotherapy and CBM may be more effective in treating anxiety disorders than either treatment alone.

• Moderate anxiety has adaptive implications for individuals.

• Integration of the downward analytical system of western culture with the upward integrative system of Chinese culture is warranted in the future, to establish a comprehensive understanding of anxiety and anxiety disorders.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are funded by the funded by the Social Science Foundation of China [20VYJ041].