Factors influencing anxiety and depression in postherpetic neuralgia patients

Abstract

Postherpetic neuralgia (PHN), one of the most common complications associated with herpes zoster, manifests as neuropathic pain that continues well into months or even years following the healing of the rash. Anxiety and depression commonly accompany PHN, affecting patients’ quality of life as well as worsening the experience of pain and compromising their adherence to treatment plans. Identifying the possible risk factors for such mood disorders is crucial to interrupting this pain-emotion loop. In this minireview, we summarize the existing literature on this issue systematically in order to provide an understanding of the risk factors that increase the incidence of anxiety and depression in PHN patients. Independent risk factors identified in the literature include female gender, old age, severe pain, chronic pain duration, wide extent of rash, high Patient Health Questionnaire-9 score, and maladaptive coping strategies. We propose a model based on clinical, psychological, and neurobiological findings to elucidate the vulnerability of PHN patients to these mood disorders.

Key Words: Postherpetic neuralgia; Anxiety; Depression; Influencing factors; Coping strategies

Core Tip: Postherpetic neuralgia frequently co-occurs with anxiety and depression, driven by distinct risk factors. Female sex, advanced age, high pain intensity, prolonged disease duration, extensive rash, elevated Patient Health Questionnaire-9 scores, and negative coping styles independently predict comorbid mood disorders. Early psychological screening and integrated pain-psychology management are essential to break the vicious painaffect cycle and improve prognosis.

INTRODUCTION

Herpes zoster, or shingles, is an infectious disease triggered by reactivation of the varicella-zoster virus, or human herpesvirus 3[1]. It reflects reactivation of latent varicella infection existing in sensory ganglia. Shingles are manifested by painful unilateral vesicles appearing in the dermatome, usually due to immune system suppression, and also cause neuralgia[2]. Postherpetic neuralgia (PHN) is the most typical complication of herpes zoster. It implies persistence of shingles-associated pain, which leads to occurrence of the high-prevalence chronic pain disorder, developing for months and even years after the lesion has healed[3]. PHN poses serious problems against the background of general issues associated with chronic pain management. The recently published updates on the global burden of chronic pain[4] indicate a necessity of improving strategies to cope with not only pain itself but also associated psychological problems and social economic consequences, especially those related to neuropathic pain conditions like PHN. PHN pain may have different types, ranging from burning, stabbing, “electric shock” sensations, and hyperalgesia. It can sometimes be felt for many years, leading to dysfunction and lowering of quality of life and intensifying the socioeconomic problem[5,6].

PHN causes persistent pain and is accompanied by serious psychological distress such as anxiousness and depression. These factors together reduce the quality of life of patients and seriously affect their personal and social functioning[7]. Studies have shown that the incidence of anxiety and depression in PHN patients is as high as 69.0% and 65.8%, respectively, suggesting that comorbid anxiety and depression is extremely common in PHN patients[8]. Anxiety and depression not only seriously affect patients’ treatment adherence, but are also closely related to poor prognosis and decreased survival rate[9]. At the same time, they can exacerbate pain perception[10], forming a chronic stress-pain-emotion-pain cycle that further intensifies the subjective experience of pain[11,12]. Therefore, a deeper understanding of the factors underlying anxious-depressive symptoms in PHN patients is of great clinical significance for breaking this cycle and achieving precision treatment.

In previous years, with the progress in neuroimaging, molecular biology, and evidence-based medicine, research on mood disorders related to PHN has made progress. Researchers are no longer limited to single-dimensional factor analysis, but are gradually shifting to a multi-dimensional integrated perspective. This article systematically retrieves and reviews English-language literature published in recent years, summarizing the influencing factors of anxious and depressive disorders in PHN patients from multiple dimensions, with the goal of serving as a reference for clinical practice and future research.

CLINICAL CHARACTERISTICS AND ASSESSNENT OF ANXIETY AND DEPRESSION IN PHN PATIENTS

Core emotional characteristics

Anxiety is a mood disorder characterized by a pattern of persistent worry, restlessness, and nervousness, among other possible symptoms, that can interfere with a person’s capacity to function effectively and enjoy daily life[13]. Patients with high levels of anxiety may manifest impaired whole autonomic neural function, especially an asymmetry in the sympathetic-vagal axis, accompanied by enhanced parasympathetic activity and vagal dysfunction[14]. Depression is characterized by a diminished capacity for pleasure or loss of enjoyment, often coupled with feelings of blame, inadequacy or despair, and in extreme instances, persistent preoccupation with death or suicidal thoughts may also occur[15].

Commonly used assessment tools

In PHN-related studies, pain intensity is often measured via the Visual Analogue Scale (VAS) or the Numerical Rating Scale[16,17]. Assessment tools for anxiety and depression include the Hamilton Anxiety Rating Scale (HAMA), the Hamilton Depression Rating Scale, and the Hospital Anxiety and Depression Scale (HADS)[18]. In addition, the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder Scale-7 are increasingly used in clinical screening due to their simplicity and speed[19].

MULTIDIMENTIONAL ANALYSIS OF INFLUENCING FACTORS

Population sociological characteristics

Age: Advanced age is recognized as a predisposing factor for subsequent anxiety and depression. Epidemiological data indicate that the estimated annual prevalence of initial herpes zoster infection in healthy people under 20 years old is about 1 per 1000 people; while for people over 80 years old, the incidence is 5 to 10 times higher[20]. Due to the decline in physiological function and cognitive ability, the elderly patients experience increased life stress, leading to feelings of loneliness and helplessness, which in turn exacerbates negative emotions and even depression[21]. Indirect evidence from general population cohorts showed that accelerated biological aging is an important risk factor for anxiety and depression. Specifically, each 5-year increase in biological age was associated with a 5.9% higher risk of incident depression [hazard ratio = 1.059, 95% confidence interval (CI): 1.033-1.085] and an 11.3% higher risk of incident anxiety (hazard ratio = 1.113, 95%CI: 1.090-1.137). The older the biological age, the greater the risk of developing depression and anxiety, which is about 6%-11%[22]. The rationale behind its working could be that the older individuals lose their neuroplasticity of central nervous system, weakening of dorsal prefrontal cortex functioning and enlargement of right amygdala, which results in dysregulation of certain parts of brain associated with mood regulation, causing anxiety and depression problems among the non-PHN elderly people[23]. While these data come from general aging and cancer literature, yet they do offer a possible biological explanation of the effects of being old age on PHN-associated depression. Yet, the effect of advanced age on depression might be mediated by many other factors such as living alone, physical limitations, preexisting sleep disorder, co-morbidity of diseases (diabetes, cardiovascular problems) and economic distresses. These risk factors tend to be correlated with each other and can cause depression independently of age factor. So, there might be no causality between age and depression.

Gender: Females constitute a key influencing factor among the determinants of depression and anxiety among PHN patients. In evidence collected from a study of a PHN population, univariate analyses indicated a high correlation between females and raised levels of depression and anxiety among PHN patients with multivariateadjusted odds ratio of 2.404 (95%CI: 1.561-3.701) for anxiety and 1.707 (95%CI: 1.062-2.741) for depression, respectively. Furthermore, results obtained through multivariate analyses indicated that being a female was an independent risk factor for higher levels of anxiety and depression among PHN patients[8]. This is supported by indirect evidence where females have been shown to be at higher risk of experiencing anxiety and depression than males with these conditions usually worse in females compared to males[24].

Various factors contribute to the development of anxiety and depression in female patients suffering from PHN. As indirect support for this, evidence from individuals without PHN shows that women tend to be more susceptible to negative stimuli and have higher levels of emotional awareness[25]; in contrast, women show greater sensitivity to pain, which is due to hormones being responsible for the nociceptive processing process, and greater activity in the limbic system during exposure to noxious stimuli[26]. Functional magnetic resonance imaging in a healthy population revealed differences between genders in the processing of emotions, wherein women have demonstrated higher activity in the amygdala in response to negative stimuli and marked activity in the anterior cingulate cortex of the orbitofrontal lobe while recruiting fewer dorsolateral prefrontal areas than men[27]. Thus, PHN patients that are females constitute a high-risk population for developing depression and anxiety. Early recognition and proper treatment of women’s mental problems will positively impact their prognosis. At the same time, the elevated risk of women developing psychiatric disorders could be affected by a number of confounding factors including pain management differences, hormonal changes, the stress associated with childcare responsibilities, and social inequality, all of which have not been controlled for in the reviewed literature.

Factors related to the clinical characteristics of the disease

Pain intensity: Pain intensity in patients with PHN is positively and independently associated with the risk of anxiety and depression[8]. The more severe the pain, the higher the incidence and severity of anxiety and depression[28]. The VAS score is the gold standard for assessing pain intensity. A neuroimaging study of PHN patients in 2022 (n = 50) showed that pain intensity (VAS score) was significantly positively correlated with patients’ depression (Hamilton Depression Rating Scale) and anxiety (HAMA) scores. Multivariate regression analysis further confirmed that in PHN patients, the strength of functional connectivity between the ventromedial prefrontal cortex and the occipital cortex, as well as anxiety and depression scores, are independent factors affecting pain intensity[29]. Indirect evidence from general communitydwelling adult populations showed that subjects with mild, moderate and severe pain at baseline had a 20%, 32% and 39% increased risk of developing significant depressive symptoms after 2 years of follow-up, respectively. In fully adjusted models (controlling for sociodemographic factors, comorbidities, physical inactivity, loneliness, and functional impairments), the odds ratios for mild, moderate, and severe pain vs no pain were 1.20 (95%CI: 1.06-1.35), 1.32 (95%CI: 1.20-1.46), and 1.39 (95%CI: 1.19-1.63), respectively[30]. In addition, studies in patients with lumbar spinal stenosis have shown that patients with moderate to severe pain have significantly higher Generalized Anxiety Disorder Scale-7 scores, anxiety-VAS scores, stress-VAS scores, and depression-VAS scores than patients with mild pain[31]. The neural mechanisms by which pain intensity affects mood involve multiple brain regions. Pain intensity is significantly correlated with structural changes in the amygdala and anterior cingulate cortex, with activation of the amygdala primarily driving the emotional processing of pain, leading to the transformation of pain from sensation to emotional memory[32]. This two-way interaction between pain and depression is quite evident. According to the landmark study by Bair et al[33], depression and pain often occur together and have similar pathophysiological mechanisms like imbalance in monoamine neurotransmitters and HPA axis disturbance. It is important to know about this comorbidity for overcoming the “vicious circle” for PHN patients. Pain management not only relieves pain itself but helps in avoiding the development of depressions by controlling inflammation response in the body and controlling monoamine neurotransmitter production like serotonin and dopamine[34]. The connection between the degree of pain and anxiety might also be bidirectional, because not only anxiety can increase pain sensitivity due to central sensitization, but pain can cause the appearance of anxiety or make it worse. Almost all cross-sectional studies fail to determine the direction of causality. Therefore, the discovered connection should be regarded as bidirectional one and not as a cause-and-effect relationship.

Increased duration of pain: Pain duration is another influencing factor for anxiety and depression in PHN patients. Indirect evidence from patients with musculoskeletal conditions reveals that patients living with persistent pain and anxiety and depression have longer pain duration and higher pain severity[35]. Additionally, findings from multiple sclerosis patients suggest that elderly patients with a longer disease course have a higher pain threshold and lower energy expectations[36]. A cross-sectional study in general chronic pain patients found that pain duration was strongly positively correlating with depression scores (Spearman’s r = 0.314, P < 0.001), and multivariate regression analysis shows that pain duration is an independent risk predictor for patients’ depressive mood and poor quality of life (β = -0.208, P < 0.001), suggesting that the psychological burden of patients increases significantly with the duration of the disease[37]. Even though there is sparse evidence to suggest this in PHN, it appears that similar mechanisms may underlie the relationship between pain duration and mood disorders in PHN. The relationship between pain duration and depression is potentially confounded by disability and treatment status and possibly even withdrawal from social settings as these phenomena typically go hand in hand with increased pain duration and should be controlled for in future research.

Mechanistic framework (chronic pain - stress sensitization - affective dysregulation): Chronic pain in PHN is constantly stimulating the stress system leading to the sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic outflow. This leads to an elevation of cortisol and catecholamine secretion[38]. Contrary to the rapid stimulation of these mediators in acute pain, chronic pain leads to lasting changes in both cortisol and catecholamines. The changes include elevated baseline and magnified stress-reactive responses during every attack of pain[38]. In addition, the combined overactivity of the HPA and sympathetic systems leads to abnormal cortisol and catecholamine secretion patterns, creating an endocrine profile capable of exacerbating inflammatory and metabolic disorders[39]. Pro-inflammatory cytokines like interleukin-6 and tumor necrosis factor-alpha may cause blood-brain barrier dysfunction, microglia activation, and altered tryptophan metabolism from serotonin production, leading to depression[40]. In cases of PHN complicated by anxiety, there is evidence of alterations in both structure and function of the amygdala and anterior cingulate cortex, in terms of reduced grey matter volume and decreased basolateral amygdala-anterior cingulate cortex functional connectivity, and these correlate with pain severity (VSA) and anxiety (HAMA) scores[41]. Based on the foregoing data, a conceptual model called “chronic pain-stress sensitization-affective dysregulation” can be advanced, as persistent nociception activates the HPA/sympathetic system with peripheral inflammation, disturbing monoamine metabolism with consequent structural-functional alterations in the prefrontal-limbic network, causing vulnerability to depression/anxiety in PHN patients.

Extent of rash spread: The extent of rash spread is one of the factors impacting anxiety and depression in PHN patients. The varicella-zoster virus, during its first infection, lies dormant in the dorsal root ganglia and cranial ganglia; when the body’s defenses diminish, these latently infected viruses are reactivated and multiply, triggering an inflamed state in the ganglia and peripheral nerves; this, in turn, damages tissues in the areas innervated by these nerves, broadening the spread of the rash[42]. Studies have shown that univariate regression analysis confirmed that the time of rash appearance and the extent of rash dissemination are strongly associated with anxiety and depression in PHN patients, and multivariate analysis additionally verifies that the extent of rash dissemination is an autonomous risk predictor for psychological distress in PHN patients[8]. Indirect evidence from atopic dermatitis patients pointed out that patients with atopic dermatitis accompanied by anxiety and depression had significantly higher rash area, severity scores and itching than patients without emotional problems, and the more severe the condition[43]. Similarly, findings from the Jordanian population perception study suggest that extensive skin lesions not only trigger psychological distress, but also impair patients’ self-esteem and social interactions, making them more susceptible to marital instability and relationship anxiety, leading to depression and a compromised quality of life[44]. Clinicians should proactively assess the psychological state of PHN patients with widespread rash and provide enhanced support in skin care and appearance management. These observations, while derived from nonPHN skin conditions, provide plausible psychosocial mechanisms by which widespread rash may contribute to mood disturbance in PHN patients.

High PHQ-9 score: The PHQ-9 is widely considered an accurate and reliable screening tool for depression[45]. Multiple studies have shown that patients with PHN often have significant depressive mood (high baseline PHQ-9 scores)[46,47]. Indirect evidence from non-PHN populations indicates that fatigue is both a core symptom and a bridging symptom in the depression-anxiety-insomnia network[48]. A cross-sectional study in chronic low back pain patients showed that fatigue exacerbates depressed emotional states and increases the pain load and impairment in patients with chronic pain[49]. Somatic items in the PHQ-9 score (such as fatigue, changes in appetite, and sleep disturbances) may overlap with the physical manifestations of pain itself, which may lead to an inflated score. Therefore, the PHQ-9 should be used in conjunction with clinical judgment. In clinical practice, a PHQ-9 score ≥ 10 indicates moderate depression, and ≥ 15 indicates severe depression[50]. Patients with elevated PHQ-9 scores should be promptly referred to a psychiatric clinic or given antidepressant treatment.

Negative coping strategies: Coping styles refer to the cognitive adjustment behaviors and strategies that individuals adopt to adapt to the needs of the internal and external environment when facing stressful events. They can be classified into positive coping styles and negative coping styles[51]. Negative coping describes problem-solving through avoidance or withdrawal, including avoidance, self-blame, fantasy, substance abuse, etc.[52,53]. Researches have shown that women with polycystic ovary syndrome are inclined to engage in more passive coping strategies, namely withdrawal and emotional suppression, than healthy women, and these strategies are subsequently associated with markedly higher rates of anxious and depressive symptomology within this cohort[54]. In addition, cancer patients who adopt problem-oriented (other than positive coping) strategies or negative coping styles (including venting or denial) have a higher symptom burden, while patients who adopt emotion-oriented coping strategies report less anxiety and depression[55]. This finding echoes studies on psychological mechanisms in different populations. In elderly patients with hypertension, studies have confirmed that negative coping strategies such as withdrawal and self-blame are strongly associated with depressive symptoms. These unhelpful strategies often make people feel more stuck and alone, which can make their depression worse[56]. In adolescents, studies have found that anxiety symptoms lead to an increase in subsequent negative coping strategies, and the influence of coping strategies on anxious symptoms is predominantly between individuals (trait-stable) rather than fluctuating within individuals, indicating that its pathogenesis is population-specific[57].

Treatments for negative coping styles have been proven effective. A retrospective analysis in 2025 showed that white noise combined with cognitive behavioral therapy (CBT) markedly improved patients’ positive coping scores (such as problem-solving and help-seeking) and reduced anxiety and depression scores (Self-Rating Anxiety Scale/Self-Rating Depression Scale) and suicidal ideation in college students with anxiety and depression, with the improvement being significantly better than that of the CBT group alone[58]. Another study on adult mood disorders found that adding CBT to drug (quetiapine) treatment could more effectively reduce patients’ negative coping scores and depressive symptoms and significantly reduce the risk of suicide[59].

CLINICAL TREATMENTS STRATEGIES AND FUTURE RESEARCH DIRECTIONS

Clinical implications

Given the factors contributing to anxiety and depression in PHN patients, clinical management must integrate physiological, psychological, and social support strategies. Targeted early treatment methods can provide a more robust empirical grounding for the clinical management of anxiety and depression in PHN (Table 1).

Table 1 Summary of risk factors, mechanisms, evidence levels, and clinical recommendations for anxiety and depression in postherpetic neuralgia patients.

Risk factor	Evidence type	Underlying mechanism	Clinical recommendation
Advanced age	Direct (PHN) + indirect (population)	Reduced neuroplasticity; amygdala enlargement; social isolation	Geriatric assessment; sleep optimization; social support
Female sex	Direct (PHN cohort)	Hormonal pain sensitivity; stronger amygdala response; stress susceptibility	Early psychological screening; emotional support
Severe pain intensity	Direct (PHN)	Amygdala/ACC activation; central sensitization; inflammatory disturbance	Timely analgesia (gabapentin/pregabalin); pain control to VAS ≤ 4
Prolonged pain duration	Direct + indirect (chronic pain)	Cumulative stress sensitization; HPA axis hyperactivity	Early intervention; regular follow-up; multidisciplinary care
Extensive rash	Direct (PHN)	Nerve damage; body image disorder; social isolation	Skin care; appearance support; psychosocial counseling
High PHQ-9 score	Direct (PHN)	Somatic-affective overlap; neurotransmitter disturbance	PHQ-9 screening; referral if ≥ 10; antidepressant therapy
Negative coping	Indirect (cross-population)	Maladaptive stress response; cognitive avoidance	Cognitive behavioral therapy; positive coping training

The evidence levels presented in this table are derived from studies with heterogeneous designs and populations. “Direct” evidence refers to findings from postherpetic neuralgia (PHN) specific cohorts (mostly retrospective or crosssectional), whereas “indirect” evidence comes from other chronic pain populations, general population cohorts, or preclinical studies. Direct PHN evidence provides the highest specificity for risk prediction but may be subject to selection bias and limited generalizability across different clinical settings. Indirect evidence supports biological plausibility and helps fill knowledge gaps, but extrapolation to PHN patients requires caution owing to differences in disease pathophysiology and comorbidity profiles. The proposed mechanisms and clinical recommendations integrate both levels of evidence; however, their applicability should be validated in prospective PHN-focused studies. PHQ-9: Patient Health Questionnaire-9; PHN: Postherpetic neuralgia; ACC: Anterior cingulate cortex; HPA: Hypothalamic-pituitary-adrenal; VAS: Visual Analogue Scale.

Early screening is the primary step in achieving early detection and treatment of anxiety and depression in patients with PHN. Screening should be done at the time of the diagnosis, 3-month follow-up visit, and yearly thereafter for patients experiencing persistent pain due to its dynamic nature. The suggestion is that standardized psychological tests be carried out at all stages of diagnosis, follow-ups, and post-treatment stages of patients suffering from PHN, through validated measures such as HADS scale, PHQ-9 questionnaire, and Simplified Coping Style Questionnaire, to assess their mental status. The criteria of referral have been set based on clinical guidelines, such that patients who scored 10 or above with PHQ-9 or HADS score ≥ 8 are recommended for psychiatric intervention. PHQ-9 scores of ≥ 15 and HADS score of ≥ 11 indicate severe mental distress, necessitating immediate referral to a psychiatrist and possible antidepressant medication. The screening should be done on a target group, such as female gender, having high intensity pain, longer disease duration, disseminated rash, and negative coping strategies, as it will help prevent mood disorders from becoming worse and pave the way for further management. The implementation of collaborative care would involve developing an algorithm that connects pain clinic and department of psychiatry through the following steps: (1) Pain doctors screen the patient for anxiety/depression using PHQ-9/HADS; (2) Patients who require referral will be electronically referred to the psychiatrist; (3) Care plans involving pain treatment, antidepressant prescription (started by either doctor) and joint monitoring every 4 to 6 weeks until symptoms stabilize; and (4) Patients with serious depression and/or suicidal ideations would be transferred to psychiatric outpatient clinics in 72 hours.

Controlling pain is one of the important factors when it comes to decreasing anxiety and depression among PHN patients; the analgesic treatment regimen needs to be reassessed within the first 1 to 2 weeks of therapy and combined treatment changed early enough if the pain VAS rating exceeds 4. Analgesic principles should be taken into consideration in order to eliminate the detrimental effect of pain on patients’ emotional well-being at its root. Clinically, first-line calcium channel modulators such as gabapentin and pregabalin can be given priority to reduce neuronal overexcitation and pain signal transmission, thereby relieving neuropathic pain and indirectly reducing anxiety and depression[60,61]. For patients with moderate to severe mood disorders, serotonin/norepinephrine reuptake inhibitors can be combined to achieve analgesia and anti-anxiety and anti-depressant effects[62,63]. These pharmacological recommendations are in line with the international evidence-based guidelines. According to the Special Interest Group on Neuropathic Pain systematic review[64] and the European Federation of Neurological Sciences guidelines[65], calcium channel modulators (gabapentin, pregabalin) and certain antidepressants (tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors) are established as first-line treatments for neuropathic pain, including PHN, due to their efficacy in modulating central sensitization and improving mood comorbidities[64,65]. Through various treatments such as CBT, mindfulness, and meditation, individuals can develop effective strategies to cope with pain, improve functional abilities, and enhance their quality of life[66]. For depressed patients, mindfulness-based stress reduction and acceptance and commitment therapy can be combined to enhance psychological flexibility and reduce symptoms of depression and anxiety through mindfulness[67]. Psychological interventions are recommended for 4-8 consecutive weeks with weekly sessions, and monthly maintenance sessions are provided for patients with persistent symptoms.

Future research directions

Based on current research progress on the influencing factors of anxiety and depression in PHN patients, future research can focus on the following directions. First, prospective cohort studies with large sample sizes and from multiple centers should be conducted to document the changes in pain, mood status, rash, coping, and other aspects of PHN patients throughout the acute and chronic stages. This will help elucidate the causality and temporal aspects of each risk factor, test the performance of predictive models, and refine screening tools. Second, neuroimaging methods including functional magnetic resonance imaging should be used to investigate the circuitry and underlying mechanism in pain-mood interaction and then to design specific therapeutic interventions including anti-inflammatory and gut microbe modulating drugs. In addition, high-risk PHN patients including the aged, women, and patients with disseminated rashes need more research into the risk factors and treatment targets in each category, which can lead to personalized treatment strategies and promote the therapeutic effects for the anxiety and depression problems of PHN patients as a whole. Below is an organized summary of the risk factors, mechanisms, evidence strength, and clinical advice regarding PHN patients.

CONCLUSION

The prevalence rate of anxiety and depression among PHN patients is relatively high, and the causes involve a series of factors. According to this paper, based on the previous research literature, the high-risk factors involved in the development of anxiety and depression among PHN patients include being a woman, old age, severe pain level, prolonged pain time, extensive rash area, high patient health questionnaires scores, and negative coping behaviors. They work together to affect patients’ mental condition. In clinical work, the recognition of high-risk factors needs to be further improved, psychological assessment included in the treatment process, and integrated management methods applied. More future large sample prospective studies are required.