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Clinical management and outcome assessment of generalized anxiety disorder or panic disorder in refractory gastro-esophageal reflux disease: Evidence from a prospective interventional study of benzodiazepines and sertraline

Published:March 02, 2020DOI:https://doi.org/10.1016/j.cegh.2020.02.022

      Abstract

      Objective

      The aim of the study was to investigate the relationship between Gastro-esophageal reflux diseases (GERD) related symptoms and psychological symptomatology, as well as clinically diagnosed generalized anxiety disorder (GAD) or panic disorder (PD) and effectiveness of Sertraline and benzodiazepines in controlling these conditions.

      Methodology

      A 6 months prospective study was conducted in gastroenterology outpatient department of a tertiary care referral hospital. Refractory GERD was diagnosed by assessing proton pump inhibitor failure over 4 week trial of standard doses of PPIs. Therapy with Benzodiazepines and Sertraline was initiated in patients with refractory GERD having panic and anxiety symptoms associated with refractory GERD. Effectiveness of the therapy was measured using panic and agoraphobia scale and Hamilton anxiety scale. Reduction in the severity of GERD symptoms was assessed using GERD – Health related quality of life scale.

      Results

      The occurrence of PD or GAD in patients with refractory GERD in our sample was found to be 68% and 32% respectively. There was a significant decrease in the score of GERD HRQOL after the administration of sertraline and benzodiazepines when compared to the score of GERD HRQOL before administration of interventional drugs (p = 0.001).

      Conclusion

      Our study investigated the role of anxiety and panic in refractory GERD and their effect on quality of life. The results indicated that quality of life of patients were highly improved as indicated by severity scores after administration with sertraline and benzodiazepines. The novel therapy of sertraline and benzodiazepines are highly effective in controlling reflux like symptoms and coexisting anxiety and panic disorder in refractory GERD.

      Keywords

      1. Introduction

      Gastro-esophageal reflux disease (GERD) is a common condition that occurs due to retrograde movement of gastric contents and causing troublesome symptoms or complications, occurring at least 2 times per week, with an adverse effect on an individual's well-being.
      • Lo Wai-Kit
      • Mashimo Hiroshi
      Establishing the diagnosis of GERD.
      The prevalence of weekly GERD symptoms reported from population-based studies worldwide is approximately 13%, albeit subjected to geographic variation.
      • Eusebi L.H.
      • Ratnakumaran R.
      • Yuan Y.
      • Solaymani-Dodaran M.
      • Bazzoli F.
      • Ford A.C.
      Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis.
      In India, the prevalence of GERD has been gradually increasing which attributed to the growing economics and consequently change in the lifestyle. The prevalence of GERD was 22.2% in southern India. The diagnosis and treatment strategies to be adopted for appropriate management of GERD remains a challenge despite advances in understanding its etiopathogenesis.
      • Pritchett J.
      • Aslam M.
      • Slaughter J.
      • Ness R.
      • Garrett C.
      • Vaezi M.
      Efficacy of esophageal impedance/pH monitoring in patients with refractory gastroesophageal reflux disease, on and off therapy.
      Acid regurgitation and heartburn are the major symptoms in GERD and is associated with increasing health care costs and significant impact in the quality of life of these patients.
      • Lo Wai-Kit
      • Mashimo Hiroshi
      Establishing the diagnosis of GERD.
      Acid suppressive therapy with proton pump inhibitors for a period of 4–8 weeks is deemed to be the gold standard treatment for GERD and offers rapid rates of esophageal mucosal healing and ample control of the symptoms.
      • Fass R.
      Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease: putative mechanisms of failure.
      Estimates reports a partial or complete lack of response to standard once daily dose of PPIs in about 40% of patients with heartburn.
      • Hershcovici T.
      • Fass R.
      Management of gastroesophageal reflux disease that does not respond well to proton pump inhibitors.
      Failure to respond to PPI therapy has now become the most common presentation of GERD in gastrointestinal practice.
      • Nunez-Rodriguez M.H.
      • Miranda Sivelo A.
      Psychological factors in gastroesophageal reflux disease measured by scl-90-R questionnaire.
      Refractory gastro esophageal reflux disease (GERD) can be defined as the presence of typical reflux symptoms that do not respond to either once or twice daily PPI for 4 weeks.
      • Kahrilas P.J.
      • Shaheen N.J.
      • Vaezi M.F.
      American gastroenterological association medical position statement on the management of gastroesophageal reflux disease.
      The prime approach in those who have failed standard PPI therapy is to assess the medication adherence and adequacy of dietary and lifestyle modifications, followed by careful escalation or administration of an alternate PPI.
      • Subramanian Charumathi Raghu
      • Triadafilopoulos George
      Refractory gastroesophageal reflux disease.
      When these measures fail, further investigations are required which include evaluations for functional or structural defects in the esophagus. In addition to these structural defects, psychological factors including anxiety, panic and depression, can also develop in GERD patients, and require further assessment.
      • Yang X.J.
      • Jiang H.M.
      • Hou X.H.
      • Song J.
      Anxiety and depression in patients with gastroesophageal reflux disease and their effect on quality of life.
      Psychological factors and psychiatric disorders may similarly influence and exacerbate gastro-intestinal disorders, such as GERD.
      • Kamolz T.
      • Velanovich V.
      Psychological and emotionalaspectsofgastro-esophageal reflux disease.
      ,
      • Bhatia V.
      • Tandon R.K.
      Stressandthe gastro-intestinal tract.
      So, it is necessary to explore refractory GERD and its relationship with psychological factors, especially because the role of psychological co morbidity and emotional stress in PPI failure has been scarcely studied.
      • Avidan B.
      • Sonnenberg A.
      • Giblovich H.
      • Sontag S.J.
      Refluxsymptomsare associated withpsychiatric disease.
      ,
      • Haug T.T.
      • Mykletun A.
      • DahlA A.
      The prevalence ofnauseainthecommunity: psychological,socialandsomatic factors.
      Investigators have evaluated the role of tricyclic antidepressants or SSRIs to influence esophageal perception. Antidepressants may modulate esophageal sensitivity at the central nervous system and/or sensory afferents level, potentially benefitting symptomatic patients. Similarly, a serotonin reuptake inhibitor, is effective in patients with esophageal symptoms (chest pain, dysphagia, heartburn, and/or regurgitation) associated with esophageal contraction abnormalities.
      • Prakash C.
      • Clouse R.E.
      Long-term outcome from tricyclic antidepressant treatment of functional chest pain.
      ,
      • Clouse R.E.
      • Lustman P.J.
      • Eckert T.C.
      • Ferney D.M.
      • Griffith L.S.
      Low-dose trazodone for symptomatic patients with esophageal contraction abnormalities. A double-blind, placebo-controlled trial.
      Thus appropriate use of antianxiety medications such as benzodiazepines and sertraline may result in the reduction of panic and anxiety symptoms and consequent alleviation of GERD symptoms. Gastro-esophageal reflux disease (GERD), with symptoms demonstrated to impair quality of life, appears to show important variation in its prevalence.
      • Hampel H.
      • Abraham N.S.
      • El-Serag H.B.
      Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.
      Evidence suggests that psychological co-morbidity is one of the critical factors that impair the QOL of individuals with GERD, but the underlying pathophysiological mechanisms remain unclear.
      • Yang X.J.
      • Jiang H.M.
      • Hou X.H.
      • Song J.
      Anxiety and depression in patients with gastroesophageal reflux disease and their effect on quality of life.
      Thus evaluating the relationship between GERD and psychological comorbidities is helpful in determining an appropriate treatment regimen and thereby improving QOL of these patients. Thus our study aimed to evaluate the underlying psychological symptoms associated with refractory GERD and determine the effectiveness of sertraline and benzodiazepines to mitigate the distress and improve the QOL of the patients.

      2. Methodology

      Figure thumbnail fx1

      3. Results

      Sample of 120 patients were identified and followed up in the study of whom, 80 had refractory GERD. Evaluation revealed a total of 65 patients with psychiatric symptomatology, who were included in the study and provided with the interventional drugs. The psychiatric evaluation concluded that generalized anxiety disorder and panic disorder are the major psychiatric comorbidities that occur in the study population. Consequently a differential distribution of these were estimated. Patient demographics and clinical characteristics are shown in Table 1 which includes age, gender, consumption of cigarettes, hypertension and food habits. Total score of GERD-HRQOL was highest among male patients.Association between higher body surface area and refractory GERD symptoms was investigated. 86% of the refractory GERD patients had a normal body surface area (BSA) of 1.9 m2 and 14% of patients had an abnormal BSA of more than 1.9 m2. Among the refractory GERD patients with abnormal BSA, about 88.88% of patients were males and 11.12% were females. Among 65 patients, 49.23% had BMI within the range of 19.5–25.5. BMI significantly influences the GERD HRQL score (f = 75.64972; p = 0.00001) and the disease severity. The effect of BMI on total score significantly differs among the four categories, <19.5 and 19.5–25.5(t stat = −10.2065; p = 0.0001), 19.5–25.5 and 25.5–28.5(t stat = −11.3554; p = 0.00001), 25.5–28.5 and > 28.5(t stat = −2.50686; p = 0.0009524).Patients with refractory GERD had a higher BMI, were less likely to be physically active and more likely to report psychological symptomatology. Among the total of 33 male patients with refractory GERD, about 68% of patients were non-alcoholic and 32% were alcoholic. Alcohol significantly influences GERD score (p = 0.00176). In case of smoking, 54.54% were non-smokers and 45.46% were smokers and no significant differences were observed with respect to smoking among the male patients (p = 0.228) with refractory GERD. The development of reflux was higher in DM patients. 19 refractory GERD patients had DM. These patients scored between 65 and 70 in GERD-HRQL scale.
      Table 1Socio-demographic factors of patients.
      % of patients with higher GERD-HRQOL

      score
      P value
      DEMOGRAPHICS
      Age28% (age between 35 and 45)0.2508
      GenderMale52%0.4110
      Female48%
      BSANormal BSA58.9%0.0001
      Abnormal BSA41.1%
      BMI49.23%0.00001
      HABIT
      AlcoholAlcoholic32%0.00176
      Non-alcoholic68%
      SmokingSmokers45.46%0.228
      Non-smokers54.54%
      SYMPTOMSNumber of patients with higher GERD-

      HRQOL score
      Heartburn520.02894
      Regurgitation470.023331
      OTHER DISEASES
      Diabetes Mellitus190.00003
      Hypertension240.194208
      OTHERS
      Medication intake530.001
      Food habits190.12
      The most frequently reported symptoms of GERD were heartburn and was present in 52 patients. Heartburn shows a statistical significance in the severity of GERD symptoms (p = 0.02894). Similar, regurgitation also shows a statistical significance in contributing to the severity of GERD symptoms(p = 0.023331) (Fig. 1). Out of 65 patients, 53 were at higher score which shows that medication intake significantly affects quality of life of patients. Most of the patients adhered to the medication given and showed improved quality of life. The distribution of panic disorder and generalized anxiety disorder in patients with refractory GERD was found to be 68% and 32%. Among the patients with panic disorder in refractory GERD, 52% were males and 48% were females. In generalized anxiety disorder, 48% of patients were males and 52% were females.
      Fig. 1
      Fig. 1Severity of regurgita tion among GERD patients.
      Regurgitationshows a statistical significance in contributing to the severi ty of GERD symptoms (p=0.023331).
      The Pearson correlation coefficient between scores of Panic and GERD was found to be +0.2. Hence these two variables showed positive correlation. The score of Panic and agoraphobia scale showed positive correlation scores of GERD HRQOL (Fig. 2). Correlation was significant with p value < 0.001. The Pearson correlation coefficient between scores of Hamilton anxiety scale and GERD was +0.15. Hence these two variables were positively correlated, as Anxiety scores increased, the score of GERD HRQOL also increased (Fig. 3). Correlation was significant with p value < 0.001. According to Pearson Correlation, there is a significant decrease in the score of panic agoraphobia scale and Hamilton anxiety scale after the administration of standard doses of Sertraline and Benzodiazepines (interventional drugs) when compared to the scores before administration of interventional drugs. There is also significant decrease in the score of GERD HRQOL after the administration of standard doses of Sertraline and Benzodiazepines (interventional drugs) when compared to the score of GERD HRQOL before administration of interventional drugs (Fig. 4 and Fig. 5).
      Fig. 2
      Fig. 2Distribution of GAD and PD in refractory GERD.
      Fig. 3
      Fig. 3Relationship between pre-interventional and post interventional scores of GERD.
      Fig. 4
      Fig. 4Relationship between pre-interventional and post interventional scores of GERD.
      Fig. 5
      Fig. 5Relationship between pre-interventional and post interventional scores of GERD.

      4. Discussion

      The aims of the present study was to investigate the relationship between GERD-related symptoms and anxiety disorder and to assess the effectiveness of sertraline and clonazepam in controlling these conditions. The study indicated that panic disorder and anxiety disorder is common in GERD and probably makes them refractory to PPI therapy. From the assessment of the study population, we found out that heart burn and regurgitation are the major clinical presentations in refractory GERD associated with psychiatric symptomatology. Ram Dickmann et al.,
      • Dickman R.
      • Boaz M.
      • Aizic S.
      • Beniashvili Z.
      • Fass R.
      • Niv Y.
      comparison of clinical characteristics of patients with gastroesophageal reflux disease who failed proton pump inhibitor therapy versus those who fully responded.
      in his study concluded that heart burn was significantly less prevalent in those who fully responded to PPI once daily when compared to patients who failed PPI once daily and twice daily thus indicating heart burn to be significantly associated with increased occurrence in refractory GERD patients. Various reflux symptoms like heartburn and regurgitation are thus found to have significant association in refractory GERD with psychiatric comorbidities.
      Another study evaluated the frequency of reflux symptoms in patients with a diagnosed psychiatric disorder and assessed the potential risk factors for symptom occurrence.
      • Avidan B.
      • Sonnenberg A.
      • Giblovich H.
      • Sontag S.J.
      Reflux symptoms are associated with psychiatric disease.
      The presence of the psychiatric condition was found to be the prime factor associated with increased reflux in the above-mentioned study. The concurrent esophageal dysfunction was proposed to be the etiological factor for increased reflux in psychiatric disorders.
      Our study indicated a significant difference between baseline and endpoint scores of both panic and anxiety following the administration of interventional drugs. A study conducted by Hartono JL et al.
      • Hartono J.L.
      • Mahadeva S.
      • Goh K.L.
      Anxiety and depression in various functional gastrointestinal disorders: do differences exist?.
      found that anxiety can lead to non-erosive reflux disease (NERD), which is the presence of classic GERD symptoms in the absence of esophageal mucosal injury during upper endoscopy. Psychological factors play an important role in patients with GERD as per this study and have been shown to decrease QOL in these patients considerably. A cross sectional study following a similar pattern to our study conducted by Jansson C et al. has indicated that anxiety can worsen the symptoms of reflux.
      • Jansson C.
      • Nordenstedt H.
      • Wallander M.A.
      • Johansson S.
      • et al.
      Severe gastro-oesophageal reflux symptoms in relation to anxiety, depression and coping in a population-based study.
      The study revealed a high prevalence of depressive, anxiety and sleep disorders among GERD patients. In our study, the panic and agoraphobia scale (PAS) was used to measure the severity of illness in patients with panic disorder (with or without agoraphobia). Moreover, Hamilton Anxiety Rating Scale (HAM-A) was used to measure the severity of anxiety symptoms by measuring both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). But in the afore mentioned study, rating scales such as HADS were used for screening of these disorders rather than diagnoses by psychiatrists.
      You Z-H et al.
      • You Z.-H.
      • et al.
      Risk of psychiatric disorders following gastroesophageal reflux disease: a nationwide population-based cohort study.
      suggested that GERD increases the risk of developing depressive, anxiety, and sleep disorders negatively influencing their QOL. The study following a co relational and longitudinal study design indicated frequent occurrence of psychiatric disorders among GERD patients. However our study was limited to identifying the differential distribution of GAD and PD among patients with refractory GERD. Previous studies have analyzed the roles of both anxiety and depression symptoms on the incidence of GERD, as well as their negative impact on QOL in patients with GERD. The results suggested that the incidence of GERD was correlated with anxiety and depression, and QOL of patients with GERD was reduced statistically.
      • Avidan B.
      • Sonnenberg A.
      • Giblovich H.
      • Sontag S.J.
      Reflux symptoms are associated with psychiatric disease.
      Both sertraline and benzodiazepines was found to reduce the scores of panic or anxiety respectively in the patients and thereby reduces the total severity score of GERD. Various studies have demonstrated that sertraline is an effective and well tolerated treatment of anxiety disorders with the anxiolytic benefit extending to both psychic and somatic anxiety symptoms.
      • Allgulander Christer
      • Dahl Alv A.
      • Austin Carol
      • et al.
      Efficacy of sertraline in a 12-week trialfor generalized anxiety disorder.
      Benzodiazepine is also effective in the treatment of anxiety disorders, because of their rapid onset of action and their efficacy with a favorable side effect profile.
      • Cloos Jean-Marc
      • Ferreira Valérie
      Current use of benzodiazepines in anxiety disorders.
      However, there is a high risk of benzodiazepine dependence, with longer duration of benzodiazepine treatment. A thorough risk assessment guides optimal management and the necessity for referral. However, the chances of dependence was minimized in our study by gradual benzodiazepine withdrawal and maintenance treatment with SSRI. Tricyclic antidepressants and selective serotonin reuptake inhibitors have shown to improve esophageal pain by reducing psychological and mental factors, which are known to be capable of inducing GERD symptoms.
      • Faruqui A.A.
      Anxiety induced refractory gastrointestinal disorders.
      Mental health specialists in the field of psycho-gastroenterology can aid in the management of esophageal hypersensitivity, which can drive the symptom experience of a PPI non responder. Considerations for comorbid anxiety and depression in this population require careful assessment and treatment.
      • Riehl M.E.
      • Chen J.W.
      The proton pump inhibitor nonresponder: a behavioral approach to improvement and wellness.
      Furthermore, symptomatic improvement in the psychiatric symptoms is associated with parallel improvement in quality of life and occupational functioning of GERD patients.

      5. Conclusion

      The study has shown that anxiety and panic disorder is very frequent in patients with refractory GERD symptoms. Our study's findings, in the context of an interventional study, provide primary evidence about the usefulness of targeting psychological symptoms for treatment of refractory GERD. Also, these findings is an indication of the key role of psychological factors on failure of PPIs and symptom persistence. This study showed that Sertraline and Benzodiazepines are effective in reducing the overall severity of GERD by controlling the psychological symptomatology. The overall improvement in the quality of life of the patients achieved by these medicines are thus attributed to the improvement in psychological wellbeing. The study regarding the correlation of panic and anxiety with GERD is a novel concept and can be drawn out onto a wider canvas so as to estimate a stronger evidence. Further prospective interventional studies are required to confirm the impacts of treating of psychological symptoms associated with refractory GERD.

      Declaration of competing interest

      The authors declare no conflict of interest.

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