Abstract

Background. Irritable bowel syndrome (IBS) is a poorly understood disease with few effective treatments. Psychosocial factors are believed to contribute to the pathogenesis of IBS. Objective. To evaluate the evidence for psychological therapies in IBS treatment. Methods. We searched six medical databases through February 6, 2014, for randomized controlled trials (RCTs) of psychological therapies for the treatment of IBS. Two independent reviewers identified the RCTs, extracted the data, and assessed trial quality. We used the random-effect model to pool standardized mean difference (SMD) and 95% confidence interval (CI) across trials. Results. 15 RCTs that mostly evaluated cognitive behavioral therapy were included. Psychological therapies were associated with improvement in IBS symptoms severity scales (SMD −0.618; 95% CI: −0.853 to −0.383), IBS-Quality of Life (SMD 0.604; 95% CI: 0.440 to 0.768), and abdominal pain (SMD −0.282; 95% CI: −0.562 to −0.001). No statistically significant effect was observed on diarrhea or constipation. Limitations. The trials were at increased risk of bias and the overall sample size was small leading to imprecision. Conclusion. Psychological therapies may improve the quality of life and symptom severity in IBS. The effect size noted is moderate to large and is clinically meaningful.

1. Introduction

Irritable bowel syndrome (IBS) is a complex and widespread functional bowel disorder (10–20% worldwide prevalence [1]) that is not well understood. IBS typically presents as persistent diarrhea and/or constipation that is accompanied by abdominal discomfort. The symptoms as well as the underlying etiologies of IBS can vary considerably from patient to patient. Some of these causes may include diet, genetics, altered intestinal environment, and dysregulation of the enteric nervous system function. Multiple treatments targeting these possible causes have been used for several decades but have largely only been demonstrated to temporarily treat symptoms.

Recently, acknowledgment of the role of stress and psychosocial factors in some cases has led to the examination of psychological therapies targeting these factors in the treatment of IBS. In the past few decades, research has uncovered an extensive bidirectional communication network between the brain and the gut termed the brain-gut axis [2]. This provides a pathophysiologic basis for the potential therapeutic effects of psychological therapies on gut function. This has been further supported by several, small, randomized controlled trials demonstrating the preliminary efficacy of psychological therapies on IBS symptoms [37]. Hypnotherapy has been suggested to treat abdominal pain, improve quality of life, and reduce anxiety and depression in IBS without any side effects [810]. These effects persisted for several years, although definitive conclusions will require larger, higher quality studies. Cognitive behavioral therapies (CBT) and mind-body therapies (MBT) have also been studied in IBS with some studies showing preliminary efficacy [1113]. Psychological therapies are potentially efficacious in treating IBS symptoms in many patients, and unlike many pharmaceutical treatments, they have minimal side effects and can be cost-effective [1417].

To examine if psychological therapies merit incorporation in the clinical treatment of IBS, we conducted this systematic review and meta-analysis of published randomized controlled trials. To our knowledge, no existing systematic reviews with meta-analysis have addressed this question.

2. Methods

Investigators developed a protocol in advance to specify eligibility criteria, outcomes of interest, and analysis methods. The methodology and reporting of this systematic review comply with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement) [18].

2.1. Eligibility Criteria

We included randomized controlled trials that enrolled patients of unspecified gender and aged at least 18 years. Subjects of the included trials were diagnosed with irritable bowel syndrome (IBS) based on one of the following criteria: Latimer criteria, Manning criteria, Kruis criteria, Rome I criteria, Rome II criteria, Rome III criteria, or clinician defined diagnosis [12, 15, 17, 1938]. We included trials that evaluated the efficacy of psychological interventions, including cognitive-behavioral therapies, mind-body therapies, and other psychological interventions, compared to no intervention, waiting list, placebo, diet, herbal treatment, or symptomatic management. Only trials that evaluated the efficacy of psychological interventions using composite IBS symptoms severity scales, individual IBS symptoms severity scales, or quality of life scales were included.

Nonrandomized comparative studies and single arm studies were not included. We excluded trials that evaluated hypnotherapy because multiple systematic reviews have already summarized this evidence [810]. We also excluded non-English references.

2.2. Search Methods

A comprehensive search of several databases from 1966 to February 6, 2014, any language, was conducted. The databases included Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycINFO, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search strategy was designed and conducted by an experienced librarian with input from the study’s principal investigator. Controlled vocabulary supplemented with keywords was used to search for comparative studies of psychological and mind-body interventions for irritable bowel syndrome. The actual strategy is included in the Appendix.

2.3. Study Selection

Two independent blinded reviewers (OA and VS) assessed the eligibility of the candidate references for inclusion by screening titles and abstracts initially. The full-text publications were then retrieved and their eligibility was assessed. Disagreement between the two reviewers was resolved by meeting and establishing consensus. Interreviewer agreement was measured by using the Kappa statistic.

2.4. Data Collection Process

Data were abstracted from each study using a standardized and piloted Microsoft Excel spreadsheet-based extraction form. Two independent blinded reviewers (OA and VS) did the abstraction in duplicate and disagreements were resolved by meeting and establishing consensus. The following data were abstracted: description of enrolled patients (inclusion criteria, age, gender, race, and previous treatment), description of received interventions and control, follow-up monitoring, and measures of outcome.

2.5. Outcomes of Interest

The primary outcomes were the composite IBS symptoms severity scales and quality of life. Other outcomes were diarrhea, constipation, and abdominal pain.

2.6. Assessment of the Risk of Bias

Two reviewers (OA and VS) evaluated the methodological quality of the included trials. To evaluate randomized controlled trials, we used the Cochrane Risk of Bias tool [39]. We evaluated the adequacy of randomization, allocation concealment, blinding (patients, providers, data collectors, and outcome assessors), baseline imbalance, and extent of loss to follow-up. We also extracted the funding source.

2.7. Statistical Analysis

Because the outcomes of interest were evaluated in the included trials using different scales, we estimated the standardized difference in means (SMD) to measure the difference between the intervention and control groups. SMD calculation involves standardizing the effect and expressing it in standard deviation units, to allow pooling it across trials. For each trial, we calculated the change in the studied scales before and after the intervention and compared it to the change in the control group. Then DerSimonian and Laird random-effects model was used to pool SMD across trials [40].

Inconsistency across the trials was assessed using the static and Cochran’s test. value more than 50% was considered indicative of substantial heterogeneity that is due to real differences in protocols, trial populations, interventions, and/or outcomes. Also, Cochran’s test value less than 0.05 indicates that the heterogeneity is beyond chance or random error [41]. We planned to conduct formal tests to assess potential publication bias using visual inspection of funnel plots and Egger’s regression asymmetry tests but this was not possible due to the small number of trials [42].

We planned to explore possible causes of heterogeneity by conducting subgroup analyses comparing the effect size between trials that evaluated CBT versus other forms of psychotherapy, trials in which patients received prior treatment versus those who did not, trials with high risk of bias versus low risk of bias, trials in which placebo or sham therapy was used in the control arm, and trials in which the control arm received pharmacological treatment versus those that did not. Interaction test between subgroups was done as suggested by Altman and Bland [43].

Statistical analyses were conducted using Comprehensive Meta-Analysis Version 2.2 [44].

3. Results

3.1. Study Selection

A total of 1,216 references were identified through the search strategy. Screening of titles and abstracts excluded 1,160 references (Figure 1). Two reviewers performed the initial screening and had an interreviewer agreement of Kappa of 0.84. Reviewing the retrieved full texts by the two reviewers excluded 25 publications and the interreviewer agreement about study eligibility, Kappa static, was 0.87. The remaining 22 publications included 15 trials.

3.2. Study Characteristics

The 15 included RCTs enrolled 1,352 patients. The follow-up period ranged from 10 weeks to 15 months. The criteria for the included patients, baseline characteristics of the included patients, and the interventions they received are detailed in Table 2.

Greene used the Latimer criteria [38] to diagnose IBS while Fernandez used the Manning criteria [45]. Seven of the fifteen trials used Rome I criteria [46] and five trials used the Rome II criteria [47]. Corney et al. used author specified criteria [22].

The included trials evaluated multiple psychological interventions: cognitive-behavioral therapies, psychoeducational courses, mind-body therapy, psychodynamic interpersonal therapy, and contingency management [12, 15, 17, 1937].

These interventions were compared to treatment as usual and routine clinical care, providing reading material, attention control, symptom and stressful event monitoring, waiting lists, support groups, standard medical therapy, or placebo [12, 15, 17, 1937].

The mean age of the included patients ranged from 34 to 50 years. The majority of patients (1,067/1,352) were females. Five of the included trials reported previous treatment. Four of them asked the patients to continue the current treatment and the fifth study had the patients go through a 2-week washout period [12, 15, 17, 1937].

3.3. Risk of Bias within Trials

All the included trials were randomized controlled trials. Assessment of risk of bias for each of the included trials is summarized in Table 1. Nine of the fifteen trials had high risk of bias. All these nine trials did not provide details about allocation concealment. Seven of them did not report the randomization method. For the remaining two trials, one of them did not report the presence of baseline imbalances and blinding, and the other one had inadequate randomization.

Five of the fifteen included trials had moderate risk of bias. Two of the five had high loss to follow-up rate (44.5% and 50.5%). The remaining three trials did not report whether allocation was concealed or not. Only one of the fifteen trials was found to have a low risk of bias.

Thirteen of the included trials were funded by a not-for-profit organization. One study did not disclose funding source and one study was funded partially by a pharmaceutical company.

3.4. Meta-Analysis

Nine of the included trials reported change in composite IBS symptoms severity scales. Four of these trials used the Irritable Bowel Syndrome-Severity Scoring System (IBS-SSS) used by Francis et al. [48], three used the Composite Primary Symptoms Reduction (CPSR) score used by Blanchard and Schwarz [49], one used the composite Bowel Symptom Severity (BSS) score used by Spiegel et al. [50], and one used a Global GI Symptoms Severity Score [30]. Random-effects meta-analysis (Figure 2) showed a statistically significant change in composite IBS severity scales in patients who received psychological therapy compared to patients receiving control with  SD favoring psychological therapy (95% CI from −0.853 to −0.383). Moderate heterogeneity was observed ( and ).

Eight of the included trials reported change in quality of life scales. Three of the included trials used the Irritable Bowel Syndrome-Quality of Life (IBS-QOL) scale used by Drossman et al. [51, 52], two trials used the Physical Component Score of the Short Form 36 Health Survey [53], one study used the Irritable Bowel Syndrome-Quality of Life scale used by Hahn et al. [54], one study used the GI Quality-of-Life Index used by Eypasch et al. [55], and one study used the Work and Social Adjustment Scale used by Mundt et al. [56]. Random-effects meta-analysis (Figure 3) showed a statistically significant change in quality of life scales in patients receiving psychological therapy compared to patients receiving control with  SD favoring psychological therapy (95% CI from 0.440 to 0.768). No evidence of heterogeneity was observed ( and ).

Eight trials reported change in abdominal pain scales (Figure 4). There was a statistically significant change favoring psychological therapy compared to control on random-effects meta-analysis with  SD (95% CI from −0.562 to −0.001). There was strong evidence of heterogeneity ( and ).

Six trials reported changes in diarrhea scales and constipation scales (Figures 5 and 6). Random-effects meta-analyses showed no statistically significant difference in the change of diarrhea scales with  SD (95% CI from −0.912 to 0.017) and constipation scales with  SD (95% CI from −0.484 to 0.224) between subjects who received psychological therapy and who received the control . Strong evidence of heterogeneity was observed in both meta-analyses of the diarrhea scales ( and ) and the constipation scales ( and ).

3.5. Subgroup Analysis

There was no statistically significant interaction based on the type of treatment (CBT versus other forms of psychotherapy), based on the risk of bias, or based on whether the control arm received pharmacological treatment (, Table 3). There were insufficient data to conduct subgroup analyses based on whether a placebo was used in the control arm or based on whether patients received prior treatment.

4. Discussion

We conducted a systematic review and meta-analysis of randomized controlled trial evaluating the effects of psychological therapies such as cognitive-behavioral therapy (CBT) and mind-body therapy (MBT) on IBS patients’ symptoms and quality of life.

4.1. Main Findings

Our search identified 15 trials evaluating a psychological therapy on a sample of IBS patients. We excluded trials of hypnotherapy, as three reviews have already examined its effect on IBS. Outcomes were evaluated using validated scoring scales. The body of evidence varied from small in measures of diarrhea (346 subjects) and constipation (346 subjects) to moderate for the composite IBS symptom severity scales (680 patients). The conducted meta-analyses demonstrated a statistically significant effect of psychological therapies on IBS-Quality of Life and composite IBS symptom severity scales with minimal heterogeneity. In contrast, psychological therapies had no statistically significant effect on diarrhea and constipation with evidence of heterogeneity observed. Psychological therapies had a statistically significant effect on abdominal pain; however, this inference was limited by heterogeneity. It should be noted that the studies assessing these secondary outcomes might not have been adequately powered to evaluate changes in symptoms, as they were either secondary outcomes or part of a composite scale. The pooled effect sizes ranged from 0.13 SD to 0.62 SD.

The standardized difference in the means was used to express the effect size for each outcome in standard deviation unit as each outcome was assessed using different scales. According to Cohen, a difference of 0.2 SD is considered a small difference, 0.5 SD is considered moderate, and 0.8 SD is considered large [57]. Norman found that a 0.5 SD was the minimally clinically important difference (MCID) for changes in most of health-related quality of life for chronic diseases [58]. Studies were done to validate and define the MCID for the IBS-Quality of Life scale [51, 52]. The MCID was found to be 10 to 14 points which is equal to 0.5 to 0.7 standard deviation units [59]. In this meta-analysis, the psychological therapy increased the quality of life scales by 0.604 SD units (95% CI from 0.440 to 0.768) compared to control. Using the above MCID this translates to a clinically meaningful improvement in quality of life.

When Francis et al. described the IBS-Severity Scoring System (IBS-SSS), they found that a change of 50 points was sufficient to detect clinical improvement [48]. This is equal to 0.6 SD in most of the trials that used the IBS-SSS in this meta-analysis [12, 28, 33, 34]. The psychological interventions decreased the symptom severity scales by 0.618 SD (95% CI from −0.853 to −0.383) compared to control in the current meta-analysis. This translates to a clinically meaningful change consistent with improvement in the IBS symptoms severity scales.

The meta-analysis of the abdominal pain showed a statistically significant difference. We were not able to find a study that established the MCID for abdominal pain scales in patients with IBS. The psychological therapies decreased the abdominal pain scales by 0.282 SD (95% CI from −0.562 to −0.001) and by applying Cohen’s assumption [57] above this translates to a small difference. Also, this statistically significant difference was limited by the presence of heterogeneity.

The quality of evidence according to the GRADE [60] approach for the primary outcomes was low and moderate for IBS symptom severity scale and IBS-Quality of Life, respectively, rated down for high and moderate risk of bias. The quality of evidence for secondary outcomes was very low, with downratings due to the overall high risk of bias, serious imprecision, and serious inconsistency in all of them.

4.2. Strengths and Limitations

By its nature IBS is a poorly understood, heterogeneous disease with varied clinical presentations and underlying etiologies. Despite this fact, all the trials evaluated used very similar protocols and criteria for defining their sample population of IBS patients, even if the criteria for IBS have evolved over the three decades from which these trials were conducted. Further strengths of this systematic review relate to the reviewers’ measures taken to control bias. Some of these measures included study screening, quality evaluation, and data extraction in duplicate. The search strategy was comprehensive, extracting trials from multiple databases. To our knowledge, this is the first systematic review with accompanying meta-analysis to quantitatively measure the effects of psychological therapies, other than hypnotherapy, on gastrointestinal symptoms in patients with IBS.

There are many limitations in this review. The trials evaluated had many methodological limitations and were generally small. Although specific details on frequency and duration of the psychological interventions were given in the trials, the efficacy of psychological therapies such as cognitive-behavioral therapy can range considerably depending on the training and experience of the therapist. The therapy is also often modified in the presence of psychological comorbidity, which is common in IBS patients. This can result in variability in the therapy given in the different trials. There was variability in the follow-up periods as well. Publication bias is likely in a field in which evidence consists of trials with small size. Further, the efficacy of CBT or MBT could be driven primarily by improvement in general feeling of well-being and lower stress, and not specific improvement in IBS pathophysiology.

Another limitation pertains to the heterogeneity of IBS itself. IBS is now recognized as including three main subtypes: IBS-diarrhea predominant, IBS-constipation predominant, and IBS-mixed type. Many patients also develop IBS as sequelae to gastrointestinal infection or what is termed postinfectious IBS. These subtypes may have varying etiologies underlying their pathophysiology. By failing to stratify results by these subtypes, we are unable to know if there would be differences in efficacy of psychological therapies between subtypes. This would have important practical implications for the clinical incorporation of psychological therapies in the treatment of IBS. In terms of the analysis, heterogeneity that remained unexplained despite subgroup analyses lowers the confidence in the meta-analytic estimates.

5. Conclusion

Psychological therapies such as cognitive-behavioral therapy and mind-body therapy may help to improve gastrointestinal symptoms and quality of life in IBS patients. Although statistical significance was found in IBS measures of quality of life and symptom severity, these results should be interpreted with caution as trials were generally of low quality. Future trials will require larger sample sizes, longer follow-up periods, and higher quality methodology to provide a definitive recommendation on the incorporation of psychological therapies in the treatment of IBS. However, despite these concerns, psychological therapies appear to be a safe intervention and could be a practical option for patients who fail standard medical therapy.

Appendix

Actual Search Strategies

(1) Ovid

Database(s). Embase 1988 to 2014 Week 05, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present, PsycINFO 1967 to January Week 3 2014, EBM Reviews-Cochrane Central Register of Controlled Trials December 2013, EBM Reviews-Cochrane Database of Systematic Reviews 2005 to December 2013.

Search Strategy (#, Searches, Results)(1)exp Irritable Bowel Syndrome/, 19426(2)exp Irritable Colon/, 18648(3)exp Colonic Diseases, Functional/, 23156(4)(“Irritable bowel*” or “mucous colitis” or “irritable colon*” or “functional colonic disease*” or colonospasm* or “colon spasm*” or “mucomembraneous colitis” or “mucomembranous colitis” or “spastic colon*” or “spastic colitis” or “unstable colon*” or “mucous colitides” or “colonic spasm*”). mp., 27651(5)or/1–4, 29503(6)exp Psychotherapy/, 464651(7)exp mind body therapy/, 76870(8)exp mind-body therapies/, 76826(9)exp Mindfulness/, 2940(10)exp meditation/, 7934(11)exp yoga/, 5954(12)exp stress management/, 6155(13)exp relaxation therapy/, 18867(14)exp relaxation/, 31982(15)exp hypnosis/, 25313(16)exp anxiety management/, 385(17)((conditioning or psyc* or cognit* or behavior* or stress or anxiety or breath* or “insight-oriented talk” or “insight-oriented verbal” or “acceptance and commitment”) adj3 (therap* or training or treat* or technique* or procedure* or manag* or modifi* or modify or technic or technics or rehab* or restructur*)). mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui, tc, id, tm, tx, ct], 736491(18)((stress adj3 reduc*) or relaxation or meditat* or hypnotherap* or hypnos* or biofeedback or “bio-feedback” or mindful* or psychotherap* or logotherap* or psychoanaly* or neurofeedback or “sensory feedback” or suggestion* or “behaviour contracting” or “consciousness raising” or yoga or yogic or “mind-body” or mindbody or imagery). mp., 872931(19)or/6–18, 1552410(20)5 and 19, 3801(21)exp controlled study/, 4359161(22)exp randomized controlled trial/, 710055(23)((control$ or randomized or randomised) adj2 (study or studies or trial or trials)). mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui, tc, id, tm, tx, ct], 5642060(24)meta analysis/, 127132(25)meta-analys$. mp., 220461(26)exp “systematic review”/, 69727(27)(systematic* adj review$). mp., 172449(28)exp Cohort Studies/, 1569846(29)exp longitudinal study/, 1000695(30)exp retrospective study/, 825412(31)exp prospective study/, 670821(32)exp comparative study/, 2454433(33)exp clinical trial/, 1711899(34)exp cross-sectional study/, 283566(35)crossover procedure/, 39737(36)exp cross-over studies/, 97499(37)multivariate analysis/, 186446(38)((clinical or comparative or cohort or longitudinal or retrospective or prospective or concurrent or “cross-sectional” or crossover or “cross-over”) adj (study or studies or survey or surveys or analysis or analyses or trial or trials)). mp., 7311926(39)(“crossover procedure” or “cross-over procedure” or “multivariate analys*”). mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui, tc, id, tm, tx, ct], 394850(40)or/21–39, 11388240(41)20 and 40, 1798(42)from 20 keep 2161–3109, 949(43)limit 42 to (clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial or comparative study or controlled clinical trial or evaluation studies or meta analysis or multicenter study or randomized controlled trial or systematic reviews) [Limit not valid in Embase, PsycINFO, CCTR, CDSR; records were retained], 253(44)41 or 43, 1816(45)limit 44 to (book or book series or editorial or erratum or letter or note or addresses or autobiography or bibliography or biography or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in Embase, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process, PsycINFO, CCTR, CDSR; records were retained], 131(46)44 not 45, 1685(47)from 20 keep 3567–3801, 235(48)46 or 47, 1798(49)48 not (exp animals/ not exp humans/), 1626(50)from 48 keep 1741–1798, 58(51)49 or 50, 1684(52)limit 51 to yr = “1966–Current”, 1684(53)remove duplicates from 52, 1219

(2) Scopus(1)TITLE-ABS-KEY (“Irritable bowel*” or “mucous colitis” or “irritable colon*” or “functional colonic disease*” or colonospasm* or “colon spasm*” or “mucomembraneous colitis” or “mucomembranous colitis” or “spastic colon*” or “spastic colitis” or “unstable colon*” or “mucous colitides” or “colonic spasm*”)(2)TITLE-ABS-KEY ((conditioning W/3 therap*) or (conditioning W/3 training) or (conditioning W/3 treat*) or (conditioning W/3 technique*) or (conditioning W/3 procedure*) or (conditioning W/3 manag*) or (conditioning W/3 modifi*) or (conditioning W/3 modify) or (conditioning W/3 technic) or (conditioning W/3 technics) or (conditioning W/3 rehab*) or (conditioning W/3 restructur*) or (psyc* W/3 therap*) or (psyc* W/3 training) or (psyc* W/3 treat*) or (psyc* W/3 technique*) or (psyc* W/3 procedure*) or (psyc* W/3 manag*) or (psyc* W/3 modifi*) or (psyc* W/3 modify) or (psyc* W/3 technic) or (psyc* W/3 technics) or (psyc* W/3 rehab*) or (psyc* W/3 restructur*) or (cognit* W/3 therap*) or (cognit* W/3 training) or (cognit* W/3 treat*) or (cognit* W/3 technique*) or (cognit* W/3 procedure*) or (cognit* W/3 manag*) or (cognit* W/3 modifi*) or (cognit* W/3 modify) or (cognit* W/3 technic) or (cognit* W/3 technics) or (cognit* W/3 rehab*) or (cognit* W/3 restructur*) or (behavior* W/3 therap*) or (behavior* W/3 training) or (behavior* W/3 treat*) or (behavior* W/3 technique*) or (behavior* W/3 procedure*) or (behavior* W/3 manag*) or (behavior* W/3 modifi*) or (behavior* W/3 modify) or (behavior* W/3 technic) or (behavior* W/3 technics) or (behavior* W/3 rehab*) or (behavior* W/3 restructur*) or (stress W/3 therap*) or (stress W/3 training) or (stress W/3 treat*) or (stress W/3 technique*) or (stress W/3 procedure*) or (stress W/3 manag*) or (stress W/3 modifi*) or (stress W/3 modify) or (stress W/3 technic) or (stress W/3 technics) or (stress W/3 rehab*) or (stress W/3 restructur*) or (anxiety W/3 therap*) or (anxiety W/3 training) or (anxiety W/3 treat*) or (anxiety W/3 technique*) or (anxiety W/3 procedure*) or (anxiety W/3 manag*) or (anxiety W/3 modifi*) or (anxiety W/3 modify) or (anxiety W/3 technic) or (anxiety W/3 technics) or (anxiety W/3 rehab*) or (anxiety W/3 restructur*) or (breath* W/3 therap*) or (breath* W/3 training) or (breath* W/3 treat*) or (breath* W/3 technique*) or (breath* W/3 procedure*) or (breath* W/3 manag*) or (breath* W/3 modifi*) or (breath* W/3 modify) or (breath* W/3 technic) or (breath* W/3 technics) or (breath* W/3 rehab*) or (breath* W/3 restructur*) or ((“insight-oriented talk” or “insight-oriented verbal” or “acceptance and commitment”) W/3 (therap* or training or treat* or technique* or procedure* or manag* or modifi* or modify or technic or technics or rehab* or restructur*)))(3)TITLE-ABS-KEY ((stress W/3 reduc*) or relaxation or meditat* or hypnotherap* or hypnos* or biofeedback or “bio-feedback" or mindful* or psychotherap* or logotherap* or psychoanaly* or neurofeedback or “sensory feedback” or suggestion* or “behaviour contracting” or “consciousness raising” or yoga or yogic or “mind-body” or mindbody or imagery)(4)TITLE-ABS-KEY ((meta W/1 analys*) OR (systematic* W/2 review*) OR (control* W/2 stud*) OR (control* W/2 trial*) OR (randomized* W/2 stud*) OR (randomized* W/2 trial*) OR (randomised W/2 stud*) OR (randomised W/2 trial*) or “comparative stud*” OR “comparative survey*” OR “comparative analys*” OR “cohort stud*” OR “cohort survey*” OR “cohort analys*” OR “longitudinal stud*” OR “longitudinal survey*” OR “longitudinal analys*” OR “retrospective stud*” OR “retrospective survey*” OR “retrospective analys*” or “prospective stud*” OR “prospective survey*” OR “prospective analys*” or “concurrent stud*” OR “concurrent survey*” OR “concurrent analys*” or “clinical stud*” OR “clinical trial*” or “cross-sectional stud*” or “cross-sectional analys*” or “cross-over stud*” or “cross-over analys*” or “cross-over procedure” or “crossover stud*” or “crossover analys*” or “crossover procedure” or “multivariate analys*”)(5)PUBYEAR > 1965(6)1 and (2 or 3) and 4 and 5(7)PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*)(8)6 and not 7(9)DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR DOCTYPE(sh)(10)8 and not 9.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of the paper.

Authors’ Contribution

Study concept and design was made by Osama Altayar and Varun Sharma. Acquisition of data was carried out by Osama Altayar, Varun Sharma, and Larry J. Prokop. Analysis and interpretation of data was done by Osama Altayar, Varun Sharma, and Mohammad H. Murad. Drafting of the paper was done by Osama Altayar and Varun Sharma. Critical revision of the paper for important intellectual content was by Amit Sood and Mohammad H. Murad. Statistical analysis was carried out by Osama Altayar and Mohammad H. Murad. Osama Altayar, Varun Sharma, and Larry Prokop were responsible for administrative, technical, or material support. Study supervision was held by Varun Sharma and Mohammad Hassan Murad. Osama Altayar and Varun Sharma have equally contributed to this work.