Sensitivity to change and minimal clinically important difference of the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7)

Journal of Affective Disorders 265 (2020) 395–401

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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Research paper

Sensitivity to change and minimal clinically important difference of the 7item Generalized Anxiety Disorder Questionnaire (GAD-7)

T

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Anne Toussainta, ,1, Paul Hüsinga,1, Antje Gumza, Katja Wingenfeldb, Martin Härterc, Elisabeth Schrammd, Bernd Löwea a

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt- Campus Benjamin Franklin, Berlin, Germany c Department of Medical Psychology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany d Department of Psychiatry, Faculty of Medicine, University of Freiburg, Freiburg, Germany b

A R T I C LE I N FO

A B S T R A C T

Keywords: Psychometrics Anxiety Responsiveness Sensitivity to change Minimal clinically important difference

Background: Effective treatment requires regular follow-up and monitoring of symptoms. We investigated sensitivity to change and minimal clinically important difference of the Generalized Anxiety Disorder Scale (GAD7). Methods: This study included all participants from a multisite trial of chronic depression. Baseline and follow-up (12 and 48 weeks) data were used to assess treatment response. Effect sizes (ES) and standardized response means (SRM) of pre- and post-GAD-7 mean changes were calculated for subgroups of patients, who did or did not improve according to ratings in the Hamilton Rating Scale for Depression (HRSD-24). Results: N = 261 patients were included in the analyses. In the subgroup of patients who improved according to HRSD-24, GAD-7 scores were significantly lower after 12 weeks (t = −6.31, df = 120, p < .001; ES = −0.51, SRM = −0.57), and 48 weeks of treatment (t = −12.68, df = 141, p < .001; ES = −1.0, SRM = −1.7), when compared to admission. In the group who worsened, GAD-7 scores were significantly higher after 12 weeks (t = 2.96, df = 41, p = .005; ES = 0.30, SRM = 0.46), and increased after 48 weeks (t = 1.99, df = 21, p = .059; ES = 0.37, SRM = 0.43), when compared to baseline. The unchanged group showed no significant difference between baseline and follow-up. MCID was estimated 4 points on the GAD-7 total score. Limitations: Confirmation of these findings and further investigation of the GAD-7 in populations and trials focusing on anxiety-specific treatment is highly recommended. Conclusions: Results show that the GAD-7 is sensitive to detect change in psychopathology over the course of treatment.

1. Introduction Anxiety is a common condition that impacts a person's mental health, and can also have short- and long-term effects on the body. People with anxiety experience a range of psychological and physical symptoms, i.e. feeling nervous, tense, or fearful, rapid heart rate, fast breathing, or hyperventilation (Craske et al., 2009). Anxiety disorders are one of the most common mental disorders in primary care settings (Baldwin, 2018; Kessler et al., 2005; Wittchen et al., 2011). They substantially impair patients’ quality of life (Rapaport et al., 2005; Spitzer et al., 1995), and are associated with an increased use of health services and direct and indirect health care costs

(Greenberg et al., 1999; Wittchen et al., 2002). Anxiety symptoms often accompany depressive disorders (Clark and Watson, 1991). Due to their clinical relevance, it is important to identify anxiety early in the diagnostic process, and to assess changes of anxiety severity under treatment in a reliable and economic way. Existing ‘gold standard’ instruments like the Structured Clinical Interview for DSM (SCID) (First et al., 2002) are mostly time-consuming, require administration by a trained interviewer, and are therefore often considered impractical for use in busy clinical settings. The ‘Patient Health Questionnaire (PHQ)’ (Spitzer et al., 1999) was designed in order to provide a more efficient solution. The PHQ was the first self-report questionnaire for use in primary care to aid the

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Corresponding author. E-mail address: [email protected] (A. Toussaint). 1 Both authors contributed equally to this manuscript https://doi.org/10.1016/j.jad.2020.01.032 Received 28 May 2019; Received in revised form 10 December 2019; Accepted 11 January 2020 Available online 15 January 2020 0165-0327/ © 2020 Elsevier B.V. All rights reserved.

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(HRSD-24) (Hamilton, 1967) needed to be present. Exclusion criteria comprised an acute risk of suicide, a primary diagnosis of another mental or personality disorder, severe cognitive impairment, a serious medical condition, or an organic brain disorder. Also excluded were patients familiar with CBASP and/or SP psychotherapy, participating in ongoing psychotherapy, or taking an antidepressant medication. Primary outcome was depression severity after 20 weeks (24 sessions) as assessed by the HRSD-24. Written informed consent was obtained from all participants. The study was approved by the Ethics Committee of the University of Freiburg and the local ethics committees of the University of Bonn, University of Heidelberg, University of Tübingen, University Medical Center Hamburg–Eppendorf, University of Marburg, and University of Lübeck.

diagnostic process of specific disorders, using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV-TR) (APA, 2000). Its 7-item Generalized Anxiety Disorder module (GAD-7) (Spitzer et al., 2006) takes less than 3 min to complete and is easy to score. The GAD-7 is available in about 70 translations, which are freely accessible via www.phqscreeners.com. Due to its diagnostic reliability, factorial, construct, and criterion validity (Kroenke et al., 2007; Löwe et al., 2008a; Swinson, 2006), the GAD-7 is today among the most widely used anxiety measures, both in clinical practice and research (Dear et al., 2011). It can be applied for screening, diagnosis and severity assessment of anxiety disorders such as GAD (whereas scores of 10 or higher are indicative of GAD), but also social phobia, post-traumatic stress disorder and panic disorder (Spitzer et al., 2006). The GAD-7 has currently been recommended by the American Psychiatric Association as a useful instrument for measuring the severity of GAD according to the new DSM-5 criteria (APA, 2013). The ability of an instrument to detect significant change in health status over time (i.e., its sensitivity to change) is an essential requirement of an outcome measure (Kroenke et al., 2018). If it does prove responsive to treatment in the sense of appropriately reflecting meaningful changes in clinical outcomes over the course of time, the GAD-7 should reflect improvement (or worsening) in anxiety over time, measured as the difference in scores before and after a therapeutic intervention. This would underpin its practical and valid use for assessing anxiety outcomes in research and clinical practice. So far, there is limited evidence regarding the sensitivity to change of the GAD-7, particularly with respect to psychometric analyses of data from prospective clinical trials. In two studies examining acute psychiatric samples (Beard and Björgvinsson, 2014; Kertz et al., 2013), and two studies analyzing large routine cohort data sets of the English Improving Access to Psychological Therapies (IAPT) services (Gyani et al., 2013; Richards and Borglin, 2011), sensitivity to change of the GAD-7 was indicated. Dear et al. (2011) found the GAD-7 sensitive to change in two clinical trials with patients who fulfilled GAD diagnostic criteria. To examine sensitivity to change of the GAD-7 in a more homogeneous patient group and over a longer follow-up period, we used longitudinal data (baseline, 12-, and 48-weeks follow-up) from a multisite, randomized clinical trial (Schramm et al., 2017). The trial was conducted among adult outpatients with early-onset chronic depression to evaluate the efficacy of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) compared to nonspecific Supportive Psychotherapy (SP). The GAD-7 and Hamilton Rating Scale for Depression (HRSD-24) (Hamilton, 1967) were completed at baseline and all followup dates. Using the HRSD-24 as a clinician-rated index of improvement, patients were assigned to subgroups of improved, unchanged, or worsened HRSD-24 status at 12 and 48 weeks of treatment. With regard to sensitivity to change, we hypothesized that GAD-7 change scores would differ significantly between these three patient subgroups. In addition, we determined the minimal clinically important difference (MCID) in GAD-7 scores. The MCID is the smallest change in a treatment outcome that an individual patient would identify as important, and which would indicate a change in the patient's management (Wright et al., 2012).

2.2. Study measures The seven items of the Generalized Anxiety Disorder scale (GAD-7) describe the most important diagnostic criteria for GAD according to DSM-IV-TR (APA, 2000), namely the Criterion A (fear and anxiety related to a series of events or activities), Criterion B (difficulties in controlling concerns) and Criterion C (anxiety and worry are accompanied by at least three additional symptoms such as restlessness, mild fatigue, difficulty concentrating, irritability, muscle tension and sleep problems). The GAD-7 asks how often people have suffered from the seven core symptoms of GAD within the last two weeks with the response options being ‘not at all’, ‘on some days’, ‘on more than half of the days’ and ‘almost every day’ (scored 0–3, with a total score ranging from 0 to 21) (Spitzer et al., 2006). The GAD-7 has been validated within a large sample of patients in a primary care setting (Kroenke et al., 2007), and within a large general population sample in Germany (Löwe et al., 2008a). A one-factorial structure has been claimed and established, a high internal consistency (α = 0.92) has been reported and reference scores based on norms for the general population have been provided (Löwe et al., 2008a). Convergent validity was established by means of correlations with two other anxiety measures (Kroenke et al., 2007). Using the threshold score of 10, the GAD-7 has a sensitivity of 89% and a specificity of 82% for GAD (Spitzer et al., 2006). Researchers have used the GAD-7 as a treatment outcome measure in mixed anxiety and depression samples (Hammond et al., 2012; Richards and Borglin, 2011). 2.2.1. Hamilton Rating Scale for Depression (HRSD-24) The primary outcome of the trial was assessed using the clinicianrated HRSD-24 (Hamilton, 1967), which is a multiple item questionnaire, designed for adults, used to rate the severity of their depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. The patient is rated by a clinician on 24 items, scored on a 5-point scale (0 = absent; 1 = mild, 2 = moderate; 3 = severe; 4 = incapacitating). For our analyses, patients were assigned to subgroups of improved, unchanged, or worsened HRSD-24 status at 12 and 48 weeks of treatment, as we were interested in the changes that occurred after the first few weeks and at the end of treatment. It must be noted that the HRSD-24 is not explicitly designed to assess severity of anxiety. However, depression and anxiety are overlapping constructs (Kroenke et al., 2016; Sartorius et al., 1996), and worry levels are comparable in individuals with GAD and depression (Starcevic, 1995). Accordingly, the HRSD-24 has been criticized on its content validity (Bagby et al., 2004; Maier et al., 1988). Some of the HRSD-24 items capture symptoms thought to be characteristic of anxiety but not depression, with two items explicitly assessing anxiety status, operationalized as (1) anxiety psychic, demonstrated by subjective tension and irritability, loss of concentration, worrying about minor matters, apprehension, fears expressed without questioning, feelings of panic, feeling jumpy, and (2) anxiety somatic, demonstrated by physiological concomitants of anxiety, e.g. dry mouth, wind,

2. Methods 2.1. Study design and participants The paper uses data from a multi-site (8 university centers throughout Germany), evaluator-blinded, prospective, parallel-group, randomized clinical trial for chronic depression with an active control condition (Schramm et al., 2017). Patients between 18 and 65 years with early-onset major depressive disorder of at least 2 years’ duration, double depression, or recurrent major depression as defined by DSM-IVTR were recruited between March 2010 and October 2012. A scoring of at least 20 points on the 24-item Hamilton Rating Scale for Depression 396

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common measure to estimate the minimal clinically important difference (MCID) of an instrument (Wright et al., 2012). The categories were used as ordinal categories to grade therapeutic response and effect sizes (ES), and the standardized response means (SRM) of the GAD-7 were analyzed and compared. Paired t-tests were used to test for statistical significance of pre- and post-comparisons of the subgroups. Analysis of variance and Scheffé post hoc tests were carried out to compare differences in GAD-7 score changes between patient subgroups based on their improvement. Besides pre- and post-comparisons for the complete sample, GAD-7 scores were additionally examined for a subgroup of patients with an especially high GAD-7 score at baseline. These patients were identified by applying a cut-off-score at the upper quartile of the data distribution at baseline. We analyzed this specific subgroup because we expected highly impaired patients to show a greater decline in GAD-7 scores post treatment.

indigestion, diarrhea, cramps, belching, palpitations, headaches, hyperventilation, sighing, urinary frequency, sweating, giddiness, blurred vision, tinnitus. Since it explicitly contains items that measure psychic and somatic anxiety symptoms, the HRSD has been used to assess severity of anxiety in previous studies (Bramley et al., 1988; Fava et al., 2008). Therefore, we considered the HRSD-24 to be a valid criterion, which should - in response to treatment - reflect both, changes in symptoms of depression and anxiety. Both instruments (GAD-7 and HRSD-24) were administered to all participants at baseline and 12- (16 sessions), 20- (24 sessions), and 48week (32 sessions) follow-up. Assessment time was about 30 min. To investigate responsiveness to treatment and minimal clinically important difference (MCID) of the GAD-7, we used the total HRSD-24 score at 12- and 48-weeks as an external criterion to assign patients to different outcome groups, i.e. improved, unchanged, or deteriorated symptomatology. In an additional sub-analysis, the two anxiety-specific items of the HRSD-24 were used as external criterion.

2.3.2. Minimal Clinically Important Difference (MCID) The concept of MCID refers to the smallest difference in score in the domain of interest that is considered to be worthwhile or clinically important. The MCID is a context specific value (Cook, 2008; Wright et al., 2012). In our study, we aimed to establish the MCID of the GAD-7 for longitudinal monitoring of individuals. To estimate the intraindividual MCID for the GAD-7, we used the standard error of measurement (SEM, standard deviation of baseline scores multiplied by the square root of one minus the reliability coefficient) (Wrigth et al., 2012; Wyrwich et al., 1999), which can be regarded as the standard deviation of an individual score. Either one or two SEMs are an acceptable method for evaluating clinically relevant change in individual patients (Kroenke et al., 2016, 2018; Löwe et al., 2004b). To achieve an intraindividual MCID that reflects the 95% confidence interval, the standard error of measurement was multiplied by 1.96. All statistical analyses were performed with SPSS ® version 23.

2.3. Statistical analysis 2.3.1. Responsiveness to treatment Responsiveness refers to the ability of an outcome measure to accurately detect change when it has occurred (Deyo, 1984; Deyo and Centor, 1986). Sensitivity to change is a related construct, which is sometimes used synonymously. However, although an instrument's sensitivity to change can be assessed without treatment being present, the assessment of responsiveness requires an intervention and usually the presence of an additional external criterion for therapeutic response. There is no agreed-upon standard procedure to calculate sensitivity to change, as various approaches exist (Gierk et al., 2017; Hüsing et al., 2018; Löwe et al., 2004a, 2004b). In our study, we calculated standardized response means (SRMs) and effect sizes (ES) for comparisons between baseline and follow-up measures (Hevey and McGee, 1998; Schuck, 2000). Effect size indices are commonly used to estimate responsiveness because they provide a quantitative estimate and permit comparisons across different instruments and patient subgroups. The SRM (difference of mean scores at 2 assessment points divided by standard deviation of score changes) has been advocated as the most adequate effect size index of responsiveness, because it incorporates the response variance in the denominator (Wyrwich et al., 1999). For this study, the self-reported GAD-7 and interview-based HRSD-24 sum scores were assessed at baseline, 12, and 48 weeks follow-up. We calculated effect sizes and evaluated significance of change scores for the GAD-7 and the HRSD-24 sum score both (1) between baseline and 12 weeks and (2) between baseline and 48 weeks, using repeated measures ANOVAs. Additionally, we calculated standardized response means (SRM) for the GAD-7. Corresponding to other studies (Clark et al., 2009; Dear et al., 2011; Schalet et al., 2014), the largest treatment response is thereby expected during the longer time period, i.e. 48 weeks. Besides comparing change scores, we used ratings of HRSD-24 scores as companion criterion standard to divide subjects into patient subgroups with different treatment courses (worse, same, improved) at 12 and 48 weeks. Recognizing that the total score of the HRSD-24 is not designed to indicate severity of anxiety, but depression, we performed an additional sub-analysis, using ratings of a composite score of the two anxietyspecific items of the HRSD-24 only. Patients were considered to have improved if their HRSD-24 anxiety sub-score declined by 2 points or more (based on estimated SEM) from baseline to follow-up at 12 and 48 weeks, respectively, and as worsened if the score increased by 2 points or more. Again, subjects were divided into patient subgroups with different treatment courses (worse, same, improved) at 12 and 48 weeks. The three HRSD-24 change groups (worse, same, improved) were computed by determining whether the HRSD-24 score declined or improved. As cut-off we used the standard error of measurement (SEM), a

3. Results 3.1. Study participants A total of 622 patients were assessed for eligibility, 354 (56.9%) were excluded because they did not fulfill the inclusion criteria. Of the 268 randomized individuals, 137 patients were allocated to CBASP and 131 to SP. At the end of the acute phase, 128 patients (93.4%) allocated to the CBASP group and 114 patients (87.0%) allocated to the SP group were retained in the study. At the end of the extended phase, 121 patients (88.3%) in the CBASP group and 110 patients (84.0%) in the SP group were followed up. We used the complete sample (CBASP plus SP condition) for our analyses. A total of 117 patients (43.7%) fulfilled criteria for at least one concurrent Axis I psychiatric diagnosis, and 103 (38.4%) had at least one Axis II disorder. In terms of comorbid anxiety disorders, 3% of the complete sample fulfilled diagnostic criteria for GAD at baseline, 4.1% for agoraphobia, 7.1% for panic disorder, and 19% for social anxiety disorder. Of the 268 participants at baseline, complete data (GAD-7 and HRSD-24 scores) were provided by 261 patients. 65.5% were female with a mean age of 44.3 ± 12.0 years. Characteristics of the baseline sample are shown in Table 1. Complete data on the GAD-7 were provided by n = 241 patients at T1 (after 12 weeks), and n = 199 patients at T2 (48 weeks). For a more detailed description of the sample, see publication of primary outcomes (Schramm et al., 2017). 3.2. Improvement during treatment As summarized in Table 2, patients improved significantly in the HRSD-24 total score during treatment (p < .001). Effect size of the overall change model was large (f = 0.73). At baseline, the mean (SD) HRSD-24 score was 24.68 (7.3). A mean (SD) score of 20.76 (8.82) was 397

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yielded significant differences (all p < .05). Follow up after 48 weeks (T2) showed similar patterns in terms of change in GAD-7 compared to baseline. In the group who improved in their HRSD-24 score, GAD-7 scores were significantly lower (n = 142, t = −12.68, df = 141, p < 0.001, ES = −1.0 and SRM = −1.7). The group of patients who worsened showed an increase in GAD-7 scores, yet this change was not significant (n = 22, t = 1.99, df = 21, p = .059, ES = 0.37 and SRM = 0.43). The unchanged group also showed no significant change in GAD-7 scores (n = 35, t = −0.11, df = 34, p = .912, ES = −0.02 and SRM = −0.02). Analysis of variance for the 48 week follow-up was significant (p < .001) for changes among categories, with pairwise comparisons only yielding significant results for the improved group (p > .001). Results of the sub-analysis, using a composite score of the two anxiety-specific items of the HRSD-24 only (possible range 0–8) yielded a similar result pattern for the subgroups with different treatment courses (worse, same, improved) at 12 weeks, and at 48 weeks. Results for this sub-analysis are provided in the supplementary material of this article (Supplementary Table 1).

Table 1 Baseline characteristics of the sample (n = 261). Sociodemographic variables Age Female Family status Married or cohabiting Single Separated, divorced, or widowed Educational levela Low or medium High or very high Employment Full-time Part-time or in training Not employedb

M = 44.3 (SD = 12.0) n = 171 (65.5%) n = 100 (38.3%) n = 116 (44.4%) n = 45 (17.2%) n = 98 (37.8%) n = 163 (62.5%) n = 88 (33.7%) n = 87 (33.3%) n = 86 (33.0%)

a Low corresponds to at least 9 years of education, medium corresponds to at least 10 years of education, high corresponds to at least 12 or 13 years of education, and very high corresponds to at least 15 years of education (university degree). b Includes retired, housemaker, unemployed, and other.

3.4. Upper quartile analysis

observed after 12 weeks, resulting in a significant estimated mean difference of −4.17 (95% CI, 2.74–5.59; p < .001). This effect reached −9.49 (95% CI, −11.18 to −7.84; p < .001) after 48 weeks. The change in the GAD-7 score was significant between baseline, 12 and 48 weeks of follow-up, respectively (p < .001; Table 2), with a large effect size of the overall change model (f = 0.53) (Cohen, 1988). The effect size (ES) of the change score between baseline and 12 weeks was −0.26, with a standardized response mean (SRM) of −0.29. Between baseline and 48 weeks, the mean GAD-7 change score effect size was ES = −0.72 and the standardized response mean SRM = −0.67.

At baseline, the cut-off score for the upper quartile in the GAD-7 score distribution was 14. The subgroup of highly impaired patients (n = 55) showed a significant decline in their GAD-7 sum-score after 12 weeks (t = −5.68, df = 54, p < .001) and 48 weeks (t = −6.93, df = 47, p <.001), further reflecting the questionnaire's general ability to detect change over time. 3.5. Minimal Clinically Important Difference (MCID) Compared to the range of possible GAD-7 scores (0–21), the standard error of measurement was rather small (SEM = 1.94). Accordingly, the MCID for the GAD-7 was 3.8, resulting in change scores of 4 or greater to reflect a clinically relevant change in individual patients over the course of treatment.

3.3. Sensitivity to change We estimated a SEM of 4.12 for the HRSD-24 total score at baseline. Thus patients were considered to have improved if their HRSD-24 total score declined by 4 points or more from baseline to follow-up at 12 and 48 weeks, respectively, and as worsened if the score increased by 4 points or more. We conducted separate analyses for the three HRSD-24 change groups (improved, worsened, no change) at both follow-up points (T1 and T2). The results are shown in Table 3. When examining change after 12 weeks, a total of n = 126 patients improved considerably according to the HRSD-24 score, whilst n = 71 patients did not show considerate change and n = 44 patients became worse. GAD7 scores significantly declined in the improved group (t = −6.31, df = 120, p < .001), and significantly raised in the worsened group (t = 2.96, df = 41, p = .005). GAD-7 scores in the HRSD-24 unchanged group did not yield significant change (t = −1.44, df = 61, p = .156). ES of GAD-7 change scores were ES = −0.51 for the patients with considerable improvement, ES = 0.32 for the worsened group, and ES = −0.16 in the unchanged group. SRMs were −0.57 for the improved patients, 0.46 for the patients who got worse, and −0.18 for the unchanged group. Analysis of variance yielded significantly different change scores among categories (p < .001), and pairwise comparisons between worsened, unchanged and improved patient groups also

4. Discussion Patient-reported outcome measures like the GAD-7 are important tools to directly involve and improve the participation of patients in the judgment of the benefit of care received (Basch, 2017; Black et al., 2016; Kotronoulas et al., 2014; Snyder et al., 2012, 2013). Additionally, assessing symptoms as primary or secondary outcomes in clinical research is facilitated by brief, validated, self-report measures (Snyder et al., 2013; Wu et al., 2013). Therefore, such measures need to demonstrate their ability to detect meaningful changes in clinical outcomes over the course of time, i.e. the responsiveness to a specific treatment. Minimal clinically important differences (MCID) are patient derived scores that reflect changes in a clinical intervention that are meaningful for the patient (Cook, 2008). Knowing the MCID in GAD-7 scores would be helpful for clinicians in deciding if a particular patient shows a clinically meaningful response to anxiety therapy. The scores are also valuable for the researcher when assessing effect sizes in clinical trials (Kroenke et al., 2018).

Table 2 Means, changes and effect sizes of HRSD-24 and overall GAD-7 score between baseline and 12 weeks and 48 weeks follow-up. HRSD-24 total score M (SD) Mean change to baseline Baseline 12 weeks (T1) 48 weeks (T2)

24.68 (7.30) 20.76 (8.82) 15.19 (9.90)

– −4.17 −5.34

p-value

ES

GAD-7 total score M (SD)

Mean change to baseline

p-value

ES

– <.001 <.001

– −0.49 −0.65

10.91 (4.60) 9.72 (4.70) 7.60 (5.20)

– −1.14 −2.04

– .001 <.001

– −0.29 −0.51

Note. HRSD-24 = Hamilton Rating Scale for Depression, GAD-7 = Generalized Anxiety Disorder scale, M = Mean, SD = Standard deviation, ES = Effect size. 398

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−1.07

Prior to this study, there was already some evidence on the sensitivity to change of the GAD-7. Kertz et al. (2013), and Beard and Björgvinsson (2014) assessed sensitivity to change of the GAD-7 in two acute psychiatric populations (n = 232 and n = 1082, respectively). Patients with a wide range of axis 1 symptoms underwent short intensive CBT partial hospital programmes with an average duration of treatment of eight and 10 days, respectively. GAD-7 scores decreased from admission to discharge by approximately 3.5 points (Kertz et al., 2013), and 5.86 points (Beard and Björgvinsson, 2014), regardless of GAD diagnosis. Gyani et al. (2013) assessed sensitivity to change of the GAD-7 in a large routine cohort study as part of the English Improving Access to Psychological Therapies (IAPT) initiative. Data from n = 19,395 patients who had attended at least two sessions of psychological therapy were analyzed. The mean change on the GAD-7 for patients initially classed as ‘mild’ on the measure was 2.16 (SD = 4.32) in comparison to 6.77 (SD = 6.27) for patients classed as ‘severe’. Dear et al. (2011) examined sensitivity to change of the GAD-7 in two clinical trials in which all patients met GAD diagnostic criteria. They found large effect sizes on the GAD-7 from pre- to post-treatment and from post-treatment to follow-up in the treatment groups. In the current study, we monitored the course of symptoms over a longer time-period in a more homogeneous population of patients, suffering from early onset chronic depression, and undergoing evidence-based psychological treatment. The treatment included 24 sessions of either Cognitive Behavioral Analysis System of Psychotherapy (CBASP) or nonspecific supportive psychotherapy (SP) for 20 weeks in the acute phase, followed by eight continuation sessions during the next 28 weeks. Both CBASP and SP led to significant improvement in depressive symptoms and quality of life. For the full sample, there was a mean difference of 9.49 points in the HRSD-24 score after 48 weeks of treatment. In terms of anxiety, the self-rated GAD-7 total score decreased significantly from baseline over the course of treatment, with large effect sizes for the overall decline from baseline to 48 weeks (Lakens, 2013). The subgroup of patients that improved according to the HRSD-24 total score showed good effect sizes (ES) and standardized response means (SRM) for the GAD-7 when comparing baseline scores to followup. Analysis of the subgroup from the highest quartile of GAD-7 scores at baseline also indicated the instruments general ability to indicate change over time. However, patients who worsened according to the HRSD-24 total score only yielded significant declines in GAD-7 scores at 12 weeks but not after 48 weeks when compared to baseline, and ES and SRM were somewhat lower than in the group with improved HRSD24 scores. This indicates that the GAD-7 is more sensitive in detecting improvement than worsening. Compared to worsening, improvement is represented by larger absolute changes in GAD-7 scores. In terms of minimal clinically important difference (MCID), we used a conservative 2 SEM estimate and found a 4-point decline in GAD-7 scores to constitute a reliably detectable improvement (Kroenke et al., 2018). This result is in line to the MCID of 3.53 reported by Gyani et al. (2013), estimated via regression based reliable change approach. However, there are other commonly used metrics, i.e. 1 SEM or 0.5 SD (Chen et al., 2018), which might indicate the lower bounds of an MCID. In the current study, using either 1 SEM or 0.5 SD would provide an MCID estimate of 2 points for the GAD-7. This result is in line with results from Kroenke et al. (2018), who assessed the MCID of the GAD-7 using 1 SEM estimates in three different clinical trials, achieving values between 1.97 and 2.94. Our study has several limitations. All results must be interpreted with the knowledge that the intervention was not tailored to specifically treat anxiety disorders, but rather depressive psychopathology, so that our analyses are based on a patient sample suffering from chronic depression, and not primarily from anxiety disorders. We, nevertheless, considered this sample as useful to detect sensitivity to change of the GAD-7, since GAD and depression often co-occur (Clark and Watson, 1991; Hanel et al., 2009; Hettema, 2008; Ormel et al., 1994).

Note. HRSD-24 = 24-item Hamilton Rating Scale for Depression, t0 = Measurement at admission, tx = Measurement at T1 or T2, ES = Effect size, SRM = Standardized response mean.

−1.0 <0.001 −4.56 (4.29) 10.87 (4.59) n = 142 −0.02 −0.02 .912 −0.09 (4.58) 10.66 (4.35) n = 35 0.43 0.37 .059 1.77 (4.16) 9.60 (4.84) n = 22 Baseline – 48 weeks (T2)

−0.57 −0.51 <.001 −2.39 (4.16) 10.63 (4.65) n = 126 −0.18 −0.16 .155 −0.65 (3.53) 11.40 (4.05) n = 71 0.46 0.32 .005 1.64 (3.60) 10.69 (5.17) n = 44 Baseline – 12 weeks (T1)

Patients with considerable improvement (HRSD-24 score change ≤−4) Admission Difference p-value ES SRM Mto (SD) Mtx−Mt0 (SD) SRM ES Patients without considerable change Admission Difference p-value Mto (SD) Mtx−Mt0 (SD) Patients who got worse during treatment (HRSD-24 score change ≥4) Admission Difference p-value ES SRM Mto (SD) Mtx−Mt0 (SD)

Table 3 Change in GAD-7 scores, ES and SRM from baseline to 12 weeks (n = 241) and 48 weeks (n = 199), divided into subgroups of improved, unchanged and worsened patients according to changes in HRSD-24 sum score.

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measure for anxiety. A 4-point decrease can be considered a statistically important improvement within a sample of patients with major depression. Further studies should support the role of the GAD-7 in monitoring anxiety treatment over time.

Studies have found comorbid anxiety (lifetime) in 60%–65% of individuals with major depressive disorders (MDD) in a community sample (Kessler et al., 1996), and comorbid anxiety disorder in 59.2% of individuals with MDD based on DSM-IV-TR criteria (Kessler et al., 2003, 2008). In clinical trial populations, prevalence rates of concurrent (not lifetime) anxious features of approximately 40%–60% have been documented (McClintock et al., 2011). Using questionnaire scores from PHQ-8 (depression ≥ 15) and GAD-7 (anxiety ≥ 15), a study from primary care (n = 2091) found that 30% of the patients with depression and/or anxiety had both conditions (Löwe et al., 2008b). Data from the Netherlands (n = 1783 patients from psychiatry) showed that 67% of the patients with a depressive disorder (as by DSM-IV-TR criteria) had a current and 75% a lifetime comorbid anxiety disorder, and vice versa, 63% of the patients with anxiety disorders had a current and 81% a lifetime depressive disorder (Lamers et al., 2011). Thus, roughly half of all patients who have major depressive disorders experience anxious symptoms and consequently suffer from increased levels of impairment (Fava et al., 2008; Brawman-Mintzer and Lydiard, 1997). Some pharmacological and psychotherapeutic treatments are effective for both depression and anxiety disorders (Clark et al., 2011), and there is scientific evidence for an overarching psychological construct that encompasses distinct but related dimensions of depression and anxiety (Kroenke et al., 2018; Löwe et al., 2008b). In contradiction to these findings, comorbid anxiety disorders were not very common in our sample (3% GAD, 4.1% agoraphobia, 7.1% panic disorder, and 19% social anxiety disorder). Because of the specific scope of our study, we assume that symptoms of anxiety presented by our patients were diagnosed in favor of primary depressive disorders, i.e. major depressive disorder specified by high levels of anxiety symptoms. A further limitation is that the HRSD-24 score itself might not be an ideal external criterion for treatment improvement, as it primarily measures depression. However, following the same line of reasoning as above, we evaluated this sample as useful to detect treatment response in terms of symptoms of anxiety, although the trial was conducted to measure treatment effects with regard to depressive disorders. Individuals with major depressive disorders often show anxiety and sympathetic nervous system arousal, which characterizes anxious symptom features. Although depression with anxious features was not codified in the DSM-IV-TR (APA, 2000), it has been defined in the literature as either major depressive disorder with high levels of anxiety symptoms, or the concurrent (not lifetime) presence of depression and anxiety (Fava et al., 2008). Most recently, DSM-5 acknowledges this comorbidity by including a specifier ‘with anxious distress’ for depressive disorders accompanied by significant levels of anxiety (APA, 2013). Likewise, the GAD-7 has been used as an outcome measure in mixed anxiety and depression treatment studies (Hammond et al., 2012; Richards and Borglin, 2011). The study was designed to compare two different evidence-based treatments for depression (CBASP and SP). Thus, an improvement in terms of psychopathology was expected for participating patients over the course of either of the two treatment arms. This is in line with the relatively small number of patients who worsened considerably according to their HRSD-24 score. A control group might have provided additional important information. Overall, due to the homogeneity of our sample, generalizable of the results remains unclear.

Authorship statement All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript (see Conflict of Interest). Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in the Journal of Affective Disorders. CRediT authorship contribution statement Anne Toussaint: Formal analysis, Writing - original draft, Validation. Paul Hüsing: Formal analysis, Writing - original draft, Validation. Antje Gumz: Data curation, Writing - review & editing, Validation. Katja Wingenfeld: Data curation, Writing - review & editing, Validation. Martin Härter: Conceptualization, Writing - review & editing, Validation. Elisabeth Schramm: Conceptualization, Writing - review & editing, Validation. Bernd Löwe: Conceptualization, Writing - review & editing, Validation. Declaration of Competing Interest The authors have no competing interests to report. Acknowledgments We thank all patients who participated in the study. Role of funding source This study was funded by grant SCHR443/11-1 from the German Research Foundation. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2020.01.032. References American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR, 4th ed. American Psychiatric Association, Washington DC. American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 5th ed. American Psychiatric Association, Arlington, VA. Bagby, R.M., Ryder, A.G., Schuller, D.R., Marshall, M.B., 2004. The Hamilton Depression Rating Scale: has the gold standard become a lead weight? Am. J. Psychiatry 161, 2163–2177. Baldwin, D., 2018. Generalized anxiety disorder in adults: epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis. UpToDate, Waltham, MA. https://www.uptodate.com/contents/generalizedanxiety-disorder-in-adultsepidemiology-pathogenesis-clinical-manifestations-courseassessment-and-diagnosis? search=pathophysiology%20anxiety&source=search_result&selectedTitle= 1~150&usage_type=default&display_rank=1(accessed 09 April 2019). Basch, E., 2017. Patient-reported outcomes - harnessing patients' voices to improve clinical care. N. Engl. J. Med. 376, 105–108. Beard, C., Björgvinsson, T., 2014. Beyond generalized anxiety disorder: psychometric properties of the GAD-7 in a heterogeneous psychiatric sample. J. Anxiety Disord. 28, 547–552. Black, N., Burke, L., Forrest, C.B., Sieberer, U.H., Ahmed, S., Valderas, J.M., Bartlett, S.J., Alonso, J., 2016. Patient-reported outcomes: pathways to better health, better services, and better societies. Qual. Life Res. 25, 1103–1112. Bramley, P.N., Easton, A.M., Morley, S., Snaith, R.P., 1988. The differentiation of anxiety and depression by rating scales. Acta Psychiat. Scand. 77, 133–138. Brawman-Mintzer, O., Lydiard, R.B., 1997. Biological basis of generalized anxiety disorder. J. Clin. Psych. 58, 16–25.

5. Conclusions Our study could provide evidence on the utility of the GAD-7 for use in longitudinal studies to detect improvement in clinical outcome. Confirmation of these findings and further investigation of the GAD-7 in populations and clinical trials focusing on anxiety-specific therapies is highly recommended. The estimated MCID of 4 points for the GAD-7 also needs replication in different clinical populations. In summary, the sensitivity to change of the GAD-7 demonstrated in our study underlines its utility as an efficient and economical severity 400

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Chen, C.X., Kroenke, K., Stump, T.E., Kean, J., Carpenter, J.S., Krebs, E.E., Bair, M.J., Damush, T.M., Monahan, P.O., 2018. Estimating minimally important differences for the PROMIS pain interference scales: results from 3 randomized clinical trials. Pain 159, 775–782. Clark, D., 2011. Implementing NICE guidelines for the psychological treatment of depression and anxiety disorders: the IAPT experience. Int Rev Psychiatry 23, 375–384. Clark, D.M., Layard, R., Smithies, R., Richards, D.A., Suckling, R., Wright, B., 2009. Improving access to psychological therapy: initial evaluation of two UK demonstration sites. Behav. Res. Ther. 47, 910–920. Clark, L.A., Watson, D., 1991. Tripartite model of anxiety and depression: psychometric evidence and taxonomic implications. J. Abnorm. Psychol. 100, 316–336. Cohen, J., 1988. Statistical Power Analysis for the Behavioral Sciences. Erlbaum, Hillsdale, NY. Cook, E.C., 2008. Clinimetrics corner: the minimal clinically important change score (MCID): a necessary pretense. J. Man. Manip. Ther. 16, 82–83. Craske, M., Rauch, S., Ursano, R., Prenoveau, J., Pine, D., Zinbarg, R., 2009. What is an anxiety disorder? Depress Anxiety 26, 1066–1085. Dear, B.F., Titov, N., Sunderland, M., McMillan, D., Anderson, T., Lorian, C., Robinson, E., 2011. Psychometric comparison of the Generalized Anxiety Disorder Scale-7 and the Penn State Worry Questionnaire for measuring response during treatment of generalised anxiety disorder. Cogn. Behav. Ther. 40, 216–227. Deyo, R.A., 1984. Measuring functional outcomes in therapeutic trials for chronic disease. Control. Clin. Trials. 5, 223–240. Deyo, R.A., Centor, R.M., 1986. Assessing the responsiveness of functional scales to clinical change: an analogy to diagnostic test performance. J. Chronic Dis. 39, 897–906. Fava, M., Rush, A.J., Alpert, J.E., Balasubramani, G.K., Wisniewski, S.R., Carmin, C.N., Biggs, M.M., Zisook, S., Leuchter, A., Howland, R., Warden, D., Trivedi, M.H., 2008. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am. J. Psychiatry. 165, 342–351. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 2002. Structured clinical interview for DSM-IV-TR Axis I disorders, research version, patient edition (SCID-I/P). Biometrics Research. New York State Psychiatric Institute, New York. Gierk, B., Kohlmann, S., Hagemann-Goebel, M., Löwe, B., Nestoriuc, Y., 2017. Monitoring somatic symptoms in patients with mental disorders: sensitivity to change and minimal clinically important difference of the Somatic Symptom Scale - 8 (SSS-8). Gen. Hosp. Psychiatry. 48, 1–55. Greenberg, P.E., Sisitsky, T., Kessler, R.C., Finkelstein, S.N., Berndt, E.R., Davidson, J.R., Ballenger, J.C., Fyer, A.J., 1999. The economic burden of anxiety disorders in the 1990s. J. Clin. Psychiatry. 60, 427–435. Gyani, A., Shafran, R., Layard, R., Clark, D.M., 2013. Enhancing recovery rates: lessons from year one of IAPT. Beh. Res. Ther. 51, 597–606. Hamilton, M., 1967. Development of a rating scale for primary depressive illness. Br. J. Soc. Clin. Psychol. 6, 278–296. Hammond, G.C., Croudace, T.J., Radhakrishnan, M.L., Watson, L., McMillan-Shields, A., Jones, F., et al., 2012. Comparative effectiveness of cognitive therapies delivered face-to-face or over the telephone: an observational study using propensity methods. PLoS ONE 7, 9. Hanel, G., Henningsen, P., Herzog, W., Sauer, N., Schaefert, R., Szecsenyi, J., Löwe, B., 2009. Depression, anxiety, and somatoform disorders: vague or distinct categories in primary care? Results from a large cross-sectional study. J. Psychosom. Res. 67, 189–197. Hettema, J.M., 2008. The nosological relationship between generalized anxiety disorder and major depression. Depress. Anxiety. 25, 300–316. Hevey, D., McGee, H.M., 1998. The effect size statistic: useful in health outcomes research? J. Health Psychol 3, 163–170. Hüsing, P., Bassler, M., Löwe, B., Koch, S., Toussaint, A., 2018. Validity and sensitivity to change of the Somatic Symptom Disorder-B Criteria Scale (SSD-12) in a clinical population. Gen. Hosp. Psychiatry. 55, 20–26. Kertz, S., Bigda-Peyton, J., Bjorgvinsson, T., 2013. Validity of the Generalized Anxiety Disorder-7 Scale in an acute psychiatric sample. Clin. Psychol. Psychother. 20, 456–464. Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J., Walters, E.E., Wang, P.S., 2003. National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 289, 3095–3105. Kessler, R.C., Berglund, P., Demler, O., Jin, R., Merikangas, K.R., Walters, E.E., 2005. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry. 62, 593–602. Kessler, R.C., Gruber, M., Hettema, J.M., Hwang, I., Sampson, N., Yonkers, K.A., 2008. Co-morbid major depression and generalized anxiety disorders in the National Comorbidity Survey follow-up. Psychol. Med. 38, 365–374. Kessler, R.C., Nelson, C.B., McGonagle, K.A., Liu, J., Swartz, M., Blazer, D.G., 1996. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Brit. J. Psychiat. 30, 17–30. Kotronoulas, G., Kearney, N., Maguire, R., Harrow, A., Di Domenico, D., Croy, S., McGillivray, S., 2014. What is the value of the routine use of patient-reported outcome measures toward improvement of patient outcomes, processes of care, and health service outcomes in cancer care? A systematic review of controlled trials. J. Clin. Oncol. 32, 1480–1501. Kroenke, K., Baye, F., Lourens, S.G., 2018. Comparative validity and responsiveness of PHQ-ADS and other composite anxiety-depression measures. J.Affect. Disord. 246, 437–443. Kroenke, K., Spitzer, R.L., Williams, J.B.W., Monahan, P.O., Löwe, B., 2007. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann. Intern. Med. 146, 317–325. Kroenke, K., Wu, J., Yu, Z., Bair, M.J., Kean, J., Stump, T., Monahan, P.O., 2016. Patient health questionnaire anxiety and depression scale: initial validation in three clinical

trials. Psychosom. Med. 78, 716–727. Lakens, D., 2013. Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs. Front. Psychol. 4, 1–11. Lamers, F., van Oppen, P., Comijs, H.C., Smit, J.H., Spinhoven, P., van Balkom, A.J., Nolen, W.A., Zitman, F.G., Beekman, A.T., Penninx, B.W., 2011. Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). J. Clin. Psychiatry. 72, 341–348. Löwe, B., Decker, O., Müller, S., Brähler, E., Schellberg, D., Herzog, W., Herzberg, P.Y., 2008a. Validation and standardization of the generalized anxiety disorder screener (GAD-7) in the general population. Med. Care. 46, 266–274. Löwe, B., Kroenke, K., Herzog, W., Gräfe, K., 2004a. Measuring depression outcome with a brief self-report instrument: sensitivity to change of the Patient Health Questionnaire (PHQ-9). J. Affect. Disord. 81, 61–66. Löwe, B., Spitzer, R.L., Williams, J.B., Mussell, M., Schellberg, D., Kroenke, K., 2008b. Depression, anxiety and somatization in primary care: syndrome overlap and functional impairment. Gen. Hosp. Psychiatry. 30, 191–199. Löwe, B., Unützer, J., Callahan, C.M., Perkins, A.J., Kroenke, K., 2004b. Monitoring depression treatment outcomes with the patient health questionnaire-9. Med. Care. 42, 1194–1201. Maier, W., Buller, R., Philipp, M., Heuser, I., 1988. The Hamilton Anxiety Scale: reliability, validity, and sensitivity to change in anxiety and depressive disorders. J. Affect. Disord. 14, 61–68. McClintock, S.M., Husain, M.M., Bernstein, I.H., Wisniewski, S.R., Trivedi, M.H., Morris, D., Alpert, J., Warden, D., Luther, J.F., Kornstein, S.G., Biggs, M.M., Fava, M., Rush, A.J., 2011. Assessing anxious features in depressed outpatients. Int. J. Methods Psychiatr. Res. 20, 69–82. Ormel, J., VonKorff, M., Ustun, T.B., Pini, S., Korten, A., Oldehinkel, T., 1994. Common mental disorders and disability across cultures. Results from the who collaborative study on psychological problems in general health care. JAMA. 272, 1741–1748. Rapaport, M.H., Clary, C., Fayyad, R., Endicott, J., 2005. Quality-of-life impairment in depressive and anxiety disorders. Am. J. Psychiatry. 162, 1171–1178. Richards, D.A., Borglin, G., 2011. Implementation of psychological tehrapies for anxiety and depression in routine practice: two year prospective cohort study. J. Affect. Disord. 133, 51–60. Sartorius, N., Ustün, T.B., Lecrubier, Y., Wittchen, H.U., 1996. Depression comorbid with anxiety: results from the WHO study on psychological disorders in primary health care. Br. J. Psychiatry Suppl. 38, 38–43. Schalet, B.D., Cook, K.F., Choi, S.W., Cella, D., 2014. Establishing a common metric for self-reported anxiety: linking the MASQ, PANAS, and GAD-7 to Promis Anxiety. J. Anxiety Disord. 28, 88–96. Schramm, E., Kriston, L., Zobel, I., Bailer, J., Wambach, K., Backenstrass, M., Klein, J.P., Schoepf, D., Schnell, K., Gumz, A., Bausch, P., Fangmeier, T., Meister, R., Berger, M., Hautzinger, M., Härter, M., 2017. Effect of disorder-specific vs nonspecific psychotherapy for chronic depression a randomized clinical trial. JAMA Psychiatry 74, 233–242. Schuck, P., 2000. Designs und kennziffern zur ermittlung der Änderungssensitivität von fragebogen in der gesundheitsbezogenen lebensqualitätsforschung ([Designs and statistics for assessing responsiveness of questionnaires in health-related quality of life research]). [Designs and statistics for assessing responsiveness of questionnaires in health-related quality of life research]. Z. Med. Psychol 9, 125–130. Spitzer, R.L., Kroenke, K., Linzer, M., Hahn, S.R., Williams, J.B.W., deGruy 3rd, F.V., Brody, D., Davies, M., 1995. Health-related quality of life in primary care patients with mental disorders. Results from the prime-md 1000 study. JAMA 274, 1511–1517. Spitzer, R.L., Kroenke, K., Williams, J.B.W., And the Patient Health Questionnaire primary care study group, 1999. Validation and utility of a self-report version of PRIMEMD: the PHQ primary care study. JAMA. 282, 1737–1744. Spitzer, R.L., Kroenke, K., Williams, J.B.W., Löwe, B., 2006. A brief measure for assessing generalized anxiety disorder—The GAD-7. Arch. Intern. Med. 166, 1092–1097. Starcevic, V., 1995. Pathological worry in major depression: a preliminary report. Behav. Res. Ther. 33, 55–56. Snyder, C.F., Aaronson, N.K., Chouchair, A.K., Elliott, T.E., Greenhalgh, J., Halyard, M.Y., Hess, R., Miller, D.M., Reeve, B.B., Santana, M., 2012. Implementing patient-reported outcomes assessment in clinical practice: a review of the options and considerations. Qual. Life Res. 21, 1305–1314. Snyder, C.F., Jensen, R.E., Segal, J.B., Wu, A.W., 2013. Patient-reported outcomes (PROs): putting the patient perspective in patient-centered outcomes research. Med. Care. 51, 73–79. Swinson, R.P., 2006. The GAD-7 scale was accurate for diagnosing generalized anxiety disorder. Evid. Based Med. 11, 184. Wittchen, H.U., Jacobi, F., Rehm, J., Gustavsson, A., Svensson, M., Jönsson, B., Olesen, J., Allgulander, C., Alonso, J., Faravelli, C., Fratiglioni, L., Jennum, P., Lieb, R., Maercker, A., van Os, J., Preisig, M., Salvador-Carulla, L., Simon, R., Steinhausen, H.C., 2011. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur. Neuropsychopharmacol. 21, 655–679. Wittchen, H.U., Kessler, R.C., Beesdo, K., Krause, P., Höfler, M., Hoyer, J., 2002. Generalized anxiety and depression in primary care: prevalence, recognition, and management. J. Clin. Psychiatry. 63, 24–34. Wright, A., Hannon, J., Hegedus, E.J., Kavchak, A.E., 2012. Clinimetrics corner: a closer look at the minimal clinically important difference (MCID). J. Man. Manip. Ther. 20, 160–166. Wu, A.W., Kharrazi, H., Boulware, L., Snyder, C.F., 2013. Measure once, cut twice-adding patient reported outcome measures to the electronic health record for comparative effectiveness research. J. Clin. Epidemiol. 8, 12–20. Wyrwich, K.W., Tierney, W.M., Wolinsky, F.D., 1999. Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in healthrelated quality of life. J. Clin. Epidemiol. 52, 861–873.

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