Treatment-as-usual (TAU) is anything but usual: a meta-analysis of CBT versus TAU for anxiety and depression.

Journal of Affective Disorders 175 (2015) 152–167

Contents lists available at ScienceDirect

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

Review

Treatment-as-usual (TAU) is anything but usual: A meta-analysis of CBT versus TAU for anxiety and depression Sarah E. Watts, Adrienne Turnell, Natalie Kladnitski, Jill M. Newby n, Gavin Andrews Clinical Research Unit for Anxiety and Depression, Level 4 O’Brien Centre, 394-404 Victoria Street, St Vincent's Hospital, Darlinghurst, NSW, Australia

art ic l e i nf o

a b s t r a c t

Article history: Received 2 October 2014 Received in revised form 5 December 2014 Accepted 5 December 2014 Available online 15 December 2014

Objectives: There were three aims of this study, the first was to examine the efficacy of CBT versus treatment-as-usual (TAU) in the treatment of anxiety and depressive disorders, the second was to examine how TAU is defined in TAU control groups for those disorders, and the third was to explore whether the type of TAU condition influences the estimate of effects of CBT. Method: A systematic search of Cochrane Central Register of Controlled Trials, PsycINFO, and CINAHL was conducted. Results: 48 studies of CBT for depressive or anxiety disorders (n ¼6926) that specified that their control group received TAU were identified. Most (n ¼ 45/48) provided an explanation of the TAU group however there was significant heterogeneity amongst TAU conditions. The meta-analysis showed medium effects favoring CBT over TAU for both anxiety (g ¼0.69, 95% CI 0.47–0.92, po0.001, n ¼ 1318) and depression (g ¼0.70, 95% CI 0.49–0.90, po 0.001, n ¼ 5054), with differential effects observed across TAU conditions. Conclusions: CBT is superior to TAU and the size of the effect of CBT compared to TAU depends on the nature of the TAU condition. The term TAU is used in different ways and should be more precisely described. The four key details to be reported can be thought of as “who, what, how many, and any additional treatments?” & 2014 Elsevier B.V. All rights reserved.

Keywords: Treatment-as-usual Cognitive behavior therapy Meta-analysis Depression Anxiety

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Selection of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Meta-analysis strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Sub-group analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Study selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Study characteristics and treatment-as-usual definitions used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Risk of bias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Effect sizes for individual studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Sub-group analyses: comparison of the size of the effect of CBT versus TAU according to TAU subtype . . . . . . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Summary of main findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Strengths and limitations of the study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

n

Corresponding author. Tel.: þ 612 8382 1400. E-mail address: [email protected] (J.M. Newby).

http://dx.doi.org/10.1016/j.jad.2014.12.025 0165-0327/& 2014 Elsevier B.V. All rights reserved.

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S.E. Watts et al. / Journal of Affective Disorders 175 (2015) 152–167

Appendix A. Cochrane Central Register of Controlled Trials Appendix B. CINAHL search for Depression . . . . . . . . . . . . . Appendix C. PsycInfo search for Depression . . . . . . . . . . . . Appendix D. Cochrane Central Register of Controlled Trials Appendix E. CINAHL search for Anxiety . . . . . . . . . . . . . . . . Appendix F. PsycInfo search for Anxiety . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Depression and anxiety are common mental disorders and the primary cause of disability worldwide (Whiteford et al., 2013). There is a 21.4% lifetime prevalence in adults for a mood disorder and 33.7% for an anxiety disorder (Kessler et al., 2012). In attempts to identify effective treatments, researchers have investigated the benefits of psychotherapy, with cognitive behavior therapy (CBT) most widely studied. Meta-analyses have shown CBT, including computerized CBT, to be effective for individuals with depression and anxiety compared to wait-list (WL), treatment-as-usual (TAU) or a control group (Hedges g ¼0.88) (Andrews et al., 2010; Butler et al., 2006). Reflectively, the National Institute of Health Care Excellence (NICE) guidelines in the UK recommend CBT either in a self-help, computerized, individualized or group format depending on stage of illness and illness severity (NICE, 2009, 2011). In order for a particular therapy or treatment approach to have demonstrated efficacy, it must have been investigated in a randomized controlled trial (RCT). Commonly, the aim of an RCT is to identify the superiority of a new intervention and the use of a control group is used to provide evidence of this (Le Henanff et al., 2006). Yet, what constitutes an adequate control group continues to be debated. Early researchers argued that the nonspecific factors of the control group must be accounted for, and as a result recommended the use of a psychological placebo (Rosenthal and Frank, 1956). However, implementing well-designed psychological placebos has been fraught with complications (Baskin et al., 2003; Parloff, 1986), and so researchers conducting RCTs have frequently used “treatment-as-usual”, wait-list, or no treatment as alternative control conditions. There have been no systematic reviews or meta-analyses that have examined the impact of the TAU control condition on the reported treatment effects, highlighting a gap in the literature. However, the existing meta-analyses suggest the specific type of control group matters. Recently, Honyashiki et al. (2014) examined the difference between treatment effects in CBT when comparing two different types of control groups: no treatment (NT) and psychological placebo (PP) for adults with an acute depressive disorder. The results showed that CBT was superior to NT (OR 2.24, 1.32–3.88), and CBT was nominally, but not significantly, superior to PP (OR 1.30, 0.53–2.94), with NT inferior to PP (OR 1.73, 0.67–4.84). Clearly the choice of a control group, and whether or not the control group involves some form of psychological therapy, influences the outcomes of the comparative effectiveness of CBT. However, this meta-analysis did not include studies with a TAU comparison group despite TAU being more commonly used as a control condition. It is important to examine the effect of a TAU control condition because in addition to it being commonly employed as a control group, TAU is what is already being delivered clinically; therefore the results of a study should be informative of any necessitated changes to clinical practice (or not). Previous reviews have focused on examining either comparisons between a range of psychological treatments versus TAU (Flückiger et al., 2014; Wampold et al., 2011), or CBT versus a range of control groups to explore how the choice of control group

influences the estimate of effects. Wampold et al. (2011) metaanalysis of 14 studies examined the efficacy of a range of evidenced-based treatments (EBTs) for depression and anxiety compared to TAU. The EBT condition aggregated the results from RCTs of CBT as well as mindfulness-based cognitive therapy, eye movement desensitization and reprocessing, interpersonal psychotherapy and behavioral activation. They showed that although there was a significant effect when comparing EBTs to all TAU conditions (combined), there was no significant difference between the EBTs compared with TAUs that were only psychotherapeutic interventions. This review highlighted the way in which the term “treatment-as-usual” is used to describe a heterogeneous set of interventions, and that greater clarification and consideration of what the TAU condition entails is needed before drawing conclusions from past RCTs about the efficacy of EBTs. The limitation of this review was that it focused on the comparison between TAU with a broad set of evidence-based psychological interventions for depression and anxiety. There have been no previous systematic reviews that have focused solely on studies comparing a psychological therapy from one modality (e.g., cognitive behavioral therapy) with TAU. A systematic review is now needed with a consistent “treatment group” but varying TAU conditions to explore how varying TAU conditions may result in different treatment effects. CBT provides an ideal example because it has been widely studied in both depression and anxiety disorders, and compared to a range of TAU conditions. In a Cochrane Review, Gava et al. (2007) demonstrated that patients with obsessive compulsive disorder (OCD) receiving any variant of CBT exhibited significantly fewer symptoms posttreatment than those receiving TAU (SMD 1.24, 95% CI 1.61 to 0.87, I² test for heterogeneity 33.4%). However, the efficacy of CBT versus TAU in the treatment of depression and other anxiety disorders remains less clear because previous reviews have focused on comparing CBT versus a range of control groups to explore how the choice of control group influences the estimate of effects. For example, in a meta-analysis focused on anxiety and depression, Tolin (2010) examined the effects of CBT versus other psychological therapies and revealed that CBT performed better than psychodynamic therapy but not interpersonal and supportive therapies. In another recent metaanalytic review, Cuijpers et al. (2014) compared the effects of CBT for generalized anxiety disorder (GAD) to control groups that included TAU, but did not investigate the effect of CBT versus TAU in isolation, nor whether the type of TAU influenced the findings. Andrews et al. (2010) demonstrated that the size of the effect of CBT is larger when compared with WL than with TAU, i.e. when participants were prevented from receiving treatment within the waiting period CBT appears as more potent versus when participants received treatment as part of usual care, CBT appeared less efficacious. Therefore, it is important to consider CBT versus TAU further. Precisely what is meant by the term TAU when used to refer to as a control group remains elusive. The term “TAU” varies widely and depends on the knowledge, expertise and resources of the health care professionals delivering it. Accordingly, studies that compare a treatment intervention with a TAU control group are

154


difficult to interpret. The term TAU/care-as-usual/standard care is often used interchangeably. For the purposes of this study, we will use TAU to refer to all of these terms. The Consolidated Standards of Reporting Trials (CONSORT) statement provides guidelines to improve the quality of reporting of RCT's (Schulz et al., 2010). As part of these guidelines it is recommended that authors should describe each intervention, including control interventions; and if the control group is to receive TAU it is important to describe thoroughly what that constitutes, so that the description can allow a clinician wanting to use the condition to know exactly how to administer the condition that was evaluated in the trial (Glasziou et al., 2008). As such, the purposes of this article are (1) to determine the relative efficacy of CBT treatments for anxiety and depression versus a “TAU” control condition, (2) to determine how the term “TAU” is being used, and (3) explore whether the type of TAU condition influences the estimate of effects of CBT.

2. Method 2.1. Inclusion criteria (i) Types of studies. We included all trials using random allocation to an intervention and TAU control group that met the inclusion criteria for type of participant, intervention and outcome, and were published in English in a peer reviewed journal. Randomized control trials with multiple arms were also included as long as the inclusion criteria were met. (ii) Types of participants. Males and females aged 18 and above with the presence of a depressive or anxiety disorder of any severity were included. The presence of co-morbidity was acceptable (i.e., co-morbid psychological or physical conditions were included) and the participant may have been at any stage of the disorder (e.g., first episode of depression versus chronic major depressive disorder). Studies were not excluded if the participants were also taking medication, nor did the location of the participant warrant exclusion (i.e. inpatients versus outpatients). (iii) Types of interventions. The experimental group condition must have received CBT (including media delivered/computerized CBT) to provide treatment for the depressive and/or anxiety disorder. The intervention must have included a minimum of six sessions, of any frequency, and could have been delivered with or without clinical/technical assistance (for example, self-help treatments were included), and with/without telephone support. The control condition must have specified that the comparison group received TAU. (iv) Outcome. The primary outcome was based on changes on selfreported measures of depression and anxiety symptoms in the short term (i.e., upon completion of the intervention). Scales such as the Beck Depression Inventory (BDI; Beck et al., 1996), The Penn State Worry Questionnaire (PSWQ; Meyer et al., 1990) and the Beck Anxiety Inventory (BAI; Beck et al., 1988) were included.

2.2. Excluded studies Studies of interventions designed to prevent relapse of depression or anxiety disorders were excluded. Other mental disorders such as substance abuse, eating disorders, grief, stress or tinnitus were excluded. Cost-effectiveness studies were excluded. Interventions that included additional or modified components of CBT were excluded (for example, mindfulness CBT). Studies conducted with a highly specific population using their “standard services” as

the control group were excluded (for example, a women's shelter or prison inmates). 2.3. Data analysis 2.3.1. Selection of studies An initial search was undertaken by review authors (SW, AT). Full articles of the studies identified by review authors were obtained and independently reviewed (by NK or AT and SW) to determine eligibility. Any conflicts of disagreement regarding study inclusion were discussed and content area experts were consulted when required. Outcome data at post-treatment were extracted and other information extracted included details of the participants; number of treatment sessions; primary symptom outcome measure; date of publication; number of participants randomized and medication use. The data were extracted by one reviewer (NK or AT). The quality of each study was assessed by two reviewers (NK or AT and SW) using Cochrane's Collaboration tool for assessing risk of bias (Higgins et al., 2011). 2.3.2. Meta-analysis strategy For each study we extracted mean, standard deviations and the number of participants at the measurement nearest posttreatment to calculate the effect sizes. In some cases where this data were not reported the mean difference and p values were used. The meta-analyses were performed by computing standardized differences in means using Comprehensive Meta-Analysis, Version 2.2.064 (Bornstein et al., 2011). For all studies, Hedge's g using a 95% confidence interval and the associated z and p values were calculated. A random effect model was used to allow the true effect sizes to differ. In the calculation of the effect sizes, we distinguished between studies based on the primary disorder of treatment: i) anxiety, ii) depression and iii) mixed anxiety and depression. To test for homogeneity of effect sizes, an indicator of heterogeneity in percentages (the I2 statistic) was calculated, where 0% indicates no heterogeneity, 25% indicates low heterogeneity, 50% indicates moderate heterogeneity and 75% indicates high heterogeneity (Higgins et al., 2003). 2.3.3. Sub-group analyses For each study, we extracted details about what the TAU condition entailed (if it was described), and three independent reviewers (NK, AT, JN) coded the TAU condition into one of five categories: (1) Usual care received under the direct management of the GP or medical physician (not a psychiatrist) (n ¼17), (2) Usual care received from multiple service providers (e.g., counselling, pharmacotherapy, vocational rehabilitation) (n ¼10), (3) psychotherapy only (including counselling) (n ¼6), (4) minimal contact/other (n ¼8), or (5) not described/unclear (n ¼7). See Table 2 for categories. To assess the differences between subgroups (TAU subtype: GP/physician management, multiple service providers, psychotherapy only, minimal contact/other, not described/ unclear), we conducted subgroup analyses using the mixed effect model approach. In this model, a random-effects model is used to pool studies within subgroups (e.g., psychotherapy only), and we tested for significant differences between subgroups using a fixedeffects model.

3. Results 3.1. Study selection This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Standards (Moher et al., 2009). A systematic search of Cochrane Central Register of


Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO was conducted on the 3rd of March 2014. Please refer to Appendices A–F for a description of the search terms and methods used. A total of 13 duplicates were removed and the remaining 4268 studies were searched for depressive disorders. Seven duplicates were removed and the remaining 3521 records were searched for anxiety disorders (see Fig. 1). The full text of 90 putative studies was assessed for eligibility; after which 42 studies were excluded from the meta-analysis, leaving 48 studies that met the inclusion criteria for the meta-analysis (please refer to references marked with an asterisk for a list of included studies). 3.2. Study characteristics and treatment-as-usual definitions used

Identification

Participant and treatment characteristics are shown in Table 1 and the definitions used in describing TAU are presented in Table 2. There were 29 studies for depressive disorders, 14 studies for anxiety disorders (panic disorder n ¼ 2, posttraumatic stress disorder n¼ 6; hypochondriasis n¼ 1; social phobia n ¼2; generalized anxiety disorders [GAD] n¼ 2; multiple anxiety disorders n ¼1) and five studies that examined transdiagnostic depressive and anxiety disorders (total studies n¼ 48). Most studies (n¼45/48) provided a description of the TAU group, yet these definitions varied widely with less than a third of studies outlining who provided the care for this group, with primary care physicians being the most common (primary care physicians n¼17/48; psychologist n¼7/48; not specified n¼14/48). The number of sessions with a provider was infrequently reported in the TAU (n¼5/48), in

Records identified through database searching the Cochrane Library (Depression n =2610; Anxiety n =1458)

comparison to the number of CBT sessions that were reported in all studies. Most participants in the TAU condition could have medication provided as part of this condition (n¼41/48) and referrals could be made to other health professionals (n¼15/48). 3.3. Risk of bias The risk of bias for the included studies is presented in Table 3. Most studies were assessed with a low risk of bias in random sequencing (low risk n ¼31/48; unclear risk n ¼16/48; high risk n ¼1/48); over half of the studies concealed allocation of participants and were evaluated with a low risk (low risk n ¼20/48; unclear n ¼20/48); most studies were unclear when reporting on the blinding of subjects (unclear n ¼35/48 low risk n ¼2/48; high risk n ¼11/48); the majority of studies reported blinding of personnel unclearly as is usual in studies using self report scales (low risk n ¼8/38; unclear n ¼30/48; high risk n ¼10/48), while most studies reported blinding of therapy personnel for outcome assessment adequately (low risk n ¼29/48; high risk n ¼ 3/48; unclear n ¼16/48); most studies reported attrition adequately with a low risk of bias (low risk n¼ 30/48; unclear n¼ 15/48; high risk n ¼3/48) and reporting bias was evaluated as unclear in 48 studies. 3.4. Effect sizes for individual studies The studies with their effects on primary measures are displayed as a forest plot in Figs. 2–5. The overall effect for CBT versus TAU was significant (po0.001) and medium in size (g¼ 0.63, 95% confidence

Records identified through database searching the CINAHL (Depression n = 175; Anxiety n = 31)

Records identified through database searching the PSYCHINFO (Depression n = 1496;Anxiety n =2039)

Included

Eligibility

Screening

Duplicates removed (Depression n = 13; Anxiety n = 7)

Records excluded (Anxiety n = 3495)

Full-text articles excluded, with reasons by two reviewers (n =11) 1= participants aged under 18yrs; 3 = depression; 1=study protocol; 1= subthreshold hypochondriasis; 2= follow up data; anxiety and depression studies =3

7789 records screened (Depression n = 4268 Anxiety n = 3521)

Full-text articles assessed for eligibility (Depression n =64) Anxiety n = 26)

Studies included in qualitative synthesis (Depression n = 31; Anxiety n = 15; Depression and Anxiety n = 5)

Records excluded (Depression n = 4204)

Full-text articles excluded, with reasons by two reviewers (n =34) Protocol only = 2; not academic journals =2; < 6 sessions of CBT = 6; follow up studies= 10; symptoms of depression only = 3; CBT not used = 1; anxiety =1; age not reported =1; cost effectiveness study= 1= predictors; anxiety and depression studies =6; other =4)

(n = 51)

Studies included in quantitative synthesis (meta-analysis) Depression=29 Anxiety=14 Depression and Anxiety=5 (n = 48)

155

Records excluded (Depression n = 1: unable to extract data; n =1 subset of data from previous study) Anxiety n = 1: unable to extract data)

Fig. 1. Depression and anxiety search flow diagram.

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Table 1 Participant and study characteristics by disorder. Study

Post N Mean age Tx, TAU Tx, TAU

Primary outcome measure

Who delivered CBT? (GP/nurse/mental health professional/psychologist/other)

Who delivered TAU? (GP/nurse/ mental health professional/ other)

Max no. of CBT sessions

Max no. of TAU sessions

Was medication use permitted in participants?

Could medication be used in TAU?

Effect size Hedge's g

Panic disorder

20, 12

39.9, 39.9

PDSS

Therapists

Therapists

15

Unclear

Yes

Yes

0.63

PTSD

9, 10

27.1, 31.4

IES-R

Psychologists, psychiatrist

Staff at psychiatric clinics

15

Unclear

Yes

Yes

1.69

Hypochondriasis 85, 76

40.66, 44.29

Whitely Index

Therapists.

PCP

6

Unclear

Yes

Unclear

0.53

Social phobia

27, 28

FQ-SOC

Psychologists, psychiatrists

Psychologists, psychiatrists

14

6

No

No

0.73

PTSD

7, 14

PCL

Psychologists, social workers

Unclear

12

Unclear

Unclear

Unclear

1.56

PTSD PTSD

9, 12 24, 23

PDS-I PCL

Social workers, registered nurse Psychologists, social workers

Social workers, registered nurse Psychologists, social workers

12 12

12 Unclear

Yes Yes

No No

1.14 0.56

Social phobia

28, 18

35.08, 32.75 45.77, 45.77 43.1, 43.1 53.13, 53.62 36.1, 35.8

Psychiatrists

18

Unclear

Yes

Yes

0.49

PTSD

32, 27

Unclear

16

Unclear

Yes

Yes

0.44

PTSD

13, 13

45.13, 43.30 34.8, 33.7

Social phobia Clinical psychologist, nurse, psychiatrist composite CAPS PhD and masters-level clinicians PSS-I

Psychiatrists, psychologists, social worker

Unclear

Yes

Yes

1.73

Panic disorder

90, 89

40.6, 41.9

Behavioral health specialist, PCP

Psychiatrists, psychologists, social 15 worker PCP 6

Unclear

Yes

Yes

0.27

Physician

Unclear

Yes

Yes

0.22

Post-doctoral and residency-level 8 clinicians 10 Masters-level therapists, predoctoral intern, post-bachelor's level therapist

Unclear

Yes

No

1.06

Unclear

Yes

No

0.90

Multiple anxiety 446, disorders 430 GAD 5, 4

43.3, 43.7

Composite measure of remission BSI-12

70.6, 70.6

PSWQ

GAD

65, 50

66.6, 67.3

PSWQ

Masters-level therapists, pre-doctoral intern, and post-bachelor's level therapist.

61, 61

HRSD

Therapists

Physician

Unclear

Unclear

Yes

Yes

0.26

50.3 (MR), 44.4 (TR), 45.0

CES-D

Computerized

Unclear

Unclear

Unclear

Yes

Unclear

0.14

Depression

697, 646 36 (MR), 48 (TR), 77 58, 58

22.6, 22.7

PHQ-8

Self-help

Self-help

Unclear

Unclear

Yes

Yes

1.42

Depression

9, 12

48, 42

BDI

Computerized

Unclear

8

Unclear

Yes

Unclear

0.83

Depression

48, 19

42.71,41.86 PHQ-9

Trained facilitators

Unclear

14

Unclear

Yes

Yes

0.25

Depression

36, 36

SCL-90

Therapists

Therapists

Unclear

Unclear

Yes

Yes

0.18

Depression

199, 226 95, 97

44.3, 45.1

BDI-II

Computerized

GP

9

5

Yes

Yes

0.15

Depression

41, 44

52.4, 54.0

BDI

Psychologist

Psychologist

12

Unclear

Yes

No

0.79

Depression Berkman et Depression al., 2003 Clarke et al., Depression 2005

Clarke et al., 2009 Cooper et al., 2011 Cramer et al., 2011 Cuijpers et al., 2005 De Graaf et al., 2009 Duarte et al., 2009

Social workers, registered nurses, psychologists Post-doctoral and residency-level clinicians

8


Anxiety Addis et al., 2004 Asukai et al., 2010 Barsky and Ahern, 2004 Cottraux et al., 2000 Difede et al., 2007 Feske, 2008 Forbes et al., 2012 Mortberg et al., 2007 Mueser et al., 2008 Nacasch et al., 2011 Roy-Byrne et al., 2005 Roy-Byrne et al., 2010 Stanley et al., 2003 Stanley et al., 2009

Disorder

Depression

50, 51

41.17, 38.54

PHQ-9

Unclear

PCP

8

Unclear

Yes

Yes

1.96

Depression

27, 27

37.5, 43.7

CES-D

Computerized

Helpline

Unclear

Unclear

Yes

No

0.77

Depression

13, 12

78, 81

GDS

Unclear

Unclear

15

Unclear

Yes

Unclear

1.93

Depression

113, 97

35.6, 34.3

BDI

Psychologists

GP

10

Unclear

Yes

Unclear

0.61

Depression

20, 20

74, 74.05

BDI

Clinical psychologists

GP

8

Unclear

No

Yes

0.40

Depression

39, 41

67.1, 65.0

BDI

Community psychiatric nurse

Unclear

10

Unclear

Yes

Unclear

0.15

Depression

14, 17

39.8, 33.1

BDI


Psychiatrists

30

Unclear

Yes

Yes

1.74

Depression

16, 16

42.6, 42.1

POMS

Doctoral students and a post-doctoral fellow

Unclear

8

Unclear

Yes

No

0.87

Depression

40, 41

55.9, 55.9

PHQ-9

Therapists with CBT training

Unclear

16

Unclear

No

Unclear

0.29

Depression

58, 55

40.5, 40.5

BDI

Clinical psychologist

Psychiatrists

8

Unclear

Yes

Yes

4.83

Depression

22, 10

36.1

BDI

Clinical psychologists, psychiatrists, nurse therapists

GP

16

Unclear

Yes

Yes

0.36

Depression

11, 11

48.4, 48.4

BDI-II

Psychiatric residents

Psychiatric residents

6

6

Yes

No

0.12

Depression

21, 21

Not reported

BDI

Unclear

12

Unclear

Yes

No

1.02

30, 30

28.8, 31.6

HRSD

Clinical psychologists, psychology intern, postdoctoral fellow in psychology, predoctoral graduate in psychology Clinical psychologists

GP

Unclear

Unclear

No

Yes

0.25

18, 16

41

BDI

GP

6

Unclear

Yes

Yes

0.46

64, 55

74.4, 72.8

BDI-II

Therapist with post-grad qualification in cognitive therapy CBT therapists

GP

12

Unclear

Yes

Yes

0.17

172, 176 44.7, 44.0

SCL

Psychotherapists

Unclear

8

Unclear

Yes

Unclear

0.25

20, 20

47.3, 44.8

BDI

Graduate students in psychology

PCP

Unclear

Unclear

Yes

Yes

0.44

26, 28

39.41, 44.66

CES-D

Self-help

Unclear

Unclear

Unclear

Yes

Unclear

0.60

56, 62

36, 37

BDI

Psychologists

GP

12

Unclear

No

No

0.41

206, 213

49.2, 50.0

BDI

CBT Therapists

GP

18

Unclear

Yes

Yes

0.41

72, 71

40.7, 41.9

SCL-90

Psychologist, psychiatric nurses, social workers, participants

20

Unclear

No

0.38

25, 26

59.3, 62.6

BDI-II, BAI

Masters-level psychologists

Unclear Psychologist, psychiatric nurses, social workers, psychiatric trainee and psychiatrist Masters-level psychologists 7

Unclear

Yes

Unclear

0.69

50, 51

43.7, 45.7

BDI-II, BAI

Computerized

GP

8

Unclear

Yes

Yes

0.44

92, 93

43.6, 43.4

BDI-II, BAI

Computerized

GP

8

Unclear

Yes

Yes

0.25

Depression Scott and Freeman, 1992 Scott et al., Depression 1997 Serfaty et al., Depression 2009 Simon et al., Depression 2004 Simoni et al., Depression 2013 Songprakun Depression and McCann, 2012 Ward et al., Depression 2000 Wiles et al., Depression 2013 Anxiety and depression Den Boer et Depression and al., 2007 anxiety Depression and anxiety Depression and anxiety Depression and anxiety

157

Hynninen et al., 2010 Proudfoot et al., 2003 Proudfoot et al., 2004


DwightJohnson et al., 2011 Farrer et al., 2011 Hyer et al., 2008 Kessler et al., 2009 Laidlaw et al., 2008 Lincoln and Flannaghan, 2003 Miller et al., 1989 Mohr et al., 2000 Mohr et al., 2011 Mukhtar et al., 2011 Power and Freeman, 2012 Rieu et al., 2011 Safren et al., 2009

Notes: BAI¼ Beck Anxiety Inventory; BDI ¼ Beck Depression Inventory; BSI-12¼ 12-item Brief Symptom Inventory; CAPS ¼ Clinician Administered PTSD Scale; CES-D ¼ Centre for Epidemiological Studies Depression Scale; FQSOC¼ Fear Questionnaire-Social Phobia Scale; GAD ¼generalized anxiety disorder; GDS ¼Geriatric Depression Scale; GP ¼ General Practitioner; HADS-A ¼Hospital Anxiety and Depression Scale-Anxiety Subscale; HDRS ¼ Hamilton Depression Rating Scale; HRSD¼ Hamilton Rating Scale for Depression; IES-R ¼Impact of Event Scale-Revised; PCL ¼PTSD Checklist; PCP¼ Primary Care Provider/Primary Care Physician; PDSS ¼ Panic Disorder Severity Scale; PDSI¼ PTSD Diagnostic Scale-Interview; PHQ-8 ¼Patient Health Questionnaire 8; PHQ-9 ¼Patient Health Questionnaire-9; POMS ¼Profile of Mood States Depression–Dejection Scale; PSS-I ¼PTSD Symptom Scale-Interview Version; PSWQ ¼Penn State Worry Questionnaire; PTSD ¼posttraumatic stress disorder; SCL-90 ¼Symptom Check list-90; SCL ¼ Symptom Checklist Depression Scale.

No Yes 6 Depression and anxiety Van Beek et al., 2013

60, 53

48.7, 49.9

HDRS, HADS-A


Cardiac emergency unit staff/ cardiologist

Unclear

Could medication be used in TAU? Was medication use permitted in participants? Max no. of TAU sessions Max no. of CBT sessions Who delivered TAU? (GP/nurse/ mental health professional/ other) Who delivered CBT? (GP/nurse/mental health professional/psychologist/other) Primary outcome measure Post N Mean age Tx, TAU Tx, TAU Disorder Study

Table 1 (continued )

0.10


Effect size Hedge's g

158

interval (CI) 0.50–0.76, n¼6926) favoring CBT over TAU in the treatment of depression, anxiety, and mixed anxiety and depression1. In each meta-analysis heterogeneity between studies was moderate and significant for CBT for anxiety (I2 ¼69.61%, Q¼42.78, p¼ 0.00), high and significant for depression (I2 ¼89.44%, Q¼265.37, p¼0.00); and low and nonsignificant for CBT for mixed anxiety and depression (I2 ¼ 0%, Q¼ 4.35, p¼0.88). The meta-analysis showed medium effects favoring CBT over TAU for both anxiety (g¼ 0.69, 95% CI 0.47–0.92, p o0.001, n¼ 1318) and depression (g ¼0.70, 95% CI 0.49–0.90, p o0.001, n¼ 5054). When examining studies that aimed to treat mixed anxiety and depression the effects were small for CBT over TAU for anxiety (g ¼0.34, 95% CI 0.17–0.50, po 0.001, n ¼554) and for depression (g ¼0.44, 95% CI 0.27–0.61, po 0.001, n¼ 554). 3.5. Sub-group analyses: comparison of the size of the effect of CBT versus TAU according to TAU subtype In the subgroup analysis, we compared the size of the mean effect comparing CBT to TAU for subgroups based on TAU comparison subtype (GP/physician management, multiple service providers, psychotherapy only, minimal contact/other, not described/ unclear), and found significant overall differences (p o0.05). The largest effects were observed comparing CBT to minimal contact/ other therapies (n ¼9, g¼ 0.71, I2 ¼71%) and the smallest differences were observed comparing CBT to GP/physician management (n ¼20, g¼ 0.32, I2 ¼69%), with the remaining effects of moderate size: multiple service providers (n ¼10, g ¼0.56, I2 ¼95%), psychotherapy only (n ¼7, g¼ 0.57, I2 ¼ 53%), and not described/ unclear (n¼ 7, g ¼0.55, I2 ¼51%).

4. Discussion 4.1. Summary of main findings This study aimed to determine the efficacy of CBT treatments for anxiety and depression that use a TAU control condition. The results suggest that CBT was more efficacious than TAU in the treatment of depression, anxiety and mixed anxiety and depression. The impact of CBT on clinical outcome was similar for studies that aimed to treat anxiety or depression; however, the effect was smaller in studies of transdiagnostic therapies, when the intervention aimed to treat both disorders as their primary target. The very few comparisons of transdiagnostic treatment versus TAU may be a possible explanation for these results. An alternative reason may be because at least two of the transdiagnostic studies included in this review were conducted in the United Kingdom where TAU may be considered to be of a high standard encompassing pharmacological and psychological treatment. The second aim of this study was to determine how the term TAU is used in the reporting of studies. Overall, our results showed that the majority of studies (n ¼45/48) provided a description of the TAU group, yet they varied widely in the amount of detail provided. Information about the content, intensity, frequency, treatment type and the provider of the treatment was rarely outlined, making it problematic for trials to be replicated and difficult for study results to be interpreted. The TAU conditions were highly heterogeneous across the studies and notably, the risk of bias evaluations revealed that some studies included in the meta-analysis were lacking in quality. 1 We repeated this analysis after omitting studies of computerized and selfhelp CBT protocols. The overall controlled effect size was: g¼ 0.68, 95% CI:0.53– 0.84.


159

Table 2 Treatment-as-usual definition and category by disorder. Study

Treatment-as-usual definition

Anxiety Addis et al., 2004

TAU therapists were instructed to provide whatever treatment they deemed appropriate for the clients they treated. Asukai et al., 2010 Patients receiving TAU upon joining the study continued that same treatment including supportive counselling along with drug treatment including SSRIs, anti-depressants, minor tranquilizers, sleeping pills or both. Barsky and Ahern, No definition provided. 2004 Cottraux et al., TAU included one 30 min supportive therapy session every 2 weeks, for 12 weeks of the trial. Therapists 2000 stressed the value of therapy, used empathic listening, reformulation, clarification, recapitulation and showed positive consideration. Advice, exposure homework, psychoanalytic interpretations or cognitive modification techniques were prohibited. Patients received no manuals. Difede et al., 2007 Participants were given the results of the evaluation and referred back to the original source (e.g. Occupational health, Employee Assistance Program) for assistance obtaining treatment through community providers. Feske, 2008 TAU consisted of 9–12 sessions of the standard treatment provided at the clinic and included one weekly, 60-min individual counselling session (i.e., one weekly TAU protocol session). In addition, TAU clients received one weekly, 90-min group treatment session (e.g., anger management). Forbes et al., 2012 The purpose of TAU was to provide baseline comparison of what treatment would usually be received by veterans presenting at Veterans and Veterans Family Counselling Service Mortberg et al., TAU followed routine psychiatric practice. The psychiatrist and the patient discussed and decided 2007 numbers of visits, telephone consultations between visits, and choice of medication and other steps in treatment. Sessions usually lasted 45 min and included routine psychiatric procedures such as support, a review of progress, side-effects and any other adverse effects. TAU did not involve exposure instructions or cognitive interventions. All patients were prescribed medication. Mueser et al., TAU clients continued to receive usual services received before enrollment in the program. No cognitive 2008 restructuring or exposure therapy treatment was available to this group but supportive counselling and trauma-related problems were available. Comprehensive mental health treatment at these centers included: pharmacological treatment and monitoring, case management, supportive counselling, access to psychiatric rehab programs such as vocational rehabilitation. Nacasch et al., Non-directive, psycho dynamically oriented therapy that focused on daily occurrences of distress and 2011 relationship issues, childhood experiences, object relations themes, and daily crisis experienced by the patients. The therapy was not focused on the traumatic event, which was only discussed when brought up by the patient. Roy-Byrne et al., TAU was typically pharmacotherapy, from their primary care physician and subjects could also be referred 2005 or self-refer to mental health resources available to them in the community. Roy-Byrne et al., TAU subjects continued to be treated by their physician in the usual manner with no intervention (i.e., 2010 with medication, counselling [7/17 clinicians has limited in-clinic mental health resources, usually a single clinician with limited familiarity with evidence-based psychotherapy], or referral to a mental health specialist). Stanley et al., Received weekly telephone calls to assess symptom severity and the need for immediate treatment (e.g. 2003 suicidal ideation). Stanley et al., Telephoned biweekly during the first 3 months of the study by the same therapists to provide support and 2009 ensure patient safety. Calls lasted approximately 15 min. Therapists reminded patients to call project staff if symptoms worsened and suggested contacting their primary care practitioner for medical problems. Depression Berkman et al., TAU patients received only the care provided by their physicians. 2003 Clarke et al., 2005 TAU was linked to a Health Maintenance Organization website that provided static information about depression but no interactive skills training. Clarke et al., 2009 TAU was linked to a Health Maintenance Organization website that provided static information about depression but no interactive skills training. Cooper et al., 2011 No definition provided. Cramer et al., 2011 Participants given an information booklet. This booklet contained details of local support organizations such as local mental health organizations, counselling services, carers groups and Black and minority ethnic services. Participants were allowed to continue taking (or start) any antidepressants or other medication prescribed by their GP. Cuijpers et al., TAU was treatment as delivered in current daily practice in the mental health centers in the Netherlands. 2005 In TAU, a multidisciplinary team chooses a therapeutic approach which is tailored to the individual's needs, taking into account the specific constellation of problems and characteristics of each different patient. As a result, any kind of therapy may be chosen from a wide variety of approaches. Severely ill patients were allowed to receive antidepressant medication in addition to the treatment to which they were randomised. De Graaf et al., TAU delivered by the participants own GP who was advised to follow the guidelines from the Dutch 2009 College of General Practitioners. TAU can include 4–5 consultations, held every second week, and antidepressant treatment if indicated. Duarte et al., 2009 A brief individualized psychological consultation (30–50 min) routinely available and conducted on a weekly basis by the unit's psychologist. This consisted of providing general guidelines about the treatment and emotional support for the patients' psychological suffering related to the disease and treatment. Dwight-Johnson Providers were free to provide any usually available care for depression, including antidepressants or et al., 2011 referral to outside services. Farrer et al., 2011 Participants were invited to use the helpline, which provided usual emergency or support services if required.

Was TAU provided by primary care?

TAU category

No

Unclear/not described Multiple providers

No

No No

Unclear/not described Psychotherapy only

No

Multiple providers

No

Psychotherapy only

No

Unclear/not described Multiple providers

No

No

Multiple providers

No

Psychotherapy only

Yes

GP/physician

Yes

GP/physician

No

Minimal/other

No

Minimal/other

Yes

GP/physician

No

Minimal/other

No

Minimal/other

No

Unclear/not described Minimal/other

No

No

Multiple providers

Yes

GP/physician

No

Psychotherapy only

Yes

GP/physician

No

Minimal/other

160


Table 2 (continued ) Study

Hyer et al., 2008


The TAU group received the usual therapies in the long-term care setting. This particular nursing facility is active, with daily activities involving frequent socialization and games, as well as special events. Kessler et al., 2009 Usual care from their general practitioner while on an 8-month waiting list for online CBT. Laidlaw et al., TAU required that the management of depression was carried out by GPs in the community using standard 2008 service delivery models. TAU could include involvement of GPs, Community Psychiatric Nurses and other mental health services as individual circumstances dictated, consistent with reports in the literature. TAU could include any combination of physical treatment for depression, such as prescription of antidepressant medication, physical review, and referral for non-counselling interventions by Community Psychiatric Nurse teams or other services (e.g. social services). Treatment could also be no treatment if that is what the GP considered to be appropriate. Following randomization, patients in this group had no further contact with the research community Lincoln and psychiatric nurse. Flannaghan, 2003 Miller et al., 1989 The treatment consisted of three major components: a) usual hospital milieu, b) pharmacotherapy, and c) medication and management sessions with a psychiatrist. Hospital Milieu. While in the hospital, all patients took part in usual hospital activities which included: daily meetings with nursing staff, occupational therapy groups, social work evaluation of the family, and other typical unit activities. However, patients in the study did not receive any other specific form of psychotherapy beyond those described as part of the study. Pharmacotherapy. As opposed to previous studies, we chose not to utilize the usual medication protocol of increasing dosages of a single antidepressant Medication and Management Sessions. All patients met with their psychiatrist for a series of 20-min management and medication sessions. These sessions occurred once a day during the patient's inpatient stay and 6–8 times during the 20-week outpatient period. Psychiatrists followed the clinical management guidelines of the NIMH Collaborative Psychotherapy of Depression study regarding the content of the management sessions Mohr et al., 2000 The condition consisted of the usual care available through Kaiser Permanente Medical Care Program of Northern California including antidepressant medication and psychotherapy. Mohr et al., 2011 Veterans assigned to TAU continued to receive care through their Community Based Outpatient Clinics and any non-Veteran Affairs they might use. Although receipt of psychotherapy excluded a veteran from entering the study, veterans were free to access all available mental health services once enrolled. Mukhtar et al., TAU patients received medication prescribed by their psychiatrists, or received other forms of treatment, 2011 such as those administered by traditional healers. Patients attended any follow-up psychiatrist appointments that were required. The psychiatrists monitored the dosage of medication taken by the patients. Power and TAU referred to routine treatment by GP in the Primary Care setting, with one of the standard Freeman, 2012 antidepressants. Rieu et al., 2011 For the TAU group, six 45 min sessions were provided by a psychiatric registrar, the session were not structured and consisted of symptom severity assessment, biography exploration and supportive sessions. Safren et al., 2009 TAU included a single-session intervention for treatment adherence and a letter to the patient's provider documenting her or his continued depression. Scott and TAU treatments were provided in primary care and lasted up to 16 weeks. General practitioners were Freeman, 1992 asked to manage each case as he or she would normally, and this included referral to other agencies. Scott et al., 1997 TAU included whatever medication, counselling and referral was deemed appropriate by the participant's GP. Serfaty et al., 2009 TAU allowed for whatever medication, routine support, or referral to other services was felt appropriate by the GP.The only constraint was to refrain from referring patients for CBT or other brief talking therapies unless absolutely necessary. Participants could discuss their problems and their physical health, and pain management could be reviewed, medication prescribed, and referrals made to luncheon clubs or day centers. Antidepressant medication as a routine part of TAU was not constrained. Simon et al., 2004 TAU referred to usual primary care treatment. Simoni et al., 2013 Participants continued to receive medical care at the participating community clinic as usual. At the clinic, medically stable patients are scheduled for appointments with a primary care provider (a physician or consulting pharmacist) every 3 months. Patients who report psychiatric symptoms are typically first evaluated by the primary care providers, who may prescribe psychoactive medications or be referred to counselling services provided by masters-level therapists at a local mental health clinic. Patients who are judged to pose a risk to themselves or to others due to psychiatric symptomatology are immediately referred to emergency care. Songprakun and No description provided. McCann, 2012 Ward et al., 2000 General practitioners treated patients in this group according to their usual practice, but were asked to refrain from referral for psychological interventions unless this was imperative. Wiles et al., 2013 No restrictions were placed on the treatment options for patients randomised to be managed as usual by their general practitioner. Participants could be referred for counselling, CBT, or to secondary care, when such treatment was clinically appropriate. Anxiety and depression Den Boer et al., Psychological therapy delivered by professionals not according to a study protocol. Interpersonal 2007 psychotherapy and CBT could be part of the treatment and were provided by a psychologist. In other cases, supportive treatment was given by a psychiatric nurse or social worker focusing on problem-solving and coping strategies. Treatment consisted typically of 10–20 visits of 30–45 min each, throughout the first 6– 12 months. Follow-up contacts with therapist were provided if needed. Hynninen et al., Participants received telephone contact with the study personnel every two weeks in the intervention 2010 period of seven weeks, in order to monitor their psychological status and assess suicidal ideation. The telephone calls, facilitated by the student therapists, lasted 5–10 min, and no interventions beyond


TAU category

No

Unclear/not described GP/physician GP/physician

Yes Yes

No

Unclear/not described

No

Multiple providers

No

Multiple Providers Multiple providers

No

No

Multiple providers

Yes

GP/physician

No No

Psychotherapy only Minimal/other

Yes

GP/physician

Yes

GP/physician

Yes

GP/physician

Yes No

GP/physician Multiple providers

No Yes

Unclear/not described GP/physician

Yes

GP/physician

No

Psychotherapy only

No

Minimal/other


161

Table 2 (continued ) Study

Proudfoot et al., 2003

Proudfoot et al., 2004

Van Beek et al., 2013



assessment of symptom level and basic information about symptoms of anxiety and depression were delivered. Patients received whatever treatment their GP prescribed. Besides any medication, this included Yes discussion of problems with GP, provision of practical/social help, referral to a counsellor, referral to a practice nurse, referral to mental health professionals (psychologist, psychiatrist, community psychiatric nurse, counsellor), or further physical investigation. Yes Patients received whatever treatment their GP prescribed. Besides any medication, this included discussion of problems with GP, provision of practical/social help, referral to a counsellor, referral to a practice nurse, referral to mental health professionals (psychologist, psychiatrist, community psychiatric nurse, counsellor), or further physical investigation. Reassured by the cardiologist that their complaints (chest pain) were not caused by cardiac disease. TAU Yes was tailored to the individual needs of the patient. However, TAU did not include psychotherapy, including CBT, or antidepressants.

Our subgroup analyses revealed that the size of the effect of CBT compared to TAU depended on the nature of the TAU condition. The smallest differences were found for comparisons between CBT and GP/ physician management, and the largest difference for use of “minimal contact” TAU comparison groups. The latter sub-group included TAU groups that involved assessment and risk monitoring but no psychotherapy, as well as the provision of information leaflets and handouts. Given that previous studies have yielded mixed and often nonsignificant results comparing CBT to alternative psychological therapies, it was surprising that there was a larger (positive) difference between CBT and TAU that involved psychotherapy, in contrast to the smaller differences observed between CBT and TAU received under the management of the GP/primary care provider. In several studies however the GP managed “treatment-as-usual” involved pharmacological therapy in combination with referral for psychological therapy. Therefore, individuals in these GP managed TAU groups may be receiving best practice management. Further scrutiny of the frequency, intensity, duration and type of treatment received in “usual care” under GP supervision is needed to explore these results further. In the future it may also be worthwhile exploring how varying TAU conditions effects are influenced by different modes of CBT (e.g. professional contact versus computerized CBT). Direct comparisons with the existing literature pertaining to the efficacy of CBT versus TAU for anxiety and depressive disorders are difficult as previous reviews have not focused solely on the studies using TAU, or have examined the effect of TAU when compared to a range of treatments. Nevertheless, in keeping these considerations in mind some parallels between current and previous research can be observed. Meta-analyses have shown CBT, including computerized CBT, to be effective for individuals with depression and anxiety compared to TAU or an alternative control group (Andrews et al., 2010; Gava et al., 2007). The results found in the present review are comparable to these findings. Wampold et al. (2011) showed a medium sized effect versus TAU in the treatment of anxiety and depression and this was similar to the overall medium-sized effect found in the present review. Our results show that the TAU label is used to describe a heterogeneous set of interventions. Those in the TAU condition were most frequently managed under the care of the primary care physician or general practitioner, but “TAU” frequently involved multiple referral options and treatment delivered by multiple treatment providers. The large variability in the use of TAU found in this review echoes findings from other meta-analyses that have examined evidence-based treatments versus TAU in adults with depression or/and anxiety (Flückiger et al., 2014; Wampold et al., 2011). We recommend that researchers investigating the efficacy of CBT compared to TAU need to consider the aims of using TAU as

TAU category

GP/physician

GP/physician

GP/physician

the control condition and provide more precise details about what the TAU condition entails. At a minimum it is recommended that (i) the provider of the treatment in TAU is reported; (ii) the content of the contact is described (i.e. counselling, primary care medical consultation, medication or other); (iii) the number and duration of sessions are documented; and (iv) if other referrals are described, the outcomes depicted i.e., if a referral is made to another health professional then report (i), (ii) and (iii). It is also worth noting that the country and standard of health care provided in the country (or state) may determine the size of treatment effects and it may be important to consider TAU on an individual level, that is, collate what each person receives, when and who from. Our findings showed that CBT was superior to TAU, with on average a medium effect size difference, and provided further evidence of the efficacy of CBT for depression and anxiety. The results of the present review are somewhat inconsistent with those of an earlier review by Cuijpers et al. (2005), which showed that CBT was only more effective than TAU for individuals with more severe depression and there was no difference between CBT and TAU for individuals with low depression scores. However, Cuijpers et al. (2005) contained a relatively homogenous TAU condition because TAU consisted of services, including psychotherapy, offered to clients of mental health centers, which as discussed previously, is an exception rather than the rule when considering other reviews. Recently, Honyashiki et al. (2014) showed that CBT was superior to no treatment and the results from the present meta-analysis may be seen as supportive of this conclusion. However, we caution against viewing TAU as equivalent to no treatment (despite some studies labelling no treatment by the primary care practitioner as TAU) and we agree with previous suggestions in the literature that TAU should refer to an actual treatment (Wampold et al., 2011). 4.2. Strengths and limitations of the study The strengths of the review are the inclusion of studies that investigated different modes of TAU and the examination of treatment for depression, or anxiety, or mixed anxiety and depression disorders. Limitations include the restriction to studies published in English; the exclusion of studies that did not report adequate information to be included in the meta-analysis and the small number of studies that examined transdiagnostic treatments for anxiety and depression versus TAU. In addition, because we sought to focus on the differences across TAU conditions, we did not explore the heterogeneity amongst CBT interventions. It is also possible that there are also critical differences amongst CBT

162


Table 3 Risk of bias by disorder. Study

Anxiety Addis et al., 2004 Asukai et al., 2010 Barsky and Ahern, 2004 Cottraux et al., 2000 Difede et al., 2007 Feske, 2008 Forbes et al., 2012 Mortberg et al., 2007 Mueser et al., 2008 Nacasch et al., 2011 Roy-Byrne et al., 2005 Roy-Byrne et al., 2010 Stanley et al., 2003 Stanley et al., 2009 Depression Berkman et al., 2003 Clarke et al., 2005 Clarke et al., 2009 Cooper et al., 2011 Cramer et al., 2011 Cuijpers et al., 2005 De Graaf et al., 2009 Duarte et al., 2009 Dwight-Johnson et al., 2011 Farrer et al., 2011 Hyer et al., 2008 Kessler et al., 2009 Laidlaw et al., 2008 Lincoln and Flannaghan, 2003 Miller et al., 1989 Mohr et al., 2000 Mohr et al., 2011 Mukhtar et al., 2011 Power and Freeman, 2012 Rieu et al., 2011 Safren et al., 2009 Scott and Freeman, 1992 Scott et al., 1997 Serfaty et al., 2009 Simon et al., 2004 Simoni et al., 2013 Songprakun and McCann, 2012 Ward et al., 2000 Wiles et al., 2013 Anxiety and depression Den Boer et al., 2007 Hynninen et al., 2010 Proudfoot et al., 2003 Proudfoot et al., 2004 Van Beek et al., 2013

Random sequence

Allocation concealment

Blinding of subjects

Blinding of personnel

Blinding of outcome assessment

Attrition reported

Reporting bias

Unclear Low risk Low risk Low risk Low risk Unclear Low risk Low risk Low risk Low risk Low risk Low risk Unclear Low risk

Unclear Unclear Low risk Unclear Low risk Unclear Low risk Unclear Low risk Unclear Low risk Low risk Unclear Low risk

Low risk Unclear Unclear Unclear Unclear Unclear Unclear Unclear High risk Unclear High risk Unclear Unclear High risk

Unclear Unclear Low risk Unclear Low risk Unclear Unclear Unclear Unclear Unclear High risk Unclear Unclear High risk

Unclear Low risk Low risk Low risk Low risk Unclear Low risk Unclear Low risk Low risk Low risk Low risk Unclear Low risk

Low risk Low risk Low risk Unclear Low risk Unclear Low risk High risk Low risk Low risk Low risk Low risk Low risk Low risk

Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear

Low risk Low risk Low risk Low risk Low risk Low risk Unclear Low risk Low risk

Low risk Low risk Low risk Low risk Low risk Low risk Unclear Low risk Unclear

High risk High risk Unclear Unclear High risk High risk Unclear Unclear Unclear

Low risk Unclear Low risk Low risk Low risk High risk Unclear Unclear Unclear

Unclear Unclear Unclear Low risk Low risk Low risk Unclear Low risk Low risk

Unclear Unclear Unclear Unclear Low risk High risk Low risk Low risk Unclear

Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear

Low risk Unclear Low risk Low risk Low risk


Unclear Unclear High risk Unclear Unclear

Unclear Unclear Unclear Low risk High risk

Unclear Low risk Unclear Low risk Low risk

Unclear Low risk Unclear Low risk Low risk

Unclear Unclear Unclear Unclear Unclear

Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Low risk Low risk Low risk Unclear

Unclear Unclear Unclear Unclear Unclear Unclear Unclear Low risk Unclear Low risk Unclear Low risk Unclear

Unclear Unclear Unclear Unclear Unclear Low risk Unclear Unclear Unclear Unclear Unclear High risk Unclear

Unclear Unclear Unclear Unclear High risk Unclear Unclear Unclear Unclear Low risk Unclear High risk Unclear

High risk Unclear Low risk Low risk Low risk Low risk Low risk High risk Unclear Low risk Low risk Low risk High risk

Unclear Low risk Low risk Unclear Low risk Unclear Low risk Unclear High risk Low risk Unclear Low risk Low risk

Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear

High risk Low risk

Low risk Low risk

Unclear High risk

Unclear High risk

Low risk Unclear

Unclear Low risk

Unclear Unclear


Low Low Low Low Low

Unclear High risk Unclear Unclear Unclear

Unclear High risk Low Low Unclear

Low risk Unclear Unclear Unclear Low risk

Low Low Low Low Low

Unclear Unclear Unclear Unclear Unclear

Study name

risk risk risk risk risk

Statistics for each study Hedges's g

Addis, et al., 2004 Asukai, et al., 2010 Barksy, et al., 2004 Cottraux, et al., 2000 Difede, et al., 2007 Feske, et al., 2008 Forbes, et al., 2012 Mortberg, et al., 2007 Mueser, et al., 2008 Nacasch, et al., 2011 Roy-Byrne, et al., 2005 Roy-Byrne, et al., 2010 Stanley, et al., 2003 Stanley, et al., 2009

0.63 1.69 0.53 0.73 1.56 1.14 0.56 0.49 0.44 1.73 0.27 0.22 1.06 0.90

Hedges's g and 95% CI

Lower Upper limit limit -0.09 0.78 0.21 0.20 0.57 0.24 -0.01 -0.10 -0.07 0.85 0.01 0.09 -0.21 0.52

risk risk risk risk risk

Relative weight

1.34 2.60 0.84 1.25 2.55 2.04 1.14 1.08 0.95 2.61 0.53 0.36 2.33 1.29

5.79 4.29 10.67 7.83 3.80 4.36 7.25 7.06 8.00 4.47 11.41 12.77 2.61 9.69 -2.00

-1.00 Favours TAU

0.00

1.00 Favours CBT

Fig. 2. Cognitive behavior therapy versus treatment-as-usual for anxiety.

2.00


protocols (e.g., therapist factors, dose and duration of CBT) that may account for some of the heterogeneity we observed in this study.

5. Conclusion It is essential that future researchers describe the TAU condition clearly enough to allow for replication and interpretation of results.

Study name

Statistics for each study

163

We recommend four key details to be reported that can be simply thought of as “who, what, how many, and any treatment additions?” The present meta-analysis provides evidence that CBT was more efficacious than TAU in the treatment of depression, anxiety, and mixed anxiety and depression. Yet, our results show that the term “TAU” is not a homogenous comparison condition; instead it is being used to refer to a varied set of interventions, treatment providers, and referral pathways. Future researchers should aim to carefully elucidate their objectives when using a TAU arm, precisely describe this


Hedges's Lower Upper g limit limit Berkman, et al., 2003 Clarke et al., 2005 Clarke et al., 2009 Cooper et al., 2011 Cramer et al., 2011 Cuijpers et al., 2005 De Graaf, et al., 2009 Duarte, et al., 2009 Dwight et al.,2011 Farrer et al., 2011 Hyer et al., 2008 Kessler et al., 2009 Laidlaw et al.,2008 Lincoln, et al.,2003 Miller et al., 1989 Mohr et al., 2011 Mohr et al., 2000 Mukhtar, et al., 2011 Power et al., 2012 Rieu et al., 2011 Safren et al., 2009 Scott et al., 1992 Scott et al., 1997 Serfaty et al., 2009 Simon et al., 2004 Simoni et al., 2013 Songarakun et al., 2012 Ward et al., 2000 Wiles et al., 2013

0.26 0.14 1.42 0.83 0.25 0.18 0.15 0.79 1.96 0.77 1.93 0.61 0.40 0.15 1.74 0.29 0.87 4.83 0.36 0.12 1.02 0.25 0.46 0.17 0.25 0.44 0.60 0.41 0.41

0.18 -0.22 1.01 -0.04 -0.28 -0.01 -0.14 0.35 1.49 0.22 1.00 0.33 -0.22 -0.28 0.93 -0.14 0.16 4.10 -0.37 -0.69 0.39 -0.26 -0.21 -0.19 0.04 -0.18 0.06 0.05 0.22

Relative weight

0.35 0.50 1.82 1.69 0.77 0.37 0.43 1.23 2.44 1.31 2.86 0.88 1.01 0.58 2.56 0.73 1.58 5.56 1.10 0.92 1.66 0.75 1.13 0.53 0.46 1.05 1.14 0.78 0.60

4.39 3.89 3.77 2.46 3.42 4.26 4.08 3.68 3.58 3.36 2.31 4.09 3.16 3.69 2.60 3.69 2.89 2.83 2.82 2.62 3.11 3.49 3.01 3.89 4.23 3.16 3.38 3.88 4.26 -4.00

-2.00

0.00

Favours TAU

2.00

4.00

Favours CBT

Fig. 3. Cognitive behavior therapy versus treatment-as-usual for depression.

Study name



Hedges's LowerUpper g limit limit Den boer et al., 2007a Den boer et al., 2007b Hynninen et al., 2011a Hynninen et al., 2011b Proudfoot et al., 2003a Proudfoot et al., 2003b Proudfoot et al., 2004a Proudfoot et al., 2004b van Beek, et al., 2013a van Beek, et al., 2013b

0.38 0.43 0.69 0.42 0.44 0.51 0.25 0.46 0.10 0.36

0.05 0.10 0.13 -0.13 0.05 0.12 -0.04 0.17 -0.35 -0.09

R el a t i v e weight

0.71 0.76 1.25 0.97 0.84 0.90 0.54 0.76 0.55 0.82

12.90 12.84 4.50 4.67 9.09 9.02 16.81 16.50 6.89 6.78 -1.00

-0.50

Favours TAU

0.00

0.50

Favours CBT

Fig. 4. Cognitive behavior therapy versus treatment-as-usual mixed anxiety and depression.

1.00

164


Group by Comparison



Hedges's Lower Upper g limit limit

Anxiety Depression Mixed - Anxiety

0.69

0.47

0.92

0.70

0.49

0.90

0.34

0.17

0.50

Mixed - Depression

0.44

0.28

0.61

Overall

0.50

0.41

0.60 -1.00

-0.50

0.00

Favours TAU

0.50

1.00

Favours CBT

Fig. 5. Cognitive behavior therapy versus treatment-as-usual, sub grouped by disorder.

condition, and investigate the effects of TAU on the individual level, according to the intervention that the individual actually received. It is important that researchers are clear about what constitutes this control condition and consider carefully if this condition is better described as no treatment, a waiting list control or TAU. This will ensure that accurate interpretations can be made from research trials and ultimately, enhance the speed in which efficacious and beneficial treatments are made available for individuals with anxiety and depression.

Funding source Departmental funds were used for this research.

Conflict of interest The authors declare no conflict of interest.

Acknowledgments We thank Dr. Louise Mewton and two anonymous reviewers for their suggestions on the earlier versions of the manuscript.

Appendix A. Cochrane Central Register of Controlled Trials (CENTRAL) CENTRAL was searched on the 3rd of March 2014 and 2610 studies were identified. The following search strategy was used: 1. 2. 3. 4. 5. 6.

Mesh descriptor: [Cognitive Therapy] explode all trees (therapn or psychotherapn):ti,ab (depressn or dysthymin and disordern) #1 and #2 and #3 Internet or computern (#1 or #5) and #4

Appendix B. CINAHL search for Depression The search was run 3rd March, 2014 and identified 175 records using EBSCO CINAHL (Cumulative Index to Nursing and Allied Health Literature) and was searched as follows: 1. (MH “Clinical Trials þ”) 2. TI (clinicn N1 trialn) OR AB (clinicn N1 trialn)

3. TI ((singln or doubln or trebln or tripln) and (blindn or dummy or mask)) OR AB ((singln or doubln or trebln or tripln) and (blindn or dummy or mask)) 4. TI (randomi?ed or randomly) OR AB (randomi?ed or randomly) 5. AB (randomn N3 allocatn) or AB n(randomn N3 assignn) 6. (MH “Random Assignment”) 7. PT clinical trial 8. (MH “Placebos”) 9. TI placebon OR AB placebon 10. AB (control N3 trialn) or AB (control N3 study) or AB (control N3 studies) 11. S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 12. (MM “Depression þ”) 13. (Depressive Disordern or Dysthymin Disordern) 14. (MM “Behavior and Behavior Mechanisms þ”) 15. (“activity scheduling” or brief or cognitive or computer or internet or cognitive behavior therapy or “social skilln” or short term or “short-term” or “time-limited” or “time limited”) 16. (S14 AND S15) 17. behavio#r W3 modificationn 18. cognitive W3 modificationn 19. behavio#r W3 contractn 20. behavio#r W3 treatn 21. cognitive W3 treatn 22. behavio#r W3 therapn 23. cognitive W3 therapn 24. (cognitive or therapist or “therapeutic technique” or internet or computern) 25. S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 26. S11 AND S12 AND S13 AND S25.

Appendix C. PsycInfo search for Depression The search was run 3rd March, 2014 and identified 1496 records. OVID PsycINFO as searched as follows: 1. 2. 3. 4. 5. 6. 7. 8.

Clinical Trials.sh. Treatment Effectiveness Evaluation.sh. Mental Health Program Evaluation.sh. randomi#ed.mp. randomly.mp. pla#ebo$.mp. trial$.ti,ab. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp. 9. clinical study.ep. 10. limit 9 to “2000 treatment outcome/clinical trial”


11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

21. 22. 23. 24.

25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

experimental study.mp. limit 11 to “2000 treatment outcome/clinical trial” multicenter study.mp. limit 13 to “2000 treatment outcome/clinical trial” assigned.mp. and control group.ab. randomized$.ab,ti. ((random$ or randomi$) and (experiment$ or evalu$ or effe?t $) and treat$).mp. (doubleblind$ or double-blind$).ti,ab.\ or/1-18 major depression/ or anaclitic depression/ or dysthymic disorder/ or endogenous depression/ or postpartum depression/ or reactive depression/ or recurrent depression/ or treatment resistant depression/ atypical depression/ or/20-21 exp Behavior Therapy/ (behavior therapy/ or aversion therapy/ or conversion therapy/ or dialectical behavior therapy/ or exposure therapy/ or implosive therapy/ or reciprocal inhibition therapy/ or response cost/ or systematic desensitization therapy/) exp Cognitive Behavior Therapy/ (cognitive behavior therapy/ or acceptance and commitment therapy/) exp Cognitive Techniques/ (cognitive techniques/ or cognitive restructuring/ or cognitive therapy/ or self instructional training/) Behavior Contracting/ Assertiveness Training/ or Behavior Modification/ or Sensitivity Training/ Social Skills Training/ exp Problem Solving/ (problem solving/ or anagram problem solving/ or cognitive hypothesis testing/ or group problem solving/ or heuristics/) Internet/ or computern/ or/22-34 (19 and 22 and 35)

Appendix D. Cochrane Central Register of Controlled Trials (CENTRAL) CENTRAL was searched on the 3rd of March 2014 and 1458 records were identified. The following search strategy was used: 1. Mesh descriptor: [Cognitive Therapy] explode all trees 2. (therapn or psychotherapn):ti,ab 3. (anxiety or anxious or panic or (phobian or phobicn or agoraphobin or claustrophobin or acrophobin or ophiodophobin) or (PTSD or Posttrauman or post-trauman or (post next trauman)) and disordern 4. #1 and #2 and #3 5. Internet or computern 6. (#1 or #5) and #4

Appendix E. CINAHL search for Anxiety CBT for Anxiety: The search was run 3rd March, 2014 and identified 31 records. EBSCO CINAHL (Cumulative Index to Nursing and Allied Health Literature) as searched as follows: 1. (MH “Clinical Trials þ”) 2. TI (clinicn N1 trialn) OR AB (clinicn N1 trialn)

165

3. TI ((singln or doubln or trebln or tripln) and (blindn or dummy or mask)) OR AB ((singln or doubln or trebln or tripln) and (blindn or dummy or mask)) 4. TI (randomi?ed or randomly) OR AB (randomi?ed or randomly) 5. AB (randomn N3 allocatn) or AB n(randomn N3 assignn) 6. (MH “Random Assignment”) 7. PT clinical trial 8. (MH “Placebos”) 9. TI placebon OR AB placebon 10. AB (control N3 trialn) or AB (control N3 study) or AB (control N3 studies) 11. S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 12. (MM “Anxiety þ ”) 13. (anxiety disorders or obsessive compulsive disorder or social phobia or social anxiety or panic disorder or generalined anxiety disorder or posttraumatic stress disorder) 14. (MM “Behavior and Behavior Mechanisms þ”) 15. (“activity scheduling” or brief or cognitive or computer or internet or cognitive behavior therapy or “social skilln” or short term or “short-term” or “time-limited” or “time limited”) 16. (S14 AND S15) 17. behavio#r W3 modificationn 18. cognitive W3 modificationn 19. behavio#r W3 contractn 20. behavio#r W3 treatn 21. cognitive W3 treatn 22. behavio#r W3 therapn 23. cognitive W3 therapn 24. (cognitive or therapist or “therapeutic technique” or internet or computern) 25. S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 26. S11 AND S12 AND S13 AND S25.

Appendix F. PsycInfo search for Anxiety CBT for Anxiety: The search was run 3rd March, 2014 and identified 2, 039 records. OVID PsycINFO as searched as follows: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

21. 22.

Clinical Trials. sh. Treatment Effectiveness Evaluation.sh. Mental Health Program Evaluation.sh. randomi#ed.mp. randomly.mp. pla#ebo$.mp. trial$.ti,ab. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp. clinical study.ep. limit 9 to “2000 treatment outcome/clinical trial” experimental study.mp. limit 11 to “2000 treatment outcome/clinical trial” multicenter study.mp. limit 13 to “2000 treatment outcome/clinical trial” assigned.mp. and control group.ab. randomized$.ab,ti. ((random$ or randomi$) and (experiment$ or evalu$ or effe?t $) and treat$).mp. (doubleblind$ or double-blind$).ti,ab.\ or/1-18 anxiety disorders/ or generalized anxiety disorder/ or obsessive compulsive disorder/ or panic disorder/ or posttraumatic stress disorder/ phobias/ or agoraphobia/ or social phobia/ panic attack/ or panic/ or panic disorder/

166


23. 0 or 21 or 22 24. exp Behavior Therapy/ 25. (behavior therapy/ or aversion therapy/ or conversion therapy/ or dialectical behavior therapy/ or exposure therapy/ or implosive therapy/ or reciprocal inhibition therapy/ or response cost/ or systematic desensitization therapy/) 26. exp Cognitive Behavior Therapy/ 27. (cognitive behavior therapy/ or acceptance and commitment therapy/) 28. exp Cognitive Techniques 29. (cognitive techniques/ or cognitive restructuring/ or cognitive therapy/ or self instructional training/) 30. Behavior Contracting/ 31. Assertiveness Training/ or Behavior Modification/ or Sensitivity Training/ 32. Social Skills Training/ 33. exp Problem Solving/ 34. (problem solving/ or anagram problem solving/ or cognitive hypothesis testing/ or group problem solving/ or heuristics/) 35. internet/ or computern/ 36. or/24-35 37. (19 and 23 and 36) References2 nAddis, M.E., Hatgis, C., Krasnow, A.D., Jacob, K., Bourne, L., Mansfield, A., 2004. Effectiveness of cognitive-behavioral treatment for panic disorder versus treatment as usual in a managed care setting. J. Consult. Clin. Psychol. 72, 625–635. Andrews, G., Cuijpers, P., Craske, M.G., McEvoy, P., Titov, N., 2010. Computer therapy for the anxiety and depressive disorders is effective, acceptable and practical health care: a meta-analysis. PLoS One 5, 1–6. nAsukai, N., Saito, A., Tsuruta, N., Kishimoto, J., Nishikawa, T., 2010. Efficacy of exposure therapy for Japanese patients with posttraumatic stress disorder due to mixed traumatic events: a randomized controlled study. J. Trauma. Stress 23, 744–750. nBarsky, A.J., Ahern, D.K., 2004. Cognitive behavior therapy for hypochondriasis: a randomized controlled trial. J. Am. Med. Assoc. 291, 1464–1470. Baskin, T., Tierney, S., Minami, T., Wampold, B., 2003. Establishing specificity in psychotherapy: a meta-analysis of structural equivalence of placebo controls. J. Consult. Clin. Psychol. 71, 973–979. Beck, A.T., Epstein, N., Brown, G., Steer, R., 1988. An inventory for measuring clinical anxiety: psychometric properties. J. Consult. Clin. Psychol. 56 (6), 893–897. Beck, A.T., Steer, R.A., Brown, G.K., 1996. Manual for the Beck Depression InventoryII. Psychological Corporation, San Antonio, TX. nBerkman, L.F., Blumenthal, J., Burg, M., Carney, R.M., Catellier, D., Cowan, M.J., Schneiderman, N., et al., 2003. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. J. Am. Med. Assoc. 289, 3106–3116. Bornstein, M., Hedges, L., Higgins, L., Rothstein, H., 2011. Comprehension MetaAnalysis. Version 2 [Computer Software]. Biostat, Englewood, NJ. Butler, A.C., Chapman, J.E., Forman, E.M., Beck, A.T., 2006. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin. Psychol. Rev. 26, 17–31. nClarke, G., Kelleher, C., Hornbrook, M., Debar, L., Dickerson, J., Gullion, C., 2009. Randomized effectiveness trial of an Internet, pure self-help, cognitive behavioral intervention for depressive symptoms in young adults. Cogn. Behav. Ther. 38, 222–234. nClarke, G., Eubanks, D., Kelleher, C., O’Connor, E., DeBar, L.L., Lynch, F., Gullion, C., et al., 2005. Overcoming depression on the internet (ODIN) (2): a randomized trial of a self-help depression skills program with reminders. J. Med. Internet Res. 7, e16. nCooper, C.L., Hind, D., Parry, G.D., Isaac, C.L., Dimairo, M., O’Cathain, A., Sharrack, B., et al., 2011. Computerised cognitive behavioral therapy for the treatment of depression in people with multiple sclerosis: external pilot trial. Trials 12, 259. nCottraux, J., Note, I., Albuisson, E., Yao, S., Note, B., Mollard, E., Coudert, A., et al., 2000. Cognitive behavior therapy versus supportive therapy in social phobia: a randomized controlled trial. Psychother. Psychosom. 69, 137–146. nCramer, H., Salisbury, C., Conrad, J., Eldred, J., Araya, R., 2011. Group cognitive behavioral therapy for women with depression: pilot and feasibility study for a randomised controlled trial using mixed methods. BMC Psychiatry 11, 82–93.

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Effectiveness and cost effectiveness of cognitive behavioral therapy (CBT) in clinically depressed adolescents: individual CBT versus treatment as usual (TAU).

Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture.

Intrinsic Tau Acetylation Is Coupled to Auto-Proteolytic Tau Fragmentation.

Work-related CBT versus vocational services as usual for unemployed persons with social anxiety disorder: A randomized controlled pilot trial.

A randomized controlled trial of Mindfulness-Based Cognitive Therapy (MBCT) versus treatment-as-usual (TAU) for chronic, treatment-resistant depression: study protocol.

Tau Biology and Tau-Directed Therapies for Alzheimer's Disease.

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy.

HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology.

Tau passive immunization inhibits not only tau but also Aβ pathology.

Neuroinflammation is not a Prerequisite for Diabetes-induced Tau Phosphorylation.

Tau propagation, different tau phenotypes, and prion-like properties of tau.

Microtubule-associated protein tau is essential for long-term depression in the hippocampus.

Time for tau.

TTBK2: a tau protein kinase beyond tau phosphorylation.

Tau 2: a probe for a Ser conformation in the amino terminus of tau.

Tau protein induces bundling of microtubules in vitro: comparison of different tau isoforms and a tau protein fragment.

Anti-tau antibody reduces insoluble tau and decreases brain atrophy.

Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology.

First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model.

Neuronal activity enhances tau propagation and tau pathology in vivo.

Psychodynamic therapies versus treatment as usual for depression.

Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation.

Tau protein is essential for stress-induced brain pathology.

- mice.