EFFICACY OF METACOGNITIVE THERAPY

This thesis submitted to the University of Manchester for the degree of Doctor of Philosophy (PhD) In the Faculty of Biology, Medicine and Health

2016

PIA CALLESEN

SCHOOL OF PSYCHOLOGICAL SCIENCES

LIST OF CONTENTS LIST OF APPENDICES ...... 10 LIST OF TABLES ...... 11 LIST OF FIGURES ...... 13 ABSTRACT ...... 14 DECLARATION ...... 15 COPYRIGHT STATEMENT ...... 16 ACKNOWLEDGEMENTS ...... 17 LIST OF ABBREVIATIONS ...... 18 1.1 INTRODUCTION ...... 19

1.1.1 Effectiveness and efficacy ...... 20

1.1.2 Outline of this thesis: ...... 20

1.1.3 The history of depression ...... 22

1.1.4 Assessment and diagnosis of Major Depressive Disorder (MDD) ...... 23

1.2.1 Models of Major depressive Disorder ...... 25

1.2.2 Beck’s cognitive model of depression ...... 25

1.2.3 The Cognitive Triad ...... 25

1.2.4 Schemas ...... 26

1.2.5 Cognitive errors ...... 27

1.2.6 The meta-cognitive model of depression: The Self-regulatory Executive function (S-REF) model ...... 28

1.2.7 The S-REF model explained ...... 28

1.2.8 The Cognitive Attentional Syndrome - CAS ...... 30

1.2.9 The three components of the CAS ...... 30

1.2.10 Metacognition ...... 32

1.2.11 Rumination ...... 32

2 of 229 1.2.12 Worry ...... 33

1.3 Conclusions ...... 33

2 STUDY 1: A SYSTEMATIC REVIEW OF META-ANALYSES INVESTIGATING PSYCHOLOGICAL TREATMENTS FOR MAJOR DEPRESSIVE DISORDER ...... 34 2.1 Abstract ...... 34

2.1.1 Background ...... 34

2.1.2 Methods ...... 34

2.1.3 Conclusion ...... 34

2.2 Introduction ...... 35

2.2.1 Method ...... 36

2.2.2 Search Strategy ...... 36

2.2.3 Eligibility Criteria ...... 37

2.2.4 Selection of Meta-Analytic Reviews ...... 37

2.2.5 Data Extraction ...... 38

2.2.6 Review Selection & Objectives ...... 40

2.2.7 Characteristics of Meta-analytic Reviews ...... 50

2.2.8 Treatment Comparisons ...... 50

2.2.9 Diagnosis & Patient Samples ...... 54

2.2.10 Mean pre-treatment severity of patients in included studies ...... 54

2.2.11 Treatment Sessions & Overall Duration of Therapy ...... 55

2.2.12 Definitions of Outcome ...... 56

2.2.13 Post-treatment Outcomes of Meta-analysis ...... 56

2.2.14 Psychotherapy vs. Controls ...... 57

2.2.15 Psychotherapy vs. Psychotherapy ...... 57

2.2.16 Psychotherapy vs. Medication ...... 58

3 of 229 2.2.17 Psychotherapy vs. Combined therapy ...... 58

2.2.18 Follow-up results ...... 58

2.2.19 Psychotherapy vs. Controls ...... 59

2.2.20 Psychotherapy vs. Psychotherapy ...... 59

2.2.21 Psychotherapy vs. ADM ...... 59

2.2.22 Psychotherapy vs. Combined therapy ...... 59

2.2.23 Conclusions ...... 60

2.2.24 Within Review Risk of Bias ...... 61

2.2.25 Assessments of Review Biases ...... 61

2.2.26 Search ...... 61

2.2.27 Eligibility criteria ...... 62

2.2.28 Assessments of study validity ...... 62

2.2.29 Synthesis methods ...... 63

2.2.30 Summary of Risk of Bias ...... 64

2.2.31 Across Review Risk of Bias ...... 64

2.2.32 Treatment integrity ...... 64

2.2.33 Treatment duration ...... 65

2.2.34 Pre-treatment severity ...... 66

2.2.35 Definitions of treatment outcome ...... 66

2.3 Overall Discussion ...... 67

2.3.1 Discussion of efficacy of treatments ...... 68

2.3.2 Psychotherapeutic efficacy at post-treatment ...... 68

2.3.3 Comparison of psychotherapy with medication ...... 69

2.3.4 Comparison of psychotherapy alone & combined with medication ...... 70

2.3.5 Discussion of the Risk of Bias Across Reviews ...... 71

4 of 229 2.4 Concluding Remarks ...... 74

3 STUDY 2: METACOGNITIVE THERAPY IN RECURRENT DEPRESSION - A CASE REPLICATION SERIES IN DENMARK ...... 75 3.1 Abstract ...... 75

3.1.1 Background ...... 75

3.1.2 Methods ...... 75

3.1.3 Conclusion ...... 75

3.2 Introduction ...... 76

3.3 Research question...... 79

3.4 Methods ...... 79

3.4.1 Design ...... 79

3.4.2 Participants ...... 79

3.4.3 Patient 1 ...... 80

3.4.4 Patient 2 ...... 80

3.4.5 Patient 3 ...... 81

3.4.6 Patient 4 ...... 81

3.5 Outcome Measures ...... 81

3.6 Procedure ...... 82

3.6.1 Assessment ...... 82

3.6.2 Treatment ...... 82

3.6.3 Therapists ...... 83

3.7 Data Analysis ...... 84

3.8 Results ...... 84

3.8.1 Clinically Significant Change ...... 87

3.9 Discussion ...... 87

5 of 229 4 STUDY 3: COGNITIVE-BEHAVIOURAL THERAPY VS. META- COGNITIVE THERAPY FOR DEPRESSION: A RANDOMISED CLINICAL TRIAL89 4.1 Abstract ...... 89

4.1.1 Background ...... 89

4.1.2 Objectives ...... 89

4.1.3 Methods ...... 89

4.1.4 Findings ...... 89

4.1.5 Interpretaions ...... 90

4.1.6 Trial Registration and funding ...... 90

4.2 Introduction ...... 91

4.3 Study Aims ...... 93

4.3.1 Research hypotheses ...... 94

4.4 Methods ...... 94

4.4.1 Participants and sampling procedures ...... 94

4.4.2 Inclusion criteria ...... 95

4.4.3 Exclusion criteria ...... 95

4.4.4 Sample characteristics at baseline ...... 95

4.5 Outcome measures ...... 98

4.5.1 Primary outcome measures: ...... 98

4.5.2 Secondary outcome measures: ...... 99

4.5.3 Included variables ...... 103

4.6 Ethics ...... 103

4.7 Adverse events ...... 104

4.8 Trial design ...... 104

4.8.1 Deviations from protocol ...... 104

6 of 229 4.8.2 Randomisation ...... 105

4.8.3 Blinding ...... 105

4.8.4 Interventions ...... 105

4.8.5 Cognitive behaviour Therapy (CBT) ...... 105

4.8.6 Meta-cognitive therapy for depression (MCT) ...... 107

4.8.7 Treatment differences ...... 111

4.9 Competency and treatment adherence ...... 111

4.10 Results ...... 113

4.10.1 Number of sessions, drop-out rates and treatment expectancy ...... 114

4.10.2 Data Analysis ...... 114

4.11 Primary outcomes ...... 116

4.11.1 Descriptive statistics ...... 116

4.11.2 Mixed model ANOVA ...... 117

4.11.3 ANCOVA ...... 118

4.11.4 Effect sizes Cohen’s d ...... 119

4.12 Clinical Significant Change & Reliable Change ...... 120

4.12.1 Test-retest reliability ...... 120

4.12.2 Cut-off calculations for BDI-II and HDRS ...... 120

4.12.3 Reliable change calculation ...... 121

4.12.4 Algorithm for categorization ...... 123

4.12.5 Results for BDI-II ...... 124

4.12.6 Results for HDRS ...... 127

4.13 Secondary outcomes ...... 130

4.13.1 Descriptive statistics ...... 130

4.13.2 Secondary Outcomes: Mixed model ANOVA ...... 131

7 of 229 4.13.3 Secondary Outcomes: ANCOVA ...... 132

4.13.4 Effect sizes Cohen’s d for secondary variables ...... 134

4.14 The Therapeutic Alliance ...... 135

4.14.1 Discussion ...... 138

4.14.2 Comparison of MCT versus CBT ...... 138

4.14.3 The effect of the Therapeutic Alliance ...... 141

4.15 Limitations ...... 141

4.16 Generalizability ...... 143

5 Study 4: METACOGNITIVE THERAPY IN TRANSDIAGNOSTIC GROUPS – AN UNCONTROLLED OPEN TRIAL ...... 144 5.1 Abstract ...... 144

5.1.1 Background ...... 144

5.1.2 Methods ...... 144

5.1.3 Conclusions ...... 144

5.2 Introduction ...... 145

5.3 The aim of the study and null hypothesis ...... 147

5.4 Methods ...... 147

5.4.1 Design ...... 147

5.4.2 Participants ...... 147

5.4.3 Measures ...... 150

5.4.4 Procedure ...... 151

5.5 Transdiagnostic MCT ...... 151

5.5.1 The therapists ...... 151

5.6 Results ...... 151

5.6.1 Descriptive statistics ...... 152

8 of 229 5.6.2 Mixed model ANOVA ...... 155

5.6.3 Treatment Effect Sizes (Cohen’s d) ...... 161

5.6.4 Clinical significant change ...... 164

5.7 Discussion ...... 166

6 GENERAL DISCUSSION ...... 168 6.1 Highlights from this thesis ...... 168

6.1.1 Strengthening a new paradigm for treating mental disorders ...... 171

6.1.2 Moving away from the “Tool-box” idea ...... 172

6.1.3 Overall limitations ...... 173

6.2 Future research suggestions ...... 173

7 REFERENCES ...... 175

9 of 229 LIST OF APPENDICES Appendix 1: Search Filters used to Search Electronic Databases in Study One ...... 191

Appendix 2: Screening Tool used to Assess the Eligibility of Reviews in Study One . 202

Appendix 3: Composite Tool used to Extract Substantive & Quality Data* from

Individual Reviews in Study One ...... 203

Appendix 4: Synthesis Methods of Reviews in Study 1 ...... 206

Appendix 5: Details of five Borderline Reviews Included in Study 1 ...... 209

Appendix 6: Ethical approval...... 211

Appendix 7: Participant information & Consent ...... 214

Appendix 8: Efficacy variables & Timeline ...... 216

Appendix 9: Use of scoring sheets for research ...... 217

Appendix 10: Count of participants ...... 218

Appendix 11: Cognitive Therapy Checklist ...... 220

Appendix 12: Metacognitive Therapy Checklist ...... 221

Appendix 13: Activity Schedule ...... 222

Appendix 14: Restructuring form ...... 223

Appendix 15: Normal distribution BDI-II, Hamilton and total HADS ...... 224

Appendix 16: New Plan Summary Sheet ...... 228

Word count: 48.870

10 of 229 LIST OF TABLES Table 1: Summary of the diagnostic criteria from DSM-V for a major depressive episode from (Connor, Wells, & Fisher, 2015):...... 24

Table 2: Eligibility Criteria for Included Meta-analytic Reviews ...... 38

Table 3: Objectives of Included Meta-analytic Reviews...... 42

Table 4: Characteristics of Meta-analytic Reviews: Post-treatment Comparisons ...... 44

Table 5: Characteristics of Meta-analytic Reviews: Follow-up Comparisons...... 48

Table 6: Studies Used for Post-treatment Comparisons in Reviews...... 52

Table 7: Studies Used for Follow-up Comparisons in Reviews ...... 53

Table 8: Different approaches to a negative thought...... 78

Table 9: Descriptive statistics on the main outcome measures at pre-treatment, post- treatment and follow-up...... 84

Table 10: Demographic Variables ...... 96

Table 11: Average treatment adherence to CBT and MCT ...... 112

Table 12: Distribution of LOCF ...... 115

Table 13: Mean scores and standard deviation for primary and secondary outcome variables ...... 116

Table 14: Within subject effect sizes...... 119

Table 15: Between group effect sizes...... 119

Table 16: Standard errors of differences from pre to post for BDI-II ...... 122

Table 17: Standard errors of differences from pre to post for HDRS ...... 122

Table 18: Logical functions used in excel sheets ...... 123

Table 19: Results for BDI-II post-treatment ...... 125

Table 20: BDI-II pre to follow-up ...... 126

Table 21: Recovery rates for HDRS pre to post-treatment...... 128

11 of 229 Table 22: HDRS pre to follow-up ...... 129

Table 23: Standard deviations and mean for secondary outcome variables for CBT and

MCT ...... 131

Table 24: Mixed model ANOVA ...... 132

Table 25: ANCOVA analysis of post-treatment differences ...... 133

Table 26: Adjusted means at post-treatment outcomes...... 134

Table 27: Within subject ES’s...... 134

Table 28: Between group effect sizes...... 135

Table 29: Mean difference in working alliance...... 136

Table 30: ANCOVA Post-treatment and follow-up ...... 137

Table 31: Demographic Variables ...... 149

Table 32: Primary Reason for seeking treatment ...... 149

Table 33: Number of problems reported by patients ...... 150

Table 34: Descriptive Statistics ...... 153

Table 35: Means and Standard Deviations for outcome measures ...... 154

Table 36: Mixed Model ANOVAS ...... 156

Table 37: ANCOVA models ...... 159

Table 38: Adjusted means by diagnosis ...... 160

Table 39: Effect sizes on all outcome variables (whole group) ...... 162

Table 40: Effect sizes for three sub-groups over time ...... 163

Table 41: Reliable Change and cut-off scores based on method a ...... 164

Table 42: Total sample reliable change from pre- to post-treatment...... 165

12 of 229 LIST OF FIGURES Figure 1: The S-REF model ...... 29

Figure 2: PRISMA Diagram - Selection of reviews ...... 41

Figure 3: Scores on the Beck Depression Inventory BDI-II ...... 85

Figure 4: Distribution of levels of depression measured on the BDI-II ...... 98

Figure 5: Consort Diagram (study 3) ...... 113

Figure 6: Mixed model ANOVA effect of time (BDI-II) ...... 117

Figure 7: Mixed model ANOVA effect of time (HDRS) ...... 117

Figure 8: Recovery rates BDI-II study 3 ...... 124

Figure 9: Recovery rates at follow-up for BDI-II ...... 127

Figure 10 Recovery rates for the HDRS post-treatment: ...... 128

Figure 11: Recovery rates HDRS – Follow-up ...... 130

Figure 12: Flow-chart (study 4) ...... 152

Figure 13: Depression score by diagnostic group ...... 157

Figure 14: Anxiety score by diagnostic group ...... 158

Figure 15: Clinical Significant Change Index ...... 165

13 of 229 THE UNIVERSITY OF MANCHESTER Pia Callesen, Doctor of Philosophy (PhD)

Efficacy of Metacognitive Therapy Year of submission: 2016

ABSTRACT This PhD investigated the efficacy of individual therapies for depression and went on to test metacognitive therapy (MCT) for major depressive disorder (MDD) in individual therapy and in transdiagnostic groups consisting of a range of disorders Study 1 included a systematic review of meta-analyses comparing the effects of individual therapy for MDD across studies. The findings show small to moderate effect sizes between g=0.25 to d= 0.69 and recovery rates 34% to 47.9% for ITT analyses. However, studies are biased and lack objective definitions of recovery, remission and clinically meaningful change which makes comparisons across studies challenging. Study 2 aimed to test MCT in a single case study with four depressed Danes in an outpatient setting. Three out of four patients reached recovery levels (BDI-II ≤ 8) in only five to eleven sessions and all four patients were recovered at 6-months follow-up. Study 3 involved a large randomised clinical trial (n= 153) in which the effect of MCT was compared to cognitive behaviour therapy (CBT) for MDD. Patients were allocated to up to 24 sessions of treatment and were assessed at pre, post and 6 months follow-up on primary and secondary measures. The mean number of sessions were significantly lower for MCT (5.5; SD = 2.4 versus 6.7; SD = 4.7) and MCT showed a higher completion rate (73.6% versus 65.4%). Both treatments were associated with significant improvements in depression measured with the HDRS and BDI-II. MCT was superior in its effects on the BDI-II and on secondary measures, showing a clear advantage of MCT. . Large ES were detected in both MCT and CBT. Using Jacobson and Truax (1991) criteria revealed that 76% reached recovery levels at post-treatment in MCT whereas 54% reached recovery in CBT. These findings were maintained for both conditions at 6-months follow-up. Study 4 evaluated the effect of MCT in a 6-week treatment protocol for mixed groups of diagnosis in an open trial (n= 131). Significant improvements were observed in outcomes and 85% of patients were reliably improved at post-treatment as measured on the HADS. These findings were maintained at follow- up and the treatment appeared effective in both anxious and depressed cases. In conclusion existing treatments for depression are effective but there is much room for increasing efficacy. MCT appeared more effective than a current treatment of choice; CBT in depression. MCT was also associated with significant improvement in anxiety and depression in patients in a transdiagnostic group setting. The results support the future study and implementation of MCT as an effective treatment option.

14 of 229 DECLARATION

No portion of the work referred to in this thesis has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning.

15 of 229 COPYRIGHT STATEMENT i. The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and s/he has given The University of Manchester certain rights to use such Copyright, including for administrative purposes. ii. Copies of this thesis, either in full or in extracts and whether in hard or electronic copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as amended) and regulations issued under it or, where appropriate, in accordance with licensing agreements which the University has from time to time. This page must form part of any such copies made. iii. The ownership of certain Copyright, patents, designs, trademarks and other intellectual property (the “Intellectual Property”) and any reproductions of copyright works in the thesis, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property and/or Reproductions. iv. Further information on the conditions under which disclosure, publication and commercialisation of this thesis, the Copyright and any Intellectual Property University

IP Policy (see: http://documents.manchester.ac.uk/display.aspx?DocID=24420), in any relevant thesis restriction declarations deposited in the University Library, The University Library’s regulations (see http://www.library.manchester.ac.uk/about/regulations/) and in The University’s policy on Presentation of Theses.

16 of 229 ACKNOWLEDGEMENTS I would like to thank my husband Lasse Mandal Christiansen for all his help and support on this exciting and bumpy journey.

I would also like to address my gratitude to my supervisor Professor Adrian Wells for taking a chance and believing in me all the way. He is a huge inspiration to me. Without him this thesis would not have been possible.

A special thanks to psychologists Carsten Juul, Charlotte Koch Andersen and Søren Formann at CEKTOS for their help and commitment to help me in my work. Especially Carsten Juul has offered his great help and support along the way.

Finally, Professor Peter Fisher and PhD. Student Lora Capobianco deserves my gratitude as well as Jonas Høgh Jeppesen, Louise Kavin, psychologist Lennart Holm, Anne B Jensen and Sisse Find Nielsen who have helped me to make this thesis possible.

17 of 229 MetaDep = Meta-cognitive Therapy (MCT)

LIST OF ABBREVIATIONS versus Cognitive Behaviour Therapy (CBT) for Depression: A Randomised Clinical Trial

MM = Metacognitive model ACT = Acceptance and Commitment Therapy NBRS = Negative beliefs about rumination ADHD = Attention Deficit/Hyperactivity scale Disorder NICE = National Institute of Health and Care ADM = Anti-depressive medication Excellence ANCOVA = Analysis of covariance OCD = Obsessive Compulsive disorder ANOVA = Analysis of variance PC = Pia Callesen BAI = Becks Anxiety Inventory PBRS = Positive beliefs about rumination BDI-II = Becks Depression Inventory II scale CBT = Cognitive behaviour therapy PTSD = Post traumatic disorder CEKTOS = Center for Kognitiv og RC = Reliable Change Metakognitiv Terapi RCI = Reliable Change Index CFT = Compassion-focused therapy RCT = Randomised controlled trial CJ = Carsten Juul RRS = Rumination Response Scale CKA = Charlotte Koch Andersen SAPAS = Standardised Assessment of DAS-Form A+B = Dysfunctional Attitude Personality – Abbreviated Scale Scale A and B SCID = Structured Clinical Interview for DOW = Ditte Okmann Woodhouse DSM disorders ES = Effectsize SD = Socratic Dialogue GP = General practitioner SF = Søren Formann HAI = Harvarth Alliance Inventory S- REF model = Self-Regulatory Executive HADS = Hospital Anxiety and depression Function Model Scale SUSARs = Suspected unexpected serious HDRS = Hamilton Rating Scale for adverse events Depression YSI = Youngs Schema Inventory - short LOCF = Last Observation Carried Forward version MBCT = Mindfulness-based cognitive WHO = World Health Organization therapy MCT = Meta-cognitive therapy MCQ-30 = Meta-cognitive Questionnaire MDD = Major depressive disorder MDD–S = Major Depressive Disorder Scale

1.1 INTRODUCTION

Major depressive disorder (MDD) is considered one of the largest healthcare problems worldwide. Despite an increase in research and development of treatments the number of depressed individuals is increasing. In 2012 the number of individuals estimated to suffer from MDD worldwide was 121 million Kessler (2012). Today the illness has increased to 350 million people worldwide (Kessler, Sampson, Berglund, Gruber, Al- Hamzawi, Andrade, Bunting, Demyttenaere, Florescu, & de Girolamo, 2015). It is predicted that MDD will be the 2nd largest health problem by the year 2020 (Lanier, 2003).

MDD causes a great deal of human suffering, loss of life quality, income and in some cases suicide. The condition involves symptoms of low mood, loss of interest, feelings of guilt or worthlessness, disturbed sleep and/or appetite, low energy and poor concentration. These problems can become chronic or recurrent and lead to substantial impairments in an individual's ability to take care of his or her everyday responsibilities. Medication and psychotherapy are the most widely used treatments for MDD today.

In Denmark, most patients attending a session at their GP for a mental problem like depression will receive pharmacological help as the first choice of treatment. Over 300.000 prescriptions for anxiety-reducing drugs were issued in Denmark in 2012 alone (SSI, 2012) and over 45.000 prescriptions for anti-depressives. This is a total of more than 750.000 prescriptions within a population of only 5.6 million inhabitants. The number of prescriptions for antidepressants are surprisingly high considering the growing evidence that psychological treatment is just as effective as pharmacological treatment for low to moderate levels of depression (Cuijpers, de Beurs, van Spijker, Berking, Andersson, & Kerkhof, 2013b; Cuijpers, Sijbrandij, Koole, Andersson, Beekman, & Reynolds, 2013c).

However, looking at the literature the effects of medication and psychotherapy are limited or even in some instances declining. A recent meta-analysis looking at the effects of cognitive behaviour therapy over the years from its introduction in the 1970's

by Dr Aaron T. Beck and until today reveals that the effects of CBT as an anti- depressive therapy have been falling steadily and significantly (Johnsen & Friborg, 2015) The reasons for this decline in treatment effect is still unknown. Some speculate that the introduction and implementation of other paradigms incorporated in CBT e.g. Compassion-focused therapy (Hofmann, Grossman, & Hinton, 2011) and mindfulness (McCarney, Schulz, & Grey, 2012) do not fit the original model of CBT and instead of enhancing its effectiveness might have muddled the purity of the treatment and resulted in an decrease in effectiveness.

Others argue that the lack of CBT training and education diminishes the quality of the treatment. Only a minority of practitioners have been educated by the originator of the paradigm, Beck himself. Today most CBT training is done by private practitioners and centres that have not had their original training at the Beck Institute in Philadelphia. These links of separation might have diluted the effect of CBT over the years. In order to reverse this trend high-quality therapy training needs to be used and interventions practised with a high level of treatment fidelity. In addition, it is crucial to develop alternative and potentially more effective treatments for MDD to halt the expansion of this disorder.

1.1.1 Effectiveness and efficacy Throughout the literature single case studies and RCTs have evaluated different treatment approaches to MDD. Generally effectiveness research refers to a broad range of effectiveness studies without any rigour or controlled design and statistical analysis. Efficacy research, on the other hand refers to studies that use much more objective and controlled statistical methods and attempt to control biases. This PhD will primarily focus on the efficacy of MCT for MDD and transdiagnostic groups.

1.1.2 Outline of this thesis: The introduction of this thesis presents an outline of the history and diagnosis of depression. Diagnostic systems for MDD are discussed and then two treatment

20 of 229

approaches for depression are presented: Beck’s cognitive model of depression and Wells’s metacognitive model of depression.

The next part of the thesis presents four studies:

Study 1 consists of a systematic review of meta-analyses evaluating the effects of psychological therapy for depression at post-treatment and follow-up. In addition, this chapter will include a discussion of the methodological limitations and biases in these reviews.

Study 2 includes a single case study testing metacognitive therapy (MCT) for depression in four Danish outpatients. Others have evaluated MCT for depression in single case studies, but this was the first time MCT was evaluated in the country of Denmark.

Study 3 involves a large parallel and randomised clinical trial comparing individual cognitive therapy (CBT) with meta-cognitive therapy (MCT) in 153 patients. Patients were evaluated at pre-treatment, post-treatment and at 6 months follow-up. The study will implement knowledge from study 1 in order to reduce the risk of potential biases. This is the first time MCT been evaluated and compared with CBT for depression in a definitive trial.

Study 4 evaluates MCT in a transdiagnostic group therapy setting involving 131 patients suffering from mixed diagnoses including stress, OCD, anxiety, PTSD and depression in a Danish outpatient clinic. This study was the first of its kind to test MCT in a large outpatient setting in mixed diagnostic groups.

The last section will include the highlights from this thesis and an overall discussion of the implications of the current studies and suggest directions for future work in the field.

21 of 229

1.1.3 The history of depression

The earliest clinical usage of the term “depression” may have been German psychiatrist Emil Kreapelin in the late 19th century, who suggested viewing different kinds of melancholia as different kinds of depressive states (Lewis, 1934). Kreapelin unified many types of mood disorders into manic-depressive insanity, assuming underlying brain pathology, but also offered a view that origins of mood disorder could be endogenous (internally) or exogenous (externally) caused.

In 1920 this view was partly supported by German psychiatrist Kurt Schneider, using the terms endogenous depression and reactive depression (Mapother, 1926). Even though this may have been misunderstood, as Schneider pointed to reactivity in mood and not from outside events.

A competing view to Kreapelin’s psychobiological theory was Sigmund Freud’s psychoanalytical approach. In his essay “Mourning and Melancholia”, Freud argued that melancholia had the same symptoms as mourning and depressed mood, but that melancholy was depressed mood without a cause – or at least an unknown, unconscious cause (Carhart-Harris, Mayberg, Malizia, & Nutt, 2008) Mourning could be recovered without treatment, but melancholy could not, and required psychoanalysis to find the subliminal roots of the disorder.

Freud theorized that objective loss, such as loss of a relationship – through death or another cause – would result in subjective loss because the depressed individual had identified with the object of affection through an unconscious, narcissistic process called libidinal cathexis (the process of investment in mental or emotional energy in a person, object or idea) of the ego (Freud, 1984). Such a loss will, according to Freud, result in severe melancholic symptoms which are more deep and profound than the similar mourning, because not only is the outside world viewed negatively, so is the ego itself during the process of libidinal cathexis. Freud believed that the patient’s blow to the ego is revealed through expressions of blame, inferiority and unworthiness. It is

22 of 229

important to note that Freud also thought of past life experiences as influencing the process of libidinal cathexis.

A new view of depression was developed by Aaron Beck in the 1960’s theorizing that depression stems from a negative cognitive triad of negative thinking patterns, which consisted of “schemas” about oneself, ones future, others and the world (Beck, Rush, Shaw, & Emery, 1979 ).

1.1.4 Assessment and diagnosis of Major Depressive Disorder (MDD)

There are two major diagnostic protocols available when diagnosing MDD. The newest version of the Diagnostic and Statistical manual of mental disorders - DSM-V (American Psychiatric, American Psychiatric, & Force, 2013) and the International Classification of Diseases - ICD-10 produced by the World Health organisation (Organization, 1992). DSM is typically used in the USA and other non-European countries whereas ICD-10 is normally used primarily in Europe. There are many similarities and a few differences in these two manuals for diagnosing MDD. Both DSM-V and ICD-10 mark out typical core depressive symptoms that involve low mood for at least 2 weeks and impairments in social, physical and cognitive functioning. In DSM-V MDD is classified as a mood disorder and is classified as a single episode or recurrent MDD. The category Depressive Disorder Not Otherwise specified is diagnosed if the depressive episode's manifestation does not meet the criteria for a major depressive episode.

The ICD-10 diagnosis does not use the term major depressive disorder but lists very similar criteria for the diagnosis of a depressive episode (mild, moderate or severe); the term recurrent may be added if there have been multiple episodes without mania. There seem to be very few differences between DSM and ICD-10. A comparison study from 1999 showed a 83% overlap in the categorisation of the systems for depression (Andrews, Slade, & Peters, 1999) When assessing MDD one of the most popular

23 of 229

screening interviews is SCID-I based on DSM (Spitzer, Williams, Gibbon, & First, 1992).

Table 1: Summary of the diagnostic criteria from DSM-V for a major depressive episode from (Connor, Wells, & Fisher, 2015): 1. Depressed mood most of the time 2. Loss interest /pleasure in everyday activities 3. Weight loss or weight gain (change in appetite) 4. Change in sleeping patterns – sleeping too much or minimally 5. Psychomotor agitation or retardation 6. Tiredness, feeling fatigued, lacked energy 7. Feeling of worthlessness or guilt 8. Poor concentration, difficulty in making decisions 9. Frequent thoughts of death, including thoughts and plans of suicide or suicide attempts.

The above symptoms have to be present for at least two weeks and the core symptoms of depressed mood or lack of pleasure/interests need to be present. The condition needs to be severe enough to impair everyday social and work-related activities (Spitzer et al., 1992).

24 of 229

1.2.1 Models of Major depressive Disorder Today the most widely used model for MDD are the bio-psychosocial model in which depression is caused by an interaction between neurochemical imbalance in the brain and external life stress (Health & Services, 1999). A large volume of research has highlighted the biological aspects of depression and enhanced the belief that depression is caused by biological factors or high levels of genetic vulnerability (Sullivan, Neale, & Kendler, 2014). However, psychological models offer a different account based on learning, cognitive and interpersonal processes.

The psychological treatment paradigms of focus in this PhD are based on the approaches of Beck (Beck, Rush, Shaw, & Emery, 1979) and Wells (Wells, 2009b).

In the following sections brief presentation of the underlying theoretical models behind these two approaches will be presented.

1.2.2 Beck’s cognitive model of depression The cognitive model of depression postulates three specific concepts to explain the development and maintenance depression (Beck et al., 1979 ).

1.2.3 The Cognitive Triad This consists of three major cognitive patterns that stimulate the patient to regard himself, his future and his experiences in an idiosyncratic way. The first component involves the patient’s negative view of himself as defective, inadequate, diseased or deprived. He/she attributes the current condition as a result of psychological, moral or physical defects in him/herself. This patient believes that s/he lacks skills essential to attain happiness.

The second component of the cognitive triad consists of the person’s way of interpreting his/her experiences in a negative way. The world is seen as making exceedingly high demands or presenting too many obstacles to reach desired life goals. Interactions with the environment are often misinterpreted as defeat or deprivation.

25 of 229

The third component consists of a negative view of the future. The depressed individual anticipates that the current problems and suffering will continue always - current problems of feeling down, being inanimate, frustrated, and deprived is expected to continue indefinitely.

The symptoms MDD are viewed as consequences of these negative cognitive patterns. As an example, if a patient through biased thinking interprets a situation as being rejected will react with the same negative affect (sadness, anger) that occurs with actual rejection.

Some patient’s behaviours including inactivity is thought to stem from pessimism and hopelessness. If the patient expects negative outcome of activity, he/she is less likely to undertake goal seeking. Depressed patients can become dependent on others simply because the individual sees him/herself as helpless and overestimates the difficulty of normal tasks. The explanation of the depressed patient’s physical symptoms, like apathy and low energy, is thought to be beliefs that the person is doomed to fail in all efforts.

1.2.4 Schemas The schema concept attempts to explain why a depressed patient maintains his negative attitudes despite objective evidence of positive factors in his/her life. All situations in a person’s everyday life consist of a vast array of stimuli; the schema theory assumes that every person will try to combine this broad range of stimuli into patterns that conceptualize the situation, these are called schemas.  Facing a specific situation, a schema related to this situation is activated. This schema is the basis for “moulding” data into cognitions. Situations are categorized and evaluated through a matrix of schemas, and the actual schema activated in a situation is determines how the individual will structure experiences.  Schemas can be inactive for long periods of time and activated in specific situations and determine the person’s response in the current situation. In the

26 of 229

depressive state, the persons conceptualization of specific situations are re- evaluated by the individual to fit active or inactive dysfunctional schemas and the patient loses control over his thinking processes and becomes unable to activate other less dysfunctional schemas

1.2.5 Cognitive errors These systematic errors in the depressed patient’s thinking result in negative concepts despite contradictory evidence. These errors can be:

1) Arbitrary inference - drawing conclusions in the absence of evidence to support a conclusion or when evidence supports contrary conclusions Selective abstraction - focusing on a detail taken out of context and ignore more relevant features of the situation and conceptualizing this in the light of the negative schema 2) Overgeneralization - the tendency to draw general rules or conclusion isolated events 3) Magnification or minimization - errors in evaluating the significance of an event 4) Personalization - the patients tendency to attribute external events to himself even despite contrary evidence 5) Dichotomous thinking - the tendency to place all experiences in one of two opposite categories - e.g. either flawless or defective

The cognitive model is essentially an information processing model in which predisposition to depression is based on schemas developed through early experiences, forming negative concepts about oneself, the future and the external world. These schemas are assumed to be latent ready to be activated in critical circumstances (Beck et al., 1979 ). Cognitive therapy is designed to help the person realize that these negative interpretations are biased and restructure the patients’ thinking into more realistic and balanced interpretations.

27 of 229

1.2.6 The meta-cognitive model of depression: The Self-regulatory Executive function (S-REF) model The primacy of schemas and negative thoughts in depression has been challenged by Wells who states: “Everyone has negative thoughts and everyone believes those negative thoughts sometimes, and yet not everyone develop psychological disorders”, (Wells, 2009a). If believing ones negative thoughts is not enough to become depressed then what controls thinking and what is the basic underlying factor behind psychological disorder, specifically depression?

According to the researchers behind the S-REF model (Wells & Matthews, 1996b), existing cognitive theories of psychological disorders are limited in there consideration of multiple elements of cognition, neglecting other perspectives of consciousness and cognition like attention, levels of processing and the interaction between types of processing. Attention is linked closely to selection of information for processing and thus guidance of behaviour, and these processes are central to the modelling of emotional disorders guided by dysfunctional thinking (Wells & Matthews, 1996).. Beck’s original model does not aim to explain factors which modulate and control thinking itself. Therefore, Wells and Matthews believe that it is important to look beyond the content of appraisals and beliefs about the self and world and explore factors that control thinking and attention and are involved in the interpretation of thoughts (Wells & Matthews, 1996a).

1.2.7 The S-REF model explained The Self-Regulatory Executive Function model (S-REF) is an information-processing and emotional-regulation model that consists of three interacting levels that regulate emotions and cognition: a) A stimulus driven lower level of processing which is mainly involuntary and subconscious b) A more voluntary and conscious level which depends on available attentional resources and c) A store of self-knowledge in long-term memory that is metacognitive in nature and concerns how to use thinking, attention and memory.

28 of 229

These levels support the range of emotion-related processing that is available to the individual. According to the S-REF model (Wells & Matthews, 1996a) psychological disorders are linked to and maintained by the activation of a style of thinking that is referred to as the Cognitive Attentional Syndrome (CAS) (Wells, 2009b):

Figure 1: The S-REF model

Figure 1 shows how the S-REF model works. There are three levels of processing: 1) A stimulus driven lower level of processing which is mainly involuntary and subconscious, 2) A more voluntary and conscious level which depends on available attentional resources and 3) a store of self-knowledge in long-term memory on how to cope with internal or external stimuli. (Reproduced from Wells and Matthews (1996b)

29 of 229

1.2.8 The Cognitive Attentional Syndrome - CAS The S-REF model states that the maintenance of psychological disorders is linked to a syndrome of cognitive-attentional responses characterised by self-focus, mental dwelling on negative self-beliefs about the past or the future (rumination or worry), threat monitoring and dysfunctional coping strategies such as avoidance of certain activities or thoughts and emotions (The Cognitive Attentional Syndrome = CAS). The results of staying in the CAS for an extended period of time is a maintenance of depressive symptoms, inactivity, isolation, and an inability to process emotions automatically and adaptively (Wells, 2009b; Wells & Matthews, 1996b).. Typically the CAS is activated as a means of trying to deal with negative thoughts such as: “Why am I feeling so depressed?” The individual’s metacognitive beliefs determine the strategies towards such a negative thought. If the person believes that rumination will help him find answers and solutions to his problems he will spend many hours analysing his situation, previous behaviour, current emotional state and will engage in mood-checking in order to detect fluctuations early on. However, by engaging in the CAS the person maintains negative processing and gains no answer or disconfirmation, and there is a further need for self-regulation that maintains the condition (Matthews & Wells, 2000; Wells, 1995).

1.2.9 The three components of the CAS The CAS consists of three components, and is the persons response to internal mental events or coping style. However, awareness or knowledge of control and volition over the processes such as rumination that contribute to this style is incomplete and often erroneous (Wells, 2009b).

The three main components of the CAS are: 1. A preponderance of verbal conceptual activity in the form of worry and rumination

30 of 229

Depressed patients spend a prolonged period of time dwelling on the past and present with the purpose of finding answers and solutions to their depressed state. In many cases low levels of metacognitive awareness are present in which the patient hardly notices rumination. Rumination is a long chain of verbal thoughts, where the person tries to find answers to questions about why he/she is feeling depressed and why previous negative experiences have occurred. It is triggered by thoughts involving ”Why….” something happened in the past, followed by an extended inner dialogue to find answers. In some patients worry about the future and whether the depression is a permanent state or not is also apparent.

2. The tendency to maintain attention on sources of threat (self-monitoring). Many depressed individuals use a great deal of time monitoring their thoughts, feelings and bodily sensations in order to detect signs or fluctuations that could signal a deterioration of symptoms or be a sign of relapse.

3. Coping behaviours that disrupt self-regulation or the acquisition of new information that can modify erroneous knowledge. The most common maladaptive self-control strategies in depression involve avoidance and relaxation/sleeping, thought-suppression and alcohol use. Many depressed patients start to avoid social - and work related activities. All these strategies backfire and contribute to maintaining dysfunction. Most strategies provide short-term relief, but fail to provide long-term solutions to regulation of rumination. Thought suppression, for instance, is not effective and inhibits self- regulation. It contributes to further negative thoughts /emotions and prevents the individual developing a more flexible relationship with his/her own cognitions.

Several studies have confirmed the metacognitive model of depression. In a recent large scale study done in the UK researchers found that both traumatic life events and a persons’ thinking styles were equally determinant for the person developing anxiety and depression. The study concluded that ruminating

31 of 229

about negative life events appeared to be a high risk factor for anxiety and depression (Laks, Kinderman, Schwannauer, Pontin, & Tai, 2013).

1.2.10 Metacognition The CAS is a result of the control that metacognition exerts over thinking (Wells, 2009). Metacognition is a broadly used term, (Flavell, 1999; Larkin, 2010). It is defined as thinking about thinking (Flavell, 2007) and it can be usefully divided into the domains of metacognitive knowledge, strategies and experiences (Flavell, 1997) that have been expanded and applied in the metacognitive model of psychological disorder (Wells, 2000, 2009).

1.2.11 Rumination According to the S-REF model (Wells & Matthews, 1996a) excessive rumination is the main cause of depression due to extended negative thinking that maintain low mood. Rumination has the function of problem-solving and finding solutions and answers e.g. “Why did I get depressed?” What is wrong with me?” and “How do I get out of this depression?”. According to Wells rumination interferes with in-built emotional processing and lower level cognitive activities. At the same time rumination uses up processing resources necessary for executive control of cognition thereby maintaining emotion-focused and passive coping and a sense of low mood. The concept of rumination is central to psychological disorder.

A growing number of studies have demonstrated that ruminative thinking predicts depression (Papageorgiou & Wells, 2004). Rumination is distinguished from the negative automatic thoughts that are typical of depression according to the basic assumptions in CBT. Papageorgiou and Wells (2004) have argued that negative automatic thoughts, which are relatively brief, are not the cause of depression, whereas rumination consisting of long chains of repetitive negative, and self-focused thinking that occur as a response to initial negative thoughts and is the factor that prolongs low mood. This notion is supported by several studies (Hong, 2007; Papageorgiou & Wells, 2004; Raes, Williams, & Hermans, 2009).

32 of 229

1.2.12 Worry Worry is a common element of MDD and typically involves engaging in thoughts like “Will I ever get better?”, “What if I never recover?”. Worry is a strategy in which the person attempts to engage in mental preparation on uncertain outcomes (Clark & Rhyno, 2005; Mennin, Heimberg, & Turk, 2004; Pruzinsky & Borkovec, 1990). Worry is a predominantly a verbal and conscious activity which is similar to rumination but has a different time perspective and goal (Wells, 2002, 2005b).

MCT is designed to help the depressed patient identify his CAS consisting of rumination/worry, self-monitoring and maladaptive coping-strategies and reduce it to overcome depressive symptoms.

1.3 Conclusions

Both CBT and MCT are information processing models with very different explanations of what cause MDD. In CBT depression is thought to result from biased interpretation of the self and events caused by negative schemas. In MCT depression is caused by active maladaptive mental and attentional strategies that backfire and prolong self- regulation. CBT predates MCT and is the most widely tested, used and accepted intervention for most mental disorders including anxiety and depression with medium effect sizes (Watts, Turnell, Kladnitski, Newby, & Andrews, 2015).

CBT is based on schema theory in which the content of the persons thinking is the cause of low mood and biased information processing. The solution to depression in CBT is therefore to challenge and restructure dysfunctional and irrational thinking.

MCT is based on the Self-Regulatory Executive Function (S-REF) model which states that a particular cognitive attention syndrome (CAS) contributes to the development and maintaining of psychological disorders and increases the probability of relapse. The S- REF model states that the regulation of emotions is dependent on the interaction of different levels of mental processes, particularly those controlled by a metacognitive level. The solution to depression in this approach is to reduce the CAS and modify unhelpful metacognitions

33 of 229

2 STUDY 1: A SYSTEMATIC REVIEW OF META-ANALYSES INVESTIGATING PSYCHOLOGICAL TREATMENTS FOR MAJOR DEPRESSIVE DISORDER

2.1 Abstract

2.1.1 Background Major Depressive disorder (MDD) is one of the most prevalent and disabling mental disorders. The aim of this study was to perform a systematic review of meta-analyses evaluating the effects and relapse rates of individual psychotherapy for MDD. In addition, we intended to investigate and discuss biases and limitations across studies.

2.1.2 Methods A systematic search using pre-specified eligibility criteria was conducted on nine databases. Data from included meta-analytic reviews were extracted using a modified version of the University of York’s Centre for Reviews and Dissemination’s Abstract reporting format. A total of nine meta-analyses fulfilled the eligibility criteria and results were analysed both at post-treatment (n= 6527) and follow-up (n= 1485).

2.1.3 Conclusion Effect sizes were small to moderate and varied from Hedges g = 0.25 to Cohens d = 0.69. Recovery rates ranged from 31.7% (CBT) to 61.8% (ADM) and relapse rates ranged from 27% (Psychotherapy) to 61% (ADM). Psychotherapy with or without ADM showed the largest remission, however, relapse was high when only ADM was administered. Comparisons across studies were challenging because of methodological limitations and large differences in definitions of recovery/remission.

34 of 229

2.2 Introduction

Major Depression (MDD) is a mood disorder marked by the long-term presence of the following symptoms: a persistent sad or “empty” mood, hopelessness, loss of interest in daily activities, and thoughts of suicide. These symptoms inhibit the daily functioning and well-being of affected individuals (Insel & Gogtay, 2014). Major depression affects an estimated 350 million people worldwide (WHO, 2016). but despite its prevalence treatment options are limited. Pharmacological treatments, specifically SSRI anti- depressants, and CBT are the most commonly used and accepted forms of treatment. However, recent studies have illustrated that these standard treatments might be less effective than perceived. Pharmacological interventions have been shown to have a relatively small effect for patients with major depression (Kirsch & Deacon, 2008). The leading therapeutic intervention for depression, CBT, has been losing efficacy over time; a recent meta-analysis has suggested that modern-day CBT provides less relief for depressed patients than CBT provided in the 1970s (Johnsen & Friborg, 2015). Given these findings, it is necessary to determine the true level of effectiveness of current therapies and medicines.

The current treatments have been developed and implemented based on historical findings presented in research literature - specifically, the results of meta-analyses. However, the reliability of these meta-analyses has been called into question. A number of methodological difficulties may have undermined the reliability of these findings. One systematic review by (Moncrieff, Churchill, Drummond, & McGuire, 2001) used an inclusion of non-randomised studies, which poses a major risk to the validity of meta-analyses within systematic reviews. Also, in Moncrieff et al. (2001) analysis inclusion of undiagnosed individuals might threaten the generalizability of findings across clinical populations. Meta-analyses are key to creation of clinical guidance for practitioners. With the possibility of reduced reliability and validity of meta-analyses, it is vital to assess the quality of potentially influential reviews that have investigated treatments for major depressive disorder (MDD).

35 of 229

This systematic review of reviews is intended to identify and evaluate earlier published systematic meta-analyses where efficacy of treatments for MDD are included.

The aims of this study were to investigate:

 The efficacy of different therapy approaches to MDD at post-treatment and follow-up  Assess potential biases and limitations within and between reviews.

2.2.1 Method Reviews were included if they were methodologically rigorous, if the included studies were randomised controlled trials (RCTs), and if they investigated the efficacy of individual (face-to-face) psychological treatments with patients meeting official diagnostic criteria for MDD. Also, treatments must have been based on theoretical models of psychopathology. Web based interventions were not included. This approach makes it possible (using a rigorous approach) to assess the effectiveness of current psychological treatments for MDD. This approach also makes it possible to determine whether studies could provide biased results.

2.2.2 Search Strategy The following databases were used: Cochrane Library, PsychINFO. EMBASE, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE, SCOPUS, and Web of Science. An experienced reviewer (PF) designed the search filter. Search terms included: depression, depressive, major depressive disorder, depressive disorder, dysthymia, psychotherapy meta-analysis, systematic review and possible variants for each database. Furthermore, references in the identified reviews were investigated to further empty out existing base of eligible meta-analytic reviews. ‘In press’ articles were not prioritised. Search was done in November 2015. The full search strategy is presented Appendix 1.

36 of 229

2.2.3 Eligibility Criteria The eligibility criteria for reviews are shown in Table 2. There were no set limitations on publication date, duration of treatment or time of follow-up. Nor were there set limitations on outcome measures used to determine symptom severity or statistical methods used for analysis.

2.2.4 Selection of Meta-Analytic Reviews Identified articles were collected into a single database and duplicates removed. A single reviewer (PC) excluded references that did not meet the eligibility criteria based on article title. An independent reviewer screened the abstracts of remaining articles and excluded ineligible articles. Articles, which could not be excluded on the basis of title or abstract were obtained and assessed by two independent reviewers (PC/RJ) using a purpose made screening tool (see Appendix 2). This tool operationalised the eligibility criteria and permitted each eligibility criterion to be recorded as present, absent or questionable for each systematic review that included meta-analyses. Where reviewers failed to agree concerning the eligibility of reviews a third reviewer was consulted (PF).

37 of 229

Table 2: Eligibility Criteria for Included Meta-analytic Reviews

Inclusion Criteria Exclusion Criteria

Review Type Systematic review, meta-analysis or review No English translation available of randomised controlled trials Unpublished Published in peer reviewed journal

Patient Type Adults diagnosed with major depression Diagnosis based solely on screening according to a classificatory diagnostic instruments or where consistent methods were scheme not described when using published criteria

Depression treated specifically in the context of substance abuse, personality, psychotic or medical disorders

Sub syndromal depression not meeting criteria for major depression

Treatment Individual bona fide form of psychotherapy Group therapy

based on a theoretical model of Computer administered therapy psychopathology Self help interventions

Comparison Treatment as usual, waiting list control, Conditions attentional control, psychotherapy, pharmacotherapy

Outcomes Meta-analytic estimates of therapeutic Narrative review efficacy based on group-level data Reviews not using group as the unit of analysis

2.2.5 Data Extraction Substantive data from included meta-analytic reviews were extracted using a modified version of the University of York’s Centre for Reviews and Dissemination’s abstract reporting format (Dissemination, 2009). One reviewer (PC) extracted data which was checked and revised if necessary by another (RJ) concerning:

 the authors’ objectives  search methods and included designs  patient type, severity and duration of depression  comparison conditions  therapy types and diagnostic techniques used in studies

38 of 229

 setting and duration of therapy  assessment points in time  results from meta-analysis  findings of any heterogeneity of results between included studies and whether they were accounted for  authors conclusions & statements concerning implications for practice or research

The risk that any single review provided biased meta-analytic results was assessed using an instrument based on the University of Sheffield’s School of Health & Related Research (ScHARR) Systematic Review Quality Appraisal guidance (University of Sheffield, 2009). Data on risk of bias (formerly called, ‘quality data’ (Moher, Liberati, Tetzlaff, & Altman, 2009) were extracted by two independent reviewers (PC/RJ). The quality of reviews was assessed in terms of the following questions:

 was the search process adequate?  were eligibility criteria reported?  were included studies valid?  was there an assessment of study quality?  appropriate outcome measures used?  methods of data extraction reported?  appropriateness of any numerical synthesis and any sub-group analyses?  presented numerical results appropriate?  issues of generalisability addressed?

Answers to these questions were independently categorised as “yes/no” or “partially” with disagreements being resolved by discussion. Appendix 3 contains the composite instrument used to extract the risk of bias data (Moher et al., 2009). Data was analysed and compared using tables for overview.

39 of 229

2.2.6 Review Selection & Objectives The study selection procedure is shown in the PRISMA flowchart (Figure 1) with a reviewer agreement rate of 94%. Within some reviews it was found that some results met the eligibility criteria, while others did not. For these reviews non-eligible results were not included in this study. Five of ten reviews were considered borderline for inclusion and were included.

All compared efficacy of psychotherapy with alternative treatment. All of the reviews measured outcomes at post-treatment, of which five reviews provided outcome measures at follow-up (de Maat et al., 2006; Friedman et al., 2004; Leichsenring, 2001; Vittengl et al., 2007). Van Hees et al., (2013) included two studies with follow-up but without any analysis or discussions of these studies. Both post-treatment assessements (Table 4) and follow-up assessments (Table 5) are compared. Psychotherapy provided in the acute phase of MDD was investigated in six reviews, where Vittengl et al. (2007) reviewed comparisons of continuation phase psychotherapy (C-CT) with alternative treatment.

40 of 229

Figure 2: PRISMA Diagram - Selection of reviews

References identified from Cochrane Library,

PsychINFO, EMBASE, Ovid MEDLINE(R) In-Process & Other Non-Indexed

Citations, Ovid MEDLINE, SCOPUS, Web of Science Total = 6014

Excluded n = 1607 References following

duplicate removal = 4407 Excluded n = 2508 References following title screening = 1899

Excluded n = 1713 References following abstract screening = 186

Excluded n = 165

References following independent manuscript review & application of eligibility criteria = 11 Borderline reviews discussed with third assessor = 10

Excluded n = 12

Selected reviews n = 9

41 of 229

Table 3: Objectives of Included Meta-analytic Reviews.

Review Objectives of the Review

Casacalenda et al. To determine the percentages of patients achieving remission from (2002) depressive symptoms within randomised controlled trials that had directly compared psychotherapy, pharmacotherapy and control conditions.

Cuijpers et al. (2014) To determine the effects of psychotherapies compared to pill placebo in the treatment of depressive disorders de Maat et al. (2006) To determine the relative efficacy of pharmacotherapy & psychotherapy assessed at treatment termination and at follow-up for clinically homogeneous patients. A secondary objective was to investigate the impact of dropout and the severity or chronicity of depression on outcomes. de Maat et al. (2007) To determine the relative efficacy of psychotherapy & psychotherapy combined with pharmacotherapy in the acute treatment of depression for clinically homogeneous patients. A secondary objective was to investigate possible differences in dropout rates between conditions and whether differences existed in prognosis for patients suffering differing severities or durations of depression.

Friedman et al. To determine whether combined therapy was more efficacious than (2004) pharmacotherapy or psychotherapy alone as part of a broader review of the literature on combined treatment for major depressive disorder.

Leichsenring (2001) To directly compare the efficacies of Short Term Psychodynamic Therapy and CBT at post treatment and at follow-up for treatments lasting at least 13 sessions.

Parker et al. (2008) To challenge the findings of a previous meta-analysis by Gloaguen et.al (1998) where it was concluded that CBT for depression demonstrated superior post-treatment outcomes than pharmacotherapy.

Van Hees et al (2013) To determine the effects of interpersonal therapy with or without antidepressant medication on major depressive disorder compared to other forms of psychotherapy and /or pharmacotherapy.

42 of 229

Vittengl et al. (2007) To determine (i) the rate of relapse-recurrence amongst responders to acute phase cognitive therapy (A-CT) and (ii) whether A-CT reduced relapse-recurrence better than other acute phase treatments during

follow-up.

To determine whether continuation phase cognitive therapy (C-CT) reduced relapse-recurrence more than non-active control conditions

or other active continuation phase treatments at the end of C-CT and during follow-up.

43 of 229

Table 4: Characteristics of Meta-analytic Reviews: Post-treatment Comparisons Characteristics of Meta-analytic Reviews: Post-treatment Comparisons

Review Primary Therapy Diagnostic Pre- Ns Np Maximum Primary Primary Sample Results C.I BD SS SO VA S R Comparison Models Criteria treatment Therapy Outcome outcome analysed (95 Severity Sessions definition %)

Cuijpers et al. Psychotherapy vs CBT, IPT Min HDRS 10 124 6 to 20 Recovery Effect size ITT HDRS eff. Hedges g 0.14 + + + - + + (2014) ADM placebo <17 0 diff. HDRS Completer Size diff = 0.25* - > 3.0 0.36 Effect size BDI eff. 2.66 1.35 diff. BDI > Size - 3.0 5.04 Van Hees et al. Psychotherapy IPT DSM-IV 8 854 8 to 24 Recovery BDI ≤ 9 ITT IPT 38.3% + + + - + + (2013) (CBT or IPT) vs Completer 0.34 ADM or - combined 2.37 HDRS ≤ 6 31.7%

CBT CBT n/a n/a ADM ADM n/a n/a Remission HDRS ≤ 6 n/a n/a

MADRS ≤ n/a n/a 60% change

Casacalenda et Psychotherapy vs CBT DSMIII Min BD 14 6 883 6 to 20 Remission - HDRS ≤ 6 ITT Psychother 47.9% 37.8 + + + - + + al. (2002) to 20 ITT or 7 Completer apy – 57.9 ADM or controls IPT DSMIII-R Min HDRS Raskin Controls 27.7%** 15.7 13 to 14 Depression – Scale ≤ 5 39.7 PST RDC ADM 0.46 37.6 - 54.8 SWC

Remission – HDRS ≤ 6 Psychother 59.5% n/a Completer or 7 apy Controls 24.6**

44 of 229

Characteristics of Meta-analytic Reviews: Post-treatment Comparisons

Review Primary Therapy Diagnostic Pre- Ns Np Maximum Primary Primary Sample Results C.I BD SS SO VA S R Comparison Models Criteria treatment Therapy Outcome outcome analysed (95 Severity Sessions definition %)

ADM 61.8% de Maat al. Psychotherapy vs CT/CBT DSMIII-R Min BDI 10 123 16 to 24 Remission HDRS ≤ 6, ITT ADM 34.8% n/a + + + - + + (2006) 14 to 20 3 7, 8 or 9 ADM CBASP DSMIV Min HDRS HDRS ≤ 9 Psychother 37.9% n/a 10 to 20 and BDI ≤ 8 apy IPT RDC HDRS ≤ 9 Relative 0.91 0.79 and BDI ≤ 9 Risk – 1.06

BDI >15. Physician indicated need for treatment. Meeting RDC criteria for MDD for more than 2 weeks. Relapse Two BDI scores > 15 separated by 1 week. IDS > 29. Meeting criteria for MDD for more than 2 weeks or HDRS > 13.

45 of 229

Characteristics of Meta-analytic Reviews: Post-treatment Comparisons

Review Primary Therapy Diagnostic Pre- Ns Np Maximum Primary Primary Sample Results C.I BD SS SO VA S R Comparison Models Criteria treatment Therapy Outcome outcome analysed (95 Severity Sessions definition %)

Parker et al. Cognitive CBT RDC Min BDI 9 327 12 to 24 Response - BDI ≤ 7 or ITT Relative 1.795†*∂ n/a + + + - + + (2008) Therapy vs ADM 10-17 ITT 9 Completer Risk DSMIII Miin BDI ≤ 9 1.11† HDRS 12- after at least 20 12 sessions and 15 weeks of treatment. Feighner Symptom ITT Cohen’s d -0.353† - 0.81 – 0.10 reduction Completer for BDI -0.173† - 0.64 – 0.29 de Maat et al. Psychotherapy vs CT/CBT DSMIII-R Min BDI 7 903 16 to 24 Remission- HDRS ≤ 6, ITT Psychother 34% + + + - + + (2007) combined 14 to 20 ITT 7 or 8 apy therapy CBASP DSMIV Min HDRS BDI ≤ 10 Combined 46% 1.12 12 to 20 therapy – 1.56 STPP RDC BDI ≤ 9 and Relative 1.32 Δ HDRS ≤ 9 Risk BDI ≤ 8 and HDRS ≤ 9 Friedman et al. Psychotherapy vs CBASP RDC Min HDRS 3 530 6 to 20 Recovery - HDRS ≤ 6, ITT Cohen’s d +0.1¶Δ n/a +/- + + - + + (2004) combined 13 to 20 Completer 7 or 8 Completer for BDI therapy PST Feighner

CT DSMIV Relapse Retreatment Cohen’s d +0.69Δ¶ n/a for MDD or BDI ≥ 16. BDI ≥ 16 for HDRS +0.24Δ¶ for 2 weeks or more.

46 of 229

Characteristics of Meta-analytic Reviews: Post-treatment Comparisons

Review Primary Therapy Diagnostic Pre- Ns Np Maximum Primary Primary Sample Results C.I BD SS SO VA S R Comparison Models Criteria treatment Therapy Outcome outcome analysed (95 Severity Sessions definition %)

Physician indicated need for treatment. Leichsenring (2001) CBT vs STPP CBT RDC Min BDI 5 323 13 to 20 Remission HDRS ≤ 6 Unclear Cramer’s 00.08 n/a + + + - + + 10 to 17 or Φ improvemen t STPP DSMIII Min HDRS BDI ≤ 8 14 Feighner BDI & HDRS ≤ 10 SADS- Change, RDC Vittengl et al (2007a) C-CT vs non- CT DSMIII-R Min HDRS 4 234 6 to 10 Relapse/recu HDRS ≤ 9 Unclear C-CT 12% n/a + + + - + + active DSM-IV 12 to 16 rrence Controls 38% n/a controls assessed at AUC 0.61* 0.53 the end of - C-CT (41 0.68 weeks) Note: All studies settings are outpatient Key: ADM = antidepressant medication; BDI = Beck Depression Inventory; CBASP = cognitive behavioural analysis system of psychotherapy; CBT = cognitive behavioural therapy; C-CT = continuation phase cognitive therapy; CT = cognitive therapy; BA = Behavioural activation; DSM = Diagnostic & Statistical Manual of Mental Disorders; Feighner = Feighner Diagnostic Criteria for Use in Psychiatric Research; HDRS = Hamilton Rating Scale for Depression; ; ITT = Intention to treat analysis; IPT = interpersonal psychotherapy; Min = Minimum; n/a = not available; Np = total number of patients included in post-treatment analysis; Ns = maximum number of studies used in any post-treatment meta analysis; PST = problem solving therapy; RDC = research diagnostic criteria; SCID = STPP = short term psychodynamic psychotherapy; SWC = social work counselling. BD=Bibliographic details. SS=Study Selection. SO=Study Outcomes. VA=Validity Assessment. S=Synthesis. R=Result of the review

NS = number of studies used in analysis; STPP = short term psychodynamic psychotherapy. Ω = Following removal of Herceg-Baron et al (1979).

Δ = favoured combined therapy ¶ = unknown significance level ∂ = favoured CBT † = significant heterogeneity between included studies  = p < 0.05; ** = p < 0.01; *** = p < 0.001

47 of 229

Table 5: Characteristics of Meta-analytic Reviews: Follow-up Comparisons.

Review Primary Therapy Diagnost Pre- Ns Np Maximum Treatment Follow-up Primary Results C.I BD S S V S R Comparison Models ic treatment Therapy Duration Period Outcome (95%) S O A Criteria Severity at Sessions (weeks) (weeks) Start of Acute Treatment de Maat al. Psychotherapy vs CT/CBT DSMIII- HDRS mild 6 231 20 to 24 8 to 20 52 to 104 Relapse ADM 57 n/a + + + - + + (2006) ADM IPT R to moderate % DSMIV RDC Psychothe 27 n/a rapy % Relative 0.46 0.33 – Risk *** 0.65 Friedman et Psychotherapy vs CT RDC Min BDI 10 3 78 20 to 23 12 to 20 52 to 104 Relapse Cohen’s d - n/a +/- + + - + + al. (2004) combined therapy to 17 0.12 ¶Δ DSM III Min HDRS 14 Leichsenring CBT vs STPP CBT RDC Min BDI 10 4 270 16 to 20 n/a 52 to 104 Patients Cramer’s 00.1 n/a + + + - + + (2001) DSMIII to 17 remitted or Φ 2 improved STPP Min HDRS 14 Vittengl et al. C-CT vs non- CT RDC Min HDRS 5 232 10 20 to 35 69 to 312 Relapse/recurr C-CT 40 n/a + + + - + + (2007b) active controls DSMIII- 12 to 16 ence % R DSMIV Controls 73 % AUC 0.64 0.57 – + + + - + + * 0.72 Vittengl et al. A-CT vs Other CT RDC Min BDI 20 4 194 8 to 20 16 52 to 104 Relapse/recurr CT 25 n/a (2007c) depression DSMIII ence % specific DSMIII- psychotherapies R

48 of 229

Review Primary Therapy Diagnost Pre- Ns Np Maximum Treatment Follow-up Primary Results C.I BD S S V S R Comparison Models ic treatment Therapy Duration Period Outcome (95%) S O A Criteria Severity at Sessions (weeks) (weeks) Start of Acute Treatment

Other PT 29 n/a % AUC 00.5 0.42 – 0 0.58 Min HDRS 14 Vittengl et al. A-CT vs ADM CT RDC Min BDI 20 7 344 20 to 24 8 to 16 52to 104 Relapse/recurr ADM 61 n/a + + + - + + (2007d) DSMIII to 21 ence % DSMIII- R DSMIV DSMIV- TR Min HDRS CT 39 n/a 12 to 21 % AUC 0.61 0.53 – * 0.67 Vittengl et al. A-CT vs CT DSMIII Min BDI 20 3 136 20 to 24 8 to 12 52 to 104 Relapse/recurr CT 33 n/a + + + - + + (2007e) Combined DSMIV to 21 ence % therapy Min HDRS CT plus 39 n/a 14 to 21 ADM %

Key: ADM = antidepressant medication; A-CT = acute phase cognitive therapy; BDI = Beck Depression Inventory; CBT = cognitive behavioural therapy; CBASP = Cognitive Behavioural Analysis System of Psychotherapy; C-CT = continuation phase cognitive therapy; CT = cognitive therapy; DSM = Diagnostic & Statistical Manual of Mental Disorders; HDRS = Hamilton Rating Scale for Depression; IPT = interpersonal psychotherapy; Min = Minimum; n/a = not available; Np = total number of patients included in follow-up analysis Ns = number of studies used in follow-up meta analysis; RDC = research diagnostic criteria; STPP = short term psychodynamic psychotherapy. Note: all session and duration data refer to acute treatment studies providing data for follow-up comparisons except for Vittengl et al. (2007b) which refers to continuation treatments Δ = favours combined therapy ¶ = unknown significance level

* = p < 0.05; ** = p < 0.01; *** = p < 0.001 For Vittengl et al. (2007): b = C-CT vs non active controls c = A-CT vs other depression specific psychotherapies d = A-CT vs ADM e = A-CT vs combined therapy 49 of 229

2.2.7 Characteristics of Meta-analytic Reviews In order to aid clarity Table 4 and Table 5 present the characteristics of included meta- analytic reviews for post-treatment and follow-up comparisons respectively.

2.2.8 Treatment Comparisons Post-treatment Table 4 shows four reviews compared psychotherapy with anti-depressant medication (Casacalenda, Perry, & Looper, 2002; Cuijpers, Berking, Andersson, Quigley, Kleiboer, & Dobson, 2013a; De Maat, Dekker, Schoevers, & De Jonghe, 2006a; Parker, Crawford, & Hadzi‐Pavlovic, 2008b) two compared psychotherapy plus ADM (combined therapy; De Maat, Dekker, Schoevers, and de Jonghe (2007); Friedman, Detweiler-Bedell, Leventhal, Horne, Keitner, and Miller (2004)) two with controls (Casacalenda et al., 2002; Vittengl, Clark, Dunn, & Jarrett, 2007b) and one comparing different therapies (van Hees, Rotter, Ellermann, & Evers, 2013). Specific psychotherapy models were compared with alternative treatments in four reviews (Cuijpers et al., 2013a; De Maat et al., 2007; Leichsenring, 2001; Parker, Mills, & Abbey, 2008a; Vittengl et al., 2007b), and four reviews combined psychotherapy models for their comparisons with alternative treatments (Casacalenda et al., 2002; De Maat, Dekker, Schoevers, & De Jonghe, 2006b; De Maat et al., 2007; Flavell, 1999; Friedman et al., 2004; Friedman & Leslie, 2004; R., 2014; van Hees et al., 2013). The post-treatment comparison of (Vittengl, Clark, Dunn, & Jarrett, 2007a) refers to outcomes at the end of C-CT in patients responding1 to acute phase psychological treatments and were subsequently assigned to either a C-CT or a control group not receiving treatment.

1 The criteria for response employed by original authors are not presented in this review.

50 of 229

Follow-up It is important to investigate if treatment outcomes are maintained at follow-up. Table 5 shows that five reviews repeated treatment comparisons at both post-treatment and at follow-up (De Maat et al., 2006b; Leichsenring, 2001; Vittengl et al., 2007b). De Maat et al. (2006a) and Leichsenring (2001)used follow-up comparisons only on data that was available from patients included in the same post-treatment comparisons. Unlike this approach, Friedman et al. (2004) and Vittengl et al. (2007a) included follow-up data from studies that were not included in their post-treatment analyses. Cuijpers, Weitz, Twisk, Kuehner, Cristea, David, DeRubeis, Dimidjian, Dunlop, Faramarzi, Hegerl, Jarrett, Kennedy, Kheirkhah, Mergl, Miranda, Mohr, Segal, Siddique, Simons, Vittengl, and Hollon (2014) and van Hees et al. (2013) considered follow-up in some studies (Dimidjian, Hollon, & Dobson, 2006; Elkin, Shea, Watkins, Imber, Sotsky, Collins, Glass, Pilkonis, Leber, & Docherty, 1989; Schramm & Berger, 2011; Schulberg, Block, Madonia, Scott, Rodriguez, Imber, Perel, Lave, Houck, & Coulehan, 1996); yet they did not use a systematic follow-up analysis on these results. Similarly Vittengl et al., (2007d) made three additional comparisons for which there were no corresponding post- treatment results (see Table 4). Here A-CT was compared to ADM combined therapy (Vittengl et al., 2007e), or other depression targeted psychotherapies (Vittengl et al., 2007c). Vittengl et al.’s review was both to compare the efficacy of treatments and investigate prevention of relapse/recurrence. The studies included for follow-up comparisons in reviews are referenced in Table 7.

51 of 229

Table 6: Studies Used for Post-treatment Comparisons in Reviews

Casacal enda X X X X X X 2002 Cuijpers X X X X X X X X X 2014 de Maat X X X X X X X X X X 2006 de Maat X X X X X X X 2007 Friedma X X X X n 2004 Leichse nring X X X X X 2001 Parker X X X X X X X X X 2008 Van Hees X X X X X X X X 2013 Vittengl X X X X 2007

Rush,1977 Hercegbaron, 1979 McLean,1979 Blackburn, 1981 Hersen, 1984 Murphy, 1984 Beck,1985 Roter Sloane, 1985 Thompson, 1987 Elkin, 1989 Hollon, 1992 Scott,1992 Gallagher Shapiro, 1994 Murphy, 1995 Mynors Hautzinger, 1996 Schulberg, 1996 Blackburn, 1997 Jarrett, 1998 Jarrett, 1999 Jarrett, 2000 Keller, 2000 Mynors O’Hara2000 Williams, 2000 Barrettt2001 Jarrett Martin 2001 Jonghe, de 2004 Klein,2004 DeRubeis,2005 Dimidjian 2006 Blom 2007 Marchall2008 Luty 2009 Hegerl, 2010 Schramm2011 Barber 2012

-

, , 2001

Zimmer,1985

- -

Wallis, 1995 Wallis, 2000

-

Thompson, 1994

52 of 229

Table 7: Studies Used for Follow-up Comparisons in Reviews

de Maat 2006 X X X X X X

Friedman 2004 X X X

Leichsenring 2001 X X X X

Vittengl 2007 (b) X X X X X

Vittengl 2007 (c) X X X X

Vittengl 2007 (d) X X X X X X X

Vittengl 2007 (e) X X X

Blackburn, 1986 Simons,1986 Gallagher Shea, 1992 Evans,1992 Jacobson, 1993 Gallagher Shapiro, 1995 Hautzinger, 1996 Fava, 1998 Gortner, 1998 Jarrett, 1998 Jarrett, 2000 Jarrett, 2001 Fava, 2004 Hollon, 2005 Segal,2006

- -

Thompson 1990 Thompson, 1994

For Vittengl et al (2007): b = C-CT vs non active controls c = A-CT vs other depression specific psychotherapies d = A-CT vs ADM e = A-CT vs combined therapy

53 of 229

2.2.9 Diagnosis & Patient Samples Table 4 and Table 5 both show that patients included in all reviews were diagnosed with MDD using a variety of clinician rated diagnostic criteria. Diagnosis was mainly based on DSM or SCID. Post-treatment comparisons in eight reviews were based on outpatient data, where Parker et al. (2008a) included one single study Hautzinger (1996) using inpatient data (Table 4). However, this study was used in only one of four comparisons (De Maat et al., 2006a; De Maat et al., 2007; Parker et al., 2008a) also included Hautzinger (1996) but extracted data for outpatients only.

2.2.10 Mean pre-treatment severity of patients in included studies As can be seen in Table 6 and Table 7 quite a few reviews used the same studies. The overview in and Table 4 enables the possibility of comparing severity of means across studies. De Maat et al. (2006b); De Maat et al. (2007) described the mean pre-treatment severity for each of their included studies, and because studies used different versions of the HDRS, an algorithm to even out this difference was applied De Maat et al. (2006a); De Maat et al. (2007). The mean pre-treatment severity of patients across these studies fell within the mild to moderately depressed range (12 to 19.9 and 20 to 24.9 points). Corresponding mean HDRS scores were reported by Casacalenda et al. (2002)with scores ranging from 15.3 to 23.4 indicating mean severities in similar range. However, Casacalenda et al. (2002) failed to report which versions of the HDRS were used. Also with a mean score of 23.4 for Schulberg et al. (1996) approximately 50% of patients in this study may have been severely depressed, if using the De Maat et al. (2006a); De Maat et al. (2007) criteria. Cuijpers, Koole, van Dijke, Roca, Li, and Reynolds (2014) reported a broader mean baseline severity ranging from mild to severe also using HDRS, and finally van Hees et al. (2013) did not report the level of depressive symptoms at pre-treatment.

As can be seen in Table 6 the majority of studies in Friedman et al. (2004) and Parker et al, (2008) were also included in de Maat et al. (2006), suggesting that pre-treatment severity was similar. Similarly, Table 7 indicates that all of the follow-up studies included by Friedman et al. (2004) and Vittengl et al. (2007e) were also included in de

54 of 229

Maat et al.’s (2006) follow-up analysis, again confirming similar severity level. Finally, five out of seven studies in Vittengl et al. (2007d) were also included by de Maat et al. (2006), suggesting similarity in these severity ranges.

2.2.11 Treatment Sessions & Overall Duration of Therapy The studies included in the reviews varied considerably on number of sessions offered to patients. Cuijpers et al (2014) and Casacalenda et al. (2002) reviewed studies where treatment ranged from 6 to 20 sessions. The Acute treatment comparisons showed a wider range than reported for continuation treatment studies. Looking at the original articles for the included studies a median number of offered sessions for acute treatments was 20 across studies. This mean was 10 for continuation treatments.

The time spread of sessions varied considerably, except for Friedman et al. (2004) where all were scheduled for 12 weeks. The longest acute treatment duration was found in Casacalenda et al. (2002), where the spread was 34 weeks because of the inclusion of Schulberg et al. (1996) which consisted of 16 weekly acute sessions followed by four monthly continuation sessions. The highest treatment durations when looking at post- treatment analyses were reported for continuation treatments (Vittengl et al., 2007a) mainly because continuation sessions were likely to be provided less frequently than acute treatments.

Follow-up Analyses Follow-up comparisons were based on studies using a smaller number of available sessions than those found for post-treatment comparisons, except for Vittengl et al. (2007c). The median number of offered sessions and the corresponding duration of acute treatment were 20 over a mean of 16 weeks. For C-CT these values were 10 sessions over up to 27 weeks (Vittengl et al., 2007b).

55

2.2.12 Definitions of Outcome All reviews used categorical outcomes for comparison, most commonly using remission or recovery at post-treatment and relapse2 at follow-up. Only Van Hees et al. (2013), Friedman et al. (2004) and Parker et al. (2008) presented effect sizes on symptom reduction (Table 4). Most studies used a minimum severity score on either the Hamilton Rating Scale for Depression(Hamilton, 1960) or Beck Depression Inventory (BDI, Beck, Ward, and Mendelson (1961)) to assess remission. In most of Parker et al.’s (2008) studies definition of ‘response’ was assessed as a BDI score of less than 10. This BDI score represents minimal or no depression in patients according to Beck, Epstein, Brown, and Steer (1988) and this confirms that the majority of outcomes in Parker et al. (2008) were indeed estimates of remission. Both Friedman et al. (2004) and de Maat et al. (2016) used similar HDRS criteria to define post-treatment recovery showing good comparability. Most follow-up comparisons were based on the identification of relapse/recurrence following a new MDE or retreatment for depression (Table 5). However, both Table 4 and Table 5 show that all reviews are based on diverse definitions of outcome. For example, Table 4 shows that de Maat et al. (2006) included studies that defined remission as a criterion score of 6 or less on the HDRS whilst others used 7, 8 or 9. Also some studies could operationalise outcomes based on more than one criterion. One example of this was found in Friedman et al (2004) where one study defined relapse as a BDI greater than or equal to 16 or retreatment for depression (Table 4).

2.2.13 Post-treatment Outcomes of Meta-analysis The post-treatment results for this analysis are presented in Table 4. The main focus of included reviews is largely clinical significance. This means recovery or remission rate, response to therapy and relapse rates (Casacalenda et al., 2002; de Maat et al., 2006; de Maat et al., 2007; Parker et al., 2008; Vittengl et al., 2007, van Hees et al., 2013). Friedman et al. (2004) main focus were comparisons in terms of Cohen’s d. effect sizes

2 This is better described as recurrence, however, the term will be retained to correspond with the definitions used in primary studies.

56

Van Hees et al., (2013) differed in measuring results in effect size difference between conditions.

2.2.14 Psychotherapy vs. Controls Results of psychotherapy against controls showed that four reviews found significantly better outcome for psychotherapy than controls (Casacalenda et al., 2002; Vittengl et al., 2007; Cuijpers et al, 2014; van Hees et al, 2013). Remission for acute psychotherapy was found by Casacalenda et al. (2002) to be significantly better in both ITT (47.9% vs. 27.7%) and completer analyses (59.5% vs. 24.6%) than measured for controls. However, this superior performance of psychotherapy compared to controls in their completer analysis was only identified following the removal of Rounsaville, Weissman, Prusoff, and Herceg-Baron (1979), where patient attrition was considered excessive. Controls used in Casacalenda et al. (2002) consisted of different approaches, including pill placebo (3 studies), treatment as usual (TAU, 2 studies) or ‘supportive therapy’. “Supportive therapy” was intended to be a non-treatment offer where patients were given option for one therapeutic session per month together with an assessment (Rounsaville et al., 1979). In Casacalenda et al. (2002) approximately 45% of patients in the two TAU conditions were receiving ADM. In the review by Vittengl et al. (2007) the relapse/recurrence rate was found to be significantly lower at the end of C-CT than non-treatment controls (12% vs. 38%).

2.2.15 Psychotherapy vs. Psychotherapy One review (Leichsenring, 2001) found no significant difference between efficacy of acute STPP and CBT measured on remission or improvement (Table 4). Van Hees et al (2013) investigated interpersonal psychotherapy vs. CBT and other CT based treatments and did not find any significant differences measured on reduction in depressive symptoms measured on the HDRS. Van Hees et al. (2013) found inconsistent results. Overall the result for IPT and CBT was equal. Generally when comparing CBT with other CT based therapies or with IP, CBT was not found to be superior in the outcomes measured.

57

2.2.16 Psychotherapy vs. Medication Four reviews did not find that psychotherapy alone was more efficacious than ADM measured on remission or symptom reduction (Casacalenda et al., 2002; de Maat et al., 2006; Parker et al., 2008). Only Parker et al. (2008) reported one study with a single significant result favouring CBT over ADM, but concluded that this was due to bias arising from significantly higher attrition rates in the ADM condition (see Table 4). Parker et al. (2008) did, however, identify significant statistical heterogeneity between the results in all four of their meta-analytic comparisons. Table 4 shows that efficacy of psychotherapy varied considerably within the included reviews, where for example the estimated ITT psychotherapy remission rates for Casacalenda et al. (2002) were 47.9% and de Maat et al. (2006) were 37.9% Further, ITT relative risk of remission in Parker et al. (2008) and de Maat et al. (2006) were 1.795 and 0.91. Cuijpers et al (2014) found that psychotherapy did not present different effect sizes than pill placebo conditions, and van Hees et al. (2013) found that overall ADM was more effective when IPL was added than when using solely ADM.

2.2.17 Psychotherapy vs. Combined therapy Three reviews favoured combined therapy over psychotherapy, and showed no evidence of heterogeneity between included studies (de Maat et al., 2007; Friedman et al., 2004; Van Hees et al. 2013). Only de Maat et al. (2007) reported significantly higher pooled ITT remission rates for combined therapy (46%) compared to psychotherapy alone (34%). It is important to note though, that, de Maat et al. (2007) performed a sensitivity analysis revealing that combined therapy was only superior to psychotherapy alone for chronically depressed patients who scored in the moderately depressed range at pre- treatment.

2.2.18 Follow-up results Follow-up results can be found in Table 5. Two reviews presented categorical results (de Maat et al., 2006; Vittengl et al., 2007), and two presented results in terms of symptomatic reduction (Friedman et al., 2004; Leichsenring, 2001). None of the

58

reviews found statistically significant heterogeneity within the results of their included studies.

2.2.19 Psychotherapy vs. Controls Vittengl et al, 2007b, showed that that relapse rates were significantly lower for C-CT patients than no-treatment controls at follow-up (40% versus 73% respectively) over a mean of 153 weeks).

2.2.20 Psychotherapy vs. Psychotherapy Leichsenring (2001) and Vittengl et al. (2007c) did not identify CT to be superior to STPP or other psychotherapies measured at follow-up. Relapse rates at follow-up (mean = 92 weeks) were 25% and 29% for CT and other depression specific psychotherapies respectively (Vittengl et al., 2007c). Van Hees et al. (2013) included one study comparing IPT with CBASP, but found no significant differences at follow-up. Again, the general trend in the reviews point to psychotherapies being equally efficacious.

2.2.21 Psychotherapy vs. ADM In two reviews it was found that psychotherapy was superior to ADM in terms of relapse prevention at follow-up ranging between 52 to 104 weeks (de Maat et al., 2006; Vittengl et al., 2007d). Table 5 shows that relapse rate for psychotherapy patients is 27% in de Maat et al. (2006), which is lower than the 39% seen for Vittengl et al. (2007d). It is important to note, however, that relapse for ADM patients in both studies were equal at approximately 60%. As mentioned, Van Hees et al. (2013) described one study comparing IPT with ADM at follow-up but this study failed to report significant differences.

2.2.22 Psychotherapy vs. Combined therapy One review (Vittengl et al., 2007e) found no difference in relapse rate between CT and combined therapy at follow-up which was stretched over a period of 61 weeks (33%

59

and 39% respectively). Friedman et al. (2004) reported a Cohen’s d of 0.12 which favoured combined therapy, yet the result was not significant.

2.2.23 Conclusions In those papers where similar treatment comparisons were made they generally reached similar conclusions. Not surprisingly, reviews indicated that psychotherapy is more efficacious than no treatment, but that different types of psychotherapies do not differ significantly at post-treatment and follow-up, showing that long-term CBT is no more efficacious than the psychotherapies included in the selected reviews. Comparisons between psychotherapy and ADM indicated equivalent efficacy at post-treatment, but psychotherapy proved to be more effective at follow-up. Finally, as many studies have shown earlier, the combination of psychotherapy and ADM appears to be more efficacious at post-treatment, but this effect disappears at follow-up. In the next section the quality and risk of bias in the reviews will be discussed.

60

2.2.24 Within Review Risk of Bias For this analysis, the risk of producing unreliable results has been reduced by using systematic methods in the process of identification and assessment of included reviews. Risk factors that impact the validity of eligible studies include inadequate randomisation methods, differences in between-group patient attrition or general treatment integrity (Perepletchikova & Kazdin, 2005). There will be a risk of bias if studies that differ on these factors are included (Dissemination, 2009). Therefore it has been essential to identify and exclude studies of poor quality based on these basic principles. Borderline cases must be subject to sensitivity analysis to avoid biasing meta-analytic results (Dissemination, 2009).

2.2.25 Assessments of Review Biases Only one review could be characterised as a systematic review, and was characterised as such by its authors (van Hees et al, 2013). In this study there was considerable variation in the reporting of methodological details. In the quality review for this analysis it was found that only two reviews provided adequate detail in method of data extraction (de Maat et al., 2006, 2007). All included reviews did, however, clearly describe inclusion eligibility criteria. There was not found any evidence that studies in this meta-analysis were inappropriate according to the quality appraisal instrument. However, it was found that Casacalenda et al. (2002) did not sufficiently adhere to recommended methods in terms of pooling individual study effect sizes. Leichsenring (2001) and Friedman et al. (2004) did not provide confidence intervals for their main results, which meant that they failed to disclose statistical significance. All reviews discussed relevant issues concerning the generalizability of their results. Additional within-review risk of bias data is presented in Table 4 and Table 5.

2.2.26 Search The Parker et al. (2008) study was a replication of a previous meta-analysis using only studies identified in the previous work assessed for eligibility (Gloaguen et al., 1998). De Maat et al. (2006, 2007) only included studies that were published after 1980 (after

61 of 229

DSM III was published). Friedman et al., (2004) and Leichsenring (2001) provided no reason for their search time range. In four reviews a requirement of English publication was implemented (Casacalenda et al., 2002; Friedman et al., 2004; van Hees et al 2013; Cuijpers et al 2014). In this analysis, four of the included reviews included a study not published in English (de Maat et al., 2006; de Maat et al., 2007; Parker et al., 2008; Vittengl et al., 2007). The study in question is Hautzinger et al., 1996. None of the reviews included contained unpublished studies. None of the reviews included in this analysis used a search that can be categorized as a full systematic review, and de Maat et al. (2006, 2007) consequently suggested that their results were likely to be affected by search bias.

2.2.27 Eligibility criteria All reviews included were required to be RCT’s studying treatment outcomes for adults diagnosed with depression according to acknowledged criteria. Only in de Maat et al. (2006, 2007) it was required that independent reviewers agreed for study inclusion. All reviews reported eligibility criteria, these are presented with the rationale for inclusion in Table 4 and Table 5.

2.2.28 Assessments of study validity Six of the included reviews reported assessment of the validity of the studies included in their review (Table 4), although assessment according to published standards were used only in five of them (Casacalenda et al., 2002; de Maat et al., 2006; de Maat et al., 2007; Van Hees et al 2013; Cuijpers et al 2014). De Maat et al. (2006, 2007) required that eligible studies should meet published quality criteria including randomisation, reporting of attrition and the use of blinded outcome assessments. Furthermore, it was required that patients in all included studies received equivalent amounts of treatment contact to minimise possible performance bias (de Maat et al., 2006; 2007). Only in the de Maat et al. (2006, 2007) studies it was required that included studies used methods that ensured that antidepressive medication was administered at a therapeutic dose. In Casacalenda et al. (2002) all studies used blinded assessments, yet it was noted that

62 of 229

50% of studies failed to provide an adequate description of the randomisation process used.

In the remaining reviews there was no reporting of study quality in accordance to published standards. However, as can be seen from Table 6, six of eight studies in Parker et al. (2008) and three of four in Friedman et al. (2004) were also included in de Maat et al.’s (2006, 2007) reviews and consequently did meet published standards. Also, as can be seen in Table 5, all follow-up studies in Friedman et al. (2004) and Vittengl et al. (2007e) did meet de Maat et al.’s validity criteria, which the majority of studies included in Vittengl et al. (2007d) did too.

2.2.29 Synthesis methods Estimates of treatment efficacy can be based on two criteria. The first being the inclusion of patients who complete a predefined course of treatment (completer analysis), or the second being all patients who begin treatment (intention to treat analysis, ITT). Use of a Meta-analysis of individual study ITT data provides protection against the possibility of non-randomisation bias due to different attrition rates between treatments groups (Dissemination, 2009). We can see in Table 4 that three reviews provide post-treatment comparisons based on both completer and ITT data, and two only for ITT data. It was not clear which type of sample was used by Leichsenring (2001) and Vittengl et al. (2007), which also is the case for all follow-up comparisons. Unfortunately this meant that it was not possible to evaluate potential impact of patient attrition in these studies.

Synthesis of data was done using different methods. In four of the studies a fixed effects model was used (Casacalenda et al., 2002; de Maat et al., 2006, 2007; Friedman et al., 2004), where Parker et al. (2008) and Vittengl et al. (2007) used a random effects model. It was unfortunately that the model used by Leichsenring (2001) is unclear. Only Casacalenda et al. (2002) pooled effect sizes without first weighting them to account for differences in study size, creating a possibility that results could be biased by large observed treatment differences, which are more likely in smaller studies (Dissemination, 2009). All reviews included - except Casacalenda et al. (2002) - tested

63 of 229

for significant heterogeneity between individual study effect sizes. Appendix 4 presents further details of the synthesis methods used in reviews.

2.2.30 Summary of Risk of Bias The review appraisal instrument showed that De Maat et al. (2006, 2007) adhered best to systematic methods and presented the lowest overall risk of bias across the included studies. The remaining seven reviews lacked information about methods, which made it difficult to determine possible bias in results. One example is that the risk of bias in Casacalenda et al. (2002) was reduced by their post-hoc appraisal of study validity and that this study included only blinded assessments. However, the risk of bias was increased due to the possibility of poor randomisation in 50% of studies included in their study and their unconventional method of synthesis. Parker et al. (2008) on the other hand used conventional synthesis methods, but failed to report assessments of study validity, and also neglected to identify all eligible studies. Looking at Parker et al. (2008), the majority of studies in post-treatment comparisons met the validity criteria as specified by de Maat et al. (2006). Generally follow-up comparisons had greater risk of bias than post-treatment ones, due to a lack of information about type of samples used. In Leichsenring (2001) and Vittengl et al. (2007) for post-treatment outcomes, and Friedman et al.’s (2004) there was found a lack of information on significance of findings, and consequently these reviews provide the highest risk of bias.

2.2.31 Across Review Risk of Bias No review searched for unpublished studies or tested for publication bias. Examining substantive and quality data indicated that all reviews were indeed at a risk of bias due to further common methodological limitations. Also it is important to state that integrity and quality of actual psychological treatments in all studies in every review could not be assured.

2.2.32 Treatment integrity In order to make valid conclusions about treatment efficacy, treatment must be provided as intended (Perepletchikova, 2009). In studies where integrity of treatment is in doubt, it is not certain that measured differences are due to efficacy of treatment type. A way to

64 of 229

ensure confidence in integrity of psychotherapy is to ensure that therapists: (i) adhere only to the methods specific to the psychotherapy under investigation and, (ii) are competent in the use of these methods (Perepletchikova & Kazdin, 2005; Westen, Novotny, & Thompson-Brenner, 2004). Also, to make sure techniques are used correctly, therapist’s performance should be monitored to avoid misuse or improper use of treatment. The issue of treatment integrity was raised by some review authors, which led to further scrutiny here.

This concern was expressed in Friedman et al. (2004) and Vittengl et al. (2007). Also, de Maat et al. (2006, 2007) noted that included studies had retained the integrity of ADM treatments but failed to report the same for psychological treatments. Studying the manuscripts of studies included in de Maat. et al. (2006) it was found that a number of studies failed to report information on methods to ensure integrity. Furthermore, none of the studies reported methods of assessing integrity of psychotherapy during treatment period. This provides an overall risk of bias due to possible inclusion of studies that did not ensure integrity of treatment.

2.2.33 Treatment duration Overall, the reviews included used results from a range of studies that varied highly in terms of treatment duration, number of therapy session offered or the frequency of sessions (see Table 4). This broad range of differences in duration and number and frequency of treatment sessions is a challenge in terms of comparison. Psychotherapy provided over 16 weeks could create higher remission rates than if duration were shorter, and when comparing psychotherapy with ADM duration becomes even more important because ADM is considered to provide more rapid results than therapeutic interventions, making comparisons sensitive to bias in shorter duration studies (Elkin et al., 1989). It should be noted though, that findings in this study point to a conclusion that acute psychotherapy delivers lower risk of relapse than ADM measured at follow- up.

Another point concerns frequency of therapy sessions, which varied considerably between included studies. In some studies 3 sessions of CBT each week was provided

65 of 229

(de Maat et al., 2006; de Maat et al., 2007; Leichsenring, 2001)., contrasted by a study with 23 sessions offered over 20 weeks (Blackburn, Bishop, Glen, Whalley, & Christie, 1981), creating a difference of duration of 12 weeks. The important note in this connection is that if treatment intensity determines efficacy, this variation in frequency would confound findings.

2.2.34 Pre-treatment severity Another variable that varied highly in the included studies is pre-treatment severity. The range of minimum severity scores is presented in and Table 4, which show broad variations in the minimum criterion for study entry. An example is a minimum criterion range score on HDRS between 10 and 20 in Parker et al. (2008). According to the American Psychiatric Association a score of 10 on HDRS is categorised as mild, whereas a score of 20 is considered severe, showing that this study covers a very broad range of severity. This should be flagged as a matter of concern because low pre- treatment severity is found to be associated with increased response to placebo (Fournier, DeRubeis, Hollon, Dimidjian, Amsterdam, Shelton, & Fawcett, 2010; Schatzberg & Kraemer, 2000). The relatively low score of 10 as a criterion indicates that a range of patients originally scored in the mild range posing a risk that remission is not a direct consequence of treatment impact. In this case efficacy would be biased against studies using higher cut-off ranges.

2.2.35 Definitions of treatment outcome Another risk of bias is listed in Table 4 revealing that definitions of remission used in the included reviews varied considerably, indicating that remission definition was set arbitrarily and may not have been based on strict scientific accepted objective levels, which again poses a serious risk of bias and creates difficulty in comparing reviews.

The COMET Initiative The COMET Initiative (2011-2016) proposed that researchers should agree on more objective measures of remission and recovery. However, this has not been implemented widely in included studies, but could have been integrated using an objective measure

66 of 229

such as the Jacobson criteria for recovery Jacobson and Truax (1991b). Similarly, Table 5 shows that definitions of relapse were also highly variable across studies. The use of differing outcome definitions in reviews presents another serious limitation, which will be described concerning post-treatment outcomes. The same issues affect analyses of follow-up data. The majority of included studies defined remission in terms of a minimum criterion score on the BDI or HDRS (or both). For both measures, lower scores represent a more stringent definition of remission than do higher scores. For example, Zimmerman, Posternak, and Chelminski (2005) reported that 6.8% of patients scoring 10 or less on the 17-item HDRS still met DSM IV diagnostic criteria for MDD compared to 3.4% for a criterion of 7 or less, and none for 3 or less. However, none of the reviews used more objective clinical criteria such as Jacobson and Truax (1991a) criteria for clinical significant change or Frank’s (Frank, Prien, Jarrett, & et al., 1991) criteria for recovery . Included reviews frequently used different criterion scores to define remission on the BDI and HDRS. For example, the BDI ranged from 7-10 and the HDRS criterion for studies included in de Maat et al. (2006) ranged from 6 points or less to 9 points or less. Thus, studies using less stringent definitions will have contributed higher remission rates to de Maat et al.’s overall analysis than those using more stringent definitions.

The general failure to make use of objective and consistent definitions on clinical significant outcomes creates a problem for conclusions. With less stringency and objectivity actual remission could be compromised, as we cannot be certain that patients have actually objectively remitted. It is also not clear if pooling the results of these broad ranges of results have created results that are biased (Nugent, 2012). More standardised definitions of remission are needed (Matt & Navarro, 1997).

2.3 Overall Discussion

In this systematic review nine meta-analytic reviews were identified. These summarised the results of psychological treatment efficacy studies for MDD. The eligibility criteria used ensured that only randomised controlled trails examining treatment effects in samples meeting a formal diagnosis of MDD were included. The second requirement

67 of 229

that treatments should be based on theoretical models of psychopathology excluded any none bona fide treatment studies. Although only one review, was described as a systematic review, the intentions were to provide meta-analytic evidence concerning efficacy of individually provided psychological treatments for MDD. The included reviews varied considerably in risk of delivering biased results. Scrutinising substantive and quality data revealed several methodological factors that put studies at risk of introducing bias in all reviews. However, despite these irregularities, reviews that made the same treatment comparisons reached the same overall conclusions.

2.3.1 Discussion of efficacy of treatments The fact that reviews adhered to systematic review methodology to varying degrees, makes it difficult to assess degree of risk of biased results. There are some uncertainties about the nature of samples used in comparisons, making follow-up comparisons at greater risk of bias than post-treatment comparisons. Studies failed to report whether follow-up analysis was based on all patients entering treatment, on all completers or only patients remaining in contact with researchers at follow-up. In all studies, except Vittengl et al. (2007b) it was not clear if treatment was provided during follow-up period.

2.3.2 Psychotherapeutic efficacy at post-treatment The conclusion that psychotherapy was superior to control conditions at post-treatment was found in three reviews (Casacalenda et al., 2002; Vittengl et al., 2007a; Cuijpers et al, 2014) and one at follow-up (Vittengl et al., 2007b). The other two reviews comparing the relative efficacy of specific psychotherapies did not find a difference between therapy types at post-treatment (Leichsenring, 2001; van Hees et al., 2013) and follow-up (Leichsenring, 2001; Vittengl et al., 2007c). The results suggest that, bona- fide psychotherapies (in this case e.g. CBT and IPT) proved to be superior to control conditions and were equally effective in the treatment of depression. The comparison of C-CT with untreated controls in Vittengl et al. (2007b) provided the lowest risk of bias for all follow-up comparisons, as patients in the control group were guaranteed not to receive treatment. Van Hees et al., (2013) concluded that the difference between IPT

68 of 229

and CBT was not clinically significant; while IPT seemed to be more effective than wait list conditions, yet the treatment effects are small and not significant, which the authors report. (Van Hees et al., 2013).

Overall the studies included show remissions scores ranging from 38% to 48% of patients receiving individual psychotherapy at post-treatment. But remission rates due to placebo effects are most likely close to Casacalenda et al.’s control sample rate of 27.7%, based on the finding that Posternak and Miller (2001) indicated that up to 20% of patients included in depression treatment studies show remission without treatment. Study evidence also points to the conclusion that psychotherapy provided in continuation phase results in significantly better protection against possible relapses compared to psychotherapy provided in the acute phase alone. This was found for example in Vittengl et al. (2007) who showed relapse rates at post-treatment (12% vs 38%) and follow-up (40% vs. 73%) were significantly lower in C-CT samples than samples receiving psychotherapy only in the acute phase. The most reliable evidence found that as high as 73% of patients receiving only acute phase psychotherapy relapsed over a follow-up period of 153 weeks or approximately 3 years (Vittengl et al., 2007b).

2.3.3 Comparison of psychotherapy with medication The overall results of four reviews provides strong evidence of equivalent efficacy of psychotherapy and ADM at post-treatment (Casacalenda et al., 2002; de Maat et al., 2006; Parker et al., 2008; Cuijpers et al., 2014). This was supported by the highest quality review (de Maat et al., 2006). Even though Casacalenda et al. (2002) and Parker et al. (2008) were subject to risk of bias, these studies still produced the same conclusions in their analyses which included different studies than the ones included in de Maat et al. (2006). Parker et al. (2008) and Casacalenda et al. (2002) shared respectively one third and two thirds of included studies with de Maat et al. (2006). Importantly, the overall remission rate for psychotherapy of 47.9% in Casacalenda et al. (2002) was significantly higher than the 37.9% reported by de Maat et al. (2006), the latter being potentially the most reliable review. The higher rate presented by Casacalenda et al. (2002) may have resulted from the fact that this study did no use weighting of results in analyses. The conclusion then is that the most reliable evidence

69 of 229

by de Maat et al. (2006) shows that less than 40% of patients receiving psychotherapy for MDD remitted at end of treatment. Only Cuijpers et al. (2014) compared the efficacy of psychotherapy to a pill placebo. Using the HAMD scores, it was found that psychotherapy failed to be superior to pill placebo, showing only a 2.66 point difference, which is less than the 3 point cut-off implementation. With regards to ADM studies suggested that medication is more effective than a pill placebo in treatment of MDD (Kirsch, 2009; Turner, Matthews, Linardatos, Tell, & Rosenthal, 2008). The results from Cuijpers et al., (2014) suggest that psychotherapy provides similar results as medication, and that these both are equivalent in efficacy to a placebo pill.

When considering follow-up, results of the high quality review by de Maat et al., (2006) were similar to those found in Vittengl et al. (2007), who both reported that approximately twice as many ADM as psychotherapy patients relapsed over a 1-2 year period.. Exact figures from De Maat et al. (2006) was a relapse rate of 27% for psychotherapy and 57% for ADM, and the figures for Vittengl et al. (2007d) were 39% and 61% respectively. Thus, these two studies indicated that psychotherapy successfully lead to remission and provided longer lasting effects than discontinued medication. It should be noted that the majority of included studies in those two reviews were the same (Table 7).

2.3.4 Comparison of psychotherapy alone & combined with medication Three reviews investigated statistical significance of comparisons between psychotherapy and combined therapy (de Maat et al. 2007; Vittengl et al. 2007: van Hees et al, 2013). De Maat et al. (2007) concluded that combined therapy was superior to psychotherapy at post-treatment. This was based on an ITT analysis showing that remission for combined therapy was 12% higher than psychotherapy alone (46% versus 34% respectively). In contrast, to this finding, looking at follow-up over a 1 to 2 year period, Vittengl et al. (2007) failed to find significant differences in relapse rates between CT plus medication or CT alone (39% versus 33% respectively). Again, uncertainty about samples employed in this analysis and the earlier mentioned possibility that patients could have received treatment during follow-up makes the

70 of 229

Vittengl et al results at risk of bias. The most reliable conclusion on this subject is that combined therapy was superior to psychotherapy at post-treatment.

Exclusion of Ambiguous Reviews 10 articles met disagreement between the two independent reviewers (PC and RJ) about inclusion. These articles were ultimately excluded by a third independent reviewer (PF). Di Giulio (2010) was excluded because it was not published in a peer-reviewed source. Jakobsen (2014) is a collection of papers, which meant that was not qualified as a review. Both Linde, Kriston, Rucker, Jamil, Schumann, Meissner, Sigterman, and Schneider (2015) and Kriston, von Wolff, Westphal, Holzel, and Harter (2014) were excluded as they were network meta-analyses, and thus did not include summary statistics. Cuijpers et al. (2009) and Cuijpers et al. (2010) were excluded, because these used studies with inconsistent diagnostic criteria. Another study by Cuijpers et al. (2013) included patients with comorbid anxiety disorder and there was too small a sample of patients with only depression.

2.3.5 Discussion of the Risk of Bias Across Reviews Several factors may have biased the results across all reviews. Four important factors were identified.

First, one problem identified is integrity of psychological treatments which may have been inconsistent across studies included in reviews. Looking at original manuscripts in de Maat et al. (2006, 2007) it was found that studies varied heavily in terms of reporting which methods were applied to ensure integrity. While this may not reveal the actual efforts made to asses treatment integrity assurance, It is possible that studies may have been based on poor psychological treatments. Bhar and Beck (2009) argue that a majority of studies used for comparisons of CBT with STPP fail to adequately implement procedures to ensure the integrity of treatment types. Consequently, results of meta-analyses of such studies are at best ambiguous (Bhar & Beck, 2009). It is also likely that high treatment integrity is easier to achieve for medication than for psychotherapy, an indication that could possibly bias results and thus be responsible for

71 of 229

the frequent finding that psychotherapy and ADM do not show different results at post- treatment.

Second, duration of psychotherapy, number and frequency of treatment sessions varied considerably between studies included in the reviews. In a study comparing cognitive behavioural and psychodynamic-interpersonal therapy, both provided over 8 or 16 weeks, Shapiro, Barkham, Stiles, Hardy, Rees, Reynolds, and Startup (2003)concluded that longer treatment duration was more beneficial for the majority of depressed patients. Looking at severely depressed patients (BDI > 27) in this study, overall symptomatic reduction on the BDI was not different in the period between 8 and 16 week samples, but symptomatic reduction at 16 weeks was significantly greater than at 8 weeks. This means that variation in treatment duration across studies in reviews poses problems in interpreting results. This problem is evident in e.g. Parker et al. (2008) comparing post-treatment efficacies of CBT and ADM, where CBT was delivered in 12 to 24 sessions in studies lasting from 8 to 15 weeks. As it is often conclude that onset of ADM efficacy could be faster than onset of effect of CBT (Elkin et al., 1989). Overall, there is a possibility that including short versions of established therapies could lead to a general conclusion that medication is more effective than psychotherapy across all treatment durations. The highest quality review presented here indicates that psychotherapy provides as effective results as medication at post-treatment and that psychotherapy is superior in preventing relapse at follow-up. Intensity and rapidity of onset of treatment efficacy are areas that need further research.

Third, an important factor is mean pre-treatment symptom severity in patient samples used in reviews. If we can assume that level of pre-treatment depression severity significantly predicts treatment outcome, then inclusion of studies with high variation on this factor poses a problem in drawing conclusions. Some studies in de Maat et al. (2006) stratified patients by pre-treatment severity to ensure the equivalence of treatment groups (e.g. Blackburn et al. (1981)). However, group equivalence could not be guaranteed solely on the basis of non-significant differences between group means if primary studies did not use Blackburn et al.’s approach. Scrutinising DeRubeis and Crits-Christoph (1998) revealed that significantly more severely depressed patients

72 of 229

(HDRS ≥ 20) were entered into the ADM sample of Murphy, Simons, Wetzel, and Lustman (1984) according to BDI scores. The consequence of this, given that placebo effects are more marked in less severely depressed samples (Fournier et al., 2010; Schatzberg & Kraemer, 2000) is that this was a possible source of bias which could favour CBT over ADM in Murphy et al. (1984). This bias should be random and thus evened-out in larger meta-analysis, but the number of studies in any review used was 10, which is low and more would be needed,, which means that we cannot rule out this source of bias.

The final, and major source of bias is that studies used idiosyncratic definitions of remission which meant that stringency of definition of remission was variable, making conclusions concerning actual remission uncertain. This means that some studies are likely to have made conclusions based on over or underestimations concerning remission. It is not clear to what degree overall rates actually represent remission. Also, the variation in stringency between studies included in reviews creates a possibility that review conclusions were biased. Relative efficacy of treatments may therefore have been confounded with choice of outcome measure and the remission criterion employed.

To reduce risk of bias when calculating remission, studies must employ an empirically accepted definition of clinical significance to best represent remission. The use of Jacobson’s method of clinical significance seems ideal to perform this (Jacobson & Truax, 1991b) and should be used in individual randomised trials. However, the Jacobson method is not applicable in any of the included meta-analysis in this study.

2.3.6 Limitations In this study the University of Sheffield’s School of Health & Related Research (ScHARR) Systematic Review Quality Appraisal guidance (University of Sheffield, 2009) was used to assess the quality of studies and the risk of bias (Moher et al., 2009). Other more widely used assessment tools like The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials (Higgins, Altman, Gøtzsche, Jüni, Moher, Oxman, Savović, Schulz, Weeks, & Sterne, 2011) could have been used as well as

73 of 229

GRADE to formally assess strength of evidence (Guyatt, Oxman, Vist, Kunz, Brozek, Alonso-Coello, Montori, Akl, Djulbegovic, & Falck-Ytter, 2011)

2.3.7 Future recommendations This study evaluated the efficacy and risk of bias in reviews testing out treatments for depression. The studies involved large differences in how they assured treatment fidelity/adherence to protocol, duration of therapy and definitions of remission. Future studies need to further investigate the importance of these different issues on treatment outcome. This could be done with the use of meta-regression and consensus on definitions of remission, recovery relapse and recurrence (Frank et al., 1991)

2.4 Concluding Remarks

There is an increasing influence of meta-analysis as a method to make general summaries of results of psychotherapy trials for MDD within systematic reviews. This trend points to a need to assess potential problems with this approach.. The highest quality evidence from included reviews suggest that 38% to 48% of patients engaging in individual psychotherapy (usually CBT or IPT based therapies) will experience remission by the end of treatment. However, for approximately half of these patients, remission may be due to placebo effects. Strong evidence suggests that the efficacies of psychotherapy and ADM did not differ at post-treatment, where limited evidence points to a suggestion that psychotherapy is better at preventing relapse than ADM.

However, these conclusions are challenged by important methodological limitations. Firstly, it appears that psychological treatments were delivered sub-optimally in some of the primary outcome studies. Furthermore, there was considerable variability in frequency of psychotherapy sessions, durations and operational definitions of recovery and remission, and pre-treatment depression severity. These problematic factors could have reduced the validity of included reviews’ overall conclusions due to possible individual study bias which pose a risk of overall summary bias (Matt & Navarro, 1997). More high quality RCTs are now needed to overcome these limitations and to test new treatment approaches that could improve on the fairly low effects observed and reduce the overall risk of bias.

74 of 229

3 STUDY 2: METACOGNITIVE THERAPY IN RECURRENT DEPRESSION - A CASE REPLICATION SERIES IN DENMARK

3.1 Abstract

3.1.1 Background Metacognitive therapy (MCT) is a new psychological treatment for depression with promising effect sizes and recovery rates. MCT proposes that all psychological disorders are caused by the Cognitive-Attentional Syndrome (CAS). In depression the CAS involves predominantly low meta-cognitive awareness, rumination and other dysfunctional coping behaviours that backfire and result in the maintenance of the depressed mood. The main purpose of MCT is to help patients identify and reduce the CAS. Challenging positive and negative metacognitive beliefs that maintain the CAS is an important component of treatment.

3.1.2 Methods MCT was delivered to four Danes with a diagnosis of depression, and the efficacy of the treatment was examined in 5-11 sessions of 45-60 min each. This study used an A-B design and had a follow-up period of 3 - and 6 months. The primary outcome was Beck’s Depression Inventory II (BDI-II). Major depressive disorder scale (MDD-S) was used to measure CAS activity.

3.1.3 Conclusion The results of this case series demonstrated significant improvements in depressive symptoms, rumination levels and metacognitive beliefs. The effects persisted at 3 and 6 months follow-up. Some limitations to the findings include the small number of participants and a decreasing baseline score in one of the four participants. Nevertheless, it can be concluded that treatment was associated with significant symptom improvement in a small Danish population, and that MCT appears a promising treatment.

75 of 229

3.2 Introduction

A large body of clinical trials have supported the efficacy of cognitive-behavioural therapy (CBT) for depression. CBT has therefore been a primary choice for the treatment for depression for a number of years (Butler, Chapman, Forman, & Beck, 2006; DeRubeis & Crits-Christoph, 1998; Excellence & Health, 2004). The efficacy of CBT was demonstrated in a study with depressed outpatients (Gibbons, Fournier, Stirman, DeRubeis, Crits-Christoph, & Beck, 2010), where the results indicated that 61% of the patients experienced change in symptoms, however, only 36% of the entire sample had recovered when the treatment terminated. Studies have supported the superior efficacy of CBT in comparison to waiting lists and medication (Butler et al., 2006; Dobson, 1989; Sundhedsstyrelsen, 2007).

Although support for the efficacy of CBT has been presented in many trials, the majority of the studies show that only 40-58% of patients meet criteria for recovery from depression when assessed by the BDI and that approximately 30% of the patients relapse when measured at follow-up (Table 4 and Table 5). Furthermore, in comparative studies, CBT appears as effective as other psychotherapies, for example behavioural activation alone, cognitive therapy and the combination of both treatments appear equivalent (Dimidjian, Hollon, Dobson, Schmaling, Kohlenberg, Addis, Gallop, McGlinchey, Markley, Gollan, Atkins, Dunner, & Jacobson, 2006).

Across 7 meta-analytic reviews (Cuijpers, van Straten, Andersson, & van Oppen, 2008) CBT, interpersonal psychotherapy, behavioural activation treatment, problem-solving therapy, non-directive supportive treatment, psychodynamic treatment, and social skills training were compared. Except for the attrition rate for CBT being higher than in the others, no significant differences between the psychotherapies were found.

Psychotherapeutic outcomes indicate that there is a need for the development of new treatments, which aim to improve outcomes. Such attempts have used the addition of mindfulness to CBT, with the aim of reducing relapse (Segal, Williams, & Teasdale,

76 of 229

2012) as well as the development of Acceptance and Commitment Therapy (Hayes & Smith, 2005). Alongside these new developments in treatments, Adrian Wells has developed Metacognitive Therapy (Wells, 2009b).

Metacognitive therapy (MCT) is grounded on the Self-Regulatory Executive Function (S-REF) model (a metacognitive model of emotional disorder) to explain the recurrence and persistence of depression (Wells & Matthews, 2014). According to this model, a specific repetitive style of thinking called the Cognitive-Attentional Syndrome (CAS) is the main cause of psychological disorders. The CAS plays an important role in development, maintenance and relapse of disorders.

The CAS is maintained by metacognitive beliefs that patients hold about their thoughts and thinking processes (Wells & Matthews, 2014). As opposed to CBT where the content of the patients thoughts are challenged the positive and negative metacognitive beliefs are targeted in MCT. Positive metacognitive beliefs concern assumptions regarding the usefulness of rumination and worry, for example “Rumination helps me make sense of things” and “Rumination helps me find answers to my depression” and “If I analyse what is wrong with me I will find out”.

Negative meta-cognitive beliefs involve the assumption that rumination is uncontrollable and that depression is a biological disorder e.g.: “I have no control over my depressive thoughts”, “depression is a genetic/biological disorder beyond my control” and “Feeling sad for a long time is the sign of illness in my brain”. When negative thoughts and experiences arise the depressed individual uses the CAS as a way of coping and problem-solving his or her way out of the depression. However, paradoxically this process of solving depression only maintains the depressed symptoms.

In addition, individuals with depression often lack metacognitive awareness and are not fully aware of the extent of their rumination which prevents them from attempting to control it. It can be noted that a major difference between CBT and MCT is that they work on different levels: CBT works at the object level (e.g. “I am a failure”) and MCT

77 of 229

works at the meta-cognitive level (e.g. “My rumination about failure is uncontrollable”).

Table 8: Different approaches to a negative thought. Cognitive therapy (CBT) Meta-cognitive therapy (MCT) Main CBT Question: “What is the Main MCT Question: “What is the use of evidence that you are a failure?” analysing your worth?”

At this point MCT has predominantly been studied in relation to a number of anxiety disorders, such as generalised anxiety, post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (Fisher & Wells, 2008; Wells & Sembi, 2004a, 2004b; Wells, Welford, Fraser, King, Mendel, Wisely, Knight, & Rees, 2008).

MCT for MDD has also been examined in smaller trials. Attention Training (ATT – Wells, A. 1990) is a technique that is part of the MCT protocol. In a preliminary study Papageorgiou & Wells (2000) evaluated ATT in four cases of depression and showed significant reductions in depressive and anxiety-related symptoms. The effects were still present at follow-up 12 months after treatment had ended. The significant effects associated with full MCT were found in a multiple-baseline study conducted by Wells, Fisher, Myers, Wheatley, Patel and Brewin (Wells, Fisher, Myers, Wheatley, Patel, & Brewin, 2009).

In a single case series MCT was examined in six women with postnatal depression and the results showed clinically significant reductions in symptoms. Furthermore, all scores fell within the normal range post-treatment, and effect sizes were large. Treatment gains were maintained at 3 - and 6 months post-treatment by all participants (Bevan, Wittkowski, & Wells, 2013).

In an uncontrolled trial with 12 treatment-resistant depressed patients 80% were recovered after eight sessions of MCT and 70% remained recovered at follow-up (Wells, Fisher, Myers, Wheatley, Patel, & Brewin, 2012)

78 of 229

In order to expand the findings obtained so far, independent replication across alternative settings and cultures are needed in order to assess the consistency and portability of the treatment-associated effects.

3.3 Research question

The aim of the present study is to replicate (Wells et al., 2009) and examine MCT for depression in four consecutive Danish outpatients meeting the criteria for MDD in a single-case A-B systematic replication series. The treatment protocol as well as the format used in earlier studies (Wells et al., 2009; Wells et al., 2012) was followed.

3.4 Methods

3.4.1 Design In the present trial, an A-B design was used. Four Danish patients with recurrent depression received MCT treatment in 5-11 sessions, each session lasting for up to one hour. A follow-up assessment was conducted at 3 and 6 months after treatment termination. The patients were required to complete self-report questionnaires 3 times over a time span of 2 weeks (baseline) before treatment initiation. Danish Ethics approval was obtained (Appendix 6) and due to ethical issues the maximum period of baseline that could be used was two weeks with three baseline measures.

The patients received treatment every week for 45-60 min. Each session followed Wells’ treatment protocol (Wells, 2009b). Treatment ended when a score of 12 on the BDI-II for 2-5 consecutive sessions was reached. Assessment was carried out at follow- up 3 and 6 months after the treatment ended.

3.4.2 Participants The participants included in this study were four Danish individuals with a clinical diagnosis of depression. All participants were diagnosed and referred to a private NHS clinic by their General Practitioner.

The inclusion criteria were:

79 of 229

1) A primary diagnosis of depression 2) No personality disorder (assessed by the use of a brief screening instrument Standard Assessment of Personality - Abbreviated Scale (SAPAS) (Moran, 2003) 3) Absence of alcohol or substance abuse 4) No concurrent psychological treatment within 2 years preceding referral 5) No evidence of psychotic or organic illness and/or medical/physical condition underlying depression 6) Medication free or willing to remain stable on medication for at least 6 months 7) Not actively suicidal.

To ensure that this study only included patients who meet the inclusion criteria, the therapists conducted telephone interviews with the patients prior to the treatment.

3.4.3 Patient 1 Patient 1 was 20 years old, female, single, and a student. She reported one previous episode of depressive symptoms, but had no history of having received psychological treatment. No previous use of antidepressants was reported. She was ruminating over her studies “Why am I not motivated?” and “What is wrong with me?” She spent 4-7 hours a day thinking about these questions and sometimes avoided classes if she did not feel motivated to attend.

3.4.4 Patient 2 Patient 2 was 37 a year old married man who had a secondary diagnosis of generalized anxiety. He was on sick leave from his work when the treatment started. He reported that he had previously experienced at least two longer episodes of depression, where the current episode started approximately 3 months ago. He spent most of the day ruminating and worrying about his life and symptoms “Why don’t I get better?” and “Why do I feel upset all the time?” was some if his common triggers for rumination. He received a high dose of medication (100 mg Certralin) both before and during treatment.

80 of 229

The medication was taken for 3 months with limited effect at the onset of this trial. His usage of medication persisted throughout the follow-up period, but the patient reported that he had plans of terminating the use of medication shortly after follow-up assessment.

3.4.5 Patient 3 This patient was 28 years old, female, living with her male partner, and at the time unemployed. She reported a number of previous episodes of depression, and underwent psychotherapy a few years ago, but experienced little or no effect. Working in a stressful environment at her previous job triggered the current episode, which had been ongoing for approximately 2 months. She has previously been prescribed a variety of antidepressants over the last few years, but was medication free when she was included in the study.

3.4.6 Patient 4 This patient was 24 years old, female, living with her male partner with two children, and a full-time student. She estimated that her current episode of major depression had been going on for 3 months. Although unable to pinpoint the exact number of previous episodes of major depression, she reported that she had experienced several episodes since her early teens. Earlier use of eclectic psychotherapy treatment a few years ago was also reported, however with very limited effect.

3.5 Outcome Measures

Becks Depression Inventory II (BDI-II) BDI-II (Beck, Steer, Ball, & Ranieri, 1996) is a self-report scale, which measures the level of depression. It consists of 21 items, where the scores range from 0-63. Scores from 0-13 are categorized as “minimal”, 14-19 as “mild”, 20-28 as “moderate”, and 29- 63 as “severe”.

81 of 229

Major Depressive Disorder Scale (MDD-S) MDD-S (Wells, 2009) is a self-report clinical scale measuring the weekly: 1) Level of depression, 2) time spent ruminating, 3) Dysfunctional coping strategies, e.g. alcohol use and thought suppression, 4) Other dysfunctional strategies e.g. avoidance, 5) negative beliefs about rumination e.g. uncontrollability 6) positive beliefs about rumination. The MDD-S is a clinical scale developed to assess meta-cognitive progression during therapy. Its psychometric properties have not been formally tested. The scale was translated and back translated by psychologists Kristian Eli Andersen, Pia Callesen, and Stephen Austin.

BDI-II and MDD-S were both administered 3 times during the baseline phase, before every treatment session, at post-treatment, and at the 3 and 6 months follow-up.

3.6 Procedure

3.6.1 Assessment Following a telephone assessment, patients who had been referred to the Danish clinic CEKTOS (Center for Kognitiv og Metakognitiv Terapi) by their GP for treatment of depression, were invited for possible participation in the project. This was followed by a diagnostic screening procedure conducted by two clinicians, where the structured clinical interview for DSM-IV TR (2000) was used.

There was mutual agreement on diagnosis in the first 4 cases; and patient consent was sort. Following consent they were asked to complete the self-report measures and to complete the BDI-II and MDD-S on a weekly basis before the treatment commenced. With the objective to evaluate symptoms on a weekly basis, the BDI-II and MDD-S were administered and collected at the beginning of each session. The same questionnaires were given after treatment had ended and at follow-up.

3.6.2 Treatment The MCT treatment ranged from 5-11 sessions each lasting 45-60 minutes. Treatment terminated when patients scored 12 on the BDI-II for 2-5 consecutive sessions. The

82 of 229

treatment manual for depression by (Wells, 2009b) was used. The first session consisted of conducting a case formulation based on the metacognitive model for depression. In this formulation a recent rumination episode is explored and the initial trigger-thought starting off the rumination process identified. Patients were then socialized to the metacognitive model emphasizing that pervasive thinking and self-focus maintain depressive symptoms. An objective within the treatment is to enhance met-awareness and mental flexibility in bringing rumination under control (Wells, 1990). Therefore, the patients were introduced to ATT in the first session. ATT consists of a number of different sounds, where the patient is instructed to shift their attention from one sound to another. Practice of ATT was administered every session throughout treatment.

The protocol for the following three sessions consists of further enhancement of awareness of triggers for depressive rumination and challenging negative beliefs concerning the uncontrollability of rumination. In order to investigate further awareness and control of trigger-thoughts, the technique “detached mindfulness” was introduced as well as the experiment of postponing rumination. After patients’ negative belief about uncontrollability had decreased to a minimum of 10%, the next step was to challenge positive beliefs concerning the usefulness of rumination. This was done by using Socratic dialogue and behavioural experiments assessing the usefulness of rumination.

When both negative and positive beliefs were at or below 10%, the focus of the final and remaining sessions focused on limiting avoidance and enhancing alternative coping behaviour, such as incorporating more social activities/interests and planning ahead. Lastly, an individualised plan for preventing relapse was developed, which included a plan for dealing with negative thoughts and feelings in the future. The detailed protocol for MCT for depression can be found in Wells (2009).

3.6.3 Therapists Two therapists carried out the MCT treatment. Clinical psychologist Pia Callesen (PC) treated patient 1 and 2, and psychologist Anne B Jensen (AB) treated patient 3 and 4. At the time of the treatment PC had 10 years of clinical experience and had received on- going training and supervision from Professor Adrian Wells in the MCT protocol

83 of 229

AB was a less experienced therapist with only 2 years of clinical experience and no direct supervision from Professor Wells.

3.7 Data Analysis

The primary aim in single case analyses is to determine whether there is a tangible treatment effect after an intervention has been introduced. The outcome measures were the scores obtained on the BDI-II and MDD-S, which were administered across the baseline period, during treatment, and at follow-up. Thus, to determine whether clear treatment effects were present, we used visual examination of the graphed data, as done in the trial by (Wells et al., 2009). The data collected for all four patients are presented in Table 9.

3.8 Results

Table 9: Descriptive statistics on the main outcome measures at pre-treatment, post- treatment and follow-up.

Pre- 3 months 6 months treatment Post-treatment follow-up follow-up M SD M SD M SD M SD BDI-II 28.7 7.2 7.0 5.2 2.8 2.2 4.3 2.1 Level of Depression 4.5 1.7 1.0 0.7 0.5 0.6 0.5 0.6 Time spent Ruminating 5.3 1.7 1.0 8.2 0.5 0.6 0.8 0.5 Dysfunctional coping strategies 95.6 141.4 6.5 5.2 3.0 1.2 6.0 3.9 Avoidance 89.1 138.6 3.8 2.1 1.8 2.4 1.3 1.5 Negative beliefs about rumination 31.5 18.8 2.0 1.6 1.0 1.2 1.0 1.2 Positive beliefs about rumination 25.5 13.9 0.5 1.0 1.0 2.0 0.8 1.5

84 of 229

Figure 3: Scores on the Beck Depression Inventory BDI-II

85 of 229

Figure 3 presents the BDI-II score for each patient at baseline, treatment, and follow-up. As seen on the figure, patients 1 and 4 demonstrated stable or increasing BDI scores before the onset of treatment, whereas patients 2 and 3 demonstrated decreasing scores. As the latter two experienced a decrease in symptoms across the baseline period, the notion of the changes observed after the treatment being due to the treatment itself is therefore questionable.

86 of 229

However, the scores of all patients in the final session indicate a considerable improvement in symptoms. It is clear, that in the case of patients 1 and 4, introduction of treatment is associated with positive changes in their BDI scores consistently throughout treatment. A similar trend can be observed in the scores for rumination. It is difficult to determine from the graphs if change in one score precedes the other, as the scores seem to change in tandem.

Depressive symptoms and time spent ruminating were maintained in all 4 cases at follow-up 3 and 6 months after treatment. It was found that all the patients had a BDI-II and rumination score below 2. The patients did not change medication or receive any other therapy during the study or at follow-up.

Data on the MDD-S is presented in Table 12. It can be observed that both metacognitive beliefs and dysfunctional coping strategies considerably decreased. It is noteworthy to point out, that the magnitude of change in metacognitive beliefs is similar to the change found in Wells et al.’s (2002) open-trial (Wells, 2002).

3.8.1 Clinically Significant Change The results show that three out of four patients no longer met diagnostic criteria for depression as they scored below 8 on the BDI-II and this was consistent at post- treatment and at follow-up. At post-treatment, scores on the BDI showed that only one patient met criteria for mild depression, were the remaining three patients reported no or minimal depressive symptoms. At follow-up none of the patients met the criteria for depression.

3.9 Discussion

The results of this case series study indicate that MCT appear to be consistent with the results found in other studies examining treatment for depression (Wells et al., 2012). Thus, the transferability of MCT to different therapists (with varying levels of training), culture and population has been supported. It can also be noted that with basic training and on-going supervision, MCT can be delivered in 5-11 sessions. Although the

87 of 229

treatment was delivered in 4-8 sessions in the study conducted by Wells et al. (Wells et al., 2012), it could be argued that the slower rate of change was due to less experienced therapists in the present study. More experienced therapist PC showed faster and more significant effect in her treatment (remission at five sessions) whereas AB showed slower rates of change (remission at 10-11 sessions). This finding supports the idea that training and supervision in MCT is important to improve outcome.

A number of limitations can be pinpointed in the present study. Because of the small sample size, generalizability is compromised. The exclusive use of self-report questionnaires also limits validity and increases the risk of bias. Furthermore, the competency of the therapists was not assessed. This study had a short baseline period in which two of the patients showed improvement over the three-week baseline period. Based on this it is difficult to determine whether the observed treatment effect was indeed attributed to the treatment of recovery in time. As many patients experience relapse in depression typically around 12 months post treatment another limitation in this study is the relatively short follow-up period (6 months).

This preliminary study has contributed to the further evaluation of MCT for the treatment of depression, and the results of this study suggest that MCT might be applicable to outpatients receiving treatment in Denmark. The next section reports a large randomised study to assess efficacy and generalizability of MCT for depression

88 of 229

4 STUDY 3: COGNITIVE-BEHAVIOURAL THERAPY VS. META- COGNITIVE THERAPY FOR DEPRESSION: A RANDOMISED CLINICAL TRIAL

4.1 Abstract

4.1.1 Background Major Depressive Disorder (MDD) is one of the largest health problems worldwide. Psychological treatments show variable efficacy rates with approximately 50% recovery rates in ‘gold standard’ cognitive behaviour therapies (CBT’s). More effective treatments for depression are needed. Metacognitive therapy (MCT) is a new treatment for MDD that has produced promising results in preliminary studies. Hagen et al (submitted) showed very large effect sizes in a randomised trial comparing wait-list with MCT. In their study 70-80% were classified as recovered. The next step is to compare MCT with CBT in a definitive trial.

4.1.2 Objectives To compare effects of MCT and CBT for MDD at post-treatment and 6-months follow- up.

4.1.3 Methods In this study a large parallel randomised single-blind trial was conducted comparing metacognitive therapy (MCT) and Cognitive Behavioural Therapy (CBT). 155 patients diagnosed with major depressive disorder (MDD) were assigned to up to 24 sessions of either CBT or MCT and treatment terminated when remission was reached defined as two consecutives scores of ≤8 on Becks Depression Inventory II (BDI-II). A last observation carried forward (LOCF) – analysis was conducted using Cohens d, ANOVAS and reliable clinical significant change analysis done at post-treatment and at 6-months follow-up.

4.1.4 Findings Both CBT and MCT were associated with significant improvement in symptoms. MCT was significantly more effective than CBT on one of the primary outcome variables: Becks Depression Inventory (BDI-II) and the majority of secondary measures. 76% of

89 of 229

patients could be classified as recovered following MCT and 54% following CBT on objective Jacoboson and Truax-criteria. Both treatments remained effective at 6 months follow-up with patients showing stable gains over time.

4.1.5 Interpretaions Effect size and recovery rates in MCT were significantly larger than CBT at post- treatment and at 6-months follow-up. However, these findings need to be replicated with longer follow-up periods and methodological enhancements. Suggestions for future research will be discussed.

4.1.6 Trial Registration and funding ISRCTN82799488 Funded by CEKTOS

90 of 229

4.2 Introduction

Depression is considered one of the largest health problems around the world. Several different medical and psychological treatments have been developed to treat the condition with mixed effects. Therapies for depression involve interpersonal therapy (Cuijpers, Geraedts, van Oppen, Andersson, Markowitz, & van Straten, 2011), Brief psychodynamic therapy (Driessen, Hegelmaier, Abbass, Barber, Dekker, Van, Jansma, & Cuijpers, 2015) and mindfulness-based therapies (MBSR and MBCT, (Gotink, Chu, Busschbach, Benson, Fricchione, & Hunink, 2015).

The most widely tested psychological treatment for MDD is cognitive behaviour therapy (CBT). CBT was first introduced by Dr Aaron T Beck (Beck et al., 1979 ) and involves cognitive and behavioural strategies including restructuring of negative and biased thoughts and beliefs that the individual holds about the self, others and the future. Furthermore, CBT for MDD involves increasing levels of mastery and pleasurable activities. In CBT depression is caused by activated negative schemas (beliefs) e.g. "I'm unlovable" which colour the interpretation of experience and result in low mood.

The effect of CBT on MDD has been studied across multiple randomised controlled trials (RCT’s) with moderate effect sizes (Cristea, Huibers, David, Hollon, Andersson, & Cuijpers, 2015). A recent meta-analysis, however, reported that the effects of CBT as an antidepressant treatment has declined over the years (Johnsen & Friborg, 2015) suggesting that better treatments for depression are needed in order to enhance treatment outcome for this population.

An overall review of the literature (Table 4) shows that the majority of randomised trials give recovery rate of approximately 50% in ITT analysis for different psychological treatments. These include CBT, interpersonal therapy, antidepressant medication and supportive therapy. However, there are a number of biases, which make comparisons and conclusions challenging. These include treatment integrity, treatment duration and the lack of a valid and objective definition of treatment outcome and

91 of 229

clinically significant change. The present trial is designed to overcome these biases and test MCT versus CBT in a definitive trial.

Metacognitive therapy (MCT) is a relatively new treatment for depression. MCT is based on the Self-Regulatory Executive Function model (S-REF model) developed my Wells & Mathews (1994; 1996). According to this model psychological disorders are not caused by negative schemas but instead result from a style of thinking called the Cognitive Attentional Syndrome (CAS). In depression the CAS consists of voluntary mental coping strategies dominated by rumination/worry, avoidance, and mood monitoring along with other strategies that backfire and result in depressive symptoms. The cognitive attentional syndrome is driven by metacognitive beliefs such as the belief that rumination is a useful means of finding an answer to depression and the belief that depressive thinking is uncontrollable.

To date metacognitive therapy (MCT) for depression has been tested in a limited amount of studies that have shown MCT to be a promising intervention that may improve on recovery rates. For example, Dammen et al (2015) implemented a group MCT intervention on 11 depressed individuals and found that 91% of them were recovered at follow-up (Callesen, Jensen, & Wells, 2014; Dammen, Papageorgiou, & Wells, 2015; Wells et al., 2009).

Jordan, Carter, McIntosh, Fernando, Frampton, Porter, Mulder, Lacey, and Joyce (2014) conducted a randomised trial in New Zealand in which 48 depressed patients were randomised to either CBT or MCT. Effect sizes were moderate-to-large for both treatments with no significant differences on primary measures. The number of participants meeting response criteria for each condition was slightly better in MCT (52%) than CBT (44%). In addition, follow-up analysis revealed that MCT produced greater changes in measures of improved executive control and spatial working memory (Groves, Porter, Jordan, Knight, Carter, McIntosh, Fernando, Frampton, Mulder, Lacey, & Joyce, 2015). Several limitations were found in this study. First of all, Training or supervision in MCT was limited and post-hoc analyses suggested that MCT might have

92 of 229

been adversely affected by comorbidity as 48% were suffering from social anxiety in the MCT condition compared to 28% in the CBT condition.

Recently, Hagen et al (submitted) conducted a RCT comparing MCT to a wait-list condition. Results from this trial demonstrated very large effect sizes for MCT. In their trial thirty-nine patients were randomly assigned to immediate MCT (10 sessions) or to a 10-week wait list period (WL). The WL-group received 10 sessions of MCT after the waiting period. Participants receiving MCT improved significantly more than the WL group with very large controlled effect sizes for both depressive (d = 2.51) and anxious symptoms (d = 1.92). Approximately 70-80% could be classified as recovered on the BDI-II at post-treatment and 6 months follow-up following immediate MCT, whilst 5% of the WL patients recovered during the waiting period. These findings suggest that a non-hybrid, pure version of MCT may be particularly effective. .

The present randomised clinical trial is designed to test MCT for MDD by comparing it to a bona fide and benchmark treatment; CBT. The trial utilises a strict methodology intended to reduce potential biases encountered in earlier studies. All 155 patients were allocated to an equal number of treatment sessions with pre-set criteria for potential early termination. They received up to 24 sessions of therapy or until they reached an agreed recovered state. Strict session-by-session manuals for both treatments, expert supervision in both CBT and MCT and objective definitions of recovery and relapse were adopted using a conservative and clinical change index as defined by Jacobson and Truax (1991).

4.3 Study Aims

The aim of the present study were as follows:

1. To assess the relative efficacy of MCT versus CBT in the treatment of patients with major depressive disorder. Primary outcome variables were: Becks Depression Inventory –II (BDI-II) and Hamilton Depression Rating Scale (HDRS)

93 of 229

2. To assess the relative efficacy of MCT vs. CBT in the treatment of patients with major depressive disorder on secondary outcome variables: Becks Anxiety Inventory (BAI), process variables (Rumination time measured by MDD-S) and negative/positive metacognitive beliefs (NBRS/PBRS) as well as schema-related content variables (The Dysfunctional Attitude Scale – (DAS)). 3. To determine if treatment effects are maintained over a 6 months follow-up period. 4. To investigate recovery rates and clinical significant change levels in CBT and MCT 5. To assess dropout rates, treatment adherence, and the quality of the therapeutic alliance in both treatment arms in order to detect any potential differences in MCT and CBT.

4.3.1 Research hypotheses The null hypothesis predicts that there will be no significant differences in primary and secondary outcome variables and recovery rates in MCT and CBT at post treatment and at follow-up.

4.4 Methods

4.4.1 Participants and sampling procedures A total of 298 patients were referred from their general practitioner (GPs) with a diagnosis of depression and recruited from a large Danish outpatient facility called CEKTOS (Center for Kognitiv og Metakognitiv Terapi). At contact with the clinic they were offered either a wait for six months to see a National Health Service (NHS) psychologist or to participate in the trial. In Denmark the NHS is partly funded by the state and partly by the patients themselves. Therefore, a payment of 315.00 Danish kr. pr. session was administered for all participants in the trial.

The diagnosis of MDD was assessed by an independent and experienced clinical psychologist CKA using a structural interview for DSM-IV-TR (SCID). A total of 155

94 of 229

patients were randomised to receive CBT or MCT for depression. However, at assessment write up two files had missing content at pre-treatment. Thus a total of 153 were included in a final analysis using Last Observation Carried Forward (LOCF) at post treatment and at follow-up.

4.4.2 Inclusion criteria  Patients from 18-70 years of age with a main or primary diagnosis of major depressive disorder (MDD) according to the Structured Clinical Interview for DSM-IV-TR, Axis I Disorders (SCID-I)  Patients who agreed to attend therapy in this trial and had not received other psychological treatments for the current episode.  Patients in combined medical treatment as long as they were stable or willing to remain stable on medication  Patients who signed informed consent

4.4.3 Exclusion criteria  Patients suffering from psychosis, substance abuse or bipolar disorder as determined by SCID I  Patients suffering from borderline personality disorder as screened by SCID II  Patients with organic brain syndrome or mental retardation.  Female patients who were pregnant and close to giving birth  Patients who had not responded favourably to a previous trial of either CBT or MCT.

4.4.4 Sample characteristics at baseline Table 10 shows the baseline status of the two groups CBT, MCT and the total sample in the trial. The table demonstrates there was an even distribution of the variables: gender, age and marital status in the two conditions. Depressive levels were similar across the groups. In the CBT condition the mean score on the BDI-II was 22.9 and in the MCT the mean score was slightly greater 26.1. The total mean age for participants in the two groups was 35.4 (SD = 12.7). The mean age for participants in the CBT group was 35.1

95 of 229

(SD= 13.5) and for MCT 35.6 (SD=11.9). A total of 106 females and 47 males participated in the trial. In the CBT condition there were 56 females and 25 males and in the MCT condition 50 females and 22 males. 31 participants had a range of secondary co-morbid disorders including personality disorders such as narcissistic, depressive or dependent personality disorder as well as axis-I disorders like generalised anxiety disorder, social anxiety disorder and simple phobias.

50 participants in total (27 in CBT condition and 23 in MCT condition) were on sick leave because of their depression. 116 patients had suffered from the current depressive episode less than a year and a total of 92 participants in both conditions had tried other types of psychological treatments to treat earlier psychological illnesses. Finally, most of the participants in both groups were not participating in any pharmacotherapy before the start of treatment: In CBT (n=48) and in MCT (n=47). A total of 95 subjects were not taking anti-depressive medication at baseline.

The full sample characteristics are displayed in Table 10.

Table 10: Demographic Variables CBT MCT Total (n=81) (n=72) (n=153)

Gender (n) Female 56 50 106 Male 25 22 47

Age (in years) Sample mean 35,1 35,6 35,4 SD 13,5 11,9 12,7

Marital status (n) In relationship 24 21 45 Married 27 30 57 Single 29 18 47

96 of 229

Current employment (n) Employed 41 40 81 Retired 5 1 6 Sick leave 27 23 50 Unemployed 8 8 16

Co-morbid disorder (n) Depression only 65 57 122 Depression + co-morbid disorder 16 15 31

BDI-II (measured at baseline) Average BDI-II pre-treatment 22,9 26,1 24,4 SD 12,9 13,9 13,4

Duration of current MDD (n) Under a year 64 52 116 1-2 years 6 8 14 2-3 years 2 4 6 More than 5 years 1 0 1

Previous treatment (n) Yes 47 45 92 No 34 26 60

Antidepressant medication (n) On medication 31 23 54 No medication 48 47 95

Table 10 shows the overall distribution of gender, marital status, working status and level of depression. From the table it must be noted that a total of (n=50) patients from both conditions were on sick leave from work due to their depressive state and that twice as many participants were females (n=106) and males (n= 47). At baseline most of the sample could be classified as severely depressed on the BDI-II, with 81% of the

97 of 229

sample classified as moderate to severely depressed (Table 10). Figure 4 shows the overall distribution in levels of depression on the BDI-II.

Figure 4: Distribution of levels of depression measured on the BDI-II

4.5 Outcome measures

A battery of assessments were administered by an independent assessor blind to treatment allocation at pre-treatment, post-treatment and at 6- months follow-up (Appendix 9). The primary outcome measures were Beck’s Depression Inventory (BDI- II) and the Hamilton Depression Rating Scale (HDRS). We chose both a self-rating scale and an interview-based scale to order to account for effect in different ways. In addition, several secondary self-report measures were administered at pre-treatment, post-treatment and follow-up:

4.5.1 Primary outcome measures:

Depressive symptoms (Beck Depression Inventory – BDI-II)

98 of 229

The BDI was developed by Beck and his colleges in 1961 and has become one of the most widely used instruments for assessing the intensity of depression. The inventory has been revised several times and the most recent version is Becks Depression Inventory-II (Beck et al., 1996). The BDI-II is a widely used reliable instrument to assess the severity of depressive symptoms. In fact, the BDI-II shows much better internal reliability than the BDI-I (Dozois, Dobson, & Ahnberg, 1998).It is a self-report inventory consisting of 21 items, where symptoms such as sadness, loss of pleasure, changes in sleep pattern, and worthlessness are measured and rated on a four-point scale ranging from 0 (not present) to 3 (severe). All the scores are summated to form a total score, where the maximum score obtainable is 63. A score of 0-13 indicates minimal depression, 14-19 indicates mild depression, 20-28 indicates moderate depression and 29-63 indicates severe depression.

Depressive symptoms (Hamilton Depression Rating Scale) The HDRS is a well-established and widely used rater-administered scale to measure the severity of depressive symptoms (Andrews & Williams, 2014; Hamilton, 1960; Williams, 1988). The scale consists of 17 items, which are grouped into different categories, such as depressed mood, suicide, insomnia, and somatic symptoms. Eight items are scored on a 5-point scale increasing in severity, where nine items are scored on a 3-point scale. The maximum score obtainable is 53. Scores of 0-17 indicates no depression, 8-13 indicates mild depression, 14-18 indicates moderate depression, 19-22 indicates severe depression, and above 23 indicates very severe depression.

4.5.2 Secondary outcome measures:

Beck Anxiety Inventory (BAI) The BAI (Beck et al., 1988) is an inventory that measures the severity of anxiety, and was developed specifically to distinguish anxiety from depression. The inventory contains 21 items, which assess symptoms such as nervousness and fear of dying, where the items are rated on a 4-point Likert scale, which ranges from 0 (not at all) to 3 (severely). The maximum score is 63, where the cut-off point of clinical anxiety is 16 (Beck & Steer, 1990). Higher scores on the BAI suggest a greater intensity of symptoms

99 of 229

of anxiety. The BAI is viewed as an accurate measure of anxiety with high reliability and validity in non-clinical and clinical settings (Fydrich, Dowdall, & Chambless, 1992).

Meta-cognitive scales:

Major Depressive Disorder Scale (MDD-S) MDD-S is a short self-report scale designed to measure depression levels, meta- cognitive beliefs and maladaptive coping-skills over the past week. The scale was developed as an assessment tool to evaluate baseline levels and progress in MCT treatment (Wells, 2009b).

Metacognitions Questionnaire (MCQ-30) The MCQ 30 (Wells & Cartwright-Hatton, 2004) is a 30-item measure consisting of 5 subscales of beliefs which are: positive beliefs about worry, negative beliefs about thoughts concerning uncontrollability and danger, cognitive confidence, negative beliefs about the need to control thoughts, and cognitive self-consciousness (Wells & Cartwright-Hatton, 2004). Responses are rated on a 4-point Likert scale, which ranges from 1 (do not agree) to 4 (agree very much).. The scale has been found to have good construct and predictive validity and is responsive to treatment.

Negative and beliefs about rumination scales (NBRS) The NBRS is a 13-item scale that measures negative beliefs about the uncontrollability and danger of ruminating (Papageorgiou & Wells, 2003). The scale consists of 13 statements, such as ‘I will lose control if I ruminate too much’ and ‘ruminating makes me physically ill’. These statements are rated on a 4-point Likert scale ranging from 1 (do not agree) to 4 (agree very much). The NBRS show good internal consistency, validity and fit to the MCT model (Roelofs, Huibers, Peeters, Arntz, & van Os, 2010).

Positive beliefs about rumination scales (PBRS) The PBRS was developed to measure positive beliefs about rumination (Papageorgiou & Wells, 2002). The self-report scale contains 9 items consisting of statements such as

100 of 229

‘I need to ruminate about my problems to find answers to my depression’. Each stement is rated on a 4-point Likert scale ranging from 1 (do not agree) to 4 (agree very much). In studies examining the psychometric properties of the PBRS good internal consistency and validity have been demonstrated (Huibers, van Breukelen, Roelofs, Hollon, Markowitz, van Os, Arntz, & Peeters, 2014; Roelofs et al., 2010)

Rumination Response Scale (RRS) The RRS is a subscale of the Ruminative response questionnaire, RRQ (Nolen- Hoeksema & Morrow, 1991), and measures the response styles to depressed mood, which are focused on ‘the self, on symptoms, and on possible causes and consequences of the mood. The scale consists of 22 items and contains statements such as ‘think about how sad you feel’ and is rated on a scale from 1 (almost never) to 4 (almost always). (Thanoi & Klainin-Yobas) tested the psychometric properties of the RRS on 747 undergraduates and found satisfactory reliability.

Cognitive scales:

Dysfunctional Attitude Scale (DAS) The DAS is a scale that measures negative cognitions in depression, and examines the dysfunctional attitudes the individual has towards the self and the world (Weissman & Beck, 1978). The scale consists of 40 items, where each item is rated on a 7-point Likert scale ranging from 1 (fully disagree) to 7 (fully agree). The maximum score obtainable is 280, where higher scores indicate a higher intensity and presence of dysfunctional attitudes. Reliability and validity data for the DAS support its use as a measure of depressionogenic beliefs in an adult population (Oliver & Baumgart, 1985)

Young’s Schema Questionnaire (YSQ-SF) - short version The YSQ contains 16 subscales that measure early maladaptive schemas (Young & Brown, 1994), which contribute to perceptions of the self, the world and others (Rijkeboer, van den Bergh, & van den Bout, 2005). The short version consists of 75 items out of the 205 items from the long version, and measure schemas such as emotional deprivation, abandonment, and vulnerability to harm (Young & Brown,

101 of 229

1994). Each schema is rated on a 6-point scale ranging from 1 (completely untrue of me) to 6 (describes me perfectly).

Other measures:

Co-morbidity (SCID I) The SCID-I (Spitzer et al., 1992) is a semi-structured interview to be administered by a clinician, and was used to determine presence of Axis I diagnoses. The semi-structured interview consists of an introduction and nine modules.

Patient-therapist alliance (Working Alliance Inventory, WAI) The WAI is a self-report instrument used to assess the quality of alliance between the therapist and the patient and can be administered by the therapist and the patient (Horvath & Greenberg, 1989b). This 36-item inventory is based on Bordin’s theory of therapeutic alliance (Bordin, 1979), which also constitutes the three subscales of the inventory, which are: goals; the agreement of goals between therapist and patient; tasks; the agreement of the tasks throughout therapy to reach these goals; and bond, the direct relationship between therapist and patient, which involve factors such as mutual trust (Tracey & Kokotovic, 1989). Each item is rated on a 7-point Likert scale, where the options range from 1 (never) to 7 (always). The inventory has also demonstrated sufficient validity (Horvath & Greenberg, 1989a).

Patients’ expectancies about treatment outcome The Patient’ expectancies about treatment outcome contains two questions, which ask about how logical the treatment seems to the patient during participation, and to what extent the patient feels the treatment will help them reduce their symptoms. Each question was rated on a 1-5 scale ranging from ‘Not at all’ to ‘Very much’.

102 of 229

Objective measure (Concentration and attention subtests from the WAIS) Wechslers Adult Intelligence Scale (WAIS) is one of the most widely used instruments to measure intelligence and cognitive functioning (Kaufman & Lichtenberger, 2005). The instrument contains a range of subtests that measure dimensions such as verbal comprehension, perpetual reasoning, working memory and processing speed (Wechsler, 2014)). This measure was included for analyses in a separate study not reported in this thesis

4.5.3 Included variables In this thesis all primary outcome variables (BDI-II and HDRS) were included as well as specific secondary variables related to cognitive and metacognitive causal factors. These were: BAI, MDD-S, DAS, PBRS and NBRS. In addition, HAI and patients’ expectations about treatment outcome will be investigated in order to detect any potential differences between the treatments.

4.6 Ethics

The present study used the best-proven standards for CBT and MCT. All therapists were experienced clinical psychologists working under the Nordic Ethical Guidelines and according to good clinical practice standards described at Dansk Psykolog Forening (www.dp.dk). The trial design and consent form was formally approved by the Danish ethics committee on the 13th of December 2010 (see Appendix 6). All participants considered for this trial were provided with written and oral information so that they could make an informed decision about their participation (Appendix 7). This trial was conducted in compliance with the protocol approved by Manchester University and the Danish Ethics Committee (www.cvk.im.dk/cvk/). In the case of adverse events patients were excluded from the trial and helped in other ways. No deviation from the ethics protocol occurred.

103 of 229

4.7 Adverse events

In the case of adverse events like suicide attempts or sudden accidents it was decided to take action and report and exclude patients from the trial in order to get them hospitalised. However, no adverse events were reported in this trial.

4.8 Trial design

The present trial is a randomised, parallel between-groups design with 6-months follow- up (See trial consort diagram in Figure 5 and timeline (Appendix 8). [Trial Registration Number: ISRCTN82799488 - Meta-cognitive Therapy (MCT) versus Cognitive Behaviour Therapy (CBT) for Depression. Severity of depression and gender of participants were used as stratification variables during randomization. Participants were assigned to therapists within modality based on therapist availability.

Patients were allocated up to a maximum of 24 sessions of MCT or CBT and were assessed at pre-treatment, mid-treatment (at the 7th session), post-treatment and at 6- months follow-up.

Patients completed the BDI-II at the start of every session. Response was defined by 1 session of a score of 8 or below on the BDI-II. A very conservative definition of remission was established at post-assessment using a score of ≤ 7 on the HDRS and ≤ 8 on the BDI-II as the criteria. Patients could terminate treatment if they scored 8 or below on the BDI-II on 2 consecutive sessions and/or the therapist and patient agreed on termination for other reasons. Clinically significant response was defined using the Jacobson & Truax’ reliable change criteria (Jacobson & Truax, 1991a)

4.8.1 Deviations from protocol Two minor deviations from the initial registration trial ISRCTN82799488 occurred post hoc. We initially calculated a sample size of (n=128) but ended up recruiting more patients as referrals allowed to increase the sample size to (n=153) to ensure sufficient power at follow-up. Usually this would increase the risk of a type 1 error, however, this was not the case in the present trial because of very large effect sizes. In addition, we added an extra criterion for terminating treatment, which included that the patient either

104 of 229

scored below MDD threshold on the BDI-II ≤ 8 on two consecutive sessions or the therapist and patient agreed that the patient had fully recovered.

4.8.2 Randomisation Randomisation occurred after initial pre-treatment evaluation by an external and independent person who held a secret randomisation list produced by Manchester University. This list was stratified for severity of depression (high/low) and gender (males/females). Scores on the pre-treatment HDRS were used to form four groups: 1) high severity (HDRS ≥ 20), 2) low severity (HDRS ≤ 19), 3) males and 4) females. Participants were assigned to the two therapists (PC and SF) based on therapist availability.

4.8.3 Blinding All assessments were administered by an independent assessor: Charlotte Koch Andersen (CKA) CKA is a clinical psychologist with over 10 years of experience in therapy and assessment. This was a blinded study and all patients were instructed not to reveal which treatment they had received at post-assessment and follow-up. In order to control for evaluation biases the independent assessor CKA was asked to guess which treatment the patient had received at post-treatment assessment. A total of 87 post treatment guesses were obtained. A Chi-Square test showed no significant (p= 0.240) relationship between the assessors guess and treatment grouping suggesting that blinding of the assessor was conducted successfully.

4.8.4 Interventions In this study, protocols for CBT and MCT for MDD were compared. These treatment manuals included the following elements:

4.8.5 Cognitive behaviour Therapy (CBT) The CBT group received treatment using Beck’s traditional cognitive therapy (Beck et al., 1979 ) facilitated by Melanie Fennel’s depression protocol from (Hawton, 1989).

105 of 229

The overall agenda of CBT is to teach patients to identify and restructure maladaptive automatic thoughts and core beliefs/ assumptions and enhance adaptive and pleasurable activities.

In the first session an agreed ‘problem-goal’-list was developed and patients were introduced to the CBT model using a critical situation and formulation from their current life. At the end of the session, a 4-page booklet called "Coping with depression" translated into Danish was given to the patient to read about CBT for depression between session one and two (Beck & Greenberg, 1974)

In session two and beyond negative automatic thoughts were restructured using collaborative empiricism and/or behavioural experiments. This concept involves Socratic dialogue and testing of patients’ hypotheses in and between sessions in which the validity of patients' beliefs about themselves, the world and others were challenged and tested. Socratic dialogue is a therapeutic interview technique that has shown to be of vital importance in symptom reduction in CBT for depression (Braun, Strunk, Sasso, & Cooper, 2015) . Later on more schema-related restructuring was implemented. Schemas involve patients' core beliefs about themselves and are usually stated as e.g. "I am bad" or "I am worthless". In addition, activity scheduling was planned throughout treatment and patients' level of mastery and pleasure was increased. Finally relapse prevention was discussed and implemented in the last sessions.

Restructuring of negative thoughts, underlying assumptions and schemas Restructuring of negative automatic thoughts and underlying assumptions using guided discovery is one of the fundamental techniques used in CBT. In the CBT model low mood is primarily caused by the activation of negative core self-beliefs (schemas) about oneself and the world (e.g. “I’m a failure”, “no one cares about me”) and regulation of low mood is based on re-establishing a more balanced view of oneself and the world. By systematically investigating and challenging these negative statements using Socratic dialogue and restructuring forms (Appendix 14) the patient is taught to identify critical situations in which negative thoughts occur and evaluate the evidence and counter-evidence for their own interpretations. One example of this process is a patient

106 of 229

who believed 90% that everything bad in his life was his fault. This belief resulted in depressed emotions 8 (from a scale from 0-10 with 10 being the maximum low mood). When exploring this belief and challenging his “black and white”-thinking the patient was helped to identify that he was not to blame for all his misery. Other factors like his environment, illness and bad luck could also explain his situation.

Activity scheduling Another way of reducing low mood is to assess patients activity level using a ‘mastery and pleasure’-form (Appendix 13). In this form patients are instructed to evaluate each individual activity of the week and monitor how pleasurable and successful they were on a scale from 0-10. Throughout therapy, patients are encouraged to increase pleasurable activities.

Relapse prevention At the end of therapy patients are asked to summarize the main points in therapy and define old and new schemas and underlying assumptions about themselves and the world.

4.8.6 Meta-cognitive therapy for depression (MCT) Meta-cognitive Therapy (Wells, 2009b) is based on the Self-Regulatory Executive Function (S-REF) model. Negative thoughts and emotions are considered transient events unless maintained by the Cognitive Attentional Syndrome (CAS) which consists of rumination/worry, threat monitoring and other unhelpful coping strategies. In MCT the CAS is believed to be the primary cause of most mental health problems including depression.

The CAS in depression is maintained by maladaptive negative and positive metacognitive beliefs about thinking and the brain. Apart from low meta-awareness in depression where some patients have trouble identifying when they ruminate, negative metacognitive beliefs consist of uncontrollability of the CAS, e.g. “My rumination is

107 of 229

out of my control”; biological metacognitive beliefs e.g. “My brain is broken – rumination uncontrollable” and positive metacognitive beliefs e.g. “Rumination helps me find a way out of depression”.

The overall goal of this treatment is to reduce the CAS by enabling patients to develop new relationships with their negative thoughts, to enhance flexible control over response styles and acquire new and more adaptive metacognitive knowledge e.g. “Rumination is under my control”, “Depression is not a biological condition” and “Rumination will not lead to answers”.

In this trial MCT was delivered using the protocol for depression published in the book Metacognitive Therapy for Anxiety and Depression (Wells, 2009b).

In the first session an individualised MCT case formulation was derived together with the patient and was followed by socialisation to the model and information on the vicious circle of the CAS.

Attention-training (ATT) ATT is a central part of MCT for depression. At the end of the first session ATT is delivered for the first time. This technique is used to show how the control of thinking and attention is independent of internal and external events.

ATT was delivered both ‘in session’ and via homework. Before and after ATT patients’ general level of external-internal attention is evaluated with the goal of enhancing external focus during the exercise and in general in their lives.

ATT helps patients discover how they can move their attention around flexibly and that they are not destined to ruminate just because a negative thought enters their mind. Patients are encouraged to use ATT 2-3 times a day throughout treatment.

Challenging negative metacognitions

108 of 229

The most common belief maintaining the CAS in depression is the belief that rumination is uncontrollable. However, many depressed patients describe how they often find themselves unaware of their rumination not realising this is occurring until several hours into the process. Patients’ awareness is enhanced during the socialisation process and further on in treatment using identification of recent rumination episodes and homework.

Patient’s uncontrollability beliefs are challenged through open-ended questioning (Socratic dialog) and behavioural experiments using Attention Training (ATT) and detached Mindfulness (DM):

Detached Mindfulness (DM) and Rumination postponement As a way of enhancing metacognitive awareness and challenge uncontrollability beliefs DM was introduced from the second session onwards. DM is the opposite of the CAS and is defined as: “A type of inner-awareness, but in the absence of effortful processing of the self. It is awareness of the automatic and non-volitional ebb and flow of internal events, primarily thoughts.” (Wells, 2005a).

DM is practiced within and between sessions. Patients are asked to apply DM to negative thougths and to postpone any rumination or analysing to later on in the day. This ‘rumination time is not mandatory and if used should only be used for a brief period of 15 minutes. This is introduced as a means of testing beliefs about uncontrollability.

Challenge of beliefs about the biological cause of depression Later in treatment biological beliefs about depression were challenged. Many depressed patients have been told by their GP or other health professional that depression is a neurochemical or genetic illness beyond their control and that it can only be overcome my medication. Because of this, patients can be reluctant to accept the fact that they themselves primarily can control the mechanisms that maintains depressive symptoms by reducing the CAS. It is important to challenge beliefs about the biological causes of

109 of 229

depression as it supports the “broken brain” assumption and undermines the application of adaptive mental self-control that is of crucial importance in MCT.

Positive metacognitive beliefs In the last sessions positive beliefs about rumination are challenged and the negative consequences of rumination explored further. Other dysfunctional “mind-control” coping strategies such as thought-suppression, seeking reassurance, avoidance of social activities or sleeping more is also examined and reduced using the Major Depressive Disorder Scale (MDD-S; Wells, 2009)..

110 of 229

Relapse prevention Finally, in the last two sessions relapse prevention is discussed and any remaining positive and negative meta-cognitive beliefs about rumination challenged. All patients develop a therapy blueprint to reduce relapse (Appendix 16).

4.8.7 Treatment differences In summary, the main differences between the two treatments are: CBT focuses on challenging content of thoughts and beliefs about the self and world. MCT exclusively focuses on processes around these thoughts and believes reducing the extent of worry and rumination. CBT works at the object level (challenging content of thought and schemas, e.g. “I’m a failure” ) and MCT works at the meta-cognitive level (Challenging meta-cognitive beliefs about thoughts and feelings, e.g. “Rumination helps me find a solution to why I am a failure”). CBT focuses on pleasure and mastery techniques whilst MCT does not, but focuses on reinforcing flexible attentional control.

4.9 Competency and treatment adherence

In order to establish a fair and even level of competency and experience in CBT and MCT 24 patients were initially recruited to a pilot study (n=12 CBT, n=12 MCT) as training cases and not entered into the trial.

Treatment adherence and competency in both treatments is of vital importance. Highly experienced clinical psychologists PC and SF delivered therapy. PC and SF have undergone specialist training and supervision in CBT with a minimum of ten years of clinical experience in the field. Leading senior psychologist and CBT therapist Lennart Holm, with 35 years of CBT experience, supervised the CBT condition and Professor Adrian Wells, the originator of MCT, supervised the MCT treatment to ensure both treatments were given optimally and according to protocol.

All sessions were recorded on videotape and screened by external psychologists Sisse Find Nielsen (SFN) and Anny Lee (AL) for potential contamination of methods. Contamination was defined by object-level work done in the MCT condition or meta-

111 of 229

level work done in the CBT condition. SFN reviewed a random selection of sessions using a fidelity check list (Appendix 11 and Appendix 13). Some cross-contamination was exclusively found in the CBT condition (A total of 11 of SF’s CBT patients and 2 of PC’s CBT patients were contaminated with some meta-level work). No contamination was detected in the MCT condition.

In addition, 20 random videotaped sessions (10 MCT and 10 CBT) were selected at random and rated by 4 final-year postgraduate psychology students for treatment adherence using the treatment fidelity checklists for CBT and MCT. There was a very high level of treatment adherence in both the CBT and MCT conditions (Table 11)

Table 11: Average treatment adherence to CBT and MCT

CBT MCT Therapist 1 (PC) 90% 83% Therapist 2 (SF) 83% 83% Table 11 shows the average treatment adherence in CBT and MCT for the therapists in the trial in 20 randomly selected sessions.

112 of 229

4.10 Results

Figure 5: Consort Diagram (study 3)

The Consort Diagram (Figure 5) summarizes recruitment, completion and follow-up. A total of 78 participants were excluded at assessment as they did not meet the criteria for MDD as the primary diagnosis. Most of these patients suffered from borderline personality disorder, primarily anxiety, pathological jealousy, obsessive-compulsive

113 of 229

disorder (OCD), posttraumatic stress disorder (PTSD), eating disorder or attention deficit/hyperactivity disorder (ADHD).

At 6-months follow-up over 70% of participants attended assessment on the primary outcome measures. A last observation carried analysis at post-treatment and follow-up was performed on all primary and secondary variables.

4.10.1 Number of sessions, drop-out rates and treatment expectancy The mean number of sessions in CBT was 6.7 SD = 4.7 and the mean number sessions in MCT was 5.5 SD = 2.4. This difference was statistically significant t (122.35) = 2.02, p < .05. For CBT the number of sessions ranged from 2-24, whereas in MCT it ranged from 2-12.

The completion rate was 65.4% in CBT and 73.6% in MCT. We examined patient’s expectancy of the treatments and how logical the treatments seemed to the patient at the third session. No differences were detected in expectations concerning the effectiveness of the interventions CBT; M = 4.25 SD = .76, MCT; M = 4.48 SD = .67. Similarily, there was no significant difference in how logical the treatments seemed to be for the patients; CBT; M = 4.45 SD = .67 and MCT; M = 4.52 SD = .55

4.10.2 Data Analysis Data was analysed using IBM SPSS Statistics v20. A last observation carried forward (LOCF) analysis for the missing variables for primary and secondary variables was conducted and used for analysis.

114 of 229

Table 12: Distribution of LOCF

LOCF CBT MCT BDI-II from the last session to post 31.3% 22.2% BDI-II from post to 6m follow-up 32.1% 25.0% HDRS from pre to post 32.5% 23.6% HDRS from post to 6m follow-up 28.4% 22.2% BAI pre to post 33.8% 25.4% BAI post to 6m follow-up 38.8% 29.6% DAS pre to post 41.3% 29.6% DAS post to 6m follow-up 42.5% 32.4% MDD-s (rumination time) pre to post 41.3% 28.4% MDD-s (rumination time) post to 6 m follow-up 42.5% 31.3% PBRS pre to post 41.3% 28.2% PBRS post to follow-up 42.5% 31.0% NBRS pre to Post 41.3% 28.2% NBRS post to 6 m follow-up 43.8% 31.0% Note: Distribution of LOCF = Last Observation Carried Forward. Note that the BDI-II was conducted at every session. If patients did not turn up for post-treatment assessment data from their last session was reported as LOCF. BDI-II = Becks Depression Inventory II, HDRS = Hamilton Depression Inventory, BAI = Becks Anxiety Inventory, DAS = Dysfunctional Attitude Scale, (MDD-S = Rum time) = Time spend ruminating using the Major depressive Disorder Scale, PBRS = Positive Beliefs About Rumination Scale, NBRS = Negative Beliefs About Rumination Scale. One patients’ (n=1) pre-treatment HDRS was lost at assessment.

As can be seen from the overview LOCF was performed on a total of approximately 22- 32.5% for the primary variables (BDI-II and HDRS) for both pre to post and from post to 6 months follow-up.

On the other hand, secondary variables (BAI, DAS, MDD-S, PBRS and NBRS) have a relatively large missing rate resulting in a higher number of LOCF from 25% to 43.8%. When patients were not able to come back to the clinic and complete measures in the assessment battery, primary outcome measures BDI-II and HDRS were prioritized and

115 of 229

administered over Skype or telephone, thus accounting for the disparity across measures.

4.11 Primary outcomes

4.11.1 Descriptive statistics Table 13 shows the mean scores and standard deviation for primary and secondary outcome variables. At baseline most of the means in CBT and MCT are similar. See Appendix 15 for histograms of the distribution for BDI-II and HDRS.

Table 13: Mean scores and standard deviation for primary and secondary outcome variables

CBT (Cognitive Behavioural Therapy) MCT (Meta-Cognitive Therapy) Pre Post Follow-up Pre Post Follow-up BDI -II M 28.06 12.28 11.74 29.60 8.17 7.85 SD 9.27 11.47 12.62 8.08 10.92 10.82 HDRS M 16.01 7.44 6.90 16.57 6.44 5.81 SD 5.05 7.87 7.61 5.16 8.16 7.34

Table 13. Mean scores for CBT and MCT at pre, post and follow-up. SD = Standard Deviation, BDI-II = Becks Depression Inventory II, HDRS = Hamilton Depression Inventory

Table 13 shows the mean differences before and after treatment on the BDI-II and HDRS at follow-up for CBT and MCT. Large and significant reductions on both primary symptom measures were detected in each condition

116 of 229

4.11.2 Mixed model ANOVA To test for significant differences in change in depression across groups a mixed-model ANOVA was run. For the primary self-report outcome (BDI-II) there was a main effect of time F(1.56, 236.09) =346.17, p < .0005 (pre, post, 6 months follow-up). The group by time interaction was significant F (1.56, 236.09) = 7.51, p < .005, indicating superiority of the MCT intervention In each case the Huynh-Feldt correction was applied as the data violated sphericity. The effects are displayed in Figure 6:

Figure 6: Mixed model ANOVA effect of time (BDI-II)

On the HDRS there was a main effect of time F(1.59, 238.02) = 214.54, p  .0005. However, the group by time interaction was not significant F(1.59, 238.02) = 1.56, p = .22. Again the Huynh-Feldt correction was applied as the data violated sphericity. The effects are displayed graphically in Figure 7.

Figure 7: Mixed model ANOVA effect of time (HDRS)

117 of 229

4.11.3 ANCOVA Next ANCOVA’S were computed to test for between-group differences at post treatment whilst adjusting for pre-treatment scores.

For the BDI-II there was an effect of pre-treatment score on post-treatment outcomes F (1,150) = 25.21, p < .0005. The effect of treatment was significant F(1,150) = 8.27, p < .005. The adjusted means showed that post-treatment score in the MCT condition (Mean = 7.77, 95% CI: lower = 5.39, upper = 10.12) was significantly lower than the score obtained in the CBT condition (12.64, 95% CI, lower = 10.35, upper = 14.93). The unadjusted means and SD are displayed in Table 13.

For the HDRS there was an effect of pre-treatment score on post-treatment outcomes F(1,149) = 29.97, p < .005. However, the effect of treatment was not significant F(1,149) = 1.282, p = .259. The adjusted means showed that post-treatment score in MCT (Mean = 6.26, 95% CI: lower = 4.55, upper = 7.97) was only slightly lower than CBT (Mean = 7.61, 95% CI: lower = 5.99, upper = 9.23). The unadjusted means and SD are displayed in Table 13.

118 of 229

4.11.4 Effect sizes Cohen’s d Cohen’s d is a way of standardizing effect sizes so as to compare them between variables and conditions 푀 −푀 Within subject effect sizes where calculated using the following formula: 푑 = 1 2 푆퐷 푝표표푙푒푑 where M1 is the mean of pre-treatment and M2 is the mean of post-treatment and SD is the pooled standard deviation between pre- and post-treatment (Cohen, J. 1988). This was examined for each group (CBT and MCT) and for pre to post as well as pre to follow-up. The same formula was used for the between group effect sizes where M1 is the mean at post-treatment for CBT and M2 is mean at post-treatment for MCT and SD is the pooled standard deviation at post-treatment. This calculation was also performed on follow-up data.

Table 14: Within subject effect sizes.

Outcome MCT post CBT post MCT fu CBT fu BDI-II 1.85 1.36 1.82 1.36 HDRS 1.34 1.14 1.46 1.23

Both CBT and MCT have very large effect sizes, however, MCT showed higher within subject effect sizes in relation to CBT on primary outcomes.

Table 15: Between group effect sizes.

MCT – CBT MCT-CBT Outcome post follow-up BDI-II 0.36 0.33 HDRS 0.12 0.16

As seen from Table 15 between group effect sizes favour MCT at post treatment with small to medium effect sizes for BDI-II. A very small between group effect size was seen for the HDRS at post-treatment. These results were maintained at follow-up. Results confirm the mixed ANOVA analysis, where a statistical significant effect of group by time was found for BDI-II but not for HDRS.

119 of 229

4.12 Clinical Significant Change & Reliable Change

According to Jacobson and Truax (1991b) a cut-off for clinical significant change can be calculated 3 different ways. Methods a and b for calculating cut-off will be applied together with 3 different assumptions about the underlying test-retest reliability that is used to compute reliable change.

These methods are applied for both primary outcomes – BDI-II and HDRS. Results are presented in 4 different categories – Improved and recovered, improved, no change, deterioration – along with an explanation of the algorithm behind the categorization.

4.12.1 Test-retest reliability In a recent review of BDI-II, the test-retest reliability across studies ranged between 0.73-0.96 (Wang & Gorenstein, 2013). Due to uncertainty surrounding the true test- retest reliability; this range is used to examine how the results change when using different levels of reliability. The test-retest reliability values applied for BDI-II were as follows: low = 0.73, middle = 0.845, high = 0.96. Similarly a review of HDRS by Bagby, Ryder, Schuller, and Marshall (2004) shows, that across psychometric studies since 1979 the test-retest reliability measured in Pearson’s r ranged between 0.81-0.98 (Bagby et al., 2004). Using the argument above, three different reliability levels for HDRS are used: low = 0.81, middle = 0.895, high = 0.98.

4.12.2 Cut-off calculations for BDI-II and HDRS Method a

For method a cut-off is calculated using the formula 푎 = 푀1 − 2푠1, where 푀1 is mean of pre-treatment for the total sample and 푠1 is the standard deviation of pre-treatment for the total sample (Jacobson & Truax, 1991:13). In rounded numbers, the pre-treatment mean of the total sample for BDI-II is 28.78 and the standard deviation is 8.74. Using the formula above this gives a cut-off 푎 = 28.78 − 2×8.74 = 11.3. In rounded numbers the pre-treatment mean of total sample for HDRS is 16.46 and the standard

120 of 229

deviation is 5.58. Using the same formula this gives a cut-off 푎 = 16.46 − 2×5.58 = 5.3.

Method b Method b uses statistics from a normal functional population and defines the cut-off as moving from a dysfunctional population into the distribution of a functional population (Jacobson & Truax, 1991:13). Comparing BDI-II measures across cultures has been shown to be an issue (Wang & Gorenstein, 2013:14) However, since data from a normal population are not available for Denmark a sample from Norway is used instead (Aasen, 2001). Using a sample from a different country may cause problems in terms of comparing between what’s functional and what’s dysfunctional. However, choosing Norway for comparison seems to be reasonable due to similarities between the Danish and Norwegian language and cultures. The sample contained 875 adults with a mean score of 8.1 and a standard deviation of 7.5. (Aasen, 2001). Unfortunately data from a functional normal population was not available for HDRS. This excludes the use of method b and leaves us with method a.

The calculation for the cut-off for BDI-II based on method b uses the following formula: 푏 = 2푠1 − 푀0, where 푀0 is the mean from a functional normal population and

푠1 is the standard deviation of the functional normal population (Jacobson & Truax, 1991:13). Using the data from Aasen (2001) the cut off for BDI-II is as follows: 푏 = 2×7.5 − 8.1 = 6.9.

4.12.3 Reliable change calculation When categorising a change from pre to post-treatment it is important to account for the statistical uncertainty surrounding the size of the change for individual cases. According to Jacobson and Truax (1991b) this is especially important when functional and dysfunctional distributions are overlapping. In this case crossing the cut-off in itself does not guarantee a statistical reliable change (Jacobson & Truax, 1991:14). In order to deal with this problem the authors propose calculating an index to use for assessing whether a change from pre to post is statistically reliable. This variable is calculated

121 of 229

푥1−푥2 using the following formula: 푅퐶 = , where x1 represents a subject’s pre-treatment 푆푑푖푓푓 score and x2 represents the same subjects post-treatment score. Sdiff is the standard error of the differences from pre to post-treatment and describes the spread of the change scores that would be expected if no actual change had occurred. Computing Sdiff is done

2 by using the following formula: 푆푑푖푓푓 = √2(푆퐸) , where SE is the standard error of measurement. This in turn is calculated using the standard deviation from the different methods a and b together with the test-retest reliability level. The formula for this is as follows: 푆퐸 = 푠1√1 − 푟푥푥, where rxx is the test-retest reliability and s1 is the standard deviation used in method a or b. If RC for a given subject differs more than ∓1.96, then the change is unlikely to have occurred if there was in fact no change (Jacobson & Truax, 1991:14).

Since the Sdiff is the standardised within subject change method it tells us something about the “toughness” of the test. Therefore, it seems appropriate to compare Sdiff calculations across the methods. A larger Sdiff in turn sets the requirement for a greater change from pre to post in order for a given subject to be counted as having reliably changed. In addition, the cut-off point is a measure of how hard it is to gain status as recovered. To evaluate the different methods it seems useful to compare the results with these underlying numbers. The tables below show the different parameters of the methods.

Table 16: Standard errors of differences from pre to post for BDI-II

Test retest-reliability level Cut-off Pearson’s r = 0.73 Pearson’s r = 0.845 Pearson’s r = 0.96 Method a = 6.42 4.86 2.47 11.31 Method b = 5.51 4.18 2.12 6.90

Table 17: Standard errors of differences from pre to post for HDRS

122 of 229

Test-retest reliability level Cut-off Pearson’s r = 0.81 Pearson’s r = 0.895 Pearson’s r = 0.98 Method a = 5.30 3.44 2.56 1.12

4.12.4 Algorithm for categorization For computing the distribution between the 4 categories –recovered, improved, no change and deterioration – multiple excel-sheets where used to quantify subjects into the categories. The criteria for placing subjects in the different categories was programmed with simple logical functions such as “AND” and “IF” plus operators like >, < and =. As mentioned earlier reliable change was evaluated against an RC change size of ∓1.96. The table below shows the logical functions used in the excel sheets.

Table 18: Logical functions used in excel sheets

Recovered Improved No change Deterioration Logical IF post-value < IF post-value > IF -1.96 < RC IF RC > criteria cut-off AND RC cut-off AND < 1.96 1.96 < -1.96 RC < - 1.96 Note: RC=Reliable Change.

Notice that the criteria for change in the direction of functionality is a negative value since both BDI-II and HDRS counts higher values as more dysfunctional and lower values as more functional. A change from dysfunctional to functional will therefore show up as a negative value in the reliable change index. The two-fold Reliable Change (RC) criteria for recovery is defined as changing < -1.96 SD and score below cut-off on HRDS = 5.3 and BDI-II = 11.2. Converted when using Method a this would mean a Reliable Change Index (RCI) of at least 2.47x1.96 = 4.84 on the BDI-II and a RCI of at least 1.12x1.96 = 2.20 on the HDRS.

123 of 229

4.12.5 Results for BDI-II As seen in the Table 19 using method a and changing the test-retest reliability level has only little effect on the MCT group as a move from low to high test-retest reliability only changes 2% within the category “improved and recovered”. Although slightly higher, the same goes for the CBT group with a change of 6%. In addition MCT is superior to CBT on all 3 tests within method a.

Figure 8 Illustrate recovery rates for BDI-II with method a-3 (with the highest test-retest reliability):

Figure 8: Recovery rates BDI-II study 3

RECOVERY RATES - BDI-II - POST-TREATMENT CUT-OFF = 11.3, ASSUMED RELIABILITY = 0,96, RELIABLE CHANGE = < -1.96, (RCI = 4.84 ) 100% 6.17% 5.56% 90% 12.35% 18.06% 80% 70% 27.16% 60% 50% 40% 76.39% 30% 54.32% 20% 10% 0% CBT MCT

Recovered Improved No change Deterioration

As can be seen from the bar chart 54.32% were recovered at post-treatment in CBT whereas 76.39% recovered in MCT. In addition, 5.56% of patients deterioration in CBT suggesting that in some cases therapy might actually significantly increase symptoms instead of improving them.

124 of 229

Table 19: Results for BDI-II post-treatment

Method Treatment Recovered Improved No change Deteriorated CBT 48.15% 17.28% 33.33% 1.23% a-1 MCT 73.61% 6.94% 19.44% 0.00% CBT 53.09% 20.99% 23.46% 2.47% a-2 MCT 76.39% 9.72% 13.89% 0.00% CBT 54.32% 27.16% 12.35% 6.17% a-3 MCT 76.39% 18.06% 5.56% 0.00% CBT 35.80% 37.04% 24.69% 2.47% b-1 MCT 65.28% 20.83% 13.89% 0.00% CBT 35.80% 41.98% 19.75% 2.47% b-2 MCT 65.28% 20.83% 13.89% 0.00% CBT 37.04% 44.44% 12.35% 6.17% b-3 MCT 65.28% 29.17% 5.56% 0.00% Average % CBT 44.03% 31.48% 20.99% 3.50% across all MCT methods 70.37% 17.59% 12.04% 0.00%

Looking at method b, MCT again is superior to CBT at all 3 test-retest reliability levels. This time however with about a 10% drop in the category “improved and recovered” for both MCT and CBT. Interestingly, in the CBT condition 1-6% deteriorated during treatment dependent on the analysis performed.

The same calculation was run for changes from pre to follow-up for BDI-II. Results are seen in the tables below.

When comparing BDI-II recovery rates from pre- to post-treatment with pre- to follow- up it is worth noting that there is a slight improvement in the recovery rate for CBT in the pre- to follow-up analysis as indicated in the 8% difference on the average across

125 of 229

methods (from 44% in post analysis to 52% in follow-up analyses). The results for MCT indicate large recovery-rates from pre- to follow-up analyses, see Table 20

Table 20: BDI-II pre to follow-up BDI-II pre to follow-up Method Treatment Recovered Improved No change Deteriorated CBT 53.09% 16.05% 28.40% 2.47% a-1 MCT 75.00% 6.94% 18.06% 0.00% CBT 56.79% 19.75% 18.52% 4.94% a-2 MCT 76.39% 9.72% 13.89% 0.00% CBT 56.79% 25.93% 9.88% 7.41% a-3 MCT 76.39% 16.67% 6.94% 0.00% CBT 48.15% 28.40% 19.75% 3.70% b-1 MCT 62.50% 22.22% 15.28% 0.00% CBT 48.15% 29.63% 17.28% 4.94% b-2 MCT 62.50% 23.61% 13.89% 0.00% CBT 48.00% 28.00% 20.00% 4.00% b-3 MCT 63.00% 22.00% 15.00% 0.00% Average % CBT 51.83% 24.63% 18.97% 4.58% across all methods MCT 69.30% 16.86% 13.84% 0.00%

When comparing BDI-II recovery rates from pre- to post-treatment with pre- to follow- up it is worth noting that there is a slight improvement in the recovery rate for CBT in the pre- to follow-up analysis as indicated in the 8% difference on the average across methods (from 44% in post analysis to 52% in follow-up analyses). The results for MCT indicate large recovery-rates from pre- to follow-up analyses.

126 of 229

Figure 9: Recovery rates at follow-up for BDI-II

RECOVERY RATES - BDI-II - FOLLOW-UP CUT-OFF = 11.3, ASSUMED RELIABILITY = 0,96, RELIABLE CHANGE = < -1.96 (RCI = 4.84 ) 100% 7.41% 6.74% 90% 9.88% 80% 16.67%

70% 25.93% 60% 50% 40% 76.39% 30% 56.79% 20% 10% 0% CBT MCT

Recovered Improved No change Deterioration

At 6-months recovery rates using the BDI-II seem to remain at follow-up. However, instead of 6.17% now 7.41% has deteriorated in CBT.

4.12.6 Results for HDRS

The following shows results at pre to post-treatment and pre to follow-up for HDRS. Summarising, 53% recovered in CBT whereas 65% recovered in MCT. Again 1% of patients in the CBT condition had a significant worsening of symptoms. The results are displayed in Figure 10 below.

127 of 229

Figure 10 Recovery rates for the HDRS post-treatment:

RECOVERY RATES - HDRS - POST-TREATMENT CUT-OFF = 5.3, ASSUMED RELIABILITY = 0,98, RELIABLE CHANGE = < -1.96, (RCI = 2.20 ) 1.23% 100% 90% 23.69% 80% 33.33% 70% 11.11% 60% 12.35% 50% 40% 30% 65.28% 53.09% 20% 10% 0% CBT MCT

Recovered Improved No change Deterioration

Below in Table 21 three ways of calculating recovery rates are displayed using the HDRS.

Table 21: Recovery rates for HDRS pre to post-treatment.

Method Treatment Recovered Improved No change Deteriorated CBT 49.38% 7.41% 43.21% 0.00% a-1 MCT 61.11% 8.33% 30.56% 0.00% CBT 51.85% 9.88% 38.27% 0.00% a-2 MCT 63.89% 8.33% 27.78% 0.00% CBT 53.09% 12.35% 33.33% 1.23% a-3 MCT 65.28% 11.11% 23.61% 0.00% Average % CBT 51.44% 9.88% 38.27% 0.41% across all MCT 63.43% 9.26% 27.31% 0.00% methods

128 of 229

The difference in CBT between the pre to post and pre to follow-up seen for BDI is not present on the HDRS outcome. As seen from Table 22 below, results are very similar to the pre- to post-treatment analysis as indicated by the average across methods.

Table 22: HDRS pre to follow-up

Method Treatment Recovered Improved No change Deteriorated CBT 50.00% 8.75% 41.25% 0.00% a-1 MCT 63.89% 13.89% 22.22% 0.00% CBT 52.50% 8.75% 38.75% 0.00% a-2 MCT 63.89% 13.89% 22.22% 0.00% CBT 53.75% 15.00% 30.00% 1.25% a-3 MCT 63.89% 16.67% 19.44% 0.00% Average % CBT 52.08% 10.83% 36.67% 0.42% across all MCT 63.89% 14.81% 21.30% 0.00% methods

For HDRS, recovery rates largely remain the same at follow-up for both CBT and MCT. Results for method a-3 are shown in the figures below.

129 of 229

Figure 11: Recovery rates HDRS – Follow-up

RECOVERY RATES - HDRS - FOLLOW-UP CUT-OFF = 5.3, ASSUMED RELIABILITY = 0,98, RELIABLE CHANGE = < -1.96, (RCI = 2.20 ) 1.25% 100% 90% 19.44% 30% 80% 70% 16.67% 60% 15% 50% 40% 30% 63.89% 53.75% 20% 10% 0% CBT MCT

Recovered Improved No change Deterioration

4.13 Secondary outcomes

4.13.1 Descriptive statistics The table below shows standard deviations and mean for secondary outcome variables for CBT and MCT and pre-treatment, post-treatment and follow-up.

130 of 229

Table 23: Standard deviations and mean for secondary outcome variables for CBT and MCT

CBT MCT Pre Post Follow-up Pre Post Follow-up BAI M 17.14 10.26 9.53 16.52 8.51 7.8 SD 11.37 11.67 12.16 9.82 10.68 10.72 DAS M 153.16 132.1 130.73 151.66 115.27 112.48 SD 32.58 42.67 42.13 35.59 45.59 45.27 Rum time M 5.44 3.36 3.22 5.63 2.09 2.07 SD 2.12 2.52 2.75 1.87 2.62 2.45 PBRS M 21.18 17.54 17.12 21.17 13.3 13.58 SD 6.16 7.10 7.00 6.52 6.69 6.51 NBRS M 24.69 21.25 21.17 25.54 19.72 19.44 SD 7.22 7.45 7.76 7.4 6.84 6.77

As can be seen from the table there are only small differences at pre-treatment outcomes between MCT and CBT. At post-treatment however there seems to be significant differences especially for PBRS and rumination time..

4.13.2 Secondary Outcomes: Mixed model ANOVA As with the primary outcomes a Mixed model ANOVA was run to test for statistically significant differences. The results are summarised in the table below showing effects of time and the group by time interaction. Huynh-Feldt corrections were applied for all outcomes as the data violated sphericity.

131 of 229

Table 24: Mixed model ANOVA Degrees of Outcome Effect freedom F-test p BAI Time effect 1.426 102.252 < .0005 Group by time effect 1.426 0.593 .499 Error 212.447 DAS_A Time effect 1.626 93.663 < .0005 Group by time effect 1.626 7.309 < .005 Error 242.326 MDD_S_2 Time effect 1.626 93.663 < .0005 Group by time effect 1.626 7.309 < .005 Error 242.326 PBRS Time effect 1.267 92.967 < .0005 Group by time effect 1.267 10.964 < .0005 Error 188.79 NBRS Time effect 1.539 70.769 < .0005 Group by time effect 1.539 5.21 < .05 Error 229.25

Examining the time effects all secondary outcomes showed a significant effect p < .0005. In addition to that, the group by time interaction showed an effect favouring MCT on all measures (p < .05) except for BAI where there was no significant interaction [F(1.43, 212.45) = 0.59, p = .499].

4.13.3 Secondary Outcomes: ANCOVA For secondary outcomes ANCOVA’S were computed to test for between-group differences at post treatment whilst adjusting for pre-treatment scores. Table 25 below shows the results for all secondary outcomes.

132 of 229

Table 25: ANCOVA analysis of post-treatment differences

Degrees of Outcome Effect freedom F-test p Pre-treatment effect 1 128.542 < .0005 BAI Treatment effect 1 .957 .330 Error 148 Pre-treatment 1 99.082 < .0005 DAS-A Treatment 1 7.816 < .05 Error 148 Pre-treatment 1 18.665 < .0005 MDD-S-2 Treatment 1 10.071 < .005 Error 144 Pre-treatment 1 33.440 < .0005 PBRS Treatment 1 17.247 < .0005 Error 148 Pre-treatment 1 95.247 < .0005 NBRS Treatment 1 5.011 < .05 Error 148

Again all outcomes show significant effects of treatment on post-treatment outcomes (p < .05) except for BAI [F(1,148) = .96, p = .33]. Also the effect of pre-treatment on post- treatment outcomes are highly significant with p < .0005. Adding to this the adjusted means at post-treatment for MCT are consistently lower compared to CBT for all outcomes as seen in Table 26 below. However, since the difference for BAI is not significant we cannot be sure that this difference is real.

133 of 229

Table 26: Adjusted means at post-treatment outcomes

95% Confidence Interval Outcome Group Mean Lower Bound Upper Bound BAI CBT 10.055 8.235 11.874 MCT 8.741 6.810 10.672 DAS-A CBT 131.521 123.960 139.083 MCT 115.920 107.893 123.946 MDD-S-2 CBT 3.400 2.862 3.938 MCT 2.119 1.531 2.707 PBRS CBT 17.536 16.153 18.919 MCT 13.297 11.829 14.765 NBRS CBT 21.495 20.254 22.736 MCT 19.442 18.125 20.760

4.13.4 Effect sizes Cohen’s d for secondary variables Table 27: Within subject ES’s.

Outcome MCT post CBT post MCT fu CBT fu BAI 0.92 0.79 0.94 0.81 DAS 1.29 0.60 1.12 0.88 MDD_S_2 1.26 0.75 1.24 0.78 PBRS 1.07 0.49 1.05 0.55 NBRS 0.92 0.54 0.94 0.52

As seen from the Table 27 MCT was superior to CBT on all secondary outcomes although both treatments show large effect sizes. There is no large difference in BAI. Naturally, the meta-cognitive scales; MDD-s-2, PBRS and NBRS show much larger effect sizes in the MCT than the CBT condition. Surprisingly, however, the DAS, which is a cognitive measure of underlying assumptions, has a very large effect size in the MCT condition – much higher than in the CBT condition. This is a very interesting

134 of 229

finding as you would not expect MCT to be significantly more effective than CBT on a schema-related measure. At follow-up moderate to large effect sizes are seen on all measures.

Table 28: Between group effect sizes.

MCT – CBT MCT-CBT Outcome post follow-up BAI 0.21 0.19 DAS 0.39 0.45 MDD_S_2 0.47 0.43 PBRS 0.62 0.50 NBRS 0.09 0.19

As seen from Table 28 between groups effect sizes all favour MCT at post treatment with moderate effect sizes for rumination (MDD-S-2) and metacognition (PBRS). Small effect sizes were seen in BAI and NBRS. However as indicated earlier by the ANCOVA analysis the difference in BAI between groups at post-treatment was not significant when controlling for pre-treatment. These results were maintained at follow- up.

4.14 The Therapeutic Alliance

To test whether there was a difference in the assessed working alliance of patients and therapist a t-test was run to test for differences between CBT and MCT. The most widely used measure of the alliance is the Working Alliance Inventory (WAI; Horvath et al., 2011, Horvath and Greenberg, 1986 and Horvath and Greenberg, 1989). The WAI consists of three corresponding subscales designed to assess these components (i.e., Bond, Goals and Tasks subscales). In the present trial WAI was used to assess the quality of the alliance at the 3rd session for patients in both CBT and MCT. Using the WAI, the working alliance inventory scores are constructed into an additive index

135 of 229

where the highest score is 84 and the lowest is 0. Both patients and therapists where asked to evaluate the working alliance.

Table 29: Mean difference in working alliance.

95% Confidence Interval of the Difference Mean Mean difference p. Lower Upper Working CBT 71.00 Alliance - Patient’s -4.14 < .05 -8.23 -0.04 MCT 75.14 evaluation

Working CBT 72.69 Alliance - Therapist’s -2.14 .186 -5.34 1.05 MCT 74.83 evaluation

The results show a small difference between CBT and MCT in the patient’s evaluation with MCT scoring slightly higher [Mdiff = -4.14, p = 0.048]. In the therapist’s evaluation the scores showed a small difference with MCT scoring 2 points higher. However, this result was not significant and therefore we cannot reject the null-hypothesis of no difference at alpha level 0.05 [Mdiff = -4.14, p = 0.186]. Overall MCT seems to have a better working alliance compared to CBT on patient’s evaluation, although the differences are small and may reflect the differences in effectiveness between the treatments

Next, we conducted an ANCOVA analysis exploring the possibility that including working alliance assessed by the patient (using the WAI – patient version) may change the results from the previous ANCOVA for primary outcomes BDI-II and HRDS.

136 of 229

ANCOVA were run for both post-treatment outcomes and follow-up. Results are displayed in Table 30 below.

Table 30: ANCOVA Post-treatment and follow-up

Degrees of Outcome freedom F-value P-value Pre-treatment 1 17.287 < .005 Working Alliance 1 5.137 .026 BDI-II - post Treatment 1 6.741 .011 Error 92 Pre-treatment 1 25.318 < .005 BDI-II - follow- Working Alliance 1 3.607 .061 up Treatment 1 1.135 .290 Error 92

Degrees of Outcome freedom F-value P-value Pre-treatment 1 16.463 < .005 Working Alliance 1 2.435 .122 HRDS - post Treatment 1 .063 .802 Error 92 Pre-treatment 1 12.188 .001 HRDS - follow- Working Alliance 1 7.519 .007 up Treatment 1 .253 .616 Error 92

The results indicate that when including working alliance assessment, the treatment effect still remains significant at post-treatment on the BDI-II [(1.92) = 6.741, p = .011].

137 of 229

Also working alliance may have an independent effect [(1.92) = 5.137, p = .026]. However, this should be interpreted with care since this covariate analysis was done with a proxy measure and working alliance may be confounded by the treatment itself. Therefore, working alliance is just as likely to be a mediating effect as the treatment itself.

4.14.1 Discussion The present study is the first of its kind to compare MCT versus CBT for MDD in a large clinical randomised trial. The study design was robust using the same experienced and trained therapists in both conditions and with a large sample size with high power (n=155).

Sample characteristics for CBT and MCT were similar at baseline. Most participants had moderate to severe depressive symptoms, there were an even number of males/females and equivalent number of co-morbid disorders. Post-treatment assessments and randomisation was blind and conducted by an external assessor. Treatment fidelity was high (80-90%) and the study should have a good level of internal and external validity.

4.14.2 Comparison of MCT versus CBT Between groups ANCOVAS were conducted controlling for pre-treatment differences and on the entire randomised group (except the two missing cases) using LOCF . On the HDRS analysis showed substantial but not statistically significant differences in treatment outcome between MCT and CBT favouring MCT; F (1.149) = 1.282, p = .259. However, data from the HDRS must be analysed with caution because of limited training of the assessor and limitations of only using one assessor.

Looking at possibly the more reliable primary outcome variable BDI-II, MCT showed a large and statistically significant decline in symptoms for both groups from pre to post treatment. However, in the between groups ANCOVA significantly greater symptom decline was observed in MCT compared to CBT; F (1.150) = 8.27, p < .005. All

138 of 229

findings were maintained at follow-up. In addition, this large and significant decline in MCT was achieved in fewer sessions (CBT= 6.7 (SD = 4.7) and in MCT = 5.5 (SD =2.4) and with a lower drop-out rate (Completion rate was 65.4% in CBT and 73.6% in MCT)

Using Cohens d to calculate effect sizes on BDI-II, both CBT and MCT had very large effect sizes (MCT = 1.85 and CBT = 1.36) at post-treatment. For HDRS effect sizes are similarly large for both MCT (1.34) and CBT (1.14). These findings are maintained at follow-up: For BDI-II (MCT = 1.82 and CBT = 1.36) and for HDRS (MCT = 1.46 and CBT = 1.23). These effect sizes compare favourably with other published studies of CBT and MCT, being as high as other CBT trials, but lower than some other MCT studies. Interestingly, CBT showed similar or better effect sizes than in other RCT’s suggesting that perhaps the detected contamination seen in the CBT condition may have improved and enhanced the CBT outcome levels somewhat. Effect sizes in CBT are usually small to moderate d =0.24-0.69 (see Table 4).

Jacobson & Truax’s (1991) method a-3 (with the highest test-retest reliability) was implemented with 76% recovery rate in MCT at post-treatment compared to 54% in the CBT condition. In addition, approximately 5% deteriorated in CBT. It is very rare that deterioration is studied and reported in RCT’s. However, the results of this study suggest that it is important to acknowledge that not all patients profit from psychological treatments and that there might be a risk of significant deterioration in symptoms. The tradition of reporting negative effects or side-effects of treatments is much more prominent in psycho-pharmacology were these potential risks are always reported.

It appears that the treatment effects in both conditions were maintained at 6-months follow-up. These results support the short-term stability of change but longer term outcomes are important as relapse is common over longer periods in depression. Follow-up of these cases is ongoing and will be reported in a later paper.

139 of 229

Examination of recovery rates as measured by BDI-II and the HDRS in the trial are suggestive of higher rates compared with earlier similar trials (Cuijpers et al., 2013b; van Hees et al., 2013) which showed recovery rates 31.7% ( BDI-II) and 38.3% ( HDRS).

Effect sizes in the present trial were larger than those in the pilot study by Jordan and colleagues in New Zealand (Jordan et al., 2014). In their trial ITT analysis revealed MCT d=1.03 and CBT d=1.03. However, in this present trial ITT analysis showed MCT d = 1.85 and CBT d = 1.36. A major difference between these studies is that the present study utilised greater training and supervision of MCT therapists, suggesting that training and supervision in MCT is necessary in order to achieve the very large effect sizes normally associated with MCT..

ANCOVAS were run on secondary outcome measures at post-treatment. Results revealed significantly better results for MCT compared to CBT on all cognitive and meta-cognitive measures p <.0005 (PBRS, NBRS, MDD-s-2 and the DAS). Unexpectedly, patients in the MCT condition reduced negative beliefs on a cognitive level about themselves and the world as measured on the DAS to a greater extent than those in the CBT condition. This is despite the fact that no work was conducted trying to change these core beliefs in MCT. This finding suggests that there may be a link between cognitive and metacognitive levels. By reducing the time spent ruminating the content of the thinking process is automatically altered even if the content has not been directly challenged. Alternatively, the reduction in beliefs (schemas) may simply reflect symptom improvement, and since this was greater in MCT a difference in change at this schema level is also observed. These findings are challenging for the cognitive model that gives a central primary causal role to schemas in depression. The findings from the present study suggest that such schemas may just represent another symptom or be secondary to other more fundamental processes.

Patients in the CBT condition experienced a substantial and significant decline in their level of rumination and also in their perceived control over their rumination. Naturally, no intentional work was done to reduce the time spent ruminating in this condition. Of

140 of 229

course, this finding could be a consequence of the contamination of MCT in CBT. However, another option is that by restructuring underlying assumptions and thoughts patients perceive increased feelings of “control” over their thinking process and therefore eventually found themselves ruminating less.

Summarizing, the results of this randomised trial show larger effect sizes and clinical significant change than reported in other similar trials testing interventions on major depressive disorder.

4.14.3 The effect of the Therapeutic Alliance Numerous articles have argued that the therapeutic alliance is of vital importance for the effects of therapy (Horvath et al., 2011, Horvath and Symonds, 1991, Martin et al., 2000). In this trial the working alliance was slightly better in the MCT condition. However, when controlling for alliance MCT remained superior at post treatment on the BDI II. However, the working alliance may be sensitive to treatment efficacy as patients may define the alliance as good if treatment is effective for them.

4.15 Limitations

This trial contains a number of potential biases and limitations. First of all, at the start, therapists had significantly more training and experience in CBT than in MCT. More training and experience may be linked to higher skill but it could also be associated with lower adherence to a structured manual, although we found similar levels of adherence in each condition. In an attempt to increase parity in competency a training phase involving 24 cases was introduced at the start of the trial. This phase involved a total of 12 MCT cases for each therapist, which is rather a small number for training. All sessions were recorded on film and 20 sessions evaluated by external students in psychology in objective tick-box scales (Appendix 11). However, to optimise this more experienced psychologists and the Revised Cognitive Therapy Scale (CTSR) (Blackburn, James, Milne, Baker, Standart, Garland, & Reichelt, 2001) could have been used.

141 of 229

The use of the same therapists in both the CBT and MCT condition is both an advantage and a potential weakness in the study. Using the same therapists controls for the role of therapists general clinical experience, personality and other non-specific factors. On the other hand, using the same therapists also result in a substantial risk of contamination and carry-over effects between therapies. Interestingly, contamination was detected only in the CBT condition with some meta-level work appearing along with object level schema-work. No contamination was found in the MCT condition suggesting that once therapists are introduced to MCT it is much harder for therapists to stay and work at the object level (CBT). In addition, the large effect sizes in CBT might suggest that the limited introduction of meta-level work in the CBT condition could have a positive effect on the general effect size of CBT.

Another potential bias when using the same therapists is the risk of therapist preferences. Some argue that the reason MCT turned out better than CBT could be explained by the fact that the therapists preferred MCT over CBT. However, if this was the case one would expect low effect sizes in CBT. On the contrary, effect sizes and recovery rates in the CBT condition are larger than seen in other trials. Furthermore, the current study was conducted in a long established CBT clinic where alternatives to CBT would not be favoured at the outset. Therefore, it appears unlikely that the results are confounded by therapist effects.

A further bias concerns assessment. Although the assessor (CKA) has a high level of clinical experience, she was not trained in using the SCID and the HDRS. This weakens the credibility of theses scales. It is recommended that several well-trained assessors are used to ensure reliability across assessments.

Another limitation is the use of LOCF for analysis. Missing data imputation would have been more valid choice as well as the use a sensitivity analysis on the two missing cases. This would have allowed an intention to treat (ITT) analysis on all subjects.

A final limitation regards the power calculation. The number of participants in this study was not based on a statistical power analysis. However, compared to other RCT

142 of 229

this study had a very large sample size. Of course, this could increase the risk of a type 1 error. However, in this study the effect sizes were so large that this could not have been the case. The use of multiple tests increase the risk of a type 1 error and this could have been avoided using e.g. a Bonferroni correction. ANCOVAs were only conducted at post-treatment and should optimally also be done at follow-up. In addition, confidence intervals for effect sizes and significant differences in recovery rates from Jacobson and Truax’ calculations could have been tested using a Chi-square analysis.

All assessments were blinded and patients were told not to reveal which treatment condition they received. However, a final limitation in this study is the lack of reporting of blinding leakage in cases were patients accidently revealed their treatment condition.

4.16 Generalizability

Because of the large sample size and robust design, this study is likely to have a high level of internal and external validity. The results of this trial are generalizable to a depressed outpatient population. However, further RCTs are need to test MCT against other treatments in different populations. In order to enhance the design of future trials expert therapists should be used in all treatment conditions in order to ensure treatment adherence and avoid the risk of contamination of methods.

143 of 229

5 Study 4: METACOGNITIVE THERAPY IN TRANSDIAGNOSTIC GROUPS – AN UNCONTROLLED OPEN TRIAL

5.1 Abstract

5.1.1 Background Co-morbidity is very common amongst depression and other mental disorders. Different transdiagnostic treatment approaches have been developed in order to optimise treatment and offer a more unified approach suitable for mixed diagnostic groups. The Wells & Mathews (1994) S-REF model and Metacognitive therapy (MCT) is a transdiagnostic paradigm in which all psychological disorders are maintained my perseverative thinking. The present study was designed to test the efficacy of MCT when delivered in a mixed group of patients.

5.1.2 Methods A heterogenous group of 131 self-diagnosed patients received six sessions of two hours each. Anxiety and depressive symptoms as measured by the HADS was the primary outcome measure and secondary measures consisted of CAS-1. Participants were assesses at pre, mid, post-treatment and at 6 months follow-up. Mixed model ANCOVAS, Cohens d effect sizes and clinical significant change was reported for the group divided into three patient sub-groups (anxiety, depression or both).

5.1.3 Conclusions Transdiagnostic group MCT showed large clinical change rates. At post-treatment Cohen’s d for anxiety and depressive groups showed (d = 1.69 and d = 1.65 respectively). However, at follow-up effect sizes in the depression group were higher (d = 2.00) indicating a slight reduction in the effect size for the anxiety group (d = 1.34). Using Jacobson and Truax’s (1991) criteria (method a-3) clinically significant improvements were seen for 85% of patients in the whole group as measured on the HADS. Summarizing, these preliminary findings suggest that transdiagnostic group MCT potentially is an efficious treatment in mixed diagnostic groups.

144 of 229

5.2 Introduction

Most psychological paradigms like CBT offer a disorder specific treatment in the sense that they use separate protocols for treating anxiety, OCD, PTSD and depression and these are typically supported by disorder-specific case formulations and models. In most cases therapists will target the most prevalent disorder at first and the move on to the secondary, less prominent health problem. Full remission will not happen until all comorbid disorders have been treated resulting in long-term treatment methods in a large number of cases.

Studies have shown that 50% of clients suffer from a comorbid depressive or anxiety disorder (Hirschfeld, 2001). In fact, meta-analysis shows that the prevalence of anxiety disorders without depression is more rare than the opposite with 56% comorbidity Clark, 1989 (in (Stein & Hollander, 2003).This is the case for social anxiety disorder, panic disorder and GAD (Stein & Hollander, 2003).

Because of extensive co-morbidity amongst mental disorders, there is need for trans- diagnostic models and treatments, which could optimize effects, reduce the number of manuals, and promote higher, faster and more reliable remission rates. Trans-diagnostic models and treatments should not be based on specific diagnoses and they need to address more general and common factors.

Wells and Matthews (1996a) were among the first to suggest a trans-diagnostic treatment approach grounded in theory. They suggested that disorder symptoms are maintained by a common set of voluntary strategies across all disorders. Since then a large body of research has focused on developing more trans-diagnostic approaches for both anxiety and depression in groups. These include TD-CBT which draws on common elements of CBT across disorders (Cognitive restructuring and graded exposure (Barlow, McMillan, Kirkpatrick, Ghate, Barnes, & Smith, 2010; McEvoy & Nathan, 2007). Furthermore approaches such as mindfulness stress reduction, Acceptance and Commitment therapy (ACT) and mindfulness-based therapies have developed manuals for trans-diagnostic settings based on procedures drawn from

145 of 229

Buddhist writings that aim to cultivate non-judgemental awareness and acceptance of inner states, thoughts and feelings (Kabat‐Zinn, 2003).

In the literature most trials focus on comorbid anxiety disorders (Norton & Barrera, 2012; Norton, Barrera, Mathew, Chamberlain, Szafranski, Reddy, & Smith, 2013; Talkovsky & Norton, 2014, 2016), they involve small sample sizes and yield moderate effect sizes. Most previous trans-diagnostic studies have used relatively constrained samples. A systemic review and meta-analysis of 50 trans-diagnostic studies only involved 7 studies with a mixture of both primarily depressed or anxious individuals and no studies involved groups of patients with primary diagnoses of both MDD, Anxiety, OCD or PTSD in mixed groups. Results show that transdiagnostic treatments are efficacious but with a wide range of uncontrolled effect sizes ranging from 0.012 to 1.512 with only 4 studies above 1.0 (Newby, Williams, & Andrews, 2014).

Given the heterogeneity that exists amongst the so called ‘trans-diagnostic’ treatments in the literature and the paucity of treatment trials based on an a-priori trans-diagnostic model it is premature to make inferences about the effectiveness of a true trans- diagnostic treatment approach (i.e. a treatment based on a generic model and utilising the same techniques across different diagnoses treated within a single group setting). The success of trans-diagnostic treatment is likely to depend on such an approach being grounded in an evidence-based model capturing trans-diagnostic causal and maintenance mechanisms.

A leading model of this kind is the S-REF model (Wells & Matthews, 1996b). In this paradigm all psychological disorders are caused by mental strategies collectively termed the Cognitive Attentional Syndrome (CAS). The CAS consists of extended thinking in the form of rumination and worry and coping behaviours that have paradoxical effects on mental regulation (Wells et al., 2009). The CAS is conceptualised as closely linked to unhelpful underlying metacognitive beliefs about the uncontrollability of thinking and the advantages of engaging in extended negative processing such as worrying. There is substantial support for the role of worry, rumination and metacognition across

146 of 229

psychological disorders (Wells, 2009b) and for the effectiveness of treatment based on this approach (Normann, Emmerik, & Morina, 2014).

One way of improving cost-effectiveness in psychological interventions is to offer treatment in groups (Rush & Watkins, 1981) However, effects can diminish when treatments such as CBT are offered to groups instead of individually (Wierzbicki & Bartlett, 1987).

5.3 The aim of the study and null hypothesis

The study aim was to test if MCT is suitable and potentially effective in a heterogeneous group of clients with differing primary and co-morbid disorders, and whether the Cognitive Attentional Syndrome (CAS) as measured by the CAS-1 improves reliably across different presenting primary problems.

The null hypothesis states that participants would not benefit from therapy by symptom reduction in anxiety and depression as measured by the HADS. In addition, it predicted that participants would not reduce their rumination and worry as measured by the CAS- 1.

5.4 Methods

5.4.1 Design We used an uncontrolled pre-post trial design involving 131 patients who all received group MCT. All measures used were administered at pre-treatment, mid-treatment, post-treatment and 6 months follow-up. Confidentiality and patient choice in data collection was ensured. All patients were given the opportunity to withdraw from the study at any time. In addition, all patients signed a consent form before participation (Appendix 7).

5.4.2 Participants Participants were recruited as outpatients from - and treated at - a private outpatient clinic at 2 different geographic locations. The participants were a mix of patients who

147 of 229

were referred to treatment by their GP and patients seeking treatment of their own will (n=1879). Clients referred by their GP were offered waitlist for several months or group therapy with a short waiting time (study participants).

Participants from a total of 13 groups with an average of 10 participants in each group were included in the study (n=139).

There was no intake interview or screening of suitability, this was an open trial in which all consenting patients were deemed suitable and both referred and non-referred clients entered the study. Patients represented a range of different disorders. Only HADS rating combined with CAS-1 measures were used at pre-treatment and later outcome assessments in this trial.

All patients were asked at the outset of the trial to state in their own words what the main problem was that they were seeking treatment for (e.g. Anxiety, Depression, OCD). Table 32 and Table 33 show the distribution of problems and the number of problems patients in the groups were seeking help for. As can be seen quite a large number of patients reported ≥ 3 problem areas (Total n = 31). In addition, the group had a greater number of female participants (n=93) compared to males (n=38).

148 of 229

Table 31: Demographic Variables

Table Demographic Variables Total N = (N=131)

Gender (n)

Female 93

Male 38

Age (in years)

18-30 27

30-40 32

40-50 30

50-60 27

60+ 15

Table 32: Primary Reason for seeking treatment

Male Female Anxiety 11 52 Depression 6 6 Both 20 29 Not Reported 1 6

149 of 229

Table 33: Number of problems reported by patients

No. of problems Males Females 1 12 39 2 14 28 3 9 19 4 2 1 Not Reported 1 6

5.4.3 Measures The measures used were the Hospital Anxiety and Depression Scale (HADS) and the CAS-1. In a meta-analysis of 747 studies (Bjelland, Dahl, Haug, & Neckelmann, 2002)) HADS was found to perform well in assessing the symptom severity and caseness of anxiety disorders and depression in both somatic, psychiatric and primary care patients and in the general population.

The primary outcome measure was effect size and reliable change rate as reported by the HADS-score pre, post and at follow-up. Reliable change was calculated using Jacobson and Truax (1991). The HADS is a fourteen item rating scale that creates ordinal data. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. Scores above 7 are considered above cut-off for disorder (Zigmond & Snaith, 1983).

Secondary outcome measures were scores on the CAS-1 (Wells, 2009b) measuring MCT-relevant scores of: time spent dwelling on negative thoughts (i.e. worry and rumination), time spent threat monitoring and level of positive and negative beliefs about worry and rumination. The CAS-1 has earlier been demonstrated to be a good trans-diagnostic measure of general levels of psychological inflexibility (Fergus, Valentiner, McGrath, Gier-Lonsway, & Jencius, 2013).

150 of 229

5.4.4 Procedure All participants were recruited through normal referral/own inquiry at a private outpatient clinic. Participants were assigned to six weeks of two hours session per week – a total of 12 hours of therapy. Sessions were held at two different cities in Denmark. Participants were assigned to group by availability, and self-screening was performed through a form provided by the therapist.

5.5 Transdiagnostic MCT

The transdiagostic MCT used techniques drawn from a published treatment manual (Wells, 2009a) and followed a structure devised by Wells (personal communication) which was structured as follows: Structure of MCT-treatment: Session 1: Case formulation, socialization and introduction to Detached mindfulness Session 2: Detached mindfulness and challenge uncontrollability Session 3: Attention Training and Detached mindfulness Session 4: Attention Training and challenge negative metacognitive beliefs Session 5: Challenge positive metacognitive beliefs, Attention Training Session 6: Relapse prevention

Professor Wells also provided supervision to the therapists.

5.5.1 The therapists Two clinical therapists delivered the treatment: one female with level-1 training in MCT and one male, less experienced MCT therapist.

5.6 Results

The flow-chart (Figure 12) shows the flow of patients contacting the clinic for help, and the number of patients entering the transdiagnostic group intervention. Approximately 9 to 14 patients call the clinic each day, and of those approximately 8-10% chose to participate in the group. Completer analysis was conducted at post-treatment. At follow- up there was a 70% data return rate.

151 of 229

Figure 12: Flow-chart (study 4)

5.6.1 Descriptive statistics A histogram of the distribution of scores on the HADS can be found in Appendix 15. The table below shows the distribution of males and females with different self- identified problems. Because the primary variable HADS measures depression and anxiety and a rather large proportion of patients reported more than one diagnosis we split the group into three sub-groups depression, anxiety or both. This allowed us to assess the impact of the intervention across different presentations so as to gauge the ‘transdiagnostic’ effect. As can be seen in Table 34, the sample contains 63 patients with anxiety and as seen in Table 34 below, 82.5% of those are female. There seems to be a significant difference in the frequencies of males and females across groups of

152 of 229

identified problems as compared with observed expected frequencies. A chi square test indicates that this difference is statistically significant [p = 0.008].

Table 34: Descriptive Statistics

Sex Age Male Female Mean Anxiety (n=63) 17,5% 82,5% 41,14 Depression Diagnosis (n=12) 50,0% 50,0% 36,75 Both (n=49) 40,8% 59.2% 44,63

The mean age in the subgroups ranged from 37 to 45 years. A one way ANOVA indicates that this difference was not statistically significant [F(2,123)=2.25, p = .109]. The table below shows means and standard deviations for six different outcomes distributed across pre, post and follow-up treatment and presenting problem.

153 of 229

Table 35: Means and Standard Deviations for outcome measures

Anxiety Depression Both

Follow- Follow- Follow Pre Post up Pre Post up Pre Post -up Anxiety M 12.9 7.14 7.62 11.67 6.17 4.75 13.12 7.14 6.61 SD 3.97 3.25 4.83 3.47 3.1 2.96 3.31 2.97 3.23 Depression M 7.84 3.54 4.06 10.67 4.5 2.75 10.53 4.82 4.86 SD 3.84 3.05 4.1 2.57 3.34 3.02 3.93 3.87 3.84 Dwell M 5.48 2.06 3.1 5.42 2.08 1.92 5.86 2.38 2.78 SD 1.83 1.49 2.11 0.79 1.98 1.44 1.96 1.65 2 Threat M 5.2 1.91 2.62 4.5 2.08 1.5 5.27 2.2 2.38 SD 1.93 1.44 2.08 1.68 1.93 1.51 2.19 1.73 1.86 PMC M 193.33 51.41 61.35 189 44.67 50 178.53 52.65 57 SD 69.78 59.45 66.22 74.87 70.02 84.85 68 61.4 62.26 NMC M 193.9 40.13 62.78 211.67 99.58 67.08 218.47 64.35 72.14 SD 80 44.99 74 63.33 91.66 63.26 75.59 81.85 78.85 Anxiety = anxiety levels measured on the HADS, Depression = depressive symptoms measured on the HADS, Dwell = time spend ruminating according to the CAS-1, Threat = time spend threat monitoring according to the CAS-1, PMC = positive metacognitive beliefs according to the CAS-a, NMC = negative metacognitive beliefs according to the CAS-1, M = mean, SD = Standard deviation.

154 of 229

At pre-treatment, patients who self-label their problem as anxiety on average score higher on anxiety (12.89) compared with patients who identify their problem as depression (11.67) on the HADS. The opposite goes for patients with depression, as they score higher on depression (10.67) compared with patients with anxiety (7.84). These different initial scores support the validity of the patient’s self-assessment of their main difficulties.

5.6.2 Mixed model ANOVA To test whether the treatment effects have statistical significance and were universal a mixed model ANOVA was run to test for time effects and any possible interaction between time and self-labelled problem. The interaction makes it possible to evaluate whether there are significant differences in the effects of treatment between groups of patients with different problems. The models were run on all six outcomes and can be seen in the table below.

155 of 229

Table 36: Mixed Model ANOVAS

Degrees of freedom F-test P Time 1.97 104.92 <.0005 Time * Anxiety Diagnosis 3.95 1.06 .378 Error 238.78 Time 2.00 96.67 <.0005 Time * Depression Diagnosis 4.00 3.50 .008 Error 242.00 Time 1.95 101.00 <.0005 Time * Dwell Diagnosis 3.89 1.35 .255 Error 235.51 Time 2.00 83.74 <.0005 Time * Threat Diagnosis 4.00 1.05 .380 Error 242.00 Time 1.92 145.58 <.0005 Time * PMC Diagnosis 3.84 .36 .829 Error 232.39 Time 1.97 135.49 <.0005 Time * NMC Diagnosis 3.93 1.32 .265 Error 237.72 Note: Anxiety = anxiety levels measured on the HADS, Depression = depressive symptoms measured on the HADS, Dwell = time spend ruminating according to the CAS-1, Threat = time spend threat monitoring according to the CAS-1, PMC = positive metacognitive beliefs according to the CAS-a, NMC = negative metacognitive beliefs according to the CAS-1, M = mean, SD = Standard deviation.

156 of 229

As can be seen from the Table 36 the effect of time was present for all outcomes as they were all highly significant (p < .0005) showing that the treatment was associated with significant improvements on all measures. There was an interaction between time and diagnosis only for one outcome: depression, which showed a statistical significant difference [F(4.00, 242.00) = 3.50, p = .008). This result indicates that the effect of time on the outcome depression is different depending on the patient’s self-diagnosis. Figure 13 below indicates that the change in depression score over time is highest for the depression group since initial scores are higher and end scores lower, compared to the rest of the groups.

Figure 13: Depression score by diagnostic group

157 of 229

Figure 14: Anxiety score by diagnostic group

158 of 229

5.5.3. ANCOVA models Next ANCOVA’s where run on all six outcomes to test for differences in post-treatment outcomes when controlling for pre-treatment scores. The self-diagnosis variable was included as the between-groups factor to test whether the results indicate a difference in post-treatment outcome between groups when controlling for pre-treatment symptom levels.

Table 37: ANCOVA models

Degrees of Outcome Measure freedom F-test Sig. Pre- 1 21.445 < .0005 treatment Problem 2 .195 .823 Anxiety Error 120 Pre- 1 29.286 < .0005 treatment Problem 2 .092 .912 Depression Error 120 Pre- 1 3.541 .062 treatment Problem 2 .393 .676 Dwell Error 120 Pre- 1 7.662 .007 treatment Problem 2 .512 .600 Threat Error 120 Pre- 1 6.589 .011 treatment Problem 2 .157 .855 PMC Error 120 Pre- 1 4.953 .028 treatment Problem 2 4.077 .019 NMC Error 120

As can be seen from Table 37 above the effect of pre-treatment was significant in all cases (p < .05). In addition the effect of diagnosis on post-treatment differences was only significant for the outcome NMC [F(1,120) = 4.08, p = .019]. These data suggest that on the primary emotion outcomes the treatment effect appears consistent across

159 of 229

different presenting problems. However, there was a difference in negative metacognitive beliefs (an underlying putative causal variable). The adjusted means are shown in the table below. Looking at NMC scores there was a significantly higher score for the depression group [M = 98.49] as compared to the anxiety group [M = 42.10].

Table 38: Adjusted means by diagnosis

95% Confidence Interval Adjusted Lower Measure Diagnosis means Bound Upper Bound Anxiety 7.13 6.41 7.86 Anxiety Depression 6.56 4.90 8.22 Both 7.06 6.24 7.88 Anxiety 4.08 3.28 4.87 Depression Depression 3.90 2.13 5.68 Both 4.27 3.38 5.17 Anxiety 2.08 1.68 2.47 Dwell Depression 2.11 1.21 3.02 Both 2.34 1.89 2.79 Anxiety 1.91 1.51 2.29 Threat Depression 2.21 1.31 3.11 Both 2.18 1.74 2.63 Anxiety 50.15 35.18 65.12 PMC Depression 44.28 10.05 78.51 Both 54.37 37.38 71.36 Anxiety 42.10 25.62 58.59 NMC Depression 98.49 60.92 136.06 Both 62.08 43.38 80.77

Anxiety = anxiety levels measured on the HADS, Depression = depressive symptoms measured on the HADS, Dwell = time spend ruminating according to the CAS-1, Threat = time spend threat monitoring according to the CAS-1, PMC = positive metacognitive

160 of 229

beliefs according to the CAS-a, NMC = negative metacognitive beliefs according to the CAS-1, M = mean, SD = Standard deviation.

5.6.3 Treatment Effect Sizes (Cohen’s d)

In order to test for transdiagnostic effects we need to assess if the effect size for anxiety in the anxiety group is of a similar magnitude as the effect size for depression in the depression group and whether the effects sizes for mixed are similar to those for any individual group. However, we must keep in mind that the mixed group may be more severe in their presentation.

To determine relative effect sizes Cohen’s d was calculated for the six different M1−M2 outcomes. The formula used to calculate Cohen’s d is as follows: d = , √(SDM1)+(SDM2) 2 where M1 and M2 are the means at pre-treatment and post-treatment or follow-up and the denominator is the pooled standard deviation of the two means. This calculation uses pre-treatment as control since there was no control group in this study. The results of a total sample calculation are shown in Table 39 below. The effect size was computed first for the whole group on the different outcomes and then on a separated self-labelled problem basis.

Table 39: Effect sizes on all outcome variables (whole group)

Pre to Pre to post follow-up Anxiety 1.70 1.54 Depression 1.31 1.21 Dwell 2.00 1.45 Threat 1.73 1.47 PMC 2.09 1.91 NMC 2.04 1.76 Note: Anxiety = anxiety levels measured on the HADS, Depression = depressive symptoms measured on the HADS, Dwell = time spend ruminating according to the

161 of 229

CAS-1, Threat = time spend threat monitoring according to the CAS-1, PMC = positive metacognitive beliefs according to the CAS-a, NMC = negative metacognitive beliefs according to the CAS-1, M = mean, SD = Standard deviation.

As seen in Table 39 the effect sizes are large ranging from 1.31 to 2.09 from pre to post. The pre to follow-up effect sizes are slightly lower on all outcomes ranging from 1.21 to 1.91 indicating a diminishing effect over time, however they are still large in effect. Apart from effect sizes are calculated for the total sample, an important question is whether effect sizes are similar across different presenting symptoms. A difficulty here is that anxiety and depression scores vary in their range depending on the main presenting problem which means that comparing ES on each measure across problems is inaccurate. Therefore, the Cohen’s d calculations were made for patients with different diagnoses using the same overall pooled standard deviation as in the previous calculation. This makes comparisons of effect sizes between the groups possible as they use the same denominator in the calculation. Table 40 below shows the results of this calculation.

162 of 229

Table 40: Effect sizes for three sub-groups over time Both anxiety and Anxiety Depression depression Pre to Pre to Pre to Pre to Pre to Pre to post follow-up post follow-up post follow-up Anxiety 1.69 1.34 1.61 1.76 1.76 1.66 Depression 1.15 0.95 1.65 2.00 1.53 1.43 Dwell 2.00 1.24 1.96 1.82 2.04 1.60 Threat 1.81 1.30 1.33 1.51 1.69 1.46 PMC 2.18 1.95 2.21 2.05 1.93 1.79 NMC 2.10 1.73 1.53 1.91 2.11 1.93 Note: Anxiety = anxiety levels measured on the HADS, Depression = depressive symptoms measured on the HADS, Dwell = time spend ruminating according to the CAS-1, Threat = time spend threat monitoring according to the CAS-1, PMC = positive metacognitive beliefs according to the CAS-a, NMC = negative metacognitive beliefs according to the CAS-1, M = mean, SD = Standard deviation.

In interpreting the results for anxiety and depression HADS outcome, it makes sense to compare between outcomes and between self-diagnostic groups. Thus, anxiety outcome in the anxiety group shows a large effect size for pre to post-treatment [d = 1.69]. This can be compared to the depression outcome for the depression group, where there is a similar large effect size [d = 1.65]. This indicates, that the effect of treatment is the same for the main problem across groups at post-treatment. However, at follow-up there is a difference, since the depression outcome for the depression group is higher [d = 2.00] and the anxiety outcome for the anxiety group is lower [d = 1.34] compared to post-treatment. This suggests that the symptom reduction in depression is potentially increasing over time while the same might not hold for anxiety. This comparison only makes sense in so far as the standardizer for both outcomes are similar. In this case the pooled standard deviation does not differ across the two outcomes, since the anxiety and depression scores have the same possible maximum and minimum scores. Therefore, they can be compared without major biases in interpretation of differences in values presented in the table.

163 of 229

5.6.4 Clinical significant change In the following section we examine whether patients had a significant change from pre- to post and post to follow-up using the Jacobson & Truax (1991) clinical significant change index method ‘a’. The reliable change calculations are computed for the three main outcomes, anxiety, depression and the total of the two (HADS). The reliable change in each case was: Anxiety =1.17-2.87, Depression = 1.29-3.17, and combined = 2.10-5.15 All depending on which test-retest reliability level that is used.

After examination of the literature no Danish or other meaningful test-retest on the HADS could be found. Instead of assuming an empirically based test-retest value, three levels of Pearson r were used to illustrate how the calculation was effected by this variable.

Table 41 below shows the cut-off calculations for the different measures and the standard errors of differences.

Table 41: Reliable Change and cut-off scores based on method a

Test-retest reliability level

Cut- Measure off Pearson’s r = 0.700 Pearson’s r = 0.825 Pearson’s r = 0.950 Anxiety 5.31 2.87 2.19 1.17 Depression 0.77 3.17 2.42 1.29 Total HADS 8.36 5.15 3.94 2.10

The calculations based on Jacobson & Truax originally gave a cut-off score for the depression measure of 0.77. This cut-off point makes it almost impossible to obtain the status recovered and therefore seems unrealistic. The reason for the low cut-off most likely is due to the heterogeneous sample with patients with different diagnoses and severity of illness. Because this is an open non-screened group some patients were suffering from severe depression or anxiety whilst others were scoring below cut-off on the HADS before the onset of treatment. The method a from Jacobson & Truax uses the

164 of 229

sample as representing a dysfunctional population. However, if the sample contains functional as well as dysfunctional patients, the standard deviation will be relatively large. This complicates the use of the method. In light of this problem the cut-off was not used and instead the categories recovered and improved where bundled into improved. The results of varying the methods (using the different r coefficients) are showed in the tables below for the total sample on all three measures from pre to post treatment.

Table 42: Total sample reliable change from pre- to post-treatment.

Measure Method Improved No change Aggravation Method a-1 54% 46% 0% Anxiety Method a-2 69% 31% 0% Method a-3 83% 14% 3% Method a-1 30% 70% 0% Depression Method a-2 48% 51% 1% Method a-3 70% 29% 1% Method a-1 50% 50% 0% Total Method a-2 68% 31% 1% HADS Method a-3 85% 14% 1%

The different methods seem to alter the results severely. For instance, improved rates for depression change from 30% to 70% from low to high test-retest reliability. Looking at the total HADS measure and when test-retest reliability is high (Method a-3) the total HADS yields a 85% improved score whereas it falls to 50% when using low test-retest reliability. Figure 15 shows the results achieved with method a-3 graphically.

Figure 15: Clinical Significant Change Index

3%

165 of 229

5.7 Discussion

Until now most transdiagnostic group interventions have not been based on detailed transdiagnostic models, but more on pragmatic transdiagnostic manuals. Usually effect sizes are small to moderate (Newby, McKinnon, Kuyken, Gilbody, & Dalgleish; Norton, 2008).

Wells and Matthews (1996a) S-REF model was one of the first transdiagnostic information processing theories in which all mental disorders were formulated as caused by a common syndrome: The CAS. Metacognitive therapy (MCT) is based on this model for mental disorders (Wells, 2009b). This study was designed to test the efficacy of MCT as a short group intervention (12 hours) with a mixed group of self-diagnosed patients suffering from depression, and a range of anxiety problems. No formal screening was conducted and few exclusion criteria were implemented. Treatment was delivered over six weeks of two hours sessions. This is less than half the time usually seen in other treatment paradigms but was based on estimates taken from earlier experience in delivering disorder-specific MCT group treatments.

A limited amount of research has been conducted on MCT in group settings. One study on group MCT for GAD showed that MCT was associated with positive outcomes when presented in this format. (McEvoy & Perini, 2009). Recently, Papageorgiou and Wells

166 of 229

(2014) tested a group version (12 weeks of 2 hour sessions) of MCT on 10 treatment resistant depressed individuals and showed a 70 % recovery rate at post-treatment (Papageorgiou & Wells, 2014) In another study from Norway on eleven depressed subjects 100% were recovered after a 10 week group MCT intervention. Recovery rates remained at 91% at 6 months follow-up suggesting that group MCT could be a very cost-effective treatment for depression (Dammen et al., 2015).

The present study aimed to contribute to this literature by examining the effects associated with group MCT in a large undifferentiated sample of patients. The null hypothesis was rejected as participants benefitted significantly over time during treatment as shown by reduction in anxiety and depressive symptoms measured by the HADS as the primary outcome measure. On the CAS-1, the secondary outcome measure substantial gains were also observed.

Participants were split into three categories: anxiety, depression or both representing their main presenting problem At post-treatment very large effect sizes for both anxiety and depression were detected (d = 1.69 and d = 1.65 respectively). However, at follow- up effect sizes in the depression group remained high (d = 2.00) indicating a small but not significant reduction in effect in the anxiety group over follow-up (d = 1.34).

Using Jacobson and Truax (1991) criteria (method a-3) clinically significant improvements were seen for 85% of patients in both groups combined on the HADS. However, the range of improvement rates varied widely depending on the level of reliability assumed for the HADS. Never the less, the results show that group MCT when delivered transdiagnostically is associated with substantial rates of reliable clinical improvement. In summary, the results indicate significant reductions in symptoms and large response rates at post-treatment. Effects appeared to be best maintained at 6-months follow-up by the depressed individuals but in all cases follow- up effect sizes remained large.

The strengths of the current study include the use of a heterogenous group of patients and few exclusion criteria, meaning that the results can be interpreted within a

167 of 229

transdiagnostic context. The large sample size provides a strong basis for generalising to other groups of self-selected patients. The weaknesses are that we did not use formal diagnoses and so we cannot determine whether the self-diagnoses actually represent bona-fide disorders. However, the range in HADS scores shows that patients were reporting levels of distress within the clinical range. A major limitation is the lack of a comparison or control group which means we cannot be sure that MCT was responsible for the improvement in symptoms and we cannot partial out the effects linked to time such as spontaneous remission.

The preliminary findings from this study indicate that MCT appear to be a feasible and acceptable intervention for treating mixed groups of patients suffering from a range of disorders. In the future, larger randomized and controlled studies are now needed which compare transdiagnostic group MCT to control groups and other treatments to test the efficacy of transdiagnostic group MCT.

6 GENERAL DISCUSSION Findings from the four included studies suggest that MCT might be an effective treatment for MDD and mixed diagnostic groups. In line with Normann et al. (2014) ‘s meta-analysis MCT showed very high effect sizes and recovery rates in all studies. Furthermore, effects were observed in few sessions. Findings suggest that MCT might offer an effective treatment for patients with a wide range of problems. Drop-out rates are low and results are generally maintained at follow-up, but longer term follow could not be assessed within the time-frame of this thesis.

6.1 Highlights from this thesis

MDD is a debilitating condition with severe social, occupational and economic consequences. Until now, psychological treatments for MDD show small to moderate effect sizes and a recovery rate of around 50% (Cuijpers, Andersson, Donker, & van Straten, 2011; Cuijpers et al., 2013b).

168 of 229

The results from this thesis show that a recent approach, metacognitive therapy (MCT) is a highly effective treatment for depression and is superior to CBT. Furthermore, MCT could potentially be delivered as a transdiagnostic intervention and is associated with large effect sizes in this format. The results present an optimistic outlook going forward since existing treatments, although effective, have not proven to have differential efficacy.

In summary, the following conclusions can be drawn from this thesis:

Study 1:  A systematic literature review of meta-analyses investigated efficacy in individual treatments for MDD and potential biases and limitations. In summary, effect sizes were small to moderate and varied from Hedges g 0.25 to Cohens d = 0.69. Recovery rates in ITT analyses ranged from 34% to 47.9%.. Relapse rates ranged from 27% (Psychotherapy) to 61% (ADM) at 1-2 years follow-up. Psychotherapy combined with ADM showed the largest remission, however, relapse was high when only ADM was administered. Comparisons across studies were challenging because of methodological limitations and heterogenous definitions for recovery and clinical significant change criteria across studies. Few studies operate with objective change criteria such as Jacobson & Truax’s (1991) reliable change index. Study 2:  A single case study designed to explore the use of MCT on four depressed Danes receiving MCT gave promising results. The study was a replication of Wells and collegues single case series from 2009 (Wells et al., 2009). Three out of four patients were recovered at post-treatment as measured on the BDI-II ≤ 8 in 5-11 sessions with no relapse at follow-up assessments. At 6-months follow- up all patients scored below cut-off for depression and were in remission. Findings show that MCT might work when administered in another cultural setting and with less experienced therapists.

169 of 229

Study 3:  To test the efficacy of MCT it is important to compare it to a gold standard treatment. A large randomised trial comparing the effect of CBT and MCT was conducted. Primary measures consisted of BDI-II and HDRS and several secondary measures. Within and between groups ANOVAS showed that both treatments were significantly effective across time. On the BDI-II MCT was significantly superior to CBT. In addition, MCT showed much larger effect sizes using Cohens d and larger recovery rates using Jacobson & Truax’ (1991) criteria compared to CBT (76% vs. 54%). The recovery rates for MCT are amongst the largest seen in any trial. Effects were maintained at 6-months follow-up and 1-year follow-up are now being conducted. Interestingly, schemas changed more in the MCT condition than in CBT suggesting that these core beliefs may not be the cause but merely a symptom in MDD. In summary, findings from the present study support earlier research findings evaluating MCT in RCTs. Findings suggest that higher recovery-rates might be obtained by implementing metacognitive therapy.. Study 4:  An uncontrolled open trial was conducted with the aim to investigate the transdiagnotic version of MCT in a six weeks group program in groups of 8-12 patients. Findings showed that 70-80% of participants ended up below a cut-off on primary measures at post-treatment. Very large effects sized on both anxiety and depressive symptoms were detected (d = 1.69 and d = 1.65 respectively) and these findings were maintained - especially for the depressive symptoms - at follow-up

In conclusion MCT seems to be an effective treatment for MDD and mixed diagnostic groups.

The primary findings from this thesis will now be discussed in general as well as limiations and suggestions for future clinical practice and research will be discussed.

170 of 229

6.1.1 Strengthening a new paradigm for treating mental disorders Throughout the literature mental disorders are described as caused by a combination of biological, psychosocial and other vulnerability factors. Most paradigms incorporate the idea that depression is somehow similar to physical illness like a broken brain that needs restitution, medication or long-term psychological treatment to heal.

In the CBT model, MDD is seen as a schema problem and treatment focuses on modifying beliefs and schemas about the self and the world. However, an alternative approach, the S-REF model emphasises the role of repetitive negative thinking and its control. The data in this thesis shows that treatment based on the latter approach may lead to advances in outcomes. Furthermore, this newer treatment approach appears to change schemas more than CBT, despite the fact it is not targeted at them. This raises profound questions about the content and focus in paradigms like CBT. It seems it is not necessary to focus on schemas and the content of appraisals in order to achieve strong treatment effects. It might be that schemas could be a symptom rather than a cause of MDD. This suggests that therapies potentially could focus on changing dysfunctional mental strategies like rumination and metacognitions and less on schemas.

There are clear implications for future outcome research. The result of the review of meta-analyses and the analyses of clinical significant change in the studies in this thesis raises some important issues. First, studies should move toward routinely reporting clinical significance outcomes using formal criteria that enables benchmarks to be established and cross-study comparisons to be made. Quality assessments such as Cochrane risk of bias tool GRADE could be useful tools to optimise reviews and make comparisons more attainable.

Second, the method of calculating clinical significance can give rise to widely ranging statistics as seen in the variations caused when different reliability estimates were used. This calls for clear reporting of the methods and statistics used to calculate scores so that such methods can be replicated in new studies. One suggestion is to incorporate

171 of 229

clear and objective definitions of recovery such as (Frank et al., 1991) and/or (Jacobson & Truax, 1991b)

6.1.2 Moving away from the “Tool-box” idea Several psychological paradigms operate with the idea that mental regulation is enhanced by adding more strategies to peoples’ “mental tool-box”. It has been argued that poor emotional processing is caused by the limbic system not being regulated properly by the frontal cortex in the form of realistic or logical thinking (Beck et al., 1979 ). Others believe that self-regulation is stimulated by improving the “soothing system” in the form of compassionate thinking (Gilbert, 2009). However, the metacognitive model proposes that poor emotional regulation results from the activation of the cognitive attentional syndrome (Wells, 2009).

Not with standing the emphasis on different mechanisms, many recent treatment approaches combine multiple elements and techniques from these different approaches. This leads to ‘eclectic’ forms of treatment. CBT appears to have become more ‘eclectic’ since its development in the 1970’s. However, these eclectic versions only show moderate effect sizes and approximately 50% reach remission. This rate appears to be lower than the rates that can be achieved in MCT. The implication of these effects is that progress in outcomes may be more likely to be achieved by using highly specified approaches that have high levels of theoretical consistency in the methods that they use. In combining techniques from different theories we do not know if the techniques are conceptually and theoretically compatible.

The metacognitive model and treatment is a relatively new paradigm for understanding the cause and solution to mental problems including MDD. Little is known about the impact of combining this treatment with other methods, but if the treatment is more effective than other approaches there seems to be little to gain by combining methods at this stage. Instead most gains in knowledge will be made by further comparisons of MCT against benchmark interventions.

172 of 229

Traditionally, psychological treatments are more effective in individual treatment settings than group therapy. In MCT, the current results and data from other group studies suggest that a group administered version of the treatment shows effect sizes similar to individual therapy and in the present case even when it is delivered in a transdiagnostic format (Dammen et al., 2015). The possibility of a transdiagnostic protocol allowing for a mixed group of patients suffering from anxiety and depressive disorder makes MCT a suitable potential candidate for increasing accessability to therapy. Future studies should aim to evaluate group MCT against other group therapies and examine both the efficacy and cost-effectiveness of the intervention.

6.1.3 Overall limitations A number of limitations need to be addressed. First of all, only one study (study 3) is an effectiveness study. The single case (study 1) and open trial (study 4) are feasibility studies in which MCT is tested in different settings. More adequately powered RCT studies with the use of data missing imputation analysis instead of LOCF should now be done in order to conclude the true effectiveness of MCT for MDD and in mixed diagnostic groups.

6.2 Future research suggestions

MCT appears to be an acceptable and potentially effective treatment for MDD both individually and in mixed diagnostic groups of individuals. However, new treatments tend to lose efficacy over time and may not be as effective when transported from their centres of origin. MCT has been evaluated in different countries and across disorders and there is reliable evidence of its effectiveness (e.g. Norman et al, 2014). However, the area still lacks a large number or adequately powered trials comparing MCT with the best available treatments across a wide range of disorders. The available evidence at the current time is for the use of MCT is in anxiety disorders (generalised anxiety disorder (GAD) and PTSD) in which MCT appears to be a very effective current treatment choice. It remains to be seen if this situation also emerges for other conditions such as major depressive disorder (MDD). Future studies are required to investigate this important area and replications in other settings and countries as well as using longer follow-up assessments.

173 of 229

In addition, transdiagnostic group settings need to be explored as MCT appears to lose little efficacy when applied in heterogenous diagnostic groups. Future RCTs might involve comparing group MCT to control groups and other transdiagnostic paradigms such as Mindfulness Based Cognitive Therapy (MBCT), Acceptance and Commitment Therapy (ACT) or Compassion-focused therapy (CFT).

Final remarks In conclusion the results of the series of studies conducted here support that MCT could be a brief and highly effective treatment. When comparing MCT and CBT for MDD effects favoured MCT. If these results are replicated this would be a major step forward with the potential to transform many peoples’ lives.

174 of 229

7 REFERENCES American Psychiatric, A., American Psychiatric, A., & Force, D. S. M. T. (2013). Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C.: American Psychiatric Association.

Andrews, G., Slade, T., & Peters, L. (1999). Classification in psychiatry: ICD-10 versus DSM-IV: Royal College of Psychiatrists British Journal of Psychiatry.

Andrews, G., & Williams, A. D. (2014). Internet psychotherapy and the future of personalized treatment. Depression And Anxiety, 31(11), 912-915.

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? American Journal of Psychiatry, 161(12), 2163-2177.

Barlow, J., McMillan, A. S., Kirkpatrick, S., Ghate, D., Barnes, J., & Smith, M. (2010). Health-Led Interventions in the Early Years to Enhance Infant and Maternal Mental Health: A Review of Reviews. Child and Adolescent Mental Health, 15(4), 178-185. doi:10.1111/j.1475-3588.2010.00570.x

Beck, A. T., Epstein, N., Brown, G., & Steer, R. A. (1988). An inventory for measuring clinical anxiety: Psychometric properties. . Journal Of Consulting And Clinical Psychology, 56, 893–889.

Beck, A. T., & Greenberg, R. L. (1974). Coping with depression: Institute for Rational- Emotive Therapy New York, NY.

Beck, A. T., Rush, A. J., Shaw, B. F., & Emery, G. (1979 ). Cognitive therapy of depression. New York: Guilford.

Beck, A. T., Rush, J. A., Shaw, B. F., & Emery, G. (1979). Cognitive therapy of depression (2. print. ed ed.). New York: Guilford Pr.

Beck, A. T., & Steer, R. A. (1990). Manual for the Beck anxiety inventory.

Beck, A. T., Steer, R. A., Ball, R., & Ranieri, W. (1996). Comparison of Beck Depression Inventory -IA and -II in psychiatric outpatients Journal of Personality Assessment, 57, 588–597.

Beck, A. T., Ward, C., & Mendelson, M. (1961). Beck depression inventory (BDI). Arch Gen Psychiatry, 4(6), 561-571.

175 of 229

Bevan, D., Wittkowski, A., & Wells, A. (2013). A Multiple‐Baseline Study of the Effects Associated With Metacognitive Therapy in Postpartum Depression. Journal of Midwifery & Women’s Health, 58(1), 69-75.

Bhar, S. S., & Beck, A. T. (2009). Treatment Integrity of Studies That Compare Short- Term Psychodynamic Psychotherapy With Cognitive-Behavior Therapy. Clinical Psychology-Science and Practice, 16(3), 370-378.

Bjelland, I., Dahl, A. A., Haug, T. T., & Neckelmann, D. (2002). The validity of the Hospital Anxiety and Depression Scale: an updated literature review. Journal Of Psychosomatic Research, 52(2), 69-77.

Blackburn, I.-M., James, I. A., Milne, D. L., Baker, C., Standart, S., Garland, A., & Reichelt, F. K. (2001). The revised cognitive therapy scale (CTS-R): psychometric properties. Behavioural and Cognitive Psychotherapy, 29(04), 431-446.

Blackburn, I. M., Bishop, S., Glen, A., Whalley, L., & Christie, J. (1981). The efficacy of cognitive therapy in depression: a treatment trial using cognitive therapy and pharmacotherapy, each alone and in combination. The British Journal of Psychiatry, 139(3), 181-189.

Bordin, E. S. (1979). The generalizability of the psychoanalytic concept of the working alliance. Psychotherapy: Theory, research & practice, 16(3), 252.

Braun, J. D., Strunk, D. R., Sasso, K. E., & Cooper, A. A. (2015). Therapist use of Socratic questioning predicts session-to-session symptom change in cognitive therapy for depression. Behaviour research and therapy, 70, 32-37. doi:http://dx.doi.org/10.1016/j.brat.2015.05.004

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. Clinical Psychology Review, 26(1), 17-31.

Callesen, P., Jensen, A. B., & Wells, A. (2014). Metacognitive therapy in recurrent depression: A case replication series in Denmark. Scandinavian Journal of Psychology, 55(1), 60-64. doi:10.1111/sjop.12089

Carhart-Harris, R. L., Mayberg, H. S., Malizia, A. L., & Nutt, D. (2008). "Mourning and melancholia revisited: Correspondences between principles of Freudian metapsychology and empirical findings in neuropsychiatry. Annals of General Psychiatry, 7(1), 7-9. doi:10.1186/1744-859X-7-9.

176 of 229

Casacalenda, N., Perry, J. C., & Looper, K. (2002). Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. American Journal of Psychiatry.

Clark, D. A., & Rhyno, S. (2005). Unwanted Intrusive Thoughts in nonclinicial Individuals: Implications for Clinical Disorders. In D. B. Clark (Ed.), Intrusive Thoughts in Clinical Disorders - Theory, Research and Treatment (pp. 1-29). (30 NP) New York: The Guilford Press.

Connor, M., Wells, A., & Fisher, P. L. (2015). The Nature of Depression. Treating Depression: MCT, CBT and Third Wave Therapies, 1.

Cristea, I. A., Huibers, M. J. H., David, D., Hollon, S. D., Andersson, G., & Cuijpers, P. (2015). The effects of cognitive behavior therapy for adult depression on dysfunctional thinking: A meta-analysis. Clinical Psychology Review, 42, 62-71. doi:10.1016/j.cpr.2015.08.003

Cuijpers, P., Andersson, G., Donker, T., & van Straten, A. (2011). Psychological treatment of depression: Results of a series of meta-analyses. Nordic Journal of Psychiatry, 65(6), 354-364.

Cuijpers, P., Berking, M., Andersson, G., Quigley, L., Kleiboer, A., & Dobson, K. S. (2013a). A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. The Canadian Journal of Psychiatry / La Revue canadienne de psychiatrie, 58(7), 376-385.

Cuijpers, P., de Beurs, D. P., van Spijker, B. A., Berking, M., Andersson, G., & Kerkhof, A. J. (2013b). The effects of psychotherapy for adult depression on suicidality and hopelessness: A systematic review and meta-analysis. Journal Of Affective Disorders, 144(3), 183-190.

Cuijpers, P., Geraedts, A. S., van Oppen, P., Andersson, G., Markowitz, J. C., & van Straten, A. (2011). "Interpersonal psychotherapy for depression: A meta- analysis": Correction. The American Journal Of Psychiatry, 168(6), 652.

Cuijpers, P., Koole, S. L., van Dijke, A., Roca, M., Li, J., & Reynolds, C. F., III. (2014). Psychotherapy for subclinical depression: Meta-analysis. The British Journal of Psychiatry, 205(4), 268-274.

Cuijpers, P., Sijbrandij, M., Koole, S. L., Andersson, G., Beekman, A. T., & Reynolds, C. F., 3rd. (2013c). The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons. World Psychiatry: Official Journal Of The World Psychiatric Association (WPA), 12(2), 137-148. doi:10.1002/wps.20038

177 of 229

Cuijpers, P., van Straten, A., Andersson, G., & van Oppen, P. (2008). Psychotherapy for depression in adults: A meta-analysis of comparative outcome studies. Journal Of Consulting And Clinical Psychology, 76(6), 909-922.

Cuijpers, P., Weitz, E., Twisk, J., Kuehner, C., Cristea, I., David, D., DeRubeis, R. J., Dimidjian, S., Dunlop, B. W., Faramarzi, M., Hegerl, U., Jarrett, R. B., Kennedy, S. H., Kheirkhah, F., Mergl, R., Miranda, J., Mohr, D. C., Segal, Z. V., Siddique, J., Simons, A. D., Vittengl, J. R., & Hollon, S. D. (2014). Gender as predictor and moderator of outcome in cognitive behavior therapy and pharmacotherapy for adult depression: An "individual patient data" meta- analysis. Depression And Anxiety, 31(11), 941-951.

Dammen, T., Papageorgiou, C., & Wells, A. (2015). An open trial of group metacognitive therapy for depression in Norway. Nordic Journal of Psychiatry, 69(2), 126-131. doi:10.3109/08039488.2014.936502

De Maat, S., Dekker, J., Schoevers, R., & De Jonghe, F. (2006a). Relative efficacy of psychotherapy and pharmacotherapy in the treatment of depression: A meta- analysis. Psychotherapy Research, 16(5), 562-572.

De Maat, S., Dekker, J., Schoevers, R., & De Jonghe, F. (2006b). Relative efficacy of psychotherapy and pharmacotherapy in the treatment of depression: A meta- analysis. Psychotherapy Research, 16(5), 566-578.

De Maat, S. M., Dekker, J., Schoevers, R. A., & de Jonghe, F. (2007). Relative efficacy of psychotherapy and combined therapy in the treatment of depression: A meta- analysis. European Psychiatry, 22(1), 1-8.

DeRubeis, R. J., & Crits-Christoph, P. (1998). Empirically supported individual and group psychological treatments for adult mental disorders. Journal Of Consulting And Clinical Psychology, 66(1), 37.

Di Giulio, G. (2010). Therapist, client factors, and efficacy in cognitive behavioural therapy: A meta-analytic exploration of factors that contribute to positive outcome. Dissertation Abstracts International: Section B: The Sciences and Engineering, 70(7-B), 4479.

Dimidjian, S., Hollon, S. D., & Dobson, K. S. (2006). Randomized trial of behavioural activation, cognitive therapy, and anti-depressant medication in the acute treatment of adults with major depression. . Journal Of Consulting And Clinical Psychology, 74, 658-670.

Dimidjian, S., Hollon, S. D., Dobson, K. S., Schmaling, K. B., Kohlenberg, R. J., Addis, M. E., Gallop, R., McGlinchey, J. B., Markley, D. K., Gollan, J. K., Atkins, D. C., Dunner, D. L., & Jacobson, N. S. (2006). Randomized Trial of Behavioral

178 of 229

Activation, Cognitive Therapy, and Antidepressant Medication in the Acute Treatment of Adults With Major Depression. Journal Of Consulting And Clinical Psychology, 74(4), 658-670.

Dissemination, C. (2009). Systematic Reviews: CRD's Guidance for Undertaking Reviews in Healthcare. York: University of York NHS Centre for Reviews & Dissemination.

Dobson, K. S. (1989). A meta-analysis of the efficacy of cognitive therapy for depression. Journal Of Consulting And Clinical Psychology, 57(3), 414-419.

Dozois, D. J., Dobson, K. S., & Ahnberg, J. L. (1998). A psychometric evaluation of the Beck Depression Inventory–II. Psychological Assessment, 10(2), 83.

Driessen, E., Hegelmaier, L. M., Abbass, A. A., Barber, J. P., Dekker, J. J. M., Van, H. L., Jansma, E. P., & Cuijpers, P. (2015). The efficacy of short-term psychodynamic psychotherapy for depression: A meta-analysis update. Clinical Psychology Review, 42, 1-15. doi:10.1016/j.cpr.2015.07.004

Elkin, I., Shea, M. T., Watkins, J. T., Imber, S. D., Sotsky, S. M., Collins, J. F., Glass, D. R., Pilkonis, P. A., Leber, W. R., & Docherty, J. P. (1989). National Institute of Mental Health treatment of depression collaborative research program: General effectiveness of treatments. Archives of General Psychiatry, 46(11), 971-982.

Excellence, N. I. f. C., & Health, N. C. C. f. M. (2004). Depression: management of depression in primary and secondary care: National Institute for Clinical Excellence.

Fergus, T. A., Valentiner, D. P., McGrath, P. B., Gier-Lonsway, S., & Jencius, S. (2013). The cognitive attentional syndrome: Examining relations with mood and anxiety symptoms and distinctiveness from psychological inflexibility in a clinical sample. Psychiatry Research, In press, 1-5. doi:10.1016/j.psychres.2013.04.020i

Fisher, P. L., & Wells, A. (2008). Metacognitive therapy for obsessive-compulsive disorder: A case series. Journal of Behavior Therapy and Experimental Psychiatry, 39(2), 117-132.

Flavell, J. H. (1999). Cognitive Development- Children's Knowledge About The Mind. Annu. Rev. Psychol., 50, 21-45.

Flavell, J. H. (2007). Theory of Mind Development: Retrospect and Prospect. In G. V. Ladd (Ed.), Landscapes of Childhood : Appraising the Human Developmental Sciences (pp. 38-55). (17 NP) Detroit, MI, USA: Wayne State University Press

179 of 229

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA: Journal of the American Medical Association, 303(1), 47-53.

Frank, E., Prien, R. F., Jarrett, R. B., & et al. (1991). Conceptualization and rationale for consensus definitions of terms in major depressive disorder: Remission, recovery, relapse, and recurrence. Archives of General Psychiatry, 48(9), 851- 855. doi:10.1001/archpsyc.1991.01810330075011

Freud, S. (1984). Mourning and Melancholia. In R. A. (ed.) (Ed.), On Metapsychology: The Theory of Psycholoanalysis (pp. 245–269). Aylesbury: Bucks.

Friedman, M. A., Detweiler-Bedell, J. B., Leventhal, H. E., Horne, R., Keitner, G. I., & Miller, I. W. (2004). Combined Psychotherapy and Pharmacotherapy for the Treatment of Major Depressive Disorder. Clinical Psychology: Science and Practice, 11(1), 47-68.

Friedman, O., & Leslie, A. M. (2004). A developmental shift in processes underlying successful belief-desire reasoning. Cognitive Science, 28(6), 963-977.

Fydrich, T., Dowdall, D., & Chambless, D. L. (1992). Reliability and validity of the Beck Anxiety Inventory. Journal of Anxiety Disorders, 6(1), 55-61.

Gibbons, C. J., Fournier, J. C., Stirman, S. W., DeRubeis, R. J., Crits-Christoph, P., & Beck, A. T. (2010). The clinical effectiveness of cognitive therapy for depression in an outpatient clinic. Journal Of Affective Disorders, 125(1), 169- 176.

Gilbert, P. (2009). Introducing compassion-focused therapy. Advances in psychiatric treatment, 15(3), 199-208.

Gotink, R. A., Chu, P., Busschbach, J. J., Benson, H., Fricchione, G. L., & Hunink, M. (2015). Standardised mindfulness-based interventions in healthcare: An overview of systematic reviews and meta-analyses of RCTs. PLoS ONE Vol 10(4), Apr 2015, ArtID e0124344, 10(4).

Groves, S. J., Porter, R. J., Jordan, J., Knight, R., Carter, J. D., McIntosh, V. V. W., Fernando, K., Frampton, C. M. A., Mulder, R. T., Lacey, C., & Joyce, P. R. (2015). Changes in Neuropsychological Function after Treatment with Metacognitive therapy or Cognitive Behaviour Therapy for Depression Depression And Anxiety, 32(6), 437-444. doi:10.1002/da.22341

Guyatt, G. H., Oxman, A. D., Vist, G., Kunz, R., Brozek, J., Alonso-Coello, P., Montori, V., Akl, E. A., Djulbegovic, B., & Falck-Ytter, Y. (2011). GRADE

180 of 229

guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). Journal of clinical epidemiology, 64(4), 407-415.

Hamilton, M. (1960). A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry, 23, 56–62.

Hautzinger, M. (1996). Depression Lehrbuch der Verhaltenstherapie (pp. 121-133): Springer.

Hawton, K. (1989). Cognitive behaviour therapy for psychiatric problems : a practical guide. Oxford: Oxford : Oxford University Press.

Hayes, S. C., & Smith, S. (2005). Get out of your mind and into your life: The new acceptance and commitment therapy: New Harbinger Publications.

Health, U. D. o., & Services, H. (1999). The fundamentals of mental health and mental illness. Mental health: a report of the Surgeon General. Rockville, USA: National Institute of Mental Health, 32-116.

Higgins, J. P., Altman, D. G., Gøtzsche, P. C., Jüni, P., Moher, D., Oxman, A. D., Savović, J., Schulz, K. F., Weeks, L., & Sterne, J. A. (2011). The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj, 343, d5928.

Hirschfeld, R. M. A. (2001). The Comorbidity of Major Depression and Anxiety Disorders: Recognition and Management in Primary Care. Prim Care Companion J Clin Psychiatry, 3 ((6)), 244–254.

Hofmann, S. G., Grossman, P., & Hinton, D. E. (2011). Loving-kindness and compassion meditation: Potential for psychological interventions. Clinical Psychology Review, 31(7), 1126-1132. doi:10.1016/j.cpr.2011.07.003

Hong, R. Y. (2007). Worry and rumination: Differential associations with anxious and depressive symptoms and coping behavior. Behaviour research and therapy, 45(2), 277-290.

Horvath, A. O., & Greenberg, L. S. (1989a). Development and Validation of the Working Alliance Inventory. Journal of Counseling Psychology, 36(2), 223-233.

Horvath, A. O., & Greenberg, L. S. (1989b). Development and validation of the Working Alliance Inventory. Journal of Counseling Psychology, 36(2), 223.

Huibers, M. J. H., van Breukelen, G., Roelofs, J., Hollon, S. D., Markowitz, J. C., van Os, J., Arntz, A., & Peeters, F. (2014). Predicting response to cognitive therapy and interpersonal therapy, with or without antidepressant medication, for major

181 of 229

depression: A pragmatic trial in routine practice. Journal Of Affective Disorders, 152, 146-154. doi:10.1016/j.jad.2013.08.027

Insel, T. R., & Gogtay, N. (2014). National Institute of Mental Health clinical trials: new opportunities, new expectations. JAMA Psychiatry, 71(7), 745-746.

Jacobson, N., & Truax, P. (1991a). Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal Of Consulting And Clinical Psychology, 59(1), 12.

Jacobson, N. S., & Truax, P. (1991b). Clinical significance: A statistical approach to defining meaningful change in psychotherapy research. Journal Of Consulting And Clinical Psychology, 59(1), 12-19. doi:10.1037/0022-006X.59.1.12

Jakobsen, J. C. (2014). Systematic reviews of randomised clinical trials examining the effects of psychotherapeutic interventions versus "no intervention" for acute major depressive disorder and a randomised trial examining the effects of "third wave" cognitive therapy versus mentalization-based treatment for acute major depressive disorder. Danish Medical Journal, 61(10), B4942-B4942.

Johnsen, T. J., & Friborg, O. (2015). The effects of cognitive behavioral therapy as an anti-depressive treatment is falling: A meta-analysis. Psychological Bulletin, 141(4), 747. doi:10.1037/bul0000015

Jordan, J., Carter, J. D., McIntosh, V. V., Fernando, K., Frampton, C. M., Porter, R. J., Mulder, R. T., Lacey, C., & Joyce, P. R. (2014). Metacognitive therapy versus cognitive behavioural therapy for depression: a randomized pilot study. Australian and New Zealand Journal of Psychiatry, 0004867414533015.

Kabat‐Zinn, J. (2003). Mindfulness‐based interventions in context: past, present, and future. Clinical Psychology: Science and Practice, 10(2), 144-156.

Kaufman, A. S., & Lichtenberger, E. O. (2005). Assessing adolescent and adult intelligence: John Wiley & Sons.

Kessler, R. (2012). The costs of depression. The Psychiatric Clinics Of North America, 35(1), 1-14.

Kessler, R., Sampson, N., Berglund, P., Gruber, M., Al-Hamzawi, A., Andrade, L., Bunting, B., Demyttenaere, K., Florescu, S., & de Girolamo, G. (2015). Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys. Epidemiology and Psychiatric Sciences, 24(03), 210-226.

182 of 229

Kirsch, I. (2009). Antidepressants and the placebo response. Epidemiology and Psychiatric Sciences, 18(4), 318-322.

Kirsch, I., & Deacon, B. (2008). Huedo-‐Medina, T. B., Scoboria, A., Moore, TJ, & Johnson, BT.

Kriston, L., von Wolff, A., Westphal, A., Holzel, L. P., & Harter, M. (2014). Efficacy and acceptability of acute treatments for persistent depressive disorder: A network meta-analysis. Depression And Anxiety, 31(8), 621-630.

Laks, J., Kinderman, P., Schwannauer, M., Pontin, E., & Tai, S. (2013). Psychological Processes Mediate the Impact of Familial Risk, Social Circumstances and Life Events on Mental Health. PLoS ONE, 8(10), 1-8. doi:10.1371/journal.pone.0076564

Lanier, E. (2003). Depression. Professional Safety, 48(10), 27.

Larkin, S. (2010). Metacognition in Young Children. New York: Routledge, London and New York (55 NP)

Leichsenring, F. (2001). Comparative effects of short-term psychodynamic psychotherapy and cognitive-behavioral therapy in depression: A meta-analytic approach. Clinical Psychology Review, 21(3), 401-419.

Lewis, A. J. (1934). Melancholia: A historical review. Journal of Mental Science, 80, 1- 42. doi:10.1192

Linde, K., Kriston, L., Rucker, G., Jamil, S., Schumann, I., Meissner, K., Sigterman, K., & Schneider, A. (2015). Efficacy and acceptability of pharmacological treatments for depressive disorders in primary care: Systematic review and network meta-analysis. Annals Of Family Medicine, 13(1), 69-79.

Mapother, E. (1926). Discussion of manic-depressive psychosis. British Medical Journal, 2, 872-879. doi:10.1136

Matt, G. E., & Navarro, A. M. (1997). What meta-analyses have and have not taught us about psychotherapy effects: A review and future directions. Clinical Psychology Review, 17(1), 1-32.

Matthews, G., & Wells, A. (2000). Attention, Automaticity, and Affective Disorder. Behavior Modification, 24(1), 69-93. doi:10.1177/0145445500241004

183 of 229

McCarney, R., Schulz, J., & Grey, A. (2012). Effectiveness of mindfulness-based therapies in reducing symptoms of depression: A meta-analysis. European Journal of Psychotherapy and Counselling, 14(3), 279-299.

McEvoy, P. M., & Nathan, P. (2007). Effectiveness of cognitive behavior therapy for diagnostically heterogeneous groups: a benchmarking study. Journal Of Consulting And Clinical Psychology, 75(2), 344.

McEvoy, P. M., & Perini, S. J. (2009). Cognitive behavioral group therapy for social phobia with or without attention training: A controlled trial. Journal of Anxiety Disorders, 23(4), 519-528.

Mennin, D. S., Heimberg, R. G., & Turk, C. L. (2004). Clinical Presentation and Diagnostic Features. In D. S. Mennin, R. G. Heimberg, & C. L. Turk (Eds.), Generalized Anxiety Disorder - Advances in Research and Practise (pp. 3-28). (25 NP) New York: The Guilford Press.

Moher, D., Liberati, A., Tetzlaff, J., & Altman, D. G. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine, 151(4), 264-269.

Moncrieff, J., Churchill, R., Drummond, D. C., & McGuire, H. (2001). Development of a quality assessment instrument for trials of treatments for depression and neurosis. International Journal of Methods in Psychiatric Research, 10(3), 126- 133.

Moran, P., Leese, M., Lee, T., Walters, P., Thornicroft, G. and Mann, A. (2003). Standardised Assessment of Personality Abbreviated Scale (SAPAS): preliminary validation of a brief screen for personality disorder. British Journal of Psychiatry, 183, 228-232.

Murphy, G. E., Simons, A. D., Wetzel, R. D., & Lustman, P. J. (1984). Cognitive therapy and pharmacotherapy: Singly and together in the treatment of depression. Archives of General Psychiatry, 41(1), 33-41.

Newby, J. M., McKinnon, A., Kuyken, W., Gilbody, S., & Dalgleish, T. (2015). Systematic review and meta-analysis of transdiagnostic psychological treatments for anxiety and depressive disorders in adulthood. Clinical Psychology Review, 40, 91-110.

Newby, J. M., Williams, A. D., & Andrews, G. (2014). Reductions in negative repetitive thinking and metacognitive beliefs during transdiagnostic internet cognitive behavioural therapy (iCBT) for mixed anxiety and depression. Behaviour research and therapy, 59, 52-60. doi:10.1016/j.brat.2014.05.009

184 of 229

Nolen-Hoeksema, S., & Morrow, J. (1991). A prospective study of depression and posttraumatic stress symptoms after a natural disaster: the 1989 Loma Prieta Earthquake. Journal of personality and social psychology, 61(1), 115.

Normann, N., Emmerik, A. A., & Morina, N. (2014). The efficacy of metacognitive therapy for anxiety and depression: A meta-analytic review. Depression And Anxiety, 31(5), 402-411.

Norton, P. J. (2008). An open trial of a transdiagnostic cognitive-behavioral group therapy for anxiety disorder. Behavior Therapy, 39(3), 242-250.

Norton, P. J., & Barrera, T. L. (2012). Transdiagnostic versus diagnosis‐specific CBT for anxiety disorders: A preliminary randomized controlled noninferiority trial. Depression And Anxiety, 29(10), 874-882.

Norton, P. J., Barrera, T. L., Mathew, A. R., Chamberlain, L. D., Szafranski, D. D., Reddy, R., & Smith, A. H. (2013). Effect of transdiagnostic CBT for anxiety disorders on comorbid diagnoses. Depression And Anxiety, 30(2), 168-173.

Nugent, W. R. (2012). The interchangeability of scores from different measures and meta-analytic effect size comparability. Journal of the Society for Social Work and Research Vol 3(4), Nov 2012, ArtID 213-232, 3(4).

Oliver, J., & Baumgart, E. (1985). The Dysfunctional Attitude Scale: Psychometric properties and relation to depression in an unselected adult population. Cognitive Therapy And Research, 9(2), 161-167. doi:10.1007/BF01204847

Organization, W. H. (1992). The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines: Geneva: World Health Organization.

Papageorgiou, C., & Wells, A. (2002). Positive beliefs about depressive rumination: Development and preliminary validation of a self-report scale. Behavior Therapy, 32(1), 13-26.

Papageorgiou, C., & Wells, A. (2003). An empirical test of a clinical metacognitive model of rumination and depression. Cognitive Therapy And Research, 27(3), 261-273.

Papageorgiou, C., & Wells, A. (2004). Depressive rumination: Nature, theory and treatment: John Wiley & Sons.

Papageorgiou, C., & Wells, A. (2014). Group Metacognitive Therapy for Severe Antidepressant and CBT Resistant Depression: A Baseline-Controlled Trial. Cognitive Therapy and Research, 39(1), 14-22. doi:10.1007/s10608-014-9632-x

185 of 229

Parker, D., Mills, S., & Abbey, J. (2008a). Effectiveness of interventions that assist caregivers to support people with dementia living in the community: A systematic review. International Journal of Evidence-Based Healthcare, 6(2), 137-172.

Parker, G. B., Crawford, J., & Hadzi‐Pavlovic, D. (2008b). Quantified superiority of cognitive behaviour therapy to antidepressant drugs: a challenge to an earlier meta‐analysis. Acta Psychiatrica Scandinavica, 118(2), 91-97.

Perepletchikova, F., & Kazdin, A. E. (2005). Treatment integrity and therapeutic change: Issues and research recommendations. Clinical Psychology: Science and Practice, 12(4), 365-383.

Posternak, M. A., & Miller, I. (2001). Untreated short-term course of major depression: a meta-analysis of outcomes from studies using wait-list control groups. Journal Of Affective Disorders, 66(2), 139-146.

Pruzinsky, T., & Borkovec, T. D. (1990). Cognitive and personality characteristics of worriers. Behavior Research and Therapy, 28(6), 507-512.

R., F. M. (2014). HIV among men who have sex with men and women (MSMW): Prevalence estimates, acquisition and transmission risks, and implications for interventions. Dissertation Abstracts International: Section B: The Sciences and Engineering, 74(7-B(E)), No Pagination Specified.

Raes, F., Williams, J. M. G., & Hermans, D. (2009). Reducing cognitive vulnerability to depression: A preliminary investigation of MEmory Specificity Training (MEST) in inpatients with depressive symptomatology. Journal of Behavior Therapy and Experimental Psychiatry, 40(1), 24-38.

Rijkeboer, M. M., van den Bergh, H., & van den Bout, J. (2005). Stability and discriminative power of the Young Schema-Questionnaire in a Dutch clinical versus non-clinical population. Journal of Behavior Therapy and Experimental Psychiatry, 36(2), 129-144.

Roelofs, J., Huibers, M., Peeters, F., Arntz, A., & van Os, J. (2010). Positive and Negative Beliefs About Depressive Rumination: A Psychometric Evaluation of Two Self-Report Scales and a Test of a Clinical Metacognitive Model of Rumination and Depression. Cognitive Therapy And Research, 34(2), 196-205. doi:10.1007/s10608-009-9244-z

Rounsaville, B. J., Weissman, M. M., Prusoff, B. A., & Herceg-Baron, R. (1979). Process of psychotherapy among depressed women with marital disputes. American Journal of Orthopsychiatry, 49(3), 505.

186 of 229

Rush, A. J., & Watkins, J. T. (1981). Group versus individual cognitive therapy: A pilot study. Cognitive Therapy And Research, 5(1), 95-103.

Schatzberg, A. F., & Kraemer, H. C. (2000). Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression. Biological Psychiatry, 47(8), 736-744.

Schramm, E., & Berger, M. (2011). Differential indications for psychotherapy exemplified by depression. Der Nervenarzt, 82(11), 1414-1424.

Schulberg, H. C., Block, M. R., Madonia, M. J., Scott, C. P., Rodriguez, E., Imber, S. D., Perel, J., Lave, J., Houck, P. R., & Coulehan, J. L. (1996). Treating major depression in primary care practice: eight-month clinical outcomes. Archives of General Psychiatry, 53(10), 913-919.

Segal, Z. V., Williams, J. M. G., & Teasdale, J. D. (2012). Mindfulness-based cognitive therapy for depression: Guilford Press.

Shapiro, D. A., Barkham, M., Stiles, W. B., Hardy, G. E., Rees, A., Reynolds, S., & Startup, M. (2003). Time is of the essence: A selective review of the fall and rise of brief therapy research. Psychology and Psychotherapy: Theory, Research and Practice, 76(3), 211-235.

Spitzer, R. L., Williams, J. B., Gibbon, M., & First, M. B. (1992). The structured clinical interview for DSM-III-R (SCID): I: history, rationale, and description. Archives of General Psychiatry, 49(8), 624-629.

SSI. (2012). Færre langtidsbrugere benzodiazepiner. Retrieved from København:

Stein, D. J., & Hollander, E. (2003). Anxiety Disorders Comorbid with Depression : Social Anxiety Disorder, Post-traumatiac Stress Disorder, Generalized Anxiety Disorder, and Obsessive-compulsive Disorder. London: CRC Press, 2003.

Sullivan, P. F., Neale, M. C., & Kendler, K. S. (2014). Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry.

Sundhedsstyrelsen. (2007). Referenceprogram for angstlidelser hos voksne Retrieved from København (9 NS):

Talkovsky, A. M., & Norton, P. J. (2014). Mediators of transdiagnostic group cognitive behavior therapy. Journal of Anxiety Disorders, 28(8), 919-924.

Talkovsky, A. M., & Norton, P. J. (2016). Intolerance of uncertainty and transdiagnostic group cognitive behavioral therapy for anxiety. Journal of Anxiety Disorders.

187 of 229

Thanoi, W., & Klainin-Yobas, P. Assessing rumination response style among undergraduate nursing students: A construct validation study. Nurse Education Today, 35(5), 641-646. doi:10.1016/j.nedt.2015.01.001

Tracey, T. J., & Kokotovic, A. M. (1989). Factor structure of the working alliance inventory. Psychological Assessment: A journal of consulting and clinical psychology, 1(3), 207.

Trials, C. O. M. i. E. (2011-2016). The Comet Initiative.

Turner, E. H., Matthews, A. M., Linardatos, E., Tell, R. A., & Rosenthal, R. (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. New England Journal of Medicine, 358(3), 252-260. van Hees, M. L. J. M., Rotter, T., Ellermann, T., & Evers, S. M. A. A. (2013). The effectiveness of individual interpersonal psychotherapy as a treatment for major depressive disorder in adult outpatients: a systematic review. BMC Psychiatry, 13. doi:10.1186/1471-244x-13-22

Vittengl, J. R., Clark, L. A., Dunn, T. W., & Jarrett, R. B. (2007a). Reducing relapse and recurrence in unipolar depression: A comparative meta-analysis of cognitive-behavioral therapy's effects. Journal Of Consulting And Clinical Psychology, 75(3), 475-488.

Vittengl, J. R., Clark, L. A., Dunn, T. W., & Jarrett, R. B. (2007b). Reducing relapse and recurrence in unipolar depression: a comparative meta-analysis of cognitive- behavioral therapy's effects. Journal Of Consulting And Clinical Psychology, 75(3), 475.

Wang, Y.-P., & Gorenstein, C. (2013). Psychometric properties of the Beck Depression Inventory-II: a comprehensive review. Revista Brasileira de Psiquiatria, 35(4), 416-431.

Watts, S. E., Turnell, A., Kladnitski, N., Newby, J. M., & Andrews, G. (2015). Treatment-as-usual (TAU) is anything but usual: A meta-analysis of CBT versus TAU for anxiety and depression. Journal Of Affective Disorders, 175, 152-167.

Wechsler, D. (2014). Wechsler Adult Intelligence Scale–Fourth Edition (WAIS–IV).

Weissman, A. N., & Beck, A. T. (1978). Development and validation of the Dysfunctional Attitude Scale: A preliminary investigation.

Wells, A. (1990). Panic disorder in association with relaxation induced anxiety: An attentional training approach to treatment. Behavior Therapy, 21(3), 273-280.

188 of 229

Wells, A. (1995). Metacognition and worry - A cognitive model of GAD. Behavioural and Cognitive Psychotherapy, 23, 20.

Wells, A. (2002). Worry, Metacognition and GAD. Journal of Cognitive Psychotherapy, 16(2), 179-192.

Wells, A. (2005a). Detached Mindfulness In Cognitive Therapy: A Metacognitive Analysis And Ten Techniques. Journal of Rational-Emotive and Cognitive- Behavior Therapy, 23(4), 337-355. doi:10.1007/s10942-005-0018-6

Wells, A. (2005b). Worry, Intrusive Thoughts, and Generalized Anxiety Disorder: The Metacognitive Theory and Treatment. In D. A. Clark (Ed.), Intrusive Thoughts in Clinical Disorders - Theory, Research and Treatment (pp. 119-144). (25 NP) New York: The Guilford Press.

Wells, A. (2009a). Meta-cognitive Therapy for depression and anxiety. UK, The Guilford Press, London: (127 NP) New York: Guilford Press.

Wells, A. (2009b). Metacognitive therapy for anxiety and depression / Adrian Wells. New York: New York : Guilford.

Wells, A., & Cartwright-Hatton, S. (2004). A short form of the metacognitions questionnaire: properties of the MCQ-30. Behaviour research and therapy, 42(4), 385-396.

Wells, A., Fisher, P., Myers, S., Wheatley, J., Patel, T., & Brewin, C. (2009). Metacognitive Therapy in Recurrent and Persistent Depression: A Multiple- Baseline Study of a New Treatment. Cognitive Therapy And Research, 33(3), 291-300. doi:10.1007/s10608-007-9178-2

Wells, A., Fisher, P., Myers, S., Wheatley, J., Patel, T., & Brewin, C. R. (2012). Metacognitive therapy in treatment-resistant depression: A platform trial. Behaviour research and therapy, 50(6), 367-373. doi:10.1016/j.brat.2012.02.004

Wells, A., & Matthews, G. (1996a). Modelling Cognition in Emotional Disorder - The S-REF Model Behavior Research and Therapy, 34(11/12), 881-888.

Wells, A., & Matthews, G. (1996b). Modelling cognition in emotional disorder: The S- REF model. Behaviour Research and Therapy, 34(11), 881-888.

Wells, A., & Matthews, G. (2014). Attention and Emotion (Classic Edition): A Clinical Perspective: Psychology Press.

Wells, A., & Sembi, S. (2004a). Metacognitive therapy for PTSD: A core treatment manual. Cognitive and Behavioral Practice, 11(4), 365-377.

189 of 229

Wells, A., & Sembi, S. (2004b). Metacognitive therapy for PTSD: A preliminary investigation of a new brief treatment. Journal of Behavior Therapy and Experimental Psychiatry, 35(4), 307-318.

Wells, A., Welford, M., Fraser, J., King, P., Mendel, E., Wisely, J., Knight, A., & Rees, D. (2008). Chronic PTSD Treated With Metacognitive Therapy: An Open Trial. Cognitive and Behavioral Practice, 15(1), 85-92.

Westen, D., Novotny, C. M., & Thompson-Brenner, H. (2004). The empirical status of empirically supported psychotherapies: assumptions, findings, and reporting in controlled clinical trials. Psychological Bulletin, 130(4), 631.

WHO. (2016). Depression. Retrieved from http://www.who.int

Wierzbicki, M., & Bartlett, T. S. (1987). The efficacy of group and individual cognitive therapy for mild depression. Cognitive Therapy And Research, 11(3), 337-342. doi:10.1007/bf01186284

Williams, J. B. (1988). A structured interview guide for the Hamilton Depression Rating Scale. Archives of General Psychiatry, 45(8), 742-747.

Young, J. E., & Brown, G. (1994). Young schema questionnaire. Cognitive therapy for personality disorders: A schema-focused approach, 63-76.

Zigmond, A. S., & Snaith, R. P. (1983). The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica, 67(6), 361-370.

Zimmerman, M., Posternak, M. A., & Chelminski, I. (2005). Is It Time to Replace the Hamilton Depression Rating Scale as the Primary Outcome Measure in Treatment Studies of Depression? Journal of Clinical Psychopharmacology, 25(2), 105-110.

Aasen, H. (2001). An empirical investigation of depression symptoms: norms, psychometric characteristics and factor structure of the Beck Depression Inventory-II.

190 of 229

Appendix 1: Search Filters used to Search Electronic Databases in Study One

Cochrane Library Searched 6 nov 2015

Search Filter Results

1 explode Psychotherapy/ 9320

2 psychotherap* or "behavior* NEAR/6 therap*" or behaviour* 23860 NEAR/6 therap* or biofeedback and psycho* or cognitive NEAR/6 therap* or desensiti* and psychol* or "implosive therap*" or relax* NEAR/6 therap* or relax* NEAR/6 techniq* or therap* NEAR/6 touch* (all text)

bibliotherapy or imagery and psychotherap* or counsel* or "milieu 14978 therap*" or psychosoc* or psycholog* or support* NEAR/6 group* or guide* NEAR/6 image* or "gestalt therap*" or "nondirective therap*" or "play therap*" or psychoanaly* NEAR/6 therap* or "psychotherap* process*" (all text)

4 OR 1-2 34904

5 explode Depression/ 39420

6 depressi* NEAR/3 disorder* or depressi* NEAR/3 symptom* 22192 depression or depressive* or depressed or dysthymia* (all text)

7 explode Depressive Disorder/ 11605

8 OR 5-7 45566

9 4 AND 8 8868

10 meta-analy* or metaanal* (all text) or meta-analysis.pt,ab,ti. 36574

191 of 229

11 explode Meta-Analysis as Topic explode all trees 34478

12 systematic* NEAR/4 review* or systematic* NEAR/4 overview* 52856 (all text)

13 extraction.ab. 5

14 letter or comment or editorial pt. 22823

15 10 or 11 or 12 or 13 60160

16 15AND NOT 14 50629

17 9 and 16 1008

192 of 229

PsycINFO Search 1967 to Nov 3rd 2015

Search Filter Results

1 exp Psychotherapy/ 188044

2 (psychotherap$ or "behavior$ adj6 therap$" or (behaviour$ adj6 335178 therap$) or (biofeedback and psycho$) or (cognitive adj6 therap$) or (desensiti$ and psychol$) or "implosive therap$" or (relax$ adj6 therap$) or (relax$ adj6 techniq$) or (therap$ adj6 touch$)).tw.

3 (bibliotherapy or (imagery and psychotherap$) or counsel$ or 921318 "milieu therap$" or psychosoc$ or psycholog$ or (support$ adj6 group$) or (guide$ adj6 image$) or "gestalt therap$" or "nondirective therap$" or "play therap$" or (psychoanaly$ adj6 therap$) or "psychotherap$ process$").tw.

4 exp Postpartum Depression/ or exp Recurrent Depression/ or exp 213412 Atypical Depression/ or exp Endogenous Depression/ or exp "Depression (Emotion)"/ or exp Reactive Depression/ or exp Treatment Resistant Depression/ or exp Major Depression/

5 (depressi$ adj3 disorder$).tw. 38310

6 (depressi$ adj3 symptom$).tw. 49152

7 (depression or depressive$ or depressed or dysthymia$).tw. 308992

8 or/1-3 761005

9 or/4-7 270612

10 (meta-analy$ or metaanal$).tw. 23069

11 meta-analysis.pt,ab,ti. 16871

12 exp Meta Analysis/ 3745

193 of 229

13 (systematic$ adj4 (review$ or overview$)).tw. 2355

14 or/10-14 24604

15 8 and 9 and 14 2053 ______

194 of 229

EMBASE Search 1980 to 6 nov. 2015

Search Filter Results

1 exp Psychotherapy/ 83963

2 (psychotherap$ or "behavior$ adj6 therap$" or (behaviour$ adj6 therap$) or (biofeedback and psycho$) or (cognitive adj6 therap$) or (desensiti$ and psychol$) or "implosive therap$" or (relax$ adj6 therap$) or (relax$ adj6 techniq$) or (therap$ adj6 touch$)).tw.

(bibliotherapy or (imagery and psychotherap$) or counsel$ or 478837 "milieu therap$" or psychosoc$ or psycholog$ or (support$ adj6 group$) or (guide$ adj6 image$) or "gestalt therap$" or "nondirective therap$" or "play therap$" or (psychoanaly$ adj6 therap$) or "psychotherap$ process$").tw.

4 (depressi$ adj3 disorder$).tw. 54143

5 (depressi$ adj3 symptom$).tw. 62044

6 (depression or depressive$ or depressed or dysthymia$).tw. 107754

7 Reactive Depression/ or Bipolar Depression/ or Depression/ or 320265 Recurrent Brief Depression/ or Masked Depression/ or Long Term Depression/ or Atypical Depression/ or Agitated Depression/ or Puerperal Depression/ or Postoperative Depression/ or Major Depression/ or Endogenous Depression/

8 or/1-3 334800

9 or/4-7 563767

10 (meta-analy$ or metaanal$).tw. 159047

11 meta-analysis.pt,ab,ti. 90863

195 of 229

12 exp Meta Analysis/ 100858

13 (systematic$ adj4 (review$ or overview$)).tw. 147358

14 extraction.ab. 197451

15 (letter or comment or editorial).pt. 1456990

16 or/10-14 559507

17 16 not 15 197632

18 8 and 9 and 17 334

196 of 229

MEDLINE Searched 6/11/2015

Search Filter Results

1 psychotherapy.af. 282956

2 (psychotherap$ or "behavior$ adj6 therap$" or (behaviour$ adj6 101983 therap$) or (biofeedback and psycho$) or (cognitive adj6 therap$) or (desensiti$ and psychol$) or "implosive therap$" or (relax$ adj6 therap$) or (relax$ adj6 techniq$) or (therap$ adj6 touch$)).tw.

3 (bibliotherapy or (imagery and psychotherap$) or counsel$ or 188019 "milieu therap$" or psychosoc$ or psycholog$ or (support$ adj6 group$) or (guide$ adj6 image$) or "gestalt therap$" or "nondirective therap$" or "play therap$" or (psychoanaly$ adj6 therap$) or "psychotherap$ process$").tw.

4 depression.af. 464151

5 (depressi$ adj3 disorder$).af. 113592

6 (depressi$ adj3 symptom$).af. 131375

7 Depressive Disorder.af. 59879

8 (depression or depressive$ or depressed or dysthymia$).af. 518625

9 1 or 3 or 2 439476

10 8 or 6 or 4 or 7 or 5 518669

11 10 and 9 115501

12 (meta-analy$ or metaanal$).tw. 22951

13 meta-analysis.ab,ti,pt. 16871

14 Meta-Analysis.af. 279458

15 (systematic$ adj4 (review$ or overview$)).tw. 81419

197 of 229

16 extraction.ab. 5401

17 (letter or comment or editorial).pt. 0

18 12 or 13 or 14 or 15 or 16 351190

19 11 and 18 649

198 of 229

SCOPUS Searched 03/11/2015

Search Filter Results

1 KEY(Depressi* or depressive* or depressed or dysthymia*) 1270005

2 KEY(Psychotherapy) 122112

3 KEY(“bibliotherapy or “self-help” or “self help” or (comput* and 19343 therap*) or (online and therap*))

4 2 or 3 138853

5 KEY((meta analysis) OR (metaanalysis) OR (systematic review) 2540 OR (systematic overview))

6 1 and 4 and 5 68

199 of 229

Web of Science Searched 3/11 2015

Search Filter Results

1 Topic = ((behavior* or behaviour* or cognitive or meta?cognit* or 3082695 implosive or psycho* or interpersonal or gestalt or person?cent* or activation* or bibliotherapy* or counsel* or supportive or non?directive or guided or image* or computer* or cbt) and therap*)

Document Type=(ARTICLE OR REVIEW OR CORRECTION)

2 Topic = ((behavior* or behaviour* or cognitive or meta?cognit* or 177054 implosive or psycho* or interpersonal or gestalt or person?cent* or activation* or bibliotherapy* or counsel* or supportive or non?directive or guided or image* or computer* or cbt) and psychotherap*)

Document Type=(ARTICLE OR REVIEW OR CORRECTION/ ADDITION)

3 1 OR 2 Restricted to English Language 3153567

4 Topic = Depress* Document Type=( ARTICLE OR 1266591 CORRECTION OR REVIEW ) AND Languages=(ENGLISH)

5 Topic=(dysthymi*) Document Type=( ARTICLE OR 11451 CORRECTION/ ADDITION OR REVIEW ) AND Languages = ( ENGLISH )

6 4 OR 5 1631118

7 Topic=(met*analy*) 192522

200 of 229

8 Title=("systematic review" or "systematic overview") 153254

9 7 OR 8 340488

10 Topic=(extraction) Document Type=( ARTICLE OR REVIEW 1002339 OR CORRECTION ) AND Languages=( ENGLISH )

11 9 OR 10 1330609

12 3 AND 6 25208

13 12 AND 11 1604

201 of 229

Appendix 2: Screening Tool used to Assess the Eligibility of Reviews in Study One

Article Include Criterion Present? Y/N Notes Reference ?

Reviews RCTs - psychotherapy for Depression?

Adults?

Research Diagnosis of Depression?

Individual Psychotherapy for Depression?

Adequate Controls?

Synthesis of Psychotherapy efficacy?

Psychosis/PD/Medical/Substanc e Abuse?

202 of 229

Appendix 3: Composite Tool used to Extract Substantive & Quality Data* from Individual Reviews in Study One

BIBLIOGRAPHIC DETAILS

Descriptives* (Adapted from CRDs DARE format) Quality*/ risk of bias (Adapted from ScHARR format)

Summary of Review (Our abstract):

Authors Objectives: Did the review address a clearly focused Y/N? question?

Search Methods: Was the search strategy adequate (i.e. did the Y/N? reviewers identify all relevant studies?)

STUDY SELECTION

What are the included designs in the review?

Were the inclusion/exclusion Y/N? criteria specified?

What types of therapy were included?

What attempts were made to identify the ‘purity’ of therapy?

Participants?

Diagnostic techniques?

Severity?

203 of 229

Duration?

Did the review include the right Y/N? kinds of studies?

STUDY OUTCOMES

Assessment points in time/follow up?

Comparison groups?

Measures of severity?

Outcomes used in individual studies?

Continued from previous page....

VALIDITY ASSESSMENT

How were individual studies determined suitable for inclusion?

Did the reviewers assess the Y/N? quality of the included studies?

Were appropriate outcome Y/N? measures used?

SYNTHESIS

Synthesis: Assessment of differences between Was the method of data Y/N? included studies? extraction reported?

Heterogeneity found? Y/N?

Heterogeneity accounted for Y/N?

Are appropriate sub-group Y/N? analyses presented?

If the results of the studies have been combined, was it appropriate Y/N? to do so?

204 of 229

RESULTS OF THE REVIEW

Authors’ Conclusions: Are the main results of the review presented (e.g. Y/N? numerical results included with CIs)

Justified on included Y/N? evidence?

Are issues of Justified on included generalisability Y/N? Y/N? evidence? addressed?

Authors statements concerning implications for Justified on included Y/N? practice/research? evidence?

Our Comments on the review as a whole based on the qualitative/quantitative findings

* See main text for information about origins of table design.

205 of 229

Appendix 4: Synthesis Methods of Reviews in Study 1 Review Method of Synthesis†

Casacalenda et al. Post-treatment remission percentages for each study’s treatment (2002) condition were averaged across studies to give an average remission rate. The average remission rates for each treatment condition were then assessed for significant differences using analysis of variance. No weighting of individual study results by sample size, nor testing for between study heterogeneity were described. The authors used SAS version 8.0 data analysis software.

Cuijpers et al. (2014) The effect size indicating the difference between the two groups at post-treatment was calculated. Effect sizes were calculated by substracting (at post-test) the average score of the psychotherapy group from the average score of the placebo group and divided the result by the pooled standard deviation. A a result of small samle sizes the effect size was corrected for small sample size (Hedges & Olkin, 1985)

de Maat et al. (2006) The relative efficacy of treatments within studies were calculated using odds and relative risk ratios for remission at post treatment and relapse during follow up. These effect sizes were then weighted according to study size and combined to produce an overall estimate of the odds or risk ratio for remission or relapse. The authors employed a fixed effects model, tested for heterogeneity between individual study results and used Review Manager 4.2 software of the Cochrane Collaboration. de Maat et al. (2007) As for de Maat et al. (2006) for post treatment outcomes only.

Friedman et al. The relative efficacy of treatments within studies was calculated (2004) using Cohen’s d for both symptom reduction and recovery status. Effect sizes were weighted according to study size and combined

206 of 229

to produce a Cohen’s d for both symptom reduction and recovery. Between study heterogeneity was tested for using Chi-squared analyses. Results were presented for both post treatment and follow up outcomes. The authors did not report the statistical significance of their results.

Leichsenring (2001) Success rate differences between treatments were assessed in individual studies by testing for significant differences in correlation coefficients (Cramer’s Phi). Correlation coefficients from studies were transformed and compared to test for significant heterogeneity. A weighted mean Phi value was subsequently derived for both post treatment and follow up outcomes.

Parker et al. (2008) The relative efficacy of treatments within studies were calculated using Cohen’s d for symptom reduction on the BDI and odds and risk ratios for response. These effect sizes were then weighted according to study size and combined to produce an overall estimate of symptom reduction or response. The authors employed a random effects model, tested for heterogeneity between studies, and used the META statistical package version Van Hees et al (2013) 8.01.

As a result of heterogeneity between the studies in this review the authors had difficulty doing metaanalytic comparisons. However, they compared overall effect sizes between individual studies with 95% CI.

Vittengl et al. (2007) The synthesis was based on the studywise logit transformed proportions of patients experiencing relapse or recurrence of depression by treatment type. These proportions were then weighted according to study size to provide an overall estimate of the numbers relapsing by treatment type. The authors employed a

207 of 229

random effects model and tested for heterogeneity between individual study results.

208 of 229

Appendix 5: Details of five Borderline Reviews Included in Study 1

Review Further Information

Casacalenda et al. High levels of personality disorder (PD) comorbidity (2002) was reported for 3 of the 6 constituent studies which indicated the need for referral to a third reviewer (Elkin et al., 1989; Schulberg et al., 1996; Scott and Freeman, 1992). The review was included as these studies did not treat depression specifically in the context of PD. The finding of high PD comorbidity was possibly due to a level of detail in reporting not seen in other reviews. For example, other eligible reviews included Elkin et al. (1989) but did not provide information concerning the proportion of patients with PD.

Friedman et al. Presented pooled results for group and individual (2004) psychotherapy. Consequently, only the results of comparisons that met our eligibility criteria were included.

Leichsenring (2001) High levels of reported personality comorbidity in some included studies were accepted for same reasons as for Casacalenda et al. (2002). High levels of co- morbid Generalised Anxiety Disorder and/or Panic Disorder were identified in one study which used DSM III criteria (Shapiro et al., 1994). The review was not excluded on the basis that the primary diagnosis of patients in this study was depression.

Parker et al. (2008) One of nine studies included patients with dysthymia (Hautzinger et al., 1996) whose BDI and HDRS scores were required to be greater than 20, indicating moderate depression (Gotlib and Hammen, 2002). These patients were considered as depressed according

209 of 229

to their symptom severities.

Vittengl et al. (2007) Results of comparisons that were based on studies not meeting our eligibility criteria were excluded.

210 of 229

Appendix 6: Ethical approval

Regarding the review of the trial SJ-201 (notification no. 27761), "Meta-cognitive behavioral therapy vs. cognitive therapy for depression. A clinical randomized clinical trial '(Metadep)", to the Regional Research Ethics Committee for Region Zealand.

The Regional Research Ethics Committee of the Regions Zealand has dealt with the matter at its meeting on December 6th 2010 and took the following

Decision:

This project approved under the Act on a research ethics committee system, Law no. 402 of May 28th 2003 as amended.

The approval applies to the reported test sites, the notified researcher in Denmark as well as for the specified trial period.

The approval is valid till December 31st 2013 and include the following documents:

Protocol of (undated) version -. Participant Information of (undated) version -. Consent of (undated) version -.

Implementation of the project in violation of permit is punishable by a fine or imprisonment, cf. Committee Act § 29.

Changes:

Are there significant changes in protocol documents during project implementation, these must be notified to the committee in the form of additional protocols. The changes can only be implemented after approval by the committee under committee act §23, section 1 pt. 1.

211 of 229

Review of additional protocols must be done electronically on www.drvk.dk with the already allocated notification number and password.

Significant changes include changes that may affect the safety of trial subjects, interpretation of the scientific evidence that the project is based on, and the implementation or management of the project. This could be changes in internal and/or exclusion criteria, study design, number of subjects, duration of treatment, efficacy parameters, changes of the researcher or the test sites as well as substantive amendments to the written information to the subjects.

New information means that the researcher is considering changing the procedure or stop the trial, the Committee must be informed about it.

Side effects and incidents:

The committee must be informed immediately if serious side effects or serious adverse events appears during the project , see. committee act § 22, section 3

Once a year throughout the trial the Committee shall be sent a list of all serious side effects and serious incidents which occurred during the trial together with a report on the safety of trial subjects, cf. committee act § 22, section 4

The material must be in Danish. The list of serious side effects and serious incidents may be in English, if attached with a Danish summary.

Completion:

The researcher shall, within 90 days after completion of the project inform the Committee thereof, see. committee act § 22, section 5

212 of 229

If the project is interrupted earlier than planned, a given reason hereof shall be sent to the committee within 15 days after the decision of termination, cf. § 22, section 5

If the project is not started, the reason shall be communicated to the committee.

Committee will ask for a copy of the final research report or publication referred to., cf. committee act § 22, section 2. We must in this regard point out the obligation to publish negative as well as positive test results, see. Committee Act § 14, section 1, pt. 6.

Supervision:

The committee oversees that the project is carried out in accordance with the authorization under committee act § 22, section 1

The following Committee members attended the meeting reading:  Timo Jensen  Knud Rasmussen  Eva Levinsen  Ole Marqweis  Arne Bremmelgaard  Ellen Holm  Jens Lyndrup

With kind regards Helle Dyrlund Secretary

213 of 229

Appendix 7: Participant information & Consent

PARTICIPATION INFORMATION: Meta-Cognitive Therapy Versus Cognitive Behavioural Therapy for Depression

You are hereby invited to participate in a scientific research trial at CEKTOS. Before you decide whether you would want to participate in the trial, you need to fully understand what the study is about and why we conduct this trial. We would therefore ask you to read this participant information thoroughly.

You will receive an invitation to an interview where the participant information will be thoroughly elaborated, and where you can ask any questions you may have. You are welcome to bring a family member, friend or an acquaintance for the interview. If you decide to participate in the trial, we will ask you to sign a consent form. Remember that you are entitled to time of consideration before you decide whether to sign the statement.

We are working towards optimizing our treatment of depression. Psychotherapy as usual at CEKTOS include cognitive behavioural therapy which has proven effective in several Danish and international studies. Cognitive therapy is primarily concerned with changing negative thoughts and beliefs in regard to one self, others and the world, using restructuring and Socratic dialogue, ie a special interview technique that intends to challenge the way of thinking. In addition, there are several behaviour-oriented methods working towards increasing the feeling of enjoyment and activity levels using homework tasks.

Meta-cognitive therapy is primarily concerned with changing and increases the clients meta-cognitive control using awareness training and detached mindfulness, i.e. the client learns to separate himself from his thoughts and minimize rumination and worry.

We would like to ask you if you want to participate in a study that intends to clarify which of the two forms of therapy that is best.

214 of 229

If you choose to participate in the trial, you will be invited to an initial interview and then randomly referred to the psychologist Pia Callesen to receive either traditional cognitive therapy or meta-cognitive therapy. All research participants will receive active treatment. You will be asked to fill in various questionnaires and participate in short interviews throughout the course of treatment, and 3 and 6 months after completion. This will take about 5-10 min. per. session and additionally 1.5 hr. before the course, after 6 sessions as well as 3 and 6 months after ended treatment. This is necessary to measure the impact of therapy and your learning outcome of the course. In addition, the session will be recorded on video. Both questionnaires and video will be handled with 100% confidentiality and kept safely locked away. The course of therapy will last up to 24 sessions. You may at any time and without reason withdraw your consent. There can always be the possibility of unpredictable risks and impacts associated with your participation in biomedical research, but this study does not include blood tests, pharmaceuticals and the like, and according to our experience, a possible risk will be extremely small.

Your participation in the trial may make it easier to determine which treatment will be the most appropriate to choose for future clients.

There shall be no remuneration for participation in the study, and we can not pay any transportation fees.

The person responsible for the study, Pia Callesen, is engaged in a self-funded doctorate, and this trial is part of the process. Pia Callesen has no independent economic interests in or the results of the study

As a volunteer, you have certain rights. Enclosed is a summary of your rights and you are encouraged to read it.

If you have questions about the above please do not hesitate to contact the project manager Pia Callesen directly on tel. 22 68 42 81 or e-mail: [email protected]

215 of 229

Appendix 8: Efficacy variables & Timeline

W O D D M M N P R B B H S S E

C

u

B

A D

R

A A

B

a

b

C D

f

o

I

b

m

R

I

S

I

j S S

R

f

Q

D

r

D

e

j

- -

S

i

k

S

i e

-

S S

c

-

l

c

3

i

S

c

t

t

F F

n

o

0

i

t

a

2 1

g

v

i

n

v

e

c

m

e

y

m

e

m

m

e

v

e

a

o

a

a

s

r

s

u

y

r

u

r

i

r

e

a

e

s

s

:

b

:

l

e

P X X X X

s

r

e

-

t

r

e

a

t

m

.

.

T X X X X X X X X X

r

e

a

t

m

.

s

t

a

r

t

A X X

t

e

v

e

r

y

t

r

e

a

t

m

.

s

e

s

s

i

o

n

X X X X X X X X X X X X

P

o

s

t

-

t

r

e

a

t

m

.

6 T X X X X X X X X X X X

m

i

m

.

f

o

e

l

l

o

l

w

i

n

u

p

e

216 of 229

Appendix 9: Use of scoring sheets for research

Participant ID: ______

Meta Cognitive therapy is a relatively new approach and there is need for more research to document the effect further. You are hereby requested to release your questionnaire scores for use in a research article that intends to measure the effect of our metacognitive groups. Your participation in this survey will be treated 100% confidentially. Your data will not be examined individually and will not contain any personally identifiable information. Your name will not be linked to any of your data or response. Instead, each participant will be assigned a unique ID number, and your data will only be examined together by means of this ID number. Your self-report responses will only be identified by your participant ID number. No personally identifiable information will be stored or linked to you in any way.

All information will be kept in a locked cabinet, which is only available for members of the research team. All information stored on a computer will be password protected. CEKTOS will retain data for 10 years after treatment. Only the investigator from CEKTOS want to access the data.

Your choice to release your scores is completely voluntary and if you choose to be a part of the study, you can always change your mind and decide to withdraw at any time. If you choose to withdraw from the study please contact Pia Callesen [email protected] and all scores, which you may have given, will be destroyed. You can draw from the study until August 2016. Your decision regarding your participation in the study will not affect your treatment CEKTOS in any way.

Please indicate below if you want to release your data:

I want to release my data to journal publication I do not want to release my data to journal publication

217 of 229

Appendix 10: Count of participants

Condition Total (N) non starters 36 Intention to treats (ITT) 26 completers 106 Did not turn up for first session 20 Excluded 19 Training cases 24 N total 231

Excluded Resp. Nr Reason 14 Concurent treatment 19 Binge eating disorder 22 ADHD 26 Concurrent treatment 27 Concurrent treatment 39 Binge eating disorder 43 Doesn’t want method 44 Anorexia 52 Missing data 102 ADHD 150 Concurrent Eating Disorder treatment 171 Concurrent Eating Disorder treatment 218 Pathological Jealousy 222 Binge eating & OCD 223 Sudden sick leave – chronic migraine 228 Missing data 229 PTSD

218 of 229

230 PTSD 231 OCD

219 of 229

Appendix 11: Cognitive Therapy Checklist

220 of 229

Appendix 12: Metacognitive Therapy Checklist

221 of 229

Appendix 13: Activity Schedule

0

0

0

2

2

2

2

1

1

1

1

1

1

1

1

1

1

0

T

m

A

2

1

0

3

2

1

0

9

8

7

6

5

4

3

2

1

0

9

i

uc

c

m

t

e

h you e

i

v

i

t

y

s

nj

c

h

oye

e

d

d t

u

M

he

l

e

o

a

n

–

c

d

F

t

a

i

i

vi

y

l

l

i

t

y

n for e

(N

:

0

ve

–

10). G

T

ry hour a

u

e

s

d

t

a

v

y

nt

–

not

N

t

h.

e

how

W

w

e

d

e

n

l

l

e

you m

s

d

a

y

a

s

t

e

re

T

d t

h

u

he

r

s

a

d

c

a

t

i

y

vi

t

y i

n re

l

F

a

t

r

i

i

on t

d

a

y

o how

you fe

S

e

l

a

ri

t

u

ght

r

d

now

a

y

(

G

:

0

-

10)

S

u

n

a

d

nd how

a

y

222 of 229

Appendix 14: Restructuring form

S

i

t

u

a

t

i

o

n

t

h

f

e

S

e

e

t

i

a

(

r

l

i

0

t

n

s

e

-

t

g

1

r

y

s

0

e

o

)

a

n

u

n

g

r

d

t

h

A

t

u

h

t

o

o

u

m

g

h

a

t

t

s

i

c

s

u

p

a

R

t

E

p

u

h

v

o

e

t

o

i

r

o

d

s

u

t

m

t

e

i

g

n

r

n

h

a

u

g

c

t

t

c

e

y

i

s

c

t

o

u

u

r

r

i

n

g

C

S

o

a

c

u

a

g

h

n

t

u

a

h

e

t

t

i

e

o

n

m

o

r

u

s

m

e

t

g

a

v

h

a

y

i

d

t

t

o

i

s

e

u

c

n

r

c

e

A

l

t

e

r

d

n

(

0

a

t

h

-

t

1

i

o

v

0

u

e

0

g

/

%

m

h

t

)

o

s

d

i

f

i

e

f

e

e

s

t

l

S

i

r

n

e

t

a

g

(

n

0

t

s

g

e

-

a

t

1

h

y

n

0

o

d

)

n

u

o

t

r

h

w

e

i

r

223 of 229

Appendix 15: Normal distribution BDI-II, Hamilton and total HADS

Statistics BDI_II_Pre Hamilton_Pre N Valid 153 152 Missing 0 1 Mean 28,7843 16,2763 Median 29,0000 16,0000 Mode 20,00a 13,00 Std. Deviation 8,73509 5,09408 Skewness ,194 ,230 Std. Error of Skewness ,196 ,197 Kurtosis ,138 -,594 Std. Error of Kurtosis ,390 ,391 a. Multiple modes exist. The smallest value is shown Both BDI-II and Hamilton approximate normal distributions similarly well. Also both are slightly positively skewed indicating that the distribution leans to the left of the scale (lower values).

224 of 229

Histogram

225 of 229

Statistics Total1 N Valid 131 Missing 0 Mean 21,6718 Median 22,0000 Mode 22,00 Std. Deviation 6,65460 Skewness -,331 Std. Error of Skewness ,212 Kurtosis ,299 Std. Error of Kurtosis ,420

226 of 229

As indicated by the near equality of the Mean, Median and Mode the distribution approximates a normal distribution well. The distribution does however lean to the right as indicated by negative skewness value.

227 of 229

Appendix 16: New Plan Summary Sheet New Plan Summary Sheet

MY TRIGGERS:

OLD PLAN NEW PLAN

Old responses that contribute to my symptoms New responses that overcome my symptoms

1. Thinking style (e.g.” If I have a 1. Thinking style (e.g..” If I have a negative thought, then I worry about negative thought, then I postpone the future”) worry for a day”)

2. Behaviors 2. Behavoirs

3. Attention focus 3. Attention focus

4. Reframe

Instruction: It is important to be aware of the triggers for your old way of coping, your “old plan”. When you notice a trigger or aspects of your “old plan” in action, you must shift to using your “new plan”, as described above. Under “Reframe”, write a sentence summarizing what you learned about your thoughts.

228 of 229

229 of 229