Metacognitive therapy in treatment-resistant depression: A platform trial

Behaviour Research and Therapy 50 (2012) 367e373

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Metacognitive therapy in treatment-resistant depression: A platform trialq Adrian Wells a, b, *, Peter Fisher c, Samuel Myers a, Jon Wheatley d, Trishna Patel d, Chris R. Brewin d a

University of Manchester, UK Dept of Psychology, NTNU Trondheim, Norway c University of Liverpool, UK d University College London, UK b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 18 July 2011 Received in revised form 5 January 2012 Accepted 13 February 2012

Patients with treatment-resistant depression received up to 8 sessions of metacognitive therapy (MCT) targeting attentional control, rumination, worry, and metacognitive beliefs. A baseline period was followed by weekly sessions with follow-up assessments at 6 and 12 months post treatment. Large and statistically significant improvements occurred in all symptom measures at post treatment and were maintained over follow-up. Two out of 3 process measures significantly improved at post treatment and all of these measures were improved at follow-up. Treatment was associated with similar response rates on the BDI and Hamilton rating scale. Using liberal criteria 80% of completers were classified as recovered at post treatment and 70% at follow-up on the BDI. In the intention to treat sample 66.6% were recovered at post treatment and 58.3% at follow-up. More stringent criteria showed 60% recovery rates at post treatment and at 12 m. The results suggest that MCT could be a brief and effective treatment and they provide a precedent for more definitive randomized controlled trials. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Depression treatment Metacognitive therapy Metacognition Rumination Treatment-resistant cases

Several treatments: Behavioural Activation, Cognitive Therapy, Interpersonal psychotherapy and problem solving therapy have proven efficacy in depression, producing broadly equivalent outcomes (Cuijpers, van Straten, Andersson, & van Oppen, 2008; Cuijpers, van Straten, & Warmerdam, 2007). Despite this it is increasingly acknowledged that a large proportion of patients fail to respond and approximately 30% relapse following cognitivebehavioural treatment (Dimidjian et al., 2006; Gloaguen, Cottraux, Cucherat, & Balckburn, 1998; Gortner, Gollan, Dobson, & Jacobsen, 1998). Antidepressant medication has a similar and limited efficacy (DeRubeis, Gelfand, Tang, & Simons, 1999; Parker, Crawford, & Hadzi-Pavlovic, 2008). Patients who do not respond to initial treatments and have chronic symptoms provide a good testing-ground for new treatments as they can be viewed as a group in which treatment is more likely to fail. Assessing the within-group effects of treatments can be compounded because the true benefits are over-estimated. This is because studies often do not take account of the short-term course of untreated depression (i.e. spontaneous remission). Posternak and Miller (2001) demonstrated a mean decrease of 10e15% in q This study was supported by Grant No. G0300938 from the UK Medical Research Council (MRC). * Corresponding author. University of Manchester, Academic Division of Clinical Psychology, Rawnsley Building, MRI, Manchester M13 9WL, UK. E-mail addresses: [email protected], [email protected] (A. Wells). 0005-7967/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.brat.2012.02.004

symptoms over a 4e8 week period in a meta-analysis of wait-list control groups and concluded that roughly 20% of subjects assigned to such a control group would be considered a positive response in an antidepressant trial. In light of this we aimed to control for spontaneous remission and other processes by: 1) selecting treatment-resistant cases, and 2) using a baseline period in assessing the effects associated with MCT. There have been several recent attempts to improve outcomes by reducing relapse rates in depression. Researchers have extended cognitive-behavioural therapy with continuation-phases of treatment (Jarrett et al., 2001) and with adjunctive mindfulness meditation techniques (Teasdale et al., 2000) with positive results. An alternative approach focuses on improving the acute-phase of treatment. One way to do so is to focus treatment on potential causal factors such as metacognition and mental control (Wells et al., 2009), rumination (Watkins et al., 2011) or intrusive mental imagery (Brewin et al., 2009). The present study focused on rumination and metacognition, both of which are central targets in metacognitive therapy. Metacognitive therapy (Wells, 2000, 2009) is based on the metacognitive model of psychological disorder (Wells & Matthews, 1994, 1996). Wells and Matthews proposed that negative beliefs, thoughts and emotional symptoms are common, normal and usually transient experiences. However, they persist because vulnerable individuals activate a specific pattern of thinking called the Cognitive Attentional Syndrome (CAS). The CAS consists of chains of verbal

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processing in the form of rumination and worry, a pattern of attention called ‘threat-monitoring’, and other coping and selfregulatory behaviours that have ironic effects on emotion regulation. The problem with these responses is that they extend negative thinking, lead to reduced attentional flexibility and a failure to exercise appropriate control over negative affective experience. The model assigns importance to metacognitive beliefs in generating this style of responding. Two domains are important; these are: 1) positive and 2)negative metacognitive beliefs. Positive beliefs concern the usefulness of rumination, worry, threat monitoring and coping strategies. Examples include: “Focusing on how I feel will help me know when I’m better; Analysing the causes of my sadness will give me the answer to my problem; It is better to be pessimistic than to be disappointed; Thinking the worst will make me snap out of it; Sleeping more will sort out my mind.” In addition, a powerful role is played by negative metacognition. This specifically consists of diminished meta-awareness of the extent of rumination and also metacognitive beliefs concerning the uncontrollability of rumination and the meaning of depression. Examples include the following: “I can’t control my thinking; My thoughts are caused by chemicals in my brain; Thinking like this means I’m mentally defective.” In each case positive and negative metacognitions prevent the individual from developing appropriate metacognitive awareness and using flexible metacognitive control to interrupt the CAS. Positive beliefs support the repeated use of extended negative thinking and unhelpful coping whilst the negative metacognitions prevent the person interrupting the process when it has begun. Beliefs about the dangers of sadness or the ‘biological’ causes of depression add an extra layer of worry and hypervigilance and a sense of lack of personal influence over symptoms. The depressed patient fails to see rumination and other features of the CAS as part of the problem because they consider these factors as the way to find a solution. As a result the depressed individual is enmeshed in extended self-directed negative thinking and ineffective control in response to negative thoughts and inner events when the solution is to switch-off this thinking pattern. Significant support exists for a causal role of rumination in depression. It has negative consequences for affective and cognitive regulation and adaptation in low mood and stress (NolenHoeksema, 1991; Nolen-Hoeksema & Morrow, 1991; NolenHoeksema, Morrow, & Fredrickson, 1993). These relationships have been observed in large scale longitudinal studies and in experimental manipulations of rumination supporting a causal effect (e.g. Nolen-Hoeksema, Stice, & Wade, 2007). Such studies of rumination are consistent with the metacognitive model and with other accounts of elevated rumination in depression such as the control theory approach (Martin & Tesser, 1989) and response styles theory (Nolen-Hoeksema, 1991). However, these approaches differ in their account of the causes of rumination. For example, Nolen-Hoeksema sees rumination as triggered by negative affect whilst others see it as resulting from a discrepancy between a current state and desired state (e.g. Martin & Tesser, 1989). Whilst several theories see rumination as a coping strategy, there are different views over whether rumination is adaptive or maladaptive. Martin and Tesser (1989) argue it is generally adaptive, Watkins (2008) distinguishes between adaptive and maladaptive forms, whilst in the metacognitive model (Wells & Matthews,1994) and in Nolen-Hoeksema’s (1991) account it is maladaptive. The principle differences between the Wells and Matthews model and these other approaches are that in the former: (1) rumination is seen as a broader coping strategy. Whilst it is aimed at finding the causes and solution to negative mood it is not restricted to this goal and is used to resolve other problems such as analysing past failures and mistakes; (2) the maintenance of rumination is driven by metacognition and not by mood or events; (3) disorder is seen as a problem of ‘over thinking’

with deleterious effects no matter what focus rumination takes (thus no distinction is made between good and bad content of rumination); (4) rumination is part of a wider syndrome or cognitive style (CAS) involving worry, threat monitoring and withdrawal of effortful resources that contribute to depression. There is growing empirical support for the metacognitive model. Specifically, Negative and positive metacognitive beliefs are positively associated with state and trait depression (Papageorgiou & Wells, 2001). Structural modelling has demonstrated a reasonable fit between the data and the fully specified metacognitive model in patients and non-patients (Papageorgiou & Wells, 2003; Roleofs et al., 2007). Negative metacognitive beliefs have been shown to prospectively predict depression after controlling for initial levels of depression and rumination in longitudinal studies (Papageorgiou & Wells, 2009). Furthermore, such beliefs appear to predict subsequent depressive and anxious symptoms after controlling for negative life events in longitudinal studies (e.g. Yilmaz, Gencoz, & Wells, 2011). Whilst longitudinal data are consistent with a causal effect of metacognition on depression symptoms much of the research to date has been cross-sectional and experimental manipulations of metacognition are required to provide definitive evidence of metacognitive causality. Metacognitive therapy (MCT) for depression aims to remove the CAS and modify metacognitive beliefs. It does not focus on challenging the content of schemas or negative thoughts which is central to cognitive-behaviour therapy. Four studies have examined the effects associated with therapy or one of its techniques: Attention Training (ATT: Wells, 1990) in depression. Attention training is a technique that encourages external flexible attention to be practised independently of the occurrence of internal or external events thus enhancing executive control and choice over extended processing. Papageorgiou and Wells (2000) demonstrated significant improvements in symptoms in patients suffering from recurrent major depression when treated with ATT alone. Siegle, Ghinassi, and Thase (2007) used an augmented version of ATT as an adjunct to medication and found that this treatment was superior to antidepressant medication alone. A subgroup of 6 patients were scanned using fMRI and the ATT augmented treatment appeared to be associated with reduction in right Amygdala activity under exposure to emotional stimuli. Nordahl (2009) compared a transdiagnostic version of MCT with treatment as usual (CBT) in a heterogenous sample of mixed anxiety-depression patients. MCT was as effective as CBT in improving mood and more effective at reducing anxiety and worry but the study lacked follow-up. Wells et al. (2009) conducted a multiple baseline study of MCT in a series of 4 patients with a primary diagnosis of recurrent and persistent major depressive disorder. All patients showed substantial reductions in depression, metacognition, and rumination scores over 6e8 treatment sessions. Gains appeared to be maintained over 6 month follow-up. These studies provide preliminary evidence of positive therapeutic gains associated with treatment, however the sample sizes were small and the results would be more compelling if they could be observed in patients who have not responded to other treatments. With this in mind the present study had three objectives; (1) Examine the effects associated with metacognitive therapy in treatment-resistant depression. (2) Partial-out effects of time (spontaneous remission), repeated testing, and regression to the mean in estimating treatmentassociated effects. (3) Examine change at 6 and 12 months following treatment It was hypothesised that a brief course of MCT would be associated with significant recovery rates in patients who had

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previously been unresponsive to an initial trial of antidepressant medication. Method Design This study employed a single sample of individuals all of whom received MCT and each acted as their own control. Each patient completed a baseline period ranging from 3 to 6 weeks before treatment commenced. Symptoms were measured at the beginning and end of this phase. The introduction of the baseline phase enabled us to examine the possible impact of expectancies, timebased symptom fluctuation, spontaneous improvement, regression to the mean and repeated testing on outcome scores and make any necessary adjustments in computing the effects following treatment. Note that the design of this study was not intended to be a multiple baseline replication series, such as that reported previously (Wells et al., 2009) but was an open-trial with adjustments for non-specific effects facilitated by a two-point baseline assessment period. Participants Patients were drawn from two clinical psychology waiting lists comprised of referrals from psychiatrists and general practitioners. In addition the study entry criteria were circulated to three general practice clinics calling for potential clients to be referred. There are several criteria that have been used to define treatment resistance ranging from non-response to one antidepressant to non-response to two or more (Berlim & Turecki, 2007). In this study we defined treatment resistance as failure to respond to at least a minimum dose of antidepressant medication as specified in the British National Formulary (BNF 54, BMA, 2007) when taken continuously for a minimum period of the last 6 months in the current episode. In addition it transpired that all patients had not responded to an earlier psychosocial treatment but this was not set as an initial criterion. Thus, all of the patients in this trial had not responded to a psychological treatment in the past and to an antidepressant more recently. Inclusion criteria were as follows: (1) primary diagnosis of a major ‘depressive episode’, (2) aged 18e65 years, (3) absence of borderline personality disorder, (4) not receiving current psychological treatment, (5) no cognitive-behavioural therapy in the 12 months preceding referral but earlier treatments were allowed (6) no evidence of psychotic or organic illness and/or a medical condition underlying depression, (7) stable on antidepressant medication at a recommended dose for at least 6 months, (8) not actively suicidal but suicidal ideation was allowed, (9) no current substance abuse. Suicidality was assessed at initial assessment by asking patients if they had any suicidal thoughts (the majority did), if they had made any plans and if they thought they would act on their thoughts. Patients who responded affirmatively to the last two questions were excluded. We excluded patients who had received psychological treatment in the past 12 months because of the potential risk of carryover or delayed treatment effects or interactions between previous treatments and the components of MCT. Any of these factors could obscure the interpretation of effects associated with the new treatment. Eighty-six patients were identified as potentially eligible. Of these 63 were excluded because they failed to meet study criteria or declined to participate and 23 met study criteria. Eleven of these patients did not enter treatment for the following reasons (3 failed

369

to attend during the baseline period, 2 opted out of the study, 4 patients improved during baseline, 1 patient became suicidal during baseline and 1 patient started psychological treatment elsewhere). Twelve patients met study criteria and entered the trial. Of these 11 were female and 1 of them was male. Ages ranged from 20 to 53 years (M ¼ 34.5, SD ¼ 11.7). The duration of the current depressive episode ranged from 4 to 108 months (M ¼ 28.4, SD ¼ 31.6) and the number of episodes of depression ranged from 1 to 9. Only three patients had experienced 1 episode, one patient 2 episodes, 6 patients reported 3e9 episodes and two patients were unable to state how many they had experienced. Three patients had only one diagnosis of major depression, whilst the rest had more than one diagnosis. Four had one additional diagnosis (GAD ¼ 2, panic with agoraphobia ¼ 1, sub-clinical OCD ¼ 1). Five patients had two additional diagnoses (GAD and sub-clinical PTSD ¼ 1, Avoidant personality and obsessive compulsive personality ¼ 1, social phobia and panic with agoraphobia ¼ 1, social phobia and GAD ¼ 1, agoraphobia without panic and GAD ¼ 1). All patients had received previous psychological treatments. Seven described this as counselling and 5 stated that they had been treated by a clinical psychologist. The predominant mode of treatment had included cognitive-behavioural techniques. Patients were currently taking antidepressant medication prescribed by their psychiatrist or GP as follows: Citalopram ¼ 4 (20e60 mg), Fluoxetine ¼ 3 (20e40 mg), Venlafaxine ¼ 2 (150 mg), Paroxetine ¼ 1 (20 mg), Amitriptaline ¼ 1 (75 mg), Sertraline ¼ 1 (50 mg). All had been stable on their medication for at least 6 months and they all reported minimal to no benefit from taking it. Of the sample, 5 were students, 6 were in employment and 1 was retired due to ill-health. Five were single, 4 were married, 1 was divorced and 1 was widowed. One patient had missing data on marital status. Primary and secondary measures A battery of measures was administered at the beginning of baseline, end of baseline, end of treatment and at 6 and 12 months follow-up. The primary symptom outcome measures were as follows: Hamilton Rating Scale for Depression-17 (HRSD-17, Hamilton, 1960, 1967). This is a widely used clinician-rated measure assessing the severity of depressive symptoms over the past week. Scores range from 0 to 52 with higher scores indicating greater depressive symptom severity. Beck Depression Inventory (BDI: Beck, Ward, Mendelson, Mock, & Erbaugh, 1961). This is a 21-item self-report scale assessing current level of depression. It yields a maximum total score of 63. Beck Anxiety Inventory (BAI: Beck, Epstein, Brown, & Steer, 1988). The BAI is a 21-item self-report scale designed to assess the severity of somatic and cognitive symptoms over the previous week. Scores range from 0 to 63. In addition several secondary measures of underlying psychological processes were also used: Rumination Response Scale (RRS: Nolen-Hoeksema & Morrow, 1991). The RRS is a 22-item self-report scale assessing the tendency to ruminate in response to a depressed mood. Positive Beliefs about Rumination Scale (PBRS: Papageorgiou & Wells, 2001). This is a 9-item self-report scale that assesses metacognitive beliefs about the value or usefulness of rumination. Items tap beliefs such as: “I need to ruminate about my problems in order to find answers to my depression.” Scores range from 9 to 36 with higher scores representing greater conviction in metacognitive beliefs. Negative Beliefs about Rumination Scale (NBRS: Papageorgiou, Wells, & Meina, unpublished data). The NBRS is a 13-item selfreport scale designed to assess negative beliefs concerning the

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uncontrollability and harmfulness of rumination (e.g. “Ruminating about my problems is uncontrollable”). Total scale scores range can from 13 to 52. Metacognitions Questionnaire-30 (MCQ-30: Wells & Cartwright-Hatton, 2004). These self-report measures assess five dimensions of metacognition on separate subscales: (1) positive beliefs about worry; (2) negative beliefs about thoughts relating to uncontrollability and danger, (3) cognitive confidence, (4) beliefs about the need to control thoughts, (5) cognitive selfconsciousness. For purposes of the present analysis we were interested in the uncontrollability and danger subscale. Procedure Assessment All patients were referred to clinical psychology services by their general practitioner or psychiatrist. Each patient was initially assessed separately by two clinicians using the Structured Clinical Interview for DSM-IV (First et al, 1997) and details were checked against the study inclusion/exclusion criteria. There was diagnostic agreement on all entering the trial. Patients meeting inclusion criteria gave consent for the study and the battery of measures was administered. They then waited 3e6 weeks before commencing treatment. At the end of this baseline period they completed the measures again before treatment began. The BDI and BAI were completed at each treatment session as a guide to the therapist of treatment progress. The full battery of measures was completed at post treatment and again at 6 and 12 month follow-up. The SCID and HRSD-17 were administered at pre treatment, post treatment and follow-up by AW, whilst PF acted as therapist for each of the cases. Treatment Metacognitive Therapy (MCT) consisted of a maximum of 8 weekly sessions of 40e60 min duration. Treatment could be terminated before session 8 if patient and therapist agreed that depression symptoms were no longer a problem over the last two sessions (including the present one). The treatment followed a manual and session treatment plans (Wells, 2009). In the first session a case formulation was constructed with the patient based on the metacognitive model of depression. Socialisation and engagement of the client followed in which the therapist helped the client to see how rumination and unhelpful coping strategies such as scanning for negative symptoms and reduced activity maintained depression. In the first treatment session Attention Training (ATT) was practised. This is an auditory attention monitoring exercise lasting approximately 12 min. The patient is asked to pay attention to different sounds presented at different locations and treat any internal events as “additional noise”. The rationale given for this technique was that it would help to regain awareness of control of thinking and experience how thinking and action are separate from negative thoughts and feelings. At the end of this session homework was agreed which consisted of practising ATT at least twice per day. ATT was practised at each subsequent treatment session. In the second session ATT homework was reviewed and any problems that had emerged were resolved. Most patients practised ATT several times during the week. Some had found that they had difficulty concentrating on the task because they had ruminated whilst practising. This was carefully examined by the therapist and used as an opportunity to explore faulty expectations concerning mental control and thinking. Specifically, metacognitive beliefs about the value of rumination or the uncontrollability of the process were explored and the therapist began to challenge them.

Initially, verbal methods were used to weaken beliefs that rumination was uncontrollable. This was then followed by training patients in detached mindfulness (DM). DM is not meditation but a specific way of relating to negative thoughts that act as the trigger for chains of rumination and withdrawal. First a distinction is made between a negative thought ‘trigger’ and the subsequent response to it, which usually entails extended negative thinking and behavioural and energetic withdrawal. The therapist explores with the patient if they have ever chosen to react to a negative thought in a different way, by giving up their usual response of rumination, self-analysis, dwelling on feelings, analysing the past or reduced activity. Once this distinction was understood, the therapist illustrated the concept of DM, which consists of standing back from a negative thought and not responding to it. Several strategies were used in session to convey this experience. The therapist also introduced the idea that rumination and analysing symptoms and experiences must be contained and asked the patient to set aside a rumination time of approximately 15 min that could be used for this activity if necessary each day. Emphasis was given that this period was not mandatory and that in most instances patients decide that rumination is unnecessary when the time arrives. Rumination postponement was presented as an experiment to challenge the metacognitive belief that rumination is uncontrollable. For homework, the patient was asked to continue practising ATT and to respond to negative thought triggers with detached mindfulness and rumination postponement. In sessions 3e5 the therapist focused explicitly on negative beliefs about the uncontrollability of rumination and aimed to reduce this belief to zero per cent. Similarly beliefs about the meaning and nature of depression were examined. Beliefs concerning the unremitting and biological nature of depression were challenged as these interfere with change when the patient believes that their ‘illness’ is intractable and outside of their influence. Positive beliefs concerning the advantages of rumination were challenged using verbal techniques and behavioural experiments when the negative beliefs had been dealt with. The final treatment sessions focused on examining residual levels of rumination and maladaptive coping, and on any remaining metacognitive beliefs that needed to be challenged. Fear of recurrence, which includes excessive monitoring for symptoms of mood change were identified and modified. Relapse prevention in the final session consisted of writing out a therapy blue-print containing a summary of the material covered in treatment and using a ‘plan A versus plan B’ worksheet to consolidate a new response style to negative thoughts to replace the old rumination and problematic coping style. Results Of the 12 patients entering treatment 10 completed, yielding an 83 per cent completion rate suggesting that the treatment was acceptable and engagement issues were not a significant problem. The two patients who dropped out did so after receiving 4 and 5 sessions of treatment respectively. No reason was given for discontinuation. Thus, the range of treatment sessions delivered was 4e8 (including drop-outs), but this was 5e8 amongst completers (mean ¼ 6.5). The analysis of data was conducted on an intention to treat basis (ITT, n ¼ 12) and where appropriate separate outcomes for treatment completers (n ¼ 10) is also presented. For purposes of ITT analyses the last observation carried forward (LOCF) method was used to complete the data-set. Means and standard deviations for outcome measures administered at each stage of the trial are presented in Table 1. These data

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Table 1 Means and standard deviations (in parentheses) for the primary outcome and secondary measures: intention to treat sample (n ¼ 12). Measure

Start of baseline

End of baseline

Post treatment

Six month follow-up

One year follow-up

F (df)

BDI HRSD-17 BAI RRS PBRS NBRS MCQ-neg

30.42 24.16 19.75 61.67 23.75 29.67 17.67

27.42 (8.60) 22.83 (6.75) 15.25 (11.21) 61.58 (9.86) 24.25 (6.43) 28.83(8.68) 17.33 (2.99)

11.67 8.00 7.42 42.79 13.04 20.21 10.46

12.25 7.92 7.91 40.88 13.21 19.46 10.13

12.17 8.50 7.75 41.21 13.38 18.88 10.04

27.08 29.65 10.73 19.29 26.84 10.31 20.06

(5.21) (3.99) (10.81) (11.00) (7.33) (7.68) (3.77)

(11.54) (9.25) (10.39) (18.11) (7.98) (9.31) (5.68)

show that at baseline the mean BDI score indicated severe levels of depression for the group as a whole. Baseline change Initially paired samples t-tests were computed to examine changes in symptom levels occurring during baseline. Table 1 shows that mean BDI score decreased slightly across baseline. A similar decrease was observed with the HRSD-17 and BAI. Rumination and metacognition scores remained relatively unchanged. Only one of the changes was statistically significant and that was the BAI (t(11) ¼ 2.38, p ¼ .04), but this did not remain significant following Bonferroni correction. Effects following treatment Repeated measures ANOVA’s were run on each of the outcome variables across pre treatment, post treatment, six months and 12 months. The pre-treatment scores used in the analyses were the end of baseline scores to reduce any additive effect of changes resulting from non-treatment related factors. In each case the assumption of sphericity was violated and therefore Huyn Feldt correction was applied. There was a significant effect of time for all outcome variables. Follow-up pair-wise comparisons (repeated measures t-tests) with Bonferroni correction (p ¼ .002) demonstrated significant differences between pre-treatment scores and all post treatment and follow-up scores, and no difference between post treatment and any follow-up scores on 5 out of 6 measures. The exception was the NBRS which showed a non-significant effect across the study after Bonferroni correction. But a similar measure, MCQ negative beliefs about uncontrollability and danger showed significant differences between pre treatment and post treatment and follow-up. Summary statistics for each of the outcome variables are presented in Table 1. Preepost treatment effect sizes (ES) Treatment effect sizes (Cohen’s d) were calculated using the formula:

d ¼

M1  M2 SD pooled

The ES was computed separately for the completers (n ¼ 10) and the intention to treat sample (n ¼ 12). It was computed once using the initial baseline score and again using the end of baseline score. We did this to determine the extent to which these methods would yield differences and to offer some control of non-treatment related effects. The ES are presented in Table 2. For each outcome variable the ES were very large in both the completer and the ITT samples. It is noteworthy that there are substantial differences in magnitude between the primary symptom ES computed using the first baseline compared with the end of baseline measures. These differences may reflect the

(12.18) (9.57) (10.45) (18.48) (7.91) (9.77) (5.90)

(11.16) (9.06) (10.26) (19.36) (7.92) (9.69) (5.96)

(2.08, 22.83) p < .0005 (1.17, 12.86) p < .0005 (1.81, 19.98) p ¼ .0001 (2.35, 25.86) p < .0005 (1.06, 11.70 p < .0005 (1.46,16.10) p ¼ .003 (1.36, 14.98) p < .0005

inclusion of non-specific effects in the analysis using initial baseline data and therefore interpretation of treatment effects should be confined to the first column in the table. It should be noted that within-treatment effect sizes reported in other studies may be inflated because of a failure to separate effects occurring due to time or failure to control for repeated measurement. Therefore comparison with other studies reporting within-subject effect sizes for purposes of subsequent sample size estimates should do so with reference to the second and fourth column of Table 2. Clinical significance outcomes There is no single method of determining the clinical significance of treatment outcomes. We used three complimentary methods of determination, each of which has advantages over the others. First we used Jacobson criteria (Jacobson, Roberts, Berns, & McGlinchey, 1999) and the cut-off point (14) and reliable change index (8.46) obtained for the BDI by Seggar, Lambert, and Hansen (2002). The results of this analysis are summarised in Table 3. For the completers 80% were classified as recovered at post treatment and this was 70% at 12 m follow-up. For the ITT sample these proportions were 66.6% and 58.3% respectively. A more stringent method of defining recovery is a two-fold criterion whereby patients must no longer meet diagnostic criteria and score  8 on the BDI (Frank et al., 1991). Patients are therefore defined as only improved if they no longer meet diagnostic criteria, but have BDI scores > 8. This criterion showed 60% of completers could be classified as recovered with a further 30% improved at post treatment. At follow-up it yielded 70% recovered at 6 m (20% improved) and 60% recovered at 12 m (30% improved). A commonly used criterion for establishing remission is a score of 7 on the HRSD-17 (Rush et al., 2006). The ACNP task force specify 3 consecutive weeks meeting this criterion to define remission. Although we do not have 3 consecutive weekly measures taken using the HRSD-17, we can apply the cut-off more permissively to our end of treatment, 6 and 12 month follow-up assessments. Thus, what proportion of patients had three scores at or below this cut-off across post treatment and follow-up? Nine patients met this criterion (90% completers, 75% ITT) and might therefore be classified as in remission. Table 2 Pre to post treatment effects sizes.

BDI HRSD-17 BAI RRS PBRS NBRS MCQ-neg

Intention to treat (n ¼ 12)

Completers (n ¼ 10)

End of baseline to post treatment

Initial baseline to post treatment

End of baseline to post treatment

Initial baseline to post treatment

1.55 1.83 0.72 1.29 1.55 0.96 1.51

2.09 2.32 1.16 1.26 1.40 1.11 1.53

1.65 2.72 0.79 1.54 2.24 1.08 1.87

2.29 3.91 1.24 1.58 2.10 1.26 1.79

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Table 3 Clinical significance outcomes (Jacobson criteria using Seggar et al., 2002; standardised recovery criteria; cut-off point ¼ 14, reliable change index ¼ 8.46 on the BDI). Post treatment

ITT (n ¼ 12) Comp (n ¼ 10)

Six month follow-up

One year follow-up

No change

Improve

Recover

No change

Improve

Recover

No change

Improve

Recover

3 25% 2 20%

1 8% 0 0%

8 67% 8 80%

3 25% 3 30%

2 17% 0 0%

7 58% 7 70%

4 33% 2 20%

1 8% 1 10%

7 58% 7 70%

Note: ITT: intention to treat sample; Comp: treatment completers.

Rush et al. (2006) define recovery as 4 months with a HRSD-17 score of 7 when patients are assessed every two weeks. Applying a more permissive version of this criterion to our three data points spanning post treatment, six months and 12 months follow-up, 8 patients (80% completers, 66.6% ITT) achieved recovery. Antidepressant use Although patients were asked to maintain their medication throughout treatment, 1 patient discontinued use before the final treatment session. Five further patients had discontinued their antidepressants by 12 month follow-up and a further patient had reduced the dose with a view to discontinuation. Thus 70% of completers discontinued or reduced antidepressants at their own behest during the course of the study. Discussion This study examined the effects associated with a brief course of MCT when applied to treatment-resistant depression. The outcomes were encouraging with statistically significant improvements demonstrated in depression symptom measures, rumination and metacognition. The statistically significant treatment gains were sustained over 6 and 12 month follow-up. The clinical significance data show that the treatment was associated with high recovery rates and probably high rates of more stable remission. However, our criteria for remission and recovery, although based on more than one assessment point were widely spaced across time. It is not known if this capitalizes on fluctuation in depressive symptoms or it provides a more conservative test of outcome. The follow-up data do suggest that gains could be stable with the majority of responders retaining their recovery status. The data compare well with the effects found in cognitivebehavioural therapies, where 40e58% of patients recover on the basis of the BDI (e.g. Dimidjian et al., 2006; Gortner et al., 1998). The results are encouraging because the patients in this trial were nonresponsive to antidepressant medication and previous psychological treatments. But we must also exercise caution here; we cannot be sure that they had received an optimal trial of antidepressants or psychological treatment. Although the duration of antidepressants was well above the minimum typically used to define non-response the dosage may not have been adequate in each case. Thus, it may be better to classify the patients as ‘relatively’ treatment resistant rather than absolute. This does not detract from the fact that these patients had long-standing and recurrent depression which has been shown to characterise treatment non-responders (Coffman, Martell, Dimidjian, Gallop, & Hollon, 2007) and the sample meets our objective of attempting a robust test of effects associated with the treatment. The present results are consistent with those of a multiple baseline study of MCT (Wells et al., 2009). That study showed stable gains over 6 month follow-up in a smaller sample of patients. The current findings extend these results by including a larger sample and a longer follow-up period.

The data on rumination and metacognitive beliefs showed that these variables decreased significantly during the course of treatment or follow-up. This provides some support that MCT is associated with change in underlying variables that are considered causal or maintaining factors in depression. However, scales such as the RRS, PBRS and NBRS mention depression and sadness in the items that assess rumination and beliefs about rumination introducing the possible problem of criterion contamination with symptoms. Never the less, the MCQ-30 negative beliefs scale, which improved significantly during treatment, does not assess symptoms, thereby providing some small safeguard against this potential problem. Whilst the current results are promising caution must be exercised in interpreting the findings. The sample size was small and may not represent typical health-seeking clients in an NHS setting. Specifically, 42% of the patients were students, although this is typical of a large student city like Manchester it makes generalisation difficult. There are also significant methodological limitations with no reliability data available for the HRSD and diagnostic assessments. Although we used a baseline period to minimise and partial out any effects of spontaneous recovery, patient expectancies, repeated assessment and regression to the mean, longer baselines with repeated measures may have led to greater control. However, the importance of this baseline is borne out by the fact that 4 of the original patients recruited improved over the baseline period. This monitoring allowed us to exclude these individuals from commencing the trial and therefore we believe our analysis of effects is relatively stringent compared to other studies. With the current design we cannot control for the placebo effect and nonspecific therapy factors such as therapist contact. These are different questions concerning mechanisms of action in treatment and at this stage we were concerned with the question: What are the effects associated with this treatment? These other issues remain to be addressed in subsequent studies. Only one assessor was used and data on reliability is not available, moreover the assessor was not blind to involvement in treatment or the hypotheses of the study which may have led to bias. One therapist delivered treatment which means there is no control of factors such as experience, allegiance and competency. Despite the fact that patients were followed-up for 12 months, longer term outcomes are central in the evaluation of depression treatments. At present we have no data on the longer term outcome of patients who have completed a course of MCT. In conclusion, MCT was associated with large improvements in depressive symptoms after a mean of 6.5 sessions. Treatment gains were largely sustained for 12 months following intervention. However, a randomised controlled trial is essential before we can confidently conclude that there are positive effects of this treatment. References 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, 893e897.

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