اثرات رفتاردرمانی شناختی برای نگرانی بر روی هذیان در بیماران مبتلا به روان پریشی (WIT):یک آزمایش تصادفی کنترل شده موازی، یک سو کور با تجزیه و تحلیل میانجیگری

Treatments for psychotic disorders such as schizophrenia need substantial improvement. Our approach is to study single psychotic experiences such as persecutory delusions, establish a theoretical model, and translate the knowledge gained into treatment. To build the treatment, one putative causal factor is taken at a time, changed, and the effect on the psychotic occurrence examined.1 This approach is called an interventionist-causal model approach.2 In this Article, we report the effects of targeting one causal factor—worry—in patients with persecutory delusions. Worry is an expectation of the worst happening. It consists of repeated negative thoughts about potential adverse outcomes, and is a psychological component of anxiety. Worry brings implausible ideas to mind, keeps them there, and increases the level of distress. Therefore we have postulated that worry is a causal factor in the development and maintenance of persecutory delusions, and have tested this theory in several studies.3, 4, 5, 6, 7, 8 and 9 We showed that levels of worry in patients with persecutory delusions are similar to those noted in generalised anxiety disorder;3 a dose-response association exists between levels of worry and paranoia;4 worry is a predictor of the occurrence and persistence of non-clinical paranoia in the general population5 and 6 and in experimental settings;7 and levels of worry predict the persistence of persecutory delusions.8 and 9 Other study groups are also replicating and extending these findings.10 and 11 We have translated this knowledge into treatment and shown in a pilot trial12 that a brief intervention of worry-reduction added to standard care might lead to reductions in both worry and persecutory delusions. In the terminology of the scientific literature, worry in delusions is a so-called inus condition—“an insufficient but non-redundant part of an unnecessary but sufficient disorder.”13 Persecutory delusions arise from a combination of causes, with each causal factor increasing the probability of such fears occurring. We planned our trial as a rigorous test of these mechanistic links to inform both theory and treatment. A key mechanism (worry) was targeted. The appropriate control condition was a standard care group to establish that the mechanism had been successfully targeted, which would then allow examination of the effects of the mechanism change on the central clinical occurrence (persecutory delusions). We planned an elaborate mediation analysis to substantiate the postulated mechanism of delusion change. The aim of our study was to investigate whether the intervention with cognitive behaviour therapy (CBT) would reduce levels of worry in patients with persecutory delusions and reduce the delusions themselves; the improvements would be maintained at follow-up; and the reduction in worry would mediate changes in persecutory delusions.

Treatments for psychotic disorders such as schizophrenia need substantial improvement. Our approach is to study single psychotic experiences such as persecutory delusions, establish a theoretical model, and translate the knowledge gained into treatment. To build the treatment, one putative causal factor is taken at a time, changed, and the effect on the psychotic occurrence examined.1 This approach is called an interventionist-causal model approach.2 In this Article, we report the effects of targeting one causal factor—worry—in patients with persecutory delusions. Worry is an expectation of the worst happening. It consists of repeated negative thoughts about potential adverse outcomes, and is a psychological component of anxiety. Worry brings implausible ideas to mind, keeps them there, and increases the level of distress. Therefore we have postulated that worry is a causal factor in the development and maintenance of persecutory delusions, and have tested this theory in several studies.3, 4, 5, 6, 7, 8 and 9 We showed that levels of worry in patients with persecutory delusions are similar to those noted in generalised anxiety disorder;3 a dose-response association exists between levels of worry and paranoia;4 worry is a predictor of the occurrence and persistence of non-clinical paranoia in the general population5 and 6 and in experimental settings;7 and levels of worry predict the persistence of persecutory delusions.8 and 9 Other study groups are also replicating and extending these findings.10 and 11 We have translated this knowledge into treatment and shown in a pilot trial12 that a brief intervention of worry-reduction added to standard care might lead to reductions in both worry and persecutory delusions. In the terminology of the scientific literature, worry in delusions is a so-called inus condition—“an insufficient but non-redundant part of an unnecessary but sufficient disorder.”13 Persecutory delusions arise from a combination of causes, with each causal factor increasing the probability of such fears occurring. We planned our trial as a rigorous test of these mechanistic links to inform both theory and treatment. A key mechanism (worry) was targeted. The appropriate control condition was a standard care group to establish that the mechanism had been successfully targeted, which would then allow examination of the effects of the mechanism change on the central clinical occurrence (persecutory delusions). We planned an elaborate mediation analysis to substantiate the postulated mechanism of delusion change. The aim of our study was to investigate whether the intervention with cognitive behaviour therapy (CBT) would reduce levels of worry in patients with persecutory delusions and reduce the delusions themselves; the improvements would be maintained at follow-up; and the reduction in worry would mediate changes in persecutory delusions.

Between Nov 1, 2011, to Sept 9, 2013, with the last assessments completed on March 10, 2014, we assessed 276 participants, of whom 150 were eligible, gave imformed consent, and were randomly assigned to either the CBT intervention group (n=73) or to the control group (n=77; figure 1). As with other studies of persistent psychotic occurrences, both groups had a slightly higher preponderance of men than women, the mean age was around 40 years, most were unemployed, and the main psychiatric diagnosis was schizophrenia. All but nine patients were taking antipsychotic drugs (one in the CBT group, eight in the control group). Most patients had been in contact with mental health services for many years (table 1). Full-size image (33 K) Figure 1. Trial profile PSWQ=Penn State Worry Questionnaire. CBT=cognitive behavioural therapy. Figure options Table 1. Baseline characteristics of the intention-to-treat population CBT intervention group (n=73) Control group (n=77) Age (years) 40·9 (10·5) 42·1 (12·2) Sex Male 42 (58%) 44 (57%) Female 31 (42%) 33 (43%) Ethnic origin White 68 (93%) 69 (89%) Black 1 (1%) 0 (0%) Chinese 0 (0%) 2 (3%) Indian 0 (0%) 3 (4%) Other 4 (6%) 3 (4%) Employment status Unemployed 55 (75%) 51 (66%) Part-time employed 8 (12%) 6 (7%) Full-time employed 3 (4%) 10 (13%) Self employed 1 (1%) 2 (3%) Retired 2 (3%) 6 (8%) Student 1 (1%) 2 (3%) Housewife or husband 3 (4%) 0 (0%) Intelligence quotient 100·3 (19·0) 101·8 (18·2) Diagnosis Schizophrenia 58 (79%) 53 (69%) Schizoaffective disorder 5 (7%) 6 (7%) Delusional disorder 4 (5%) 6 (7%) Psychosis NOS 6 (8%) 12 (16%) Outpatient 71 (97%) 76 (99%) Inpatient 2 (3%) 1 (1%) Inpatient admission in previous 6 months 10 (14%) 8 (10%) Chlorpromazine-equivalent dose of antipsychotic drug (mg/day) 523·2 (394·3) 475·5 (420·6) Time in contact with services <1 year 5 (8%) 7 (9%) 1–5 years 12 (16%) 17 (22%) 6–10 years 16 (22%) 12 (16%) 11–20 years 18 (25%) 26 (34%) >20 years 21 (29%) 15 (19%) Data are n (%) or mean (SD). NOS=not otherwise specified. Table options The mean number of sessions received was 5·5 (SD 1·8); 51 patients attended six sessions. In the interest of flexibility, for a few patients the intervention was provided in seven (n=7) or eight sessions (n=2) during the 8 week period. Two patients attended no therapy sessions. The remainder of the patients attended one (n=5), two (n=1), three (n=1), four (n=3), or five (n=1) sessions. Panel 1 shows patient comments about the intervention. An analysis of the effects of increasing compliance with therapy had been proposed in the published trial protocol14 but, in the event, compliance with the allocated intervention was so high that such an analysis was deemed unnecessary. Panel 1. Patient comments on the intervention Patient 1 “The discussions about preventing worry and reducing worry were extremely helpful to me. It made me see my worry as something real. The breakthrough was that I was able to, with the help of my psychologist, come up with a strategy—that is, when worry [was] gripping me I would say “‘excuse me worry, while I do…’” or “‘excuse me worry, I need to interrupt you because….’” I sometimes worry about people trying to harm me but now I can interrupt my worry and do something else. I challenge myself to do this because I know it works for me.” Patient 2 “I had no confidence in who I was and felt I avoided everyone because of my thoughts and being in company was really frightening. I found the therapy challenging and sometimes very difficult. But it was eye-opening as I didn't realise how much I worried and where the worry was coming from. To see it on paper made it more straightforward and made my life more clear. I do feel that I now try to take time out, whether that's a cup of tea or going to the shops. Just doing things that I actually enjoy doing and building on them as I was so wrapped up in anxiety I was lost. I am more relaxed at certain times of the day where I was once completely stressed. I still find it hard around people but I feel I can still build on the skills you gave me and if it's slightly better, that's good.” Patient 3 “The therapy was very rewarding. There wasn't anything I didn't like. I needed that kind of therapy at the time because if I didn't have that therapy at that time, I wouldn't be here. It was therapeutic talking about things. I listened to what you had to say and wrote down how I felt. I also tried relaxing to the tape and I ignored people when they were horrible to me. It was hard becoming disciplined but we worked as a team, that's what I liked about it. You don't get nowhere in this world if you don't work as a team. I was having a hard time and you was doing your best to stop me having a hard time. That's what I call team work; I couldn't have been able to do it by myself, no way. I thought a lot about what I thought the therapy did—it decreased my worrying but in other ways it built my confidence.” The therapist in Oxford provided the intervention to 37 participants. The two therapists in Southampton provided the intervention to 22 and 14 participants, respectively. The number of trial participants that can be used as controls for each of these three therapists was 37 for Oxford, and 23 and 13 for Southampton. In the sensitivity analyses allowing for therapist effects described in the section on mediation, trial participants were, in effect, stratified by therapist instead of centre. For inter-rater reliability tests, when rater 1 attended 23 assessments with rater 2, their reliability ratings were PSYRATS total ICC=0·99, PANSS total ICC=0·83. Rater 1 attended 18 assessments with rater 3 and their reliability ratings were PSYRATS total ICC=0·98, PANSS total ICC=0·75. When compared with standard care alone, the CBT intervention led to a significant reduction in levels of worry (table 2). The estimated mean difference in PSWQ scores at 8 weeks between the CBT-intervention group and the control group was 6·35 (SE 1·56; 95% CI 3·30–9·40; p<0·001). Persecutory delusions were also reduced in the CBT-intervention group compared with the control group; the estimated mean difference in PSYRATS scores at 8 weeks in the intervention group compared with the standard care group was 2·08 (SE 0·73; 95% CI 0·64–3·51; p=0·005). The mean treatment by follow-up time (8 and 24 weeks) interactions were estimated to be −2·43 PSWQ (SE 1·57; p=0·121) and 0·86 PSYRATS (SE 0·68; p=0·205), suggesting that at 24 weeks, the treatment effects were smaller for PSWQ, but larger for PSYRATS. However, neither of these interactions were significant and the statistical models were refined to estimate treatment effects (ie, differences in average outcome between the two randomised groups) that were assumed to be common to both follow-up times. The resulting treatment-effect estimates were 5·15 (SE 1·35; 95% CI 2·50–7·79; p<0·001; Cohen's d=0·47) and 2·50 (SE 0·65; 95% CI 1·22–3·78; p<0·001; Cohen's d=0·49). No substantial temporal trends in the mediator or the outcome between 8 and 24 weeks were noted, substantially simplifying the statistical models needed for the analysis of the associations between changes in the mediator and the corresponding changes in clinical outcome. Table 2. Primary and secondary outcome measures CBT intervention group Control group n Mean (SD) n Mean (SD) Primary measures Worry (PSWQ) 0 weeks 73 64·8 (8·6) 77 64·5 (9·5) 8 weeks 70 54·8 (10·5) 73 61·0 (12·2) 24 weeks 68 56·1 (9·7) 73 59·8 (11·0) Delusion (PSYRATS-delusion) 0 weeks 73 18·7 (3·0) 77 18·0 (3·0) 8 weeks 70 14·3 (4·8) 73 15·9 (5·1) 24 weeks 68 13·6 (5·6) 72 16·4 (4·8) Secondary measures Delusion distress (PSYRATS-distress) 0 weeks 73 6·4 (1·4) 77 6·5 (1·3) 8 weeks 70 5·1 (1·9) 73 5·8 (2·1) 24 weeks 68 5·0 (2·2) 72 6·1 (1·8) Total symptoms (PANSS) 0 weeks 73 82·0 (13·6) 76 79·0 (13·5) 8 weeks 69 70·7 (12·4) 73 75·3 (16·0) 24 weeks 68 71·5 (15·4) 71 76·3 (16·7) Paranoia (GPTS) 0 weeks 73 115·9 (27·3) 77 110·8 (27·8) 8 weeks 70 90·0 (32·2) 73 102·3 (31·7) 24 weeks 67 92·5 (32·7) 73 105·6 (32·4) Rumination (PTQ) 0 weeks 70 44·3 (9·7) 72 44·9 (9·8) 8 weeks 68 37·7 (9·7) 70 41·0 (11·7) 24 weeks 64 37·3 (10·5) 71 42·7 (10·6) Patient outcomes (CHOICE) 0 weeks 71 49·4 (17·3) 75 49·5 (18·5) 8 weeks 67 64·4 (17·1) 69 51·7 (21·1) 24 weeks 66 61·6 (21·4) 70 52·5 (22·4) Wellbeing (WEMWBS) 0 weeks 73 36·4 (9·6) 77 34·5 (9·2) 8 weeks 68 41·5 (9·1) 73 36·5 (11·3) 24 weeks 67 40·2 (10·8) 73 36·6 (10·5) CBT=cognitive behavioural therapy. PSWQ=Penn State Worry Questionnaire. PSYRATS=Psychotic Symptoms Rating Scale. PANSS=Positive and Negative Syndromes Scale. GPTS=Green et al Paranoid Thoughts Scale. PTQ=Perseverative Thinking Questionnaire. CHOICE=CHoice of Outcome In Cbt for psychosEs. WEMWBS=Warwick-Edinburgh Mental Wellbeing Scale. Table options Significant improvements were noted with the CBT treatment for all the secondary outcome measures. There were no significant treatment by follow-up time interactions (ie, intention-to-treat effects did not significantly differ between 8 weeks and 24 weeks), and therefore treatment estimates common to both follow-ups were made. Compared with standard care alone, CBT intervention reduced mean PSYRATS distress scores (0·85, SE 0·25, p=0·001, Cohen's d=0·41), PANSS psychiatric symptom scores (6·16, SE 1·69, p<0·001, Cohen's d=0·42), paranoia GPTS scores (14·68, SE 4·18, p<0·001, Cohen's d=0·45), and rumination PTQ scores (3·51, SE 1·43, p=0·014, Cohen's d=0·32). We noted improvements in the intervention group versus standard care group in psychological wellbeing WEMWBS scores (2·40, SE 1·11, p=0·03, Cohen's d=0·23) and patient chosen outcomes CHOICE scores (10·45, SE 2·42, p<0·001, Cohen's d=0·52). Treatment effects were not moderated by centre, therapist, level of worry or delusions, intellectual functioning, illicit drug use, illness perceptions, reasoning, or working memory (p>0·05). Figure 2 provides an overview of the mediation analysis. The CBT intervention reduced the worry factor by a mean of 5·66 (SE 1·32, 95% CI 3·08–8·24; p<0·001) and the delusions factor by a mean of 2·33 units (SE 0·64, 95% CI 1·08–3·58; p<0·001). The intervention directly reduced the delusion factor by a mean of 0·80 (SE 0·65, 95% CI −0·70 to 2·07; p=0·214). Each unit reduction in the worry factor produced a 0·27 change in the delusions factor (SE 0·06, 95% CI 0·15–0·39; p<0·001). The estimated indirect (mediated) effect of the intervention on the delusions factor was a reduction of 1·53 (SE 0·49, 95% CI 0·57–2·48; p=0·002). The proportion of the effect of the intervention on outcome (delusions) that is mediated by changes in worry is therefore 1·53/2·33=66%. The structural equation model fitted the data as shown by a χ2 score of 20·03 with 17 degrees of freedom (p=0·273), a root mean square error of approximation of 0·035, and comparative fit index of 0·992. Full-size image (31 K) Figure 2. Mediation analysis Rectangles or squares represent measured variables. Ellipses or circles represent latent variables (including random errors or residuals). Single headed arrows represent predisposing effects; bold arrows represent main ones of interest. Double-headed arrows represent correlations. W8=worry measures at 8 weeks. W24=worry measures at 24 weeks. D8=delusion measures at 8 weeks. D24=delusion measures at 24 weeks. e1 and e2=random residuals (worry). e3 and e4=random residuals (delusions). Figure options One concern about the validity of the estimate of effect of change in worry on change in delusions came from the possibility of confounding arising from differential therapist effects. However, when we used therapist identity as a covariate in the models instead of treatment centre (but not including a worry stratum by therapist interaction), the estimated effect of worry on delusions was unchanged: 0·27 (SE 0·06). The further addition of the therapists by treatment interactions (acknowledging that differences might occur in the effectiveness of the therapists) as covariates produced identical results. The standard care provided for each group was similar between groups (table 3). Data for the number of days in hospital is skewed for the CBT treatment group, because one patient was in hospital for 2 years before entering the trial, although they were discharged 3 months into the trial. Table 3. Standard care provided in the CBT intervention group and the control group CBT intervention group Control group n Mean (SD) n Mean (SD) 6 months before the trial Number of days in hospital 73 7·4 (26·8) 77 2.·8 (9·5) Meetings with psychiatrist 72 2·4 (3·9) 77 2·8 (4·2) Meetings with community psychiatric nurse 72 12·3 (9·9) 76 10·5 (10·1) Meetings with counsellor or therapist 72 1·5 (6·2) 77 1·1 (4·7) Visits to day-care centre 72 0·8 (4·3) 77 1·7 (10·6) GP meetings 73 3·8 (4·8) 77 2·6 (3·2) 6 months during the trial Number of days in hospital 73 3·5 (15·0) 77 0·2 (1·6) Meetings with psychiatrist 65 1·6 (1·9) 71 1·8 (2·2) Meetings with community psychiatric nurse 65 11·2 (11·3) 71 9·2 (13·9) Meetings with counsellor or therapist (outside of the trial) 61 1·0 (3·6) 66 1·1 (3·4) Visits to day-care centre 65 0·4 (2·6) 71 1·0 (6·3) GP meetings 65 2·6 (2·6) 71 2·6 (2·5) Data are n, mean (SD). CBT=cognitive behavioural therapy. GP=general practitioner. Table options Two patients did not give us permission to check medical notes at the end of the trial. No deaths, admissions to secure units, or formal complaints about therapy occurred during the trial. There were six suicide attempts (two in the treatment group, four in the control group) and two serious violent incidents (one in each allocation group). None of the adverse events were related to therapy or the assessments.