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Cognitive–behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias

  • S. Jauhar (a1), P. J. McKenna (a2), J. Radua (a2), E. Fung (a3), R. Salvador (a2) and K. R. Laws (a4)...
Abstract
Background

Cognitive–behavioural therapy (CBT) is considered to be effective for the symptoms of schizophrenia. However, this view is based mainly on meta-analysis, whose findings can be influenced by failure to consider sources of bias.

Aims

To conduct a systematic review and meta-analysis of the effectiveness of CBT for schizophrenic symptoms that includes an examination of potential sources of bias.

Method

Data were pooled from randomised trials providing end-of-study data on overall, positive and negative symptoms. The moderating effects of randomisation, masking of outcome assessments, incompleteness of outcome data and use of a control intervention were examined. Publication bias was also investigated.

Results

Pooled effect sizes were −0.33 (95% CI −0.47 to −0.19) in 34 studies of overall symptoms, −0.25 (95% CI −0.37 to −0.13) in 33 studies of positive symptoms and −0.13 (95% CI −0.25 to −0.01) in 34 studies of negative symptoms. Masking significantly moderated effect size in the meta-analyses of overall symptoms (effect sizes −0.62 (95% CI −0.88 to −0.35) v. −0.15 (95% CI −0.27 to −0.03), P = 0.001) and positive symptoms (effect sizes −0.57 (95% CI −0.76 to −0.39) v. −0.08 (95% CI −0.18 to 0.03), P<0.001). Use of a control intervention did not moderate effect size in any of the analyses. There was no consistent evidence of publication bias across different analyses.

Conclusions

Cognitive–behavioural therapy has a therapeutic effect on schizophrenic symptoms in the ‘small’ range. This reduces further when sources of bias, particularly masking, are controlled for.

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Corresponding author
P. J. McKenna, Benito Menni CASM. Germanes Hospitalàries del Sagrat Cor de Jesús, C/Doctor Antoni Pujades 38-C, 08830 - Sant Boi de Llobregat (BARCELONA), Spain. Email: mckennapeter1@googlemail.com
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Declaration of interest

None.

Footnotes
References
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Cognitive–behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias

  • S. Jauhar (a1), P. J. McKenna (a2), J. Radua (a2), E. Fung (a3), R. Salvador (a2) and K. R. Laws (a4)...
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eLetters

RE: Dose and effect in CBT for schizophrenia

Christian Gold, Principal Researcher, Professor, Uni Research Health, Bergen, Norway
26 April 2015

Many thanks to Jauhar and colleagues for their interesting and throught-provoking review of CBT for schizophrenia (1), and especially for making their data publicly available. Previous discussants (Byrne; McKenna et al.) have commented on the lack of consideration given to ’dose’ (i.e. number of sessions) of CBT. The relation between dose and effect is almost a classic in psychotherapy research (2). It has more recently been shown to be of importance in reviews of other psychosocial therapies (e.g. 3). Together with the obvious plausibility of such a relationship, this seems to be enough reason to examine the dose-effect relation carefully. I used the effect sizes calculated by Jauhar et al. and extracted the number of sessions from the original papers (I was able to do this for 32 of the 52 studies). I then ran a meta-regression (functions metagen and metareg from R package meta) for each of the four outcomes (Figure 1). Most studies used between 10 and 20 sessions, with a few outliers in both directions. The regression lines show little support for an increase of effect with dose. On the contrary, there are tendencies in the opposite direction for all outcomes. The paradoxical observation is that effects seem to be strongest when few sessions were provided (significant for positive symptoms, p = .0005).

Obviously this analysis has a number of limitations: 1. As McKenna et al. noted in their response to the comment by Byrne, participants were not randomised to different doses. 2. Dose is likely confounded with duration (4) and may also be confounded with blindness and control interventions (1). 3. There may be differences between the scheduled and the received dose, and this was not reported consistently in the original papers. 4. Dose data were not independently extracted by two people.

However, I think one can conclude from these analyses that dose is unlikely to have masked a clearer effect in these data. A more detailed re-analysis of this data set may be warranted. In general, the dosage of psychotherapy should be considered carefully in future studies.

References

1.Jauhar S, McKenna PJ, Radua J, Fung E, Salvador R, Laws KR. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. Brit J Psychiat. 2014 Jan;204(1):20-9.

2.Howard KI, Kopta SM, Krause MS, Orlinsky DE. The dose-effect relationship in psychotherapy. Am Psychol. 1986;41(2):159-64.

3.Gold C, Solli HP, Krüger V, Lie SA. Dose-response relationship in music therapy for people with serious mental disorders: systematic review and meta-analysis. Clin Psychol Rev. 2009;29(3):193-207.

4.Gold C. Quantitative psychotherapy outcome research: Methodological issues. In: Gelo OCG, Pritz A, Rieken B, editors. Psychotherapy Research: Foundations, Process, and Outcome. Vienna: Springer; 2015. p. 537-58.
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Conflict of interest: None Declared

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Author Response to Peters

Keith Laws, PhD
09 September 2014

One of the founding principles of meta-analysis is to pool data from as many studies as possible1. Among other benefits this prevents studies being preselected for consideration on arbitrary grounds. It is difficult to imagine anything more arbitrary than restricting a meta-analysis of CBTfor schizophrenia to studies that conform to some notional interpretation of the NICE guideline, as Peters seems to be suggesting, not to mention excluding any that were in Chinese.

Similarly, it would be wrong to exclude studies that used group CBT apriori. Here, though, it is entirely legitimate to examine this issue posthoc, ie to ask whether use of group vs individual CBT significantly moderates effect size. Carrying out this analysis on our data reveals thatthe pooled effect sizes for both types of intervention were closely similar in the meta-analysis of overall symptoms (ES in 7 group studies -0.24 vs -0.23 in 24 individual studies, Q=0.006, p=0.94); for positive symptoms, group CBT had a nonsignificantly smaller effect size than individual CBT (ES in 8 group studies -0.08 vs -0.25 in 23 individual studies, Q=1.73, p=0.19) (across both analyses one study employed both group and individual CBT and three were rated as 'unclear'). This may or may not be considered evidence that group CBT is less effective than individual CBT, but what it does not mean is that inclusion of group studies in our original meta-analyses somehow acted to dilute the pooled estimate - the effect sizes for studies using individual CBT are similar or lower to those we reported for all studies combined (ESs were -0.33 foroverall symptoms and -0.25 for positive symptoms).

With regard to some of the other points raised by Peters, our diagnostic criteria were broad and similar to those used by NICE, Wykes etal and the Cochrane Collaboration. We recognized the possibility that Acceptance and Commitment Therapy might be different from regular CBT and presented an analysis in the article excluding two studies using this2, 3,and another where CBT took the form predominantly of coping skills enhancement4; this did not materially affect the results. She expresses surprise over our decision to exclude studies that specifically targeted hallucinations from the meta-analysis of positive symptoms. As it happens,only three studies of hallucination-directed CBT also reported outcomes for positive symptoms. Adding the data from two of them5, 6 (data cannot be extracted from one study7) to the positive symptoms dataset produces makes no difference to the pooled effect size (ES=-0.25, CI -0.36/-0.13).

Peters argues that there was too much heterogeneity among the resultsto obtain meaningful pooled estimates. In fact, the Cochrane Collaborationarticle she cites8, recommends (i) not pooling data using meta-analysis; or (ii) investigating heterogeneity using subgroup analysis or meta-regression; or (iii) using a random-effects model for meta-analysis as this includes consideration of heterogeneity in the effect size estimate. The authors also note that 'even though a random-effects model helps to consider heterogeneity, it does not remove it - heterogeneity still needs to be considered in interpreting the results'. We used a random effects model and examined heterogeneity.

Finally, we would like to re-iterate that for those who wish to examine for themselves other points of the type raised by Peters, a detailed database of the studies we included is available at (http://www.cbtinschizophrenia.com/).

P. J. McKenna, MB, ChB, MRCPsych and J. Radua, MD, PhD, FIDMAG Germanes Hospitalaries Research Foundation, Barcelona and CIBERSAM, Spain.

K. R. Laws, PhD, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK

S. Jauhar, MB, ChB, BSc(Hons), MRCPsych, Department of Psychosis Studies, Institute of Psychiatry, London, UK.References

1. Hunt N. How science takes stock: the story of meta-analysis. New York: Sage; 1997.2. White R, Gumley A, McTaggart J, et al. A feasibility study of Acceptance and Commitment Therapy for emotional dysfunction following psychosis. Behav Res Ther 2011; 49:901-7.3. Gaudiano BA, Herbert JD. Acute treatment of inpatients with psychotic symptoms using Acceptance and Commitment Therapy: pilot results. Behav ResTher 2006; 44:415-37.4. Leclerc C, Lesage AD, Ricard N, Lecomte T, Cyr M. Assessment of a new rehabilitative coping skills module for persons with schizophrenia. Am J Orthopsychiatry 2000; 70:380-8.5. Penn DL, Meyer PS, Evans E, Wirth RJ, Cai K, Burchinal M. A randomized controlled trial of group cognitive-behavioral therapy vs. enhanced supportive therapy for auditory hallucinations. Schizophr Res 2009; 109:52-9.6. Shawyer F, Farhall J, Mackinnon A, et al. A randomised controlled trialof acceptance-based cognitive behavioural therapy for command hallucinations in psychotic disorders. Behav Res Ther 2012; 50:110-21.7. Trower P, Birchwood M, Meaden A, Byrne S, Nelson A, Ross K. Cognitive therapy for command hallucinations: randomised controlled trial. Br J Psychiatry 2004; 184:312-20.8. Ryan R. Cochrane Consumers and Communication Review Group. Heterogeneity and subgroup analyses in Cochrane Consumers and Communication Review Group reviews: planning the analysis at protocol stage. http://cccrg.cochrane.org, February 2014.

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Conflict of interest: None declared

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Citation Analysis Reveals Disproportionate Emphasis on Positive Claims in Study Abstracts

Marcus R Munafo, Professor of Biological Psychology
19 August 2014

Evidence-based medicine relies on evidence from high-quality randomized trials and observational studies (1). However, meta-analyses, the cornerstone of evidence-based medicine, may be at odds with the prevailing views of the relevant research community. One factor that may contribute to the distortion of an evidence base is selective citation of studies that support (or do not support) a particular treatment. Greenberg(2) showed that citation distortions (such as a bias against citing studies that refute or weaken a particular belief) create an unfounded impression of authority and consensus.

We used a recent meta-analysis of cognitive behavioural therapy in schizophrenia (3) to explore patterns of citations within this literature.Studies included in the meta-analysis (k = 50) were coded according to whether or not they provided support for the intervention (defined as P < 0.05 in the direction of therapeutic benefit). We also coded whether or not the study abstract reported that the study provided support for theintervention, given evidence that abstracts may over-state the findings ofa study (4). Finally, we coded which other studies within the literature (i.e., those included in the meta-analysis) were cited by each individual study. Independent coding was by two authors (DFH and NEJR), and discrepancies resolved by mutual consent.

Our results indicated that abstracts are more likely to report a favourable outcome (42 studies, 84%) compared with the data reported within the meta-analysis (20 studies, 40%). We also observed a clear pattern of citation distortion: studies that claimed support in the abstract received 138 citations (95%), while those that showed support forthe intervention on the basis of the data reported in the meta-analysis received 58 citations (40%). A binomial test indicated that the number of citations to studies with abstracts reporting a favourable outcome was greater than expected (95% of citations from 84% of abstracts, P < 0.001).

These findings could explain discrepancies between the evidence base as indicated by a meta-analysis, and the beliefs held by practitioners andclinicians within the field. While we used data from one specific literature, we have no particular reason to believe that our findings are unique to this literature. Claims from highly cited observational studies have been shown to persist even after strong contradictory evidence from randomized trials (5). Since citation distortions may be driven, in part, by inflated claims in study abstracts, readers should not rely solely on the abstract of an article.

Acknowledgements

MRM is a member of the United Kingdom Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute forHealth Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged.

References

1. Greenhalgh T, Howick J, Maskrey N, Evidence Based Medicine Renaissance G. Evidence based medicine: a movement in crisis? BMJ. 2014; 348: g3725.

2. Greenberg SA. How citation distortions create unfounded authority:analysis of a citation network. BMJ. 2009; 339: b2680.

3. Jauhar S, McKenna PJ, Radua J, Fung E, Salvador R, Laws KR. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. British Journal of Psychiatry. 2014; 204(1): 20-9.

4. Park IU, Peacey MW, Munafo MR. Modelling the effects of subjectiveand objective decision making in scientific peer review. Nature. 2014; 506(7486): 93-6.

5. Tatsioni A, Bonitsis NG, Ioannidis JP. Persistence of contradictedclaims in the literature. Journal of the American Medical Association. 2007; 298(21): 2517-26.

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Conflict of interest: None declared

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Author Response to Birchwood et al and Byrne

Peter J. McKenna, MB, ChB, MRCPsych
20 May 2014

We thank Birchwood et al and Byrne for their comments. Birchwood et al make two points that require clarification. First, their statement thatour findings from studies with high methodological rigour, particularly masking, imply that CBT has small but by no means negligible effects on positive and total symptoms 'broadly in line with the NICE review and particularly that of Wykes et al,' seems to us questionable. Wykes et al1 reported an effect size of 0.37 for positive symptoms, which reduced slightly to 0.31 in masked studies. This latter value was four times larger than the value of 0.08 we found for masked studies of positive symptoms. Ratings of bias were made for the studies included in the 2009 NICE guideline2,3; however, no analyses excluding low quality studies or otherwise examining methodological rigour were actually carried out.

Secondly, Birchwood et al's argument that a finding of significant heterogeneity among studies implies that CBT is effective in certain subgroups of patients is not formally correct. It could simply mean that there are systematic differences in effect size between studies at high and low risk of bias. Tending to support this latter interpretation, in our meta-analysis of positive symptoms there was no significant heterogeneity in either the masked (N=20, ES 0.08, I2 0%, Q=18, p=0.49) orunmasked studies (N= 8, ES 0.57, I2 23% , Q=9, p= 0.24) when they were considered separately. Heterogeneity was also not significant in the masked studies of overall symptoms (N=20, ES 0.15, I2=25%, Q=25, p=0.15), although it remained significant in the unmasked studies (N=10, ES 0.62, I2=71%, Q=31, p<0.001).

Byrne argues that our findings are limited by not considering follow-up data. We presume he is arguing here for a 'delayed action' effect of CBT, as found in the 2000 study of Sensky et al4 and an early meta-analysis by Pilling et al5. However, the meta-analyses carried out for the2009 NICE guideline2 provide only lukewarm support for such a view: the pooled effect sizes for overall symptoms were 0.27, 0.23, 0.40 and 0.19 atend of treatment, 6 months,12 months and 12-18 months follow-up, respectively, when CBT was compared to standard care; they were 0.13 at end of treatment and 0.18 at 12 months when CBT was compared to other active treatments.

Among the other issues raised, whether there is evidence for a dose effect for CBT seems to us essentially imponderable, since none of the 50+published RCTs to date has manipulated dose or duration of the intervention. Such an effect would also likely be difficult to detect using meta-analytic methods, given the many other sources of variation among the existing studies. With respect to whether or not CBT should be considered as a 'quasi-neuroleptic', we simply note that CBT was originally developed for and continues to be promoted as a treatment for positive symptoms.

P. J. McKenna, MB, ChB, MRCPsych and J. Radua, MD, PhD,FIDMAG Germanes Hospital?ries Research Foundation, Barcelona and CIBERSAM,Spain.

S. Jauhar, MB, ChB, BSc(Hons), MRCPsych, Department of Psychosis Studies, Institute of Psychiatry, London, UK.

K. R. Laws, PhD, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK.

References

1. Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapyfor schizophrenia: effect sizes, clinical models, and methodological rigor. Schizophr Bull 2008; 34:523-37.

2. NICE. Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care (update). London: National Institute of Clinical Excellence; 2009.

3. NICE. Schizophrenia (update) Appendix 15c: Psychological therapiesand psychosocial interventions study characteristics tables. London: National Institute of Clinical Excellence; 2009.

4. Sensky T, Turkington D, Kingdon D, et al. A randomized controlled trial of cognitive-behavioral therapy for persistent symptoms in schizophrenia resistant to medication. Arch Gen Psychiatry 2000; 57:165-72.

5. Pilling S, Bebbington P, Kuipers E, et al. Psychological treatments in schizophrenia: I. Meta-analysis of family intervention and cognitive behaviour therapy. Psychol Med 2002; 32:763-82.

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Conflict of interest: None declared

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Jauhar et al: An oversimplification of psychosis, its treatment, and its outcomes?

Emmanuelle Peters, Reader in Clinical Psychology
16 May 2014

This meta-analysis of randomised controlled trials in Cognitive Behaviour Therapy for psychosis (CBTp) is broadly consistent with previousresults(1) ie there is an overall significant but modest impact on psychotic symptoms, with blinded studies showing lower effect sizes than those that are not masked. However, there are a number of problems with this study and especially with its conclusions.

Jauhar et al conclude that they find the Government (including NICE)'s advocacy for CBTp "puzzling", bearing in mind the low effect sizesfound for psychotic symptoms. However I find it puzzling that the authors comment on NICE recommendations, since 1/3rd of the studies included for their overall symptoms analysis (12/34) were not based on therapies recommended by NICE in the first place (based on what we know is effectivefrom the literature so far) ie they were either group or brief CBT studies. Three further studies were in Chinese so their relevance to NICE recommendations is hard to tell.

It is a testament to the far-reaching effects of CBTp that the analyses revealed any effects at all, since the authors looked at outcomeswhich were not always targeted by the therapy. For instance, only a few ofthe 34 studies included for negative symptoms actually targeted such symptoms specifically. Furthermore, severity of positive symptoms/hallucinations was used as the outcome for studies that did not hypothesize changes in psychotic symptoms since the target was on compliance with command hallucinations(2), emotional dysfunction(3), or social functioning(4). In contrast, outcomes on depression, anxiety or distress as a result of psychotic symptoms, and trials targeting self-esteem, post-traumatic symptoms, suicidality, or substance abuse, which are all main and legitimate targets in CBTp, were all excluded.

The criteria for studies to be included in the final analyses were idiosyncratic. Perhaps the most surprising was the decision to exclude studies that targeted hallucinations specifically from their positive symptoms analyses. A separate 'supplementary' meta-analysis was carried out for those studies, with an effect size of .34, which is not reported in the abstract (where only the - lower - .25 effect on positive symptoms is reported). Clinicians familiar with clinical presentations of patients with psychosis may be surprised at their rationale for excluding trials because patients had a dual diagnosis, or had medication-resistant psychotic symptoms but with no further diagnosis specification. None of the follow-up data available was included, meaning that the Sensky et al(5) (non-significant) end of study results contribute to the findings, but the (significant) 9 months and 5 years follow-up results do not(6).

Meta-analyses can be highly informative, but they are highly prone tobias(7). Those with a "washing machine" approach, such as this one (ie amalgamating different populations - from acute inpatients to chronic outpatients, from young people with a first episode of psychosis to older adults; different therapies - from 3 sessions of Acceptance and CommitmentTherapy to 18 months of weekly cognitive therapy; different modalities - groups or individual; different targets - from compliance with command hallucinations to emotional dysfunction), tell us very little about what works for whom. Unsurprisingly the heterogeneity statistics were highly significant for all analyses, with I2 being at 50% or above (ie representing "substantial heterogeneity"), suggesting that there was too much heterogeneity to obtain meaningful pooled estimates, and that the necessary criteria for rendering a meta-analysis appropriate were not met(8).

The field of CBTp has now progressed such that it is no longer appropriate to simply lump together psychosis patients assuming that clinical presentations are the same, that therapy is for the same problem,and that the type of CBT is the same. Other recent meta-analyses, which focus on treatment-resistant patients(9), or on individually tailored, formulation-based CBT for hallucinations and delusions(10), will be more informative to clinicians and researchers about the specific effects of CBTp.

To conclude, the reported analyses reflect an over-simplification of the complexities of psychosis and psychological interventions. The biggestchallenges in psychological therapies trial methodology (and in clinical practice) are the quality/adherence of the therapy delivered and the competence of the therapists, none of which was taken into account in thisstudy. A more meaningful reading of the existing research is that the next steps are to investigate which patients benefit on which outcomes at which stages with which types of therapy, and how to ensure therapist competence (and availability).

Emmanuelle Peters, Reader in Clinical PsychologyDepartment of Psychology, Institute of Psychiatry, Denmark Hill, London SE5 8AF

References

1.Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapyfor schizophrenia: Effect sizes, clinical models, and methodological rigor. Schizophrenia Bulletin. 2008 May;34(3):523-37. PubMed PMID: ISI:000255156500016. English.2.Trower P, Birchwood M, Meaden A, Byrne S, Nelson A, Ross K. Cognitive therapy for command hallucinations: randomised controlled trial. British Journal of Psychiatry. 2004 Apr;184:312-20. PubMed PMID: ISI:000220754200007. English.3.White R, Gumley A, McTaggart J, Rattrie L, McConville D, Cleare S, et al. A feasibility study of Acceptance and Commitment Therapy for emotionaldysfunction following psychosis. Behaviour Research and Therapy. 2011 Dec;49(12):901-7. PubMed PMID: ISI:000297887500010. English.4.Granholm E, McQuaid JR, McClure FS, Auslander LA, Perivoliotis D, Pedrelli P, et al. A randomized, controlled trial of cognitive behavioral social skills training for middle-aged and older outpatients with chronic schizophrenia. Am J Psychiatry. 2005 Mar;162(3):520-9. PubMed PMID: 15741469. Epub 2005/03/03. eng.5.Sensky T, Turkington D, Kingdon D, Scott JL, Scott J, Siddle R, et al. A randomized controlled trial of cognitive-behavioral therapy for persistent symptoms in schizophrenia resistant to medication. Archives of General Psychiatry. 2000 Feb;57(2):165-72. PubMed PMID: ISI:000085086100008. English.6.Turkington D, Sensky T, Scott J, Barnes TRE, Nur U, Siddle R, et al. A randomized controlled trial of cognitive-behavior therapy for persistent symptoms in schizophrenia: A five-year follow-up. Schizophrenia Research. 2008 Jan;98(1-3):1-7. PubMed PMID: ISI:000252494100001. English.7.Murray RM. On collecting meta-analyses of schizophrenia and postage stamps. Psychological Medicine. 2014 21st March 2014.8.Cochrane Consumers and Communication Review Group; Ryan R. Heterogeneity and subgroup analyses in Cochrane Consumers and Communication Review Group reviews: planning the analysis at protocol stage. 2014 February 2014.9.Burns AM, Erickson DH, Brenner CA. Cognitive-Behavioral Therapy for Medication-Resistant Psychosis: A Meta-Analytic Review. Psychiatr Serv. 2014 Apr 1. PubMed PMID: 24686725. Epub 2014/04/02. Eng.10.van der Gaag M, Valmaggia LR, Smit F. The effects of individually tailored formulation-based cognitive behavioural therapy in auditory hallucinations and delusions: A meta-analysis. Schizophrenia Research. 2014 Jun;156(1):30-7. PubMed PMID: 24731619. Epub 2014/04/16. eng.

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Conflict of interest: EP is the Director of the Psychological Interventions Clinic for outpatients with Psychosis (PICuP), South London and Maudsley NHS Foundation Trust. She is a practising Cognitive Behaviour Therapist for psychosis (CBTp), and has conducted randomised controlled trials in CBTp.

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