Psychology Services, Bolton Salford and Trafford Mental Health Trust and Department of Psychology, University of Manchester
Psychology Services, Bolton Salford and Trafford Mental Health Trust
School of Psychiatry and Behavioural Sciences, University of Manchester
Psychology Services, Bolton Salford and Trafford Mental Health Trust
School of Psychiatry and Behavioural Sciences, University of Manchester, Manchester, UK
Correspondence: DrTony Morrison, Department of Psychology, University of Manchester, Coupland Street, Manchester M13 9PL, UK. Fax: +44 (0)161 772 3525; e-mail: tony.morrison{at}psy.man.ac.uk
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To evaluate the efficacy of cognitive therapy for the prevention of transition to psychosis.
Method A randomised controlled trial compared cognitive therapy with treatment as usual in 58 patients at ultra-high riskof developing a first episode of psychosis. Therapy was provided over 6 months, and all patients were monitored on a monthly basis for 12 months.
Results Logistic regression demonstrated that cognitive therapy significantly reduced the likelihood of making progression to psychosis as defined on the Positive and Negative Syndrome Scale over 12 months. In addition, it significantly reduced the likelihood of being prescribed antipsychotic medication and of meeting criteria for a DSMIV diagnosis of a psychotic disorder. Analysis of covariance showed that the intervention also significantly improved positive symptoms of psychosis in this population over the 12-month period
Conclusions Cognitive therapy appears to be an acceptable and efficacious intervention for people at high risk of developing psychosis.
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INTRODUCTION |
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METHOD |
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Entry criteria
Specific state risk factors were operationally defined by the presence of
either transient psychotic symptoms (termed brief limited intermittent
psychotic symptoms BLIPS) or attenuated (subclinical) psychotic
symptoms, both of which were defined using an adaptation of the PACE duration
and severity criteria (Yung et
al, 1996), based on the Positive and Negative Syndrome Scale
(PANSS; Kay & Opler, 1987)
cut-off scores. Transient symptoms are those that score 4 or more on
hallucinations, 4 or more on delusions or 5 or more on conceptual
disorganisation, last less than 1 week and resolve without antipsychotic
medication. Attenuated symptoms are those that score 3 on delusions, 23
on hallucinations, 34 on suspiciousness or 34 on conceptual
disorganisation. Examination of the PANSS and the Brief Psychiatric Rating
Scale (BPRS; Ventura et al,
2000) will confirm that these criteria are analogous to the PACE
criteria.
Trait plus state risk factors are operationally defined by the presence of an atrisk mental state defined for the purposes of this study as scoring for caseness on the General Health Questionnaire (GHQ; Goldberg & Hillier, 1979) and/or a recent deterioration in function of 30 points or more on the Global Assessment of Functioning (GAF; American Psychiatric Association, 1994) plus either a family history, indicated by a first-degree relative with a history of any psychotic disorder, or a diagnosis of schizotypal personality disorder in the participant. This is analogous to the PACE criteria for their trait plus state risk group.
Potential participants below the age of 16 years or above the age of 36 years were considered to be outside the maximum risk period for psychosis and were excluded from the study. Current or past receipt of antipsychotic medication was an exclusion criterion.
Measures
The following measures were used to assess suitability for inclusion in the
study and monitor outcomes. The PANSS is a clinician-administered, 30-item
semi-structured interview consisting of 7 items assessing positive symptoms
(e.g. hallucinations, delusions, conceptual disorganisation), 7 items
assessing negative symptoms (e.g. blunted affect, passive/apathetic social
avoidance) and 16 items assessing global psychopathology (e.g. depression,
anxiety, lack of insight, guilt). All items are scored between 1 (not present)
and 7 (severe). A number of studies have demonstrated the reliability and
validity of this scale (Kay et
al, 1988), which was used to assess both transient and
attenuated symptoms, and was the primary outcome measure used for determining
transition to psychosis. The Structured Clinical Interview for DSMIV
(SCID; American Psychiatric Association,
1994) was used to assess the presence of schizotypal personality
disorder (only the relevant subsection was administered). The 28-item version
of the General Health Questionnaire was used to assess general at-risk mental
state, using a cut-off score of 5 or more to define psychiatric caseness. The
Global Assessment of Functioning is a simple, 100-point measure of
psychological, social and occupational ability designed to be concordant with
DSMIV, and was used to assess functioning. Additional psychological
measures were administered at this baseline assessment and at monthly
monitoring sessions in order to assess cognitive, personality and social
factors, but these are not reported here.
The primary outcome measure was the rate of transition to psychosis, which was operationally defined based on the PACE criteria, using cut-off points on PANSS sub-scales (4 or more on hallucinations, 4 or more on delusions and 5 or more on conceptual disorganisation), the frequency of symptoms (at least several times a week) and their duration (more than 1 week). Secondary outcomes assumed to also represent transition to psychosis were:
These were considered to be valuable additional outcome measures, since some patients will not report psychotic experiences in an interview, but may be viewed as having psychosis by a clinician on the basis of behavioural indices. Scores on the PANSS over the 12 months were also analysed as a dimensional outcome measure of symptomatology.
Study design and intervention
The Early Detection and Intervention Evaluation (EDIE) trial was designed
as a pragmatic, single-masked (rater), randomised controlled trial. Assessors
were intended to be masked to the condition to which the patient was
allocated; however, this proved difficult in practice because the participants
often divulged information about their therapist, or used language that
suggested they were receiving cognitive therapy. The only other treatment
study reported with this population found similar difficulty in maintaining
masking (McGorry et al,
2002), and this is a common difficulty in psychological
intervention trials. Random assignment to the two conditions (monitoring only
or cognitive therapy plus monitoring) was stratified by gender and genetic
risk (whether the participant had a first-degree relative with a psychotic
diagnosis), as these are known to be risk factors within the specified age
range. A clerical worker who was independent of the study removed, at random,
a slip detailing assignment from the appropriate one of four envelopes (male,
family history; male no family history; female, family history; female, no
family history) each of which had 25 therapy and 25 monitoring assignments.
The sequence of randomisation was concealed until treatment had been
allocated; the two groups were of unequal number by chance.
Recruitment and randomisation of participants occurred between 1 December 1999 and 1 April 2002. The randomised participants were monitored at monthly intervals (using the PANSS) for a period of 12 months following initial assessment (therefore monitoring alone consisted of 13 sessions, and was not intended as an attention control or placebo condition). Assessments were conducted by research assistants (L.W., A.K., J.G. and S.P.), and good interrater reliability was established using videotaped interviews.
The local research ethics committees of Salford and Trafford and North, South and Central Manchester (UK) approved the study. Potential participants who gave informed consent following the receipt of a detailed participant information sheet were assessed using the above measures in relation to the entry criteria. If they met these criteria, they were then given the other self-report indicators of risk.
The cognitive therapy intervention was limited to a maximum of 26 sessions over 6 months and followed the principles developed by Beck (1976). It was problem-oriented, time-limited and educational; it encouraged collaborative empiricism, used guided discovery and homework tasks, and was based on a written manual. It was based on the cognitive model most appropriate to the disorder that was prioritised on a problem list agreed between the therapist and the patient. Therefore, if a transient or an attenuated psychotic symptom was prioritised, the case conceptualisations (and subsequent treatment strategies) were based on Morrisons recent integrative model of hallucinations and delusions (Morrison, 2001). This model emphasises the culturally unacceptable interpretations that people with psychosis make for events, in addition to their responses to such events and their beliefs about themselves, other people and control strategies. The central feature of our approach to the prevention of psychosis involved normalising the interpretations that people make, helping them to generate and evaluate alternative explanations, decatastrophising their fears of impending madness and helping them test out such appraisals using behavioural experiments. However, if the problem prioritised was an anxiety disorder (such as panic, social phobia, obsessivecompulsive disorder or generalised anxiety) or depression, then the appropriate models were employed (Beck et al, 1979; Clark, 1986; Clark & Wells, 1995; Wells, 1995; Salkovskis et al, 1998) and a general model of emotional dysfunction was also used (Wells & Matthews, 1994). As these models have many cognitive, affective and behavioural processes and products in common, this helped to aid generalisation across problems and was extremely useful for patients with several presenting problems. A more detailed analysis of the treatment strategies can be found in our treatment manual (French & Morrison, 2004) and a case series with high-risk patients from this study is described elsewhere (French et al, 2003). All treatment and clinical supervision were provided by experienced cognitive therapists (P.F. and A.P.M.), with the exception of one case in which the patient was seen by a trainee clinical psychologist because of a gender preference.
Both monitoring and therapy conditions incorporated elements of case management in order to resolve crises regarding social issues and mental health risks. If a participant developed a full psychosis, urgent referral to a specialist clinical team outside the trial was effected and a record made of the treatment given. Medication was not prescribed as part of the trial protocol.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS for Windows, version
10.1) was used for all statistical analysis. Comparison of the two groups was
by intention to treat (with the exception of the two individuals who
subsequently reported exclusion criteria). Missing data were recorded as
missing, with the exception of transition status, which was conservatively
assumed to be no transition if this information was not
obtainable. Most patients missed at least one monthly monitoring appointment.
The median number of assessments attended was 7 for the monitoring group
(interquartile range (IQR) 6) and 8 (IQR=7) for the therapy group. Some PANSS
interviews were conducted over the telephone (a total of 21), which led to
missing data for observational items on the negative and general sub-scales of
the PANSS. The median number of telephone assessments was 0 (IQR=2, range=3)
for the monitoring group and 0 (IQR=0, range=2) for cognitive therapy. If data
were unavailable at a particular assessment occasion, then it was
conservatively assumed (for both groups) that PANSS-defined transition had not
occurred (medication details were obtained from medical records).
Logistic regression analyses were used to compare occurrence of transition to psychosis between the two groups while controlling for the effects of potential confounding variables (age, gender, family history of psychosis and initial PANSS positive scores); number needed to treat statistics are also reported. Analysis of covariance was used to examine the effects of cognitive therapy on positive psychotic phenomena, since the mean and initial PANSS scores were shown to be normally distributed on the basis of visual inspection and consideration of skewness and kurtosis. Multiple regression analyses were performed on 12-month GHQ and GAF scores.
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RESULTS |
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Outcome measures
The proportion of patients making PANSS-defined transition to psychosis,
receiving antipsychotic medication from an independent clinician and being
rated as meeting criteria for a DSMIV psychotic disorder are shown in
Table 2, and details regarding
entry route, age, gender, probable diagnosis and treatment status of the
relevant participants are shown in Table
3.
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Predictors of transition
All logistic regression analyses used gender and family history of
psychosis as predictor variables, since randomisation was stratified using
these. These analyses also used baseline PANSS positive sub-scale scores
(since the groups differed at baseline) and age as predictor variables (as
continuous variables). Treatment group was represented as a dichotomous
variable in these analyses.
The primary logistic regression analysis was conducted using PANSS-defined transition as the dependent variable. The main effect of cognitive therapy was significant (odds ratio (OR) 0.04, 95% CI 0.010.71; P=0.028). This means that there is a 96% reduction in the odds of making a transition in the cognitive therapy group compared with those who received monitoring alone, after adjustment for age, gender, family history and baseline PANSS score. Summary statistics for the other variables are as follows: family history, OR=0.01, 95% CI 00.02, NS; age, OR=1.15, 95% CI 0.961.38, NS; gender, OR=4.59, 95% CI 0.4250.48, NS; baseline PANSS positive score, OR=1.50, 95% 1.022.20, P=0.039. From the data in Table 2, the number needed to treat to prevent PANSS-defined transition is 6.
A secondary logistic regression was performed using prescription of antipsychotic medication as the dependent variable. The main effect of cognitive therapy was significant (OR=0.06, 95% CI 0.010.57; P=0.014). This means that there is a 94% reduction in the odds of making a transition in the cognitive therapy group compared with those who received monitoring alone, after adjustment for age, gender, family history and baseline PANSS score. Summary statistics for the other variables are as follows: family history, OR=1.28, 95% CI 0.1016.00, NS; age, OR=0.99, 95% CI 0.831.20, NS; gender, OR=0.63, 95% CI 0.057.72; baseline PANSS positive score OR=1.31, 95% CI 0.941.83, NS. From the data in Table 2, the number needed to treat for preventing prescription of antipsychotic medication is 5. Another secondary logistic regression analysis was performed using a DSMIV diagnosis of a psychotic disorder as the dependent variable. Again, the main effect of cognitive therapy was significant (OR=0.04, 95% CI 0.010.57; P=0.019). This means that there is a 96% reduction in the odds of making a transition in the cognitive therapy group compared with those who received monitoring alone, after adjustment for age, gender, family history and baseline PANSS score. Summary statistics for the other variables are as follows: family history, OR=2.18, 95% CI 0.1629.12, NS; age, OR=1.11, 95% CI 0.941.31, NS; gender, OR=4.13, 95% CI 0.3844.40; baseline PANSS positive score, OR=1.42, 95% CI 0.992.03, P=0.052. From the data in Table 2, the number needed to treat for preventing someone from meeting DSMIV criteria for a psychotic disorder is 5.
Effect of therapy on psychotic experiences
In order to examine the effect of cognitive therapy on psychotic
experiences over the monitoring period, an analysis of covariance was
performed using mean PANSS positive symptom score over the 12 monitoring
sessions as the dependent variable. Initial PANSS positive score was used as a
covariate in the analysis. There was a significant effect of group on mean
PANSS positive scores (F(1,48)=4.09, P=0.049),
with cognitive therapy resulting in significantly fewer positive symptoms over
time than treatment as usual. Baseline PANSS positive score was a significant
covariate (F(1,48)=89.74, P=0.001).
Effects of therapy on functioning and distress
In order to examine the effect of cognitive therapy on functioning and
distress, multiple regression analyses were performed using direct entry with
12-month GAF and GHQ scores as dependent variables. Each analysis included
baseline score (GAF or GHQ), age, gender and cognitive therapy as predictor
variables. The multiple regression analysis was not significant for either GHQ
scores (F4,24)=2.54, P=0.066, adjusted
r2=0.18) or GAF scores (F(4,23=2.54,
P=0.067, adjusted r2=0.19). However, it should be
noted that there were many missing 12-month GAF and GHQ scores.
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DISCUSSION |
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Why cognitive therapy?
There are several problems associated with using antipsychotic medication
in an ultra-high-risk group. The risks associated with using pharmacological
interventions with false-positive cases are considerable, adherence to
antipsychotic medication regimens within this group is variable
(McGorry et al, 2002)
and the ethical position has caused some debate. In particular, it has been
suggested (Bentall & Morrison,
2002) that use of antipsychotic medication is problematic because
these drugs have harmful and stigmatising side-effects, their effect on the
developing brain in adolescents is unknown, and because they target psychotic
experiences, which may not be the priority for people at high risk. The ethics
of using cognitive therapy with this client population may, therefore, be less
controversial, especially as our patients are seeking help. We have argued
(Morrison et al,
2002) that such therapy may be well suited to the prevention of
psychosis. Its efficacy as an adjunct to routine treatments has been
demonstrated in acute psychosis (Drury
et al, 1996) and in cases of chronic, persistent
psychotic symptoms (Tarrier et
al, 1998; Sensky et
al, 2000), as well as in relapse prevention
(Gumley et al, 2003)
and emotional disorders (Clark et
al, 1994). Moreover, it is arguably less likely to result in
distressing side-effects than medication. Our results suggest that a specific
psychological intervention that is not usually associated with severe
side-effects will be an effective and acceptable alternative to antipsychotic
medication, particularly as a first line of treatment, for patients at
ultra-high risk of developing psychosis. Indeed, McGorry et al
(2002) suggested that their
general stance is that off-label use of even novel antipsychotic
medications in such patients should not be first-line treatment. It
remains to be seen whether cognitive therapy truly prevents transition to
psychosis, or merely provides a delay in onset (i.e. whether this effect would
continue throughout a longer follow-up period).
Limitations and future directions
The fact that there was a significant effect of cognitive therapy on all
psychosis-related outcome measures, both primary and secondary, suggests that
these findings are likely to be robust. However, our study has methodological
limitations. The sample size was small, and the 12-month transition rate
overall of 12% (excluding the 2 individuals with psychosis at baseline) was
lower than that of 26% in the PACE trial
(McGorry et al,
2002), perhaps owing to lower non-consent rates in this trial. It
proved impossible fully to maintain masking to treatment allocation for
assessment of the primary outcome, as had also been the case in the previous
trial in this population (McGorry et
al, 2002). The method of randomisation, which resulted in
uneven group sizes, was not ideal, but was unbiased, independent and
pragmatic. The exclusion of two participants who, at the first
post-randomisation assessment, reported having been psychotic at the time of
the baseline assessment is another issue, as the study would not have achieved
significant results had they been included in the analyses. However, it would
seem reasonable to exclude such patients when they were unambiguously
reporting that they were effectively unsuitable for inclusion for the trial at
entry, so long as this occurred at a time prior to any treatment. There were
also a number of participants lost to follow-up, and some participants did not
have complete data-sets, owing to the highly mobile nature of this population.
It should also be noted that both the monitoring and the therapy conditions
included elements of case management, such as helping people network with
appropriate services to address social problems such as housing and finances.
It is also difficult to determine whether there is a specific beneficial
effect of cognitive therapy or whether gains are attributable to non-specific
effects of having a therapeutic relationship and regular contact with a mental
health professional; however, as a pragmatic preliminary trial designed to
discover whether an intervention worked at all, these results certainly
support the further investigation of such therapy as a preventive
intervention. Formal indices of treatment integrity were not assessed,
although both therapists had close supervision and had specific
post-qualification training in cognitive therapy.
Future research in this area should attempt to address such issues. This study measured psychotic experiences rather than the distress and disability associated with them as the primary outcome; it would be desirable to measure the latter in future studies, along with service-user-defined outcomes and the occurrence of non-psychotic disorders in this population. Future studies should also attempt to evaluate side-effects and acceptability of treatment in a more formal manner; for example, the risk of stigmatisation that exists with psychological interventions should be monitored. Further research of this kind should also include a 1-month baseline period with reassessment of eligibility, in order to exclude those concealing a psychotic disorder, and, ideally, a control condition that would deliver equivalent contact with a therapist in order to control for non-specific aspects (which might also help to maintain masking).
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication November 28, 2003. Revision received April 16, 2004. Accepted for publication April 23, 2004.
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