CBT in clozapine resistant schizophrenia - journal club presentation

1. DR.R.G.ENOCH
MD Psychiatry II Yr
GMKMCH, Salem
Focusing On Clozapine Unresponsive Symptoms Trial

2. • Jan 1, 2013, and May 31, 2015.
• Psychosis Research Unit,
• Greater Manchester Mental Health NHS Foundation Trust,
• Manchester, UK

3. • Introduction
• CBT
• Aim
• Hypothesis
• Methods
• Inclusion & Exclusion criteria
• Procedures
• Statistical analysis
• Results
• Discussion
• Strength and limitations
• Conclusion

4. INTRODUCTION
• Schizophrenia is associated with significant impairment in personal
and social functioning and high economic costs.
• The mortality risk - people with schizophrenia die an average of 14.5
years earlier than those without schizophrenia.
• About 1/3rd
respond poorly to standard treatment with antipsychotic
medication.

5. TREATMENT-RESISTANT SCHIZOPHRENIA
• Treatment-resistant schizophrenia is defined as schizophrenia treated over two periods
with different antipsychotics at an adequate dose for at least 4 weeks, and symptoms are
not reduced by at least 20%.
• At least three treatments with antipsychotics of at least two different chemical classes
with doses equivalent to 1000 mg/d of chlorpromazine for a period of 6 weeks, without
significant relief.

6. • Clozapine is the treatment of choice for treatment-resistant schizophrenia, recommended
in clinical guidelines.
• However, 30–40% of patients show an inadequate response to clozapine.
• Some people cannot tolerate clozapine; serious side-effects include seizures and
agranulocytosis.
• Clozapine-resistant schizophrenia, is defined as inadequate response to treatment at a
stable dose of 400 mg or more per day for at least 12 weeks.
• The most common treatment of clozapine-resistant schizophrenia is augmentation with
another antipsychotic medication.

7. • Benefits of such augmentation is small, and evidence is limited by few, small, low-quality
studies.
• A small study examined the effects of augmentation with ECT in 39 participants, but this
was of short duration (8 weeks) and the study found no significant difference.
• CBT have found mild to moderate effects on psychotic symptoms when delivered in
combination with antipsychotic medications.
• The efficacy of augmentation of clozapine with CBT for clozapine-resistant schizophrenia
is unknown, since only one small unrandomised trial has investigated this.

8. CBT
• Cognitive behavioural therapy (CBT) is a method that aims to reduce psychological
distress and dysfunction by exploring and addressing how the integration of patient’s
thoughts, feelings and behaviours are contributing to the presenting problem.
• ASSUMPTIONS OF CBT:
1)Thinking (cognition) mediates emotions and behaviours;
2)Faulty cognitions lead to psychological distress and dysfunction;
3)Modifications in the faulty cognitions can reduce the psychological distress
• Therefore, CBT seeks to modify and replace existing faulty thoughts and behaviours with
more positive and acceptable ones that will lead to the alleviation of the presenting
problem.

9. • CBT is a combination of behavioural and cognitive therapies.
• Behavioural therapy, through the works of Ivan Pavlov, John Watson, and B.F.
Skinner
• seeks to modify learnt behaviours that are problematic and undesirable and to
replace them with more acceptable positive behaviours, particularly through the
use of consequences and reinforcers.

10. • Cognitive therapy, developed through the works of Albert Ellis and Aaron Beck
• places an emphasis on the patient’s established beliefs about themselves, others and the world
that play in the thought process which sustains problematic situations.
• Cognitive interventions use a style of questioning to probe for peoples’ thoughts and use this to
stimulate alternative ideas. This is called ‘guided discovery’.
• On the basis of these alternatives people carry out behavioural experiments to test out the
accuracy of these alternatives, and then adopt new ways of perceiving and acting.

11. COGNITIVE DISTORTIONS
• They are inaccurate thoughts that reinforce negative thought patterns or emotions.
• These inaccurate thoughts appears to be rational and accurate, but only serve to keep us
feeling bad about ourselves.
• Cognitive distortions are at the core of many cognitive-behavioral and other kinds of
psychotherapy that help a person learn to change
• By learning to correctly identify this kind of “stinking thinking,” a person can then answer
the negative thinking back, and refute (deny or disprove) it.
• By refuting the negative thinking over and over again, it will slowly diminish overtime and
be automatically replaced by more rational, balanced thinking.

12. • These illogical thought patterns are self-defeating, and can cause great anxiety or
depression for the individual.
Arbitrary interference: Drawing conclusions on the basis of insufficient or irrelevant
evidence:
Selective abstraction: Focusing on a single aspect of a situation and ignoring others.
Magnification: exaggerating the importance of undesirable events.
Minimisation: underplaying the significance of an event.
Overgeneralization: drawing broad negative conclusions on the basis of a single
insignificant event.
Personalisation: Attributing the negative feelings of others to yourself.

13. IMPLEMENTATION OF CBT
• The implementation of CBT in practice involves three stages:
assessment, intervention and evaluation.
• Assessment consists of exploring how their thoughts, feelings and behaviours are
contributing to the presenting problem in terms of frequency, intensity and duration.
• The A-B-C model is often used at the assessment stage; it requires to explore
1)the activating event,
2)their belief or attitude in relation to the event; and
3)the consequences as reflected in their behavioural or emotional reactions.

14. Interventions
Role play/skills practice:
•involve role plays of different ways of responding to voices,
•practicing difficult situations such as social interactions,
•trying out different ways of responding.
Generating alternative explanations:
•this involves generating alternative explanations for an event, in addition to the original problematic
appraisal, and considering the emotional consequences of each alternative appraisal.
Survey planning/review:
•They can compare their own experiences or thoughts with others and generate ideas for coping based
on other people’s experiences and opinions.

15. Reducing social isolation/graded activity scheduling:
• Carefully targeted activity scheduling, increasing social contacts and widening social networks can
all be used to directly achieve behavioural goals.
Modifying environment.
Metacognitive strategies
• postponing worry or rumination until a later time.
Attentional strategies : Manipulation of attentional focus can be helpful in increasing choice
and flexibility regarding attentional control and reducing self-consciousness is often useful.
relaxation techniques;
systematic desensitization; and
reinforcement, modelling.

16. CBT in schizophrenia
•In a patient with disturbing auditory hallucinations he believes that the voices must be
true, and he must obey.
•The therapist points out that the voices are just another perceptual manifestation of
automatic thoughts. As such, they are subject to flaws of logic and may be inaccurate and
misguided.
•Patients can then learn to construct rational responses even to terrifying command
hallucinations.

17. • Delusions can also be loosened by cognitive therapy techniques, in a collaborative
therapeutic relationship.
• The therapist neither accepts the patients' delusional beliefs nor confronts them harshly.
Instead, therapist and patient work together to explore the delusional beliefs, including
their etiology, functionality, relation to other themes (schemas) in their life, costs and
benefits, and so on.
• Guided discovery questioning is used to test the reasonability of the delusions, and the
patients are empowered, in that they can arrive at their own conclusions that the
delusional beliefs need to be revised.

18. Key factors influencing the effective delivery of CBT
 Therapeutic relationship – a trusting, safe, therapeutic alliance is essential
 Collaboration
• The therapist brings skills and knowedge of psychological processes, theories of emotion
and techniques that have helped others and could help the current client.
• The client is an expert in their own experience, and brings their own resources.
 Socratic dialogue/ guided discovery – is a style of questioning to both gently probe
for people’s meanings and to stimulate alternative ideas.
 Homework – the client tries things out in between therapy sessions, putting what has
been learned into practice. This is referred to as homework and sometimes includes
behavioural experiments.

19. Previous study

20. AIM
• The Focusing On Clozapine Unresponsive Symptoms (FOCUS) trial aimed to
determine whether CBT is clinically effective for people with clozapine-resistant
schizophrenia.

21. HYPOTHESIS
CBT plus treatment as usual would
•reduce the symptoms of schizophrenia,
•improve quality of life, and
•improve user defined recovery
over a 21-month follow-up period compared with treatment as usual alone

22. STUDY DESIGN AND PARTICIPANTS
• FOCUS was a pragmatic, parallel group, prospective, randomised, trial with masked
evaluation of outcomes, comparing
• CBT plus treatment as usual vs treatment as usual alone in individuals unable to tolerate
clozapine, or whose symptoms did not respond to the drug.
• Participants recruited through inpatient mental health services in five sites in the UK.
• The National Research Ethics Committee approved the FOCUS trial.
METHODS

24. RCT
•A randomized controlled trial is a type of trial which aims to reduce bias when testing a
new treatment.
•The people participating in the trial are randomly allocated to either the group receiving
the treatment under investigation or to a group receiving standard treatment as the control.
•The RCT is often considered the gold standard for a clinical trial.
•RCTs are often used to test the efficacy or effectiveness of various types of medical
intervention and may provide information about adverse effects, such as drug reactions.

25. CLASSIFICATIONS
By study design
From most to least common in the healthcare literature, the major categories of RCT study
designs are:
1.Parallel-group – each participant is randomly assigned to a group, and all the participants
in the group receive (or do not receive) an intervention.
2.Crossover – during the course of the trial, the patients cross over from one treatment to
another
3.Cluster – pre-existing groups of participants (e.g., villages, schools) are randomly selected
to receive (or not receive) an intervention.
4.Factorial – each participant is randomly assigned to a group that receives a particular
combination of interventions (e.g., group 1 receives vitamin X and vitamin Y, group 2
receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4
receives placebo X and placebo Y).

26. By outcome of interest (efficacy vs. effectiveness)
•RCTs can be classified as "explanatory" or "pragmatic."
•Pragmatic trials are designed to evaluate the effectiveness of interventions in real-life
routine practical conditions, whereas
•Explanatory trials aim to test whether an intervention works under optimal situations

27. INCLUSION CRITERIA
(1) persistent symptoms despite an adequate trial of clozapine 400 mg or for at least 12
weeks, or
•if currently augmented with a second antipsychotic that had been given for at least 12
weeks, without remission of psychotic symptoms, or
•discontinuation of clozapine because of adverse reactions or inefficacy in the past 24
months;
(2) presence of at least one psychotic symptom with a severity of
•4 or more (for hallucinations or delusions) or
•5 or more (for suspiciousness or grandiosity) on the PANSS, plus
•a PANSS total score of at least 58, which is equivalent to a clinical global impression of
being at least mildly ill;

28. INCLUSION CRITERIA
(3) in contact with mental health services and have a care coordinator;
(4) meet either ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional
disorder,
(5) aged 16 years or older; and
(6) competent and willing to provide written, informed consent.

29. EXCLUSION CRITERIA
• Alcohol or substance dependence,
• developmental disability,
• non-English speaking, and
• having received CBT within the past 12 months.

30. Randomisation and masking
• Randomisation was done by block randomization (block sizes of four or six)
• Allocation was notified to the trial manager, trial administrator, and trial therapists by email and
to the participant by letter.
• Research assistants assessing outcomes were blinded to allocation to protect against rater bias.
• If a blind break occurred, a new research assistant blinded to allocation was identified for
subsequent follow-up assessments.

32. PROCEDURES
• CBT was delivered by qualified psychologists on an individual basis over a period of 9 months
• 26 hr of treatment on weekly basis over the 9-month treatment window
• with up to four additional booster sessions in the following year.
• treatment targets often included positive symptoms, but also included social issues (eg,
improvement of relationships) and emotional difficulties (eg, anxiety and depression).
• The comparator was treatment as usual, which included care coordination from secondary care
mental health services, including community mental health teams, or inpatient settings.
• All patients received follow-up from a multidisciplinary team.

33. OUTCOMES
• The primary outcome was total PANSS score at 21 months.
• The PANSS is a 30 item rating scale designed to provide a comprehensive assessment of
schizophrenia patients.
• They have used a five factor model of PANSS
• Five components have been reported: positive, negative, emotional distress, excitement,
and disorganisation.
• The PANSS was completed
i. at baseline assessment,
ii.end of treatment (9 months), and
iii.1-year follow-up (21 months).
• PANSS total score at 21 months was selected as the primary outcome because the
durability of any treatment effect observed at the end of treatment was considered the
most important criterion.

36. OUTCOMES
SECONDARY OUTCOME
•the Psychotic Symptom Rating Scales (PSYRATS) to assess dimensions of auditory
hallucinations and delusional beliefs;
•the Personal and Social Performance Scale to assess social functioning;
•the Calgary Depression Rating Scale for Schizophrenia to assess depression; and
•the Clinical Global Impression Scale (CGI) to obtain global illness severity.
•Self-report questionnaires were used to assess self-rated recovery

38. • All serious adverse event—that are unexpected and deemed to be associated with the trial
procedures are recorded.
• Additional unwanted effects of trial participation were defined as more than a 25% increase on
PANSS total score.

39. STATISTICAL ANALYSIS
• Sample was calculated to detect a difference in means between the groups
• Statistical analysis was done after all participants completed 21 months of follow up.
• Continuous variables were summarised using mean (SD) or median (IQR),
Eg. Age - mean , no. of months with illness - median
• discrete variables were reported as absolute number and percentage.
Eg. No. of males, no of females
• The primary outcome was analysed with repeated measures from linear mixed models.

40. LINEAR MIXED MODEL
• It is similar to ANOVA
• This Linear Mixed Models procedure analyzes results from repeated measures designs in
which the outcome (here PANSS) is continuous and measured at fixed time points.
• In other words, if measurements are made repeatedly over time and you want to treat
time as continuous, you can’t do that in Repeated Measures ANOVA.
• Both Repeated Measures ANOVA and Linear Mixed Models assume that the
dependent variable is continuous, and
measured on an interval or ratio scale and that
data are normally distributed.
• Mixed models do a much better job of handling missing data.

41. • Secondary outcomes were analysed with linear mixed models, and adverse events were
analysed with a χ² test or logistic regression.
• All analyses used Stata version 14·0.

42. CHI SQUARE TEST
• It is a non parametric test.
• It is used to measure the differences between what is observed and what is expected
according to a assumed hypothesis.
• For chi square test the data are frequencies rather than number.
• If the difference between observed and expected value is zero there is no significant
difference.
• But if the difference is more there is a significant difference.

43. LOGISTIC REGRESSION
• Logistic regression is a statistical method for analyzing a dataset in which there are one or
more independent variables that determine an outcome.
• The outcome is measured with a dichotomous variable (there are only two possible
outcomes).
• only contains data coded as 1 (TRUE, success, pregnant, etc.) or 0 (FALSE, failure, non-
pregnant, etc.).
• Whether the tumor is malignant (1) or not (0)

44. RESULTS

46. Clinical and demographic data

47. • Baseline clinical and demographic data - the groups were balanced across characteristics.
• Participants assigned to CBT plus treatment as usual received a median of 21 CBT
sessions
• At 9 months, 51 blind breaks had occurred (23 of these patients were transferred to a new
assessor, so 28 remained unblinded).
• By 21 months, there were 55 blind breaks (35 patients were transferred to a new assessor,
so 20 remained unblinded).
• PANSS outcome at baseline by severity based on inclusion criteria showed no difference
between the groups

49. • The NNT offers a measurement of the impact of a therapy by estimating the number of
patients that need to be treated in order to have an impact on one person.
• Lower the NNT the more effective is the treatment

50. • Fewer suicidal crises and symptom exacerbation or outcome deterioration occurred in
the CBT group than in the treatment as usual group, and no differences in reports of
potential unwanted effects of trial participation occurred

51. DISCUSSION
• No effect of CBT on our primary outcome (21-month PANSS total), although there was a
small effect on PANSS total by the end of treatment at 9 months.
• The number needed to treat for a good outcome at 21 months, defined using the
commonly accepted more than 50% PANSS improvement threshold, was 15, which
suggests that CBT can produce lasting outcomes for a proportion of people with
clozapine-resistant schizophrenia.
• The high retention and adherence to treatment clearly show that CBT was highly
acceptable to participants.

52. • Several other small effects on secondary outcomes that are considered to be important
occurred at the end of treatment (PANSS positive symptoms, PANSS emotional distress,
PANSS excitement, and PSYRATS hallucinations) and at follow-up (self-rated recovery,
and CGI improvement), although these average effects are unlikely to be clinically
significant.
• No lasting effect of CBT at 21 months is similar to the observed effects of medications,
which also diminish when treatment ends.
• The observed average reductions in PANSS total score were estimated to be equivalent to
a rating of minimal improvement on the CGI scale.
• Self-rated recovery showed small lasting effects at 21 months, which is important to
service users.

53. STRENGTHS
• A large sample
• Sample is randomised
• the groups were balanced in the clinical and demographic data
• Research assistants are blinded thereby decreasing the chances of rater bias.
• If a blind break occurred, a new research assistant blinded to allocation was identified for
subsequent follow-up assessments.
• All serious adverse event—that are unexpected and deemed to be associated with the trial
procedures are recorded.

54. LIMITATIONS
• The concealment of allocation from participants was not possible.
• Non-specific effects such as contact time and therapeutic relationship could not be
controlled.
• The 26 h of therapy might have been an insufficient length for patients with clozapine-
resistant schizophrenia, who have problems with memory, negative symptoms, and side-
effects of polypharmacy.

55. • A small number of participants met criteria for diagnoses other than schizophrenia (eg,
delusional disorder), which might have reduced the homogeneity of the sample.
• Participants who were unable to tolerate clozapine due to side-effects have also been
included – they are not true resistant to clozapine
• Routine assessment of clozapine blood levels, have not been done
• Although attempts were made to minimise the likelihood of rater bias, this possibility
remains.

56. CONCLUSION
• There was no lasting effect of CBT for clozapine-resistant schizophrenia on our primary outcome of
psychiatric symptoms at 21 months.
• However, CBT was highly acceptable, produced small but significant improvements in psychiatric
symptoms at the end of treatment (9 months) and a lasting improvement on self rated recovery (21
months), with little evidence of adverse effects.
• Our results do not support a recommendation to routinely offer CBT for clozapine-resistant
schizophrenia.
• Can be used as a pragmatic individual trial, particularly in cases where distressing positive
symptoms exist or when patients are reluctant to consider pharmacological augmentation because
of probable side-effect burden.

57. Thank you