S74 Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384

THE MRC COMMAND TRIAL: RESULTS OF A MULTI-CENTRE, RANDOMISED

CONTROLLED TRIAL OF COGNITIVE THERAPY TO PREVENT HARMFUL

COMPLIANCEWITH COMMAND HALLUCINATIONS

Max Birchwood1, Maria Michail2, Alan Meaden3, Shon Lewis4,

Linda Davies5, Graham Dunn5, Til Wykes6, Nick Tarrier6,

Emmanuelle Peters6

1University of Warwick; 2Institute of Mental Health,School of Nursing,

Midwifery & Physiotherapy, Faculty of Medicine & Health Sciences, University

of Nottingham; 3School of Psychology, University of Birmingham, UK;4University of Birmingham, Birmingham, U.K; 5Institute of Population Health,

University of Manchester, Manchester, UK; 6King’s College London, Institute of

Psychiatry, Department of Psychology

Background: Acting on command hallucinations in psychosis can have

serious consequences for self and others and is a major source of clinical

and public concern. There are no evidence-based treatment options to

reduce this risk behaviour. Our new treatment uses cognitive therapy to

challenge the perceived power of voices to inflict harm on the voice hearer

if commands are not followed, thereby motivating compliance.

Methods: COMMAND is a pragmatic, single blind, intention-to-treat, ran-

domized controlled trial comparing Cognitive Therapy for Command Hal-

lucinations (CTCH) + Treatment as Usual (TAU) with TAU alone. Eligible

participants were from UK mental health services reporting command hal-

lucinations for at least 6 months leading to major episodes of harm to self

or others. The primary outcome was harmful compliance and secondary

outcomes: beliefs about voices’ power and related distress; psychotic and

depression symptoms. Outcome was assessed at 9 and 18 months. The trial

was registered under controlled-trials.com (ISRCTN62304114).

Findings: 197 participants were randomly assigned (98 to CTCH+TAU and

99 to TAU), representing 81.4% of eligible individuals. At 18 months, 46%

of the TAU participants fully complied compared to 28% of those receiving

CTCH+TAU (odds ratio = 0.45, 95% confidence interval 0.23 to 0.88, p=0.021).

The estimate of the treatment effect common to both follow-up points was

0.57 (95% confidence interval 0.33 to 0.98, p=0.042). The total estimated

treatment effect for voice power common to both time points was -1.819

(95% confidence interval, -3.457 to -0.181, p=0.03). Treatment effects for

secondary outcomes were not significant.

Interpretation: The trial demonstrated a large and significant reduction

in harmful compliance, in parallel with the singular target of treatment,

the perceived power of the voice. We believe this marks a significant

breakthrough in this high risk group which consumes much clinical and

public concern. Funding: Medical Research Council UK and the National

Institute for Health Research.

COMPUTER ASSISTED THERAPY FOR AUDITORY HALLUCINATIONS:

THE AVATAR CLINICAL TRIAL

Tom Craig1, Philippa Garety2, Thomas Ward2, Mar Rus-Calafell3,

Geoffrey Williams4, Mark Huckvale4, Julian Leff5

1Institute of Psychiatry, King’s College London; 2King’s College London, Institute

of Psychiatry Department of Psychology; 3King’s College London, Institute of

Psychiatry, Health Services and Population Research; 4University College

London, Speech, Hearing and Phonetic Sciences; 5University College London

Background: About 25% of people with schizophrenia continue to suffer

with persecutory auditory hallucinations (AH) despite adequate treatment.

Existing psychological therapies such as cognitive behaviour therapy are

lengthy and costly. An adaptation of “voices dialogue” therapy in which

patients are encouraged to enter into a dialogue with their voices appears

to be helpful (Romme et al 2009) and informed the development of AVATAR

therapy.

Methods: Patients create a representation of the entity they imagine as the

source of their AH using computerised face animation software. Using a

further programme, they then select and modify a speech sample (actually

the voice of the therapist) tweaking this until they are satisfied that it

matches the quality of the AH that they experience. Therapy proceeds with

patient and therapist at linked computers in separate rooms. The therapist

is able to speak either as the avatar (which the patient perceives as ap-

propriately lip and facially synced), or in his/her own voice when giving

advice and coping instructions. Therapy is provided over 7 weekly sessions

each of which lasts half an hour. The character of the “avatar” becomes

gradually more supportive and less threatening as therapy proceeds. Each

session is recorded and given to the patient on a portable MP3 player

with instructions to listen to the recording between sessions to reinforce

progress. The system was evaluated in a pilot study comparing AVATAR

therapy with treatment as usual (Leff et al 2013). We are now moving on

to a larger randomised controlled trial comparing 7 sessions of AVATAR

therapy with a supportive counselling control condition for 142 patients

with treatment-resistant auditory hallucinations.

Results: In the pilot study that included 26 patients, 14 were randomised

to AVATAR. Compared to the 12 who received TAU, patients who received

AVATAR therapy reported statistically and clinically significant reductions

in total PSYRATS score (average reduction of -8.75 points, p<0.002) and

total BAVQ-R (average reduction −5.9 points, p<0.004). Three patients

stopped hearing voices entirely. The 12 patients who were in the control

arm were subsequently offered AVATAR therapy and 8 accepted the offer. A

secondary analysis looking at within-group change across all patients who

received AVATAR therapy confirmed the results of the first analysis. The

larger replication RCT is just underway. We will present some basic descrip-

tive data, illustrative cases and demonstrate the revised AVATAR system

which is more sophisticated in the graphics and voice synchronisation.

Discussion: Results of the first pilot study were striking but the sample

was small, proved difficult to recruit and had a substantial drop-out. It was

delivered by a single highly experienced therapist. The new study will be

delivered by several therapists and will attempt to provide a control for

therapist time and attention. Outcome data will be collected by indepen-

dent research team so that we can test for the adequacy of masking of the

assessments.

References:[1] Romme et al. 2009. Living with voices: 50 stories of recovery. PCCS Books.

[2] Leff et al. 2013. Computer assisted therapy for medication-resistant auditoyr hal-

lucinations: proof of concept study. British J Psychiatry 202, 428–33.

THE RESULTS OF EYE MOVEMENT DESENSITISATION AND REPROCESSING

AND PROLONGED EXPOSURE IN PATIENTS WITH POSTTRAUMATIC

STRESS DISORDER AND CHRONIC PSYCHOTIC DISORDER

Mark van der Gaag1,2, Berber van der Vleugel3, Paul de Bont4, David van

den Berg5, Ad de Jongh6, Agnes van Minnen7

1Parnassia/VU University; 2VU University, Amsterdam, The Netherlands;3Noord-Holland Noord, Alkmaar, The Netherlands; 4Mental Health

Organization (MHO) GGZ Oost Brabant Land van Cuijk en Noord Limburg &

Behavioural Science Institute, NijCare, Radboud University, Nijmegen, The

Netherlands; 5Parnassia Psychiatric Institute, Den Haag, The Netherlands;6Department of Behavioral Sciences, Academic Centre for Dentistry Amsterdam

(ACTA), Amsterdam & Department of Behavioral Sciences, Academic Centre for

Dentistry Amsterdam (ACTA), VU University Amsterdam, The Netherlands;7Behavioural Science Institute, NijCare, Radboud University, Nijmegen & MHO

’Pro Persona’, Centre for Anxiety Disorders Overwaal, Lent, The Netherlands

Background: Many patients with schizophrenia also suffer from post-

traumatic stress disorder (PTSD). This condition is underdiagnosed and

undertreated. Hardly any evidence is available on the efficacy and safety of

trauma treatment in psychotic patients.

Methods: 155 patients with a chronic psychotic dirorder and PTSD were

randomised into three arms: Eye Movement Desensitisation and Repro-

cessing (EMDR; Shapiro protocol); Prolonged Exposure (PE; Foa protocol);

or treatment as usual (TAU). Randomisation was performed stratified by

research site by an independent randomisation agency. Both treatment con-

ditions consisted of maximum eight 90-minute sessions. Therapists were

trained in both interventions and supervised during the trial and treated

patients in both treatment conditions. All sessions were recorded on video

and treatment fidelity was checked. Assessments were performed by blind

research assistents.

Results: Both treatments were effective and hard large effect-sizes (EMDR:

d=0.76 and PE d=0.83) on total Clinician-Administered PTSD Scale scores

(CAPS) at the end of treatment. Also 66% of the treated patients no longer

fulfilled the criteria for a PTSD diagnose (DSM-IV) at the end of treatment.

The Number Needed to Treat for EMDR was 2.4 and for PE the NNT was

3.4. Most adverse events took place in the TAU condition.

Discussion: Both PTSD and PE are effective in reducing trauma symptoms

on the CAPS and bring patients into remission of no longer fulfilling the

Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384 S75

criteria of PTSD. The treatments are safe to perform. Follow-up data will be

presented also.

COGNITIVE THERAPY FOR PEOPLE WITH SCHIZOPHRENIA SPECTRUM

DISORDERS NOT TAKING ANTIPSYCHOTIC MEDICATION: A RANDOMISED

CONTROLLED TRIAL

Anthony P. Morrison1,2, Douglas Turkington3, Melissa Pyle2,

Helen Spencer4, Alison Brabban5, Graham Dunn6, Tom Christodoulides4,

Rob Dudley4, Nicola Chapman2, Paul Hutton2

1University of Manchester; 2Greater Manchester West Mental Health

Foundation Trust; 3Newcastle University; 4Northumberland, Tyne and Wear

NHS Mental Health Foundation Trust; 5University of Durham; 6Institute of

Population Health, University of Manchester, Manchester, UK

Our trial aimed to determine whether cognitive therapy (CT) is effective in

reducing psychiatric symptoms experienced by people with schizophrenia

spectrum disorders that have chosen not to take antipsychotic medica-

tion. We conducted a two-site single-blind randomised controlled trial

comparing CT plus treatment as usual (TAU) with TAU only. Participants

were followed-up for a minimum of 9 and a maximum of 18 months. 74

participants with schizophrenia spectrum disorders who had chosen not to

take antipsychotic medication psychosis (aged 16-65 years; mean 31.47;

SD 12.27) were recruited. 37 were assigned to CT and 37 to TAU. Our

primary outcome was the Positive and Negative Syndrome Scale (PANSS)

total score, which provides a continuous measure of psychiatric symptoms

associated with schizophrenia spectrum disorders on the basis of a com-

monly used structured psychiatric interview. Changes in outcomes were

analysed following the intention-to-treat principle, using random effects

regression (a repeated-measures ANCOVA) adjusted for site, age, gender

and baseline symptoms. Psychiatric symptoms were significantly reduced

in the group assigned to CT, in comparison with TAU, with an estimated

between-group effect size of −6.52 (95% CI −10.79 to −2.25, p=0.003). CT

significantly reduced psychiatric symptoms and appears safe and accept-

able in people with schizophrenia spectrum disorders who have chosen not

to take antipsychotic medication. The results have important implications

for the provision of mental health services for people with schizophrenia

spectrum disorders.

Workshop

TWENTY YEARS OF RESEARCH ON THE 22Q11.2 DELETION

SYNDROME AND SCHIZOPHRENIA: WHAT HAVEWE LEARNED

SO FAR?

Chairperson: Jacob A.S. Vorstman

Discussant: René Kahn

Tuesday, 8 April 2014 6:30 PM – 8:30 PM

Overall Abstract: The 22q11.2 deletion syndrome (22q11DS) is caused by a

well-described genetic lesion. Approximately 25% of patients with 22q11DS

develop schizophrenia, making it the strongest known single genetic risk

factor for schizophrenia. Since the first report of increased prevalence of

schizophrenia in 22q11DS individuals in 1994, there has been an increasing

research effort across the globe, aiming to elucidate the mechanisms behind

this association. The progress over the past 20 years goes well beyond en-

hancing our understanding of schizophrenia in patients with 22q11DS. The

22q11.2 deletion should also be considered as a truly unique model to study

schizophrenia. In the words of Thomas Insel, Director of the National Insti-

tute of Mental Health: “Important insights into the trajectory from risk to

disorder [schizophrenia] may be gained from ongoing longitudinal studies

of these children, comparing cognitive, affective and neural development

in those who do and do not develop psychosis . . .” (Insel, Nature, 2010).

What is it that makes the 22q11DS-model so special for schizophrenia

research? In essence, its strength lies in the fact that it tackles two major

obstacles in the field. First, it can overcome some of the difficulties inherent

in studying the very early (pre-psychosis) manifestations of schizophrenia.

In the general population, extremely large samples are required to provide

sufficient power for the prospective study of the earliest developmental

stages of the disease. In contrast, a relatively small cohort of young indi-

viduals with 22q11DS can be sufficiently powered, given that about 1 in 4

subjects will develop schizophrenia. Second, it is now widely acknowledged

that schizophrenia is highly heterogeneous with respect to genetic etiology.

Although patients may present with a similar constellation of symptoms,

each individual may have a different set of genetic variants involved in

causation. This genetic heterogeneity presents a challenge for the identi-

fication of disease-relevant biomarkers. In contrast, the common genetic

etiology of 22q11DS patients provides an opportunity for translational

studies, including those using animal models. In the present symposium,

we will review, from 5 different angles, the most important findings from

the past 20 years of schizophrenia research using the 22q11.2 deletion as

a model. Our objective is to provide participants with a comprehensive

state-of-the-art update on our current understanding of developmental risk

factors for psychosis in patients with 22q11DS as well as the implications

for the broader understanding of the pathophysiology of schizophrenia. The

following aspects will be included in our presentations: 1) genetic mech-

anisms of schizophrenia in 22q11DS, 2) neurocognitive development in

22q11DS and 3) structural and functional brain characteristics predictive of

psychotic symptom expression in 22q11DS; 4) neuropsychiatric symptoms

preceding the first psychosis in 22q11DS, and 5) biological insights derived

from 22q11DS mouse models.

THE 22Q11.2 DELETION SYNDROME AS A MODEL FOR DEMENTIA

PRAECOX

Jacob A.S. Vorstman1, Elemi Breetvelt, Sasja Duijff, René Kahn1Department of Psychiatry, Brain Center Rudolf Magnus, University Medical

Center Utrecht, The Netherlands

Kraepelin proposed the term “Dementia Praecox” – i.e. early dementia –

emphasizing the cognitive deterioration in addition – and prior – to the

onset of psychotic symptoms in schizophrenia. Since then, several studies

have replicated Kraepelin’s initial observation this cognitive deterioration.

Of particular relevance are the findings indicating that a loss of cogni-

tive skills often precedes the first psychotic episode by several years.

Consequently, psychosis is likely a manifestation of an advanced stage of

schizophrenia, even though the first psychotic episode most often marks

the beginning of medical attention and treatment. Studying the schizophre-

nia’s earliest manifestations is highly relevant. This may be likened to the

fact that it was only after it had been established that myocardial infarction

was not the starting point of cardiovascular disease, that the importance of

its early manifestations such as hypertension and cholesterol abnormalities

was understood. This turned out to be a crucial shift in thinking, allowing

for entirely novel strategies to reduce the risk of myocardial infarction.

Similarly, to further our insight into schizophrenia, research efforts should

not only be directed on its advanced stage (i.e. psychosis) but also on

its earliest manifestation; changes in cognitive and behavioral function

occurring early in childhood and preceding the first psychosis. Examining

the early trajectory is extremely challenging because it requires very large

prospective longitudinal cohorts given the % rate of the schizophrenia.

Against this background, the 22q11.2 deletion syndrome (22q11DS) can be

considered as a highly appealing model to study schizophrenia, including its

early manifestations. Approximately 25% of 22q11DS individuals develop

schizophrenia, making it the strongest single genetic risk factor known

for schizophrenia. Importantly, the core phenotype of schizophrenia in

22q11DS patients is similar to schizophrenia in patients without 22q11DS.

Therefore, it is not surprising that several research groups have endeavored

longitudinal studies where children with 22q11DS are followed into adult-

hood. The goal of this presentation is to provide an update on the results

of these studies. Results from four important clinical studies (ongoing and

recently completed) focusing on the early cognitive or behavioral charac-

teristics of 22q11DS will be presented. In the first study childhood social

functioning was retrospectively assessed in 22q11DS adults and compared

between those with and without schizophrenia. In a second (ongoing)

prospective study the predictive strength of social dysfunction with regard

to the later emergence of psychotic symptoms in 22q11DS patients is

examined. Finally, we will present findings from a longitudinal IQ study

in a cohort of children with 22q11DS as well as from a recently initiated

large international 22q11DS research consortium including prospectively

collected serial IQ measurements in 22q11DS youth. The results from this

analysis, -by far the largest cohort reported thus far -, demonstrate a clear