The British Journal of Psychiatry (2012)

200, 22–29. doi: 10.1192/bjp.bp.109.066357

Preventing progression to first-episode psychosis

in early initial prodromal states
A. Bechdolf, M. Wagner, S. Ruhrmann, S. Harrigan, V. Putzfeld, R. Pukrop, A. Brockhaus-Dumke,
J. Berning, B. Janssen, P. Decker, R. Bottlender, K. Maurer, H.-J. Möller, W. Gaebel, H. Häfner,
W. Maier and J. Klosterkötter

Background
Young people with self-experienced cognitive thought and number: NCT00204087). Primary outcome was progression to
perception deficits (basic symptoms) may present with an psychosis at 12- and 24-month follow-up.
early initial prodromal state (EIPS) of psychosis in which most
of the disability and neurobiological deficits of schizophrenia Results
have not yet occurred. A total of 128 help-seeking out-patients in an EIPS were
randomised. Integrated psychological intervention was
Aims superior to supportive counselling in preventing progression
To investigate the effects of an integrated psychological to psychosis at 12-month follow-up (3.2% v. 16.9%; P = 0.008)
intervention (IPI), combining individual cognitive–behavioural and at 24-month follow-up (6.3% v. 20.0%; P = 0.019).
therapy, group skills training, cognitive remediation and Conclusions
multifamily psychoeducation, on the prevention of psychosis Integrated psychological intervention appears effective in
in the EIPS. delaying the onset of psychosis over a 24-month time period
in people in an EIPS.
Method
A randomised controlled, multicentre, parallel group trial of Declaration of interest
12 months of IPI v. supportive counselling (trial registration None.

Early detection and intervention strategies have led to substantial basic symptoms (n = 160)15 indicate that the 12-month conversion
improvement in the prognosis of a number of non-psychiatric rate to psychosis is lower (19%) and the long-term conversion rate
medical conditions.1–3 The chronicity of schizophrenia provides higher (70% after 5.4 years) than the 12-month transition rate
the primary rationale for adapting these strategies for schizo- of the ultra-high-risk population (20–30%).4–6 Moreover, cross-
phrenia. In recent years, criteria based on subthreshold levels of sectional data indicate that levels of psychopathological
psychotic symptoms (ultra-high-risk criteria) have been found symptoms, disability, neurophysiological and neuropsychological
to predict psychosis onset within 12 months in 20–30% of deficits are lower in patients with basic symptoms than in patients
cases.4–6 This approach has provided the opportunity of indicated who fulfil ultra-high-risk criteria.17–19 Therefore, it has been
prevention efforts in individuals at imminent risk of schizo- hypothesised that people with basic symptoms might be in an
phrenia in order to reduce or prevent the devastating effects of early initial prodromal state (EIPS) of psychosis in which
the disorder.7 symptoms, disability and biological deficits are less severe than
Five randomised controlled trials (RCTs) in the ultra-high-risk in the ultra-high-risk population, and that the EIPS population
population have been completed so far. They have included may therefore be more responsive to preventive interventions than
evaluations of low-dose risperidone and cognitive–behavioural people who already fulfil ultra-high-risk criteria.20,21
therapy (CBT) combined,8 CBT alone,9,10 olanzapine alone11 However, to date, no information on the efficacy of inter-
and omega-3 fatty acids.12 Although the results of the treatment ventions in people in the EIPS is available. Therefore, the present
phase were statistically borderline10,11 or significant8,9,12 in favour RCT study has been undertaken to test the efficacy of a specifically
of the respective experimental condition, these effects were not devised integrated psychological intervention (IPI) compared with
sustained at 12-,8 24-11 or 36-month13,14 follow-up. The increased supportive counselling in individuals in an EIPS. Integrated
rate of conversion and return of prodromal symptoms to psychological intervention consists of individual CBT, modified
significantly higher levels after removing the specific intervention social skills training, cognitive remediation and multifamily
led some authors to conclude that interventions in the ultra-high- psychoeducation. It was chosen as the experimental condition
risk population merely delay conversion to psychosis rather than because (a) the applied strategies have been found to be effective
prevent it.11 in individuals at ultra-high risk and patients with psychosis;8–10,22–24
One of the reasons for the limited efficacy of indicated (b) there is no risk of exposing false positives to possible
prevention efforts might be that individuals who meet ultra-high- pharmacological side-effects; and (c) it is an established treatment
risk criteria already present with symptoms similar to psychotic for anxiety, depression and several other syndromes which are
symptoms. Thus, in the ultra-high-risk population most of the regularly present in the pre-psychotic phase.25,26 Supportive
symptoms, disability and neurobiological deficits associated with counselling was designed to provide a minimal level of support
schizophrenia might already be present15. However, certain subtle, for individuals who were seeking help and clearly in need of
self-experienced thought and perception deficits (basic symptoms) support as a result of psychiatric symptoms or concerns relating
have been described in initial prodromal states of schizophrenia, to functional domains.
which may precede the onset of subthreshold psychotic This paper presents the 12-month (post-treatment) and
symptoms.15,16 Furthermore, prospective data of people with 24-month follow-up results of the RCT. The primary outcome

22
 Integrated psychological intervention for the prevention of psychosis

measure was progression to psychosis (incidences of subthreshold Treatments

psychosis, first-episode psychosis and first-episode schizophrenia) The same research therapists delivered IPI and supportive
at 12-month and 24-month follow-up. It was hypothesised that IPI counselling, except in Cologne, where 7 patients assigned to
would significantly reduce progression to psychosis compared supportive counselling were treated by 2 additional psychiatrists,
with supportive counselling. and in Munich, where supportive counselling was delivered to
11 patients by a clinical psychologist and a psychiatrist who were
Method not involved in IPI. No formal measures of adherence to the
manual or of therapists competence were employed in the IPI
This was a multicentre, prospective, randomised trial with two or supportive counselling conditions.
parallel groups assigned to alternative out-patient interventions. The therapists delivering IPI were CBT-trained clinical
Randomisation was achieved by using computer-generated block psychologists and psychiatrists with at least 2 years of experience
randomisation stratified by centre. Both interventions were in CBT delivery. At the start of the study the therapists were
delivered over a 12-month period. Follow-up of participants was trained in IPI in a comprehensive workshop lasting for several
conducted for up to 24 months after intake. The protocol was days, and at least once yearly throughout the study. At each site,
approved by the respective institutional review boards at the therapists received expert and/or peer supervision at least once
Universities of Cologne, Bonn, Dusseldorf and Munich, Germany. every 2 weeks.
All participants provided written informed consent prior to any
research activity. This study is registered with Clinicaltrials.gov Integrated psychological intervention (IPI)
(registration number NCT00204087). Model. The stress–vulnerability model of schizophrenia30 and
the basic symptom concept15,16 serve as the framework of IPI.
Setting Thus, improving coping resources and stress management are
underlying strategies of the intervention. Given empirical evidence
The study took place at four early detection and intervention that cognitive thought and perception disorders may precede
centres located in the Departments of Psychiatry and Psycho- negative affective states, social withdrawal and decline,15,16 a
therapy at the Universities of Cologne, Bonn, Dusseldorf and specific cognitive model of the EIPS31 was developed, as an
Munich, and was funded within the German Research Network extension of the stress–vulnerability model based on recent
on Schizophrenia. All centres serve as specialised out-patient cognitive models of psychosis.32–34 In this model, biological,
departments and are designed to provide a low-threshold, non- psychological, social stress and vulnerability factors are presumed
stigmatising environment. An awareness programme was to interact to render the person at high risk for the subsequent
conducted, which aimed to engage ‘at risk’ individuals with the development of prodromal symptoms. The prodromal symptoms
early intervention services. Referrals were made from primary become manifest on exposure to a range of additional stressors,
healthcare, mental health professionals, counselling services and which again may be social, psychological or biological. The
other youth support services. occurrence of self-experienced cognitive thought and perception
deficits (basic symptoms) could then serve as triggering
Participants events for the appraisal of negative beliefs and assumptions.
Self-experience of basic symptoms may result in emotional
We used a two-step approach to identifying individuals at risk of
disturbances, such as depression or anxiety, social withdrawal
psychosis created by Häfner et al.21 First, a checklist was provided.
and decline, which jointly contribute to the development and
For those who met threshold criteria in the checklist, an interview
maintenance of symptoms and distress.
using a specially designed instrument based on the Interview for
the Retrospective Assessment of the Onset of Schizophrenia
Treatment components. The interventions draw on established
(IRAOS) was performed at the respective centre. This instrument,
strategies for first-episode or recurrent schizophrenia, anxiety
called the Early Recognition Inventory (ERIraos),27 indicated
and depressive disorders.22–26
whether the individual at risk fulfilled EIPS or subthreshold
psychosis criteria.
Individual cognitive–behavioural therapy (CBT). Individual CBT
was at the core of IPI. Based on our integrative cognitive model31
Inclusion criteria the individual CBT followed the basic principles of cognitive
Inclusion criteria were met when patients presented with at least therapy described by Beck35 as being formulation driven,
one of ten thought or perceptional basic symptom (Appendix structured, based on shared problems and goals, educational,
1), which have been found15 to predict psychosis in 19% of cases utilising guided discovery as the engine for change, involving
within 12 months and in 70% of cases within 5.4 years. A decrease homework and being time limited. Depending on the problems
in functioning in conjunction with presentation of a genetic risk presented and the case formulation, therapists adapted the
of psychosis or a history of obstetric complications has been found modules described in a manual36 (see Table 1 for modules and
to increase the risk of developing psychosis substantially.4–6,28,29 strategies applied).
For more details on the EIPS criteria see Bechdolf et al20 and
Häfner et al.21 Skills training. Scheduling and monitoring of mastery and
pleasure activities, ‘keeping well’ strategies, social perception and
social skills training and training in problem-solving were offered
Exclusion and exit criteria in a group format. Each therapy session followed a detailed
In accordance with the concept that the EIPS precedes sub- protocol which outlined the aims of the session, examples of
threshold psychotic symptoms (attenuated or brief intermittent interventions and model responses for the therapist.
psychotic symptoms), the development of subthreshold psychotic
symptoms or psychosis served as exit criteria for the trial (see Cognitive remediation. Cognitive remediation was offered to
Appendix DS1 for full exclusion and exit criteria). address thought and perception deficits (basic symptoms) directly.

23
Bechdolf et al

Table 1 Integrated psychological intervention for patients in an early initial prodromal state of psychosis
Module Topics

Individual cognitive–behavioural therapy Assessment and engagement

25 sessions Psychoeducation
Stress management
Symptom management
Crisis management
Group skills training Positive mood and enjoying
15 sessions Training social perception and social skills
Mastering difficult situations
Cognitive remediation Computer-based training of concentration, attention, vigilance and memory
12 sessions
Psychoeducational multifamily group Information and counselling of relatives or key persons
3 sessions

Applied cognitive and behavioural strategies in individual and group therapy: formulation; collaborative goal-setting; provision of information and education about stress; basic
(Appendix 1) and negative symptoms, depression, anxiety; stress monitoring, relaxation, distraction techniques; self-monitoring of symptoms, thought monitoring, cognitive
restructuring, positive coping, positive reframing and challenging, goal-setting and time management; coping enhancement techniques, normalising self-experience of
neuropsychological deficits, behavioural strategies such as thought stopping, distraction, activity scheduling; exposure techniques; cognitive restructuring of negative and
self-defeating cognitions; relapse prevention; scheduling and monitoring of mastery and pleasure activities, keeping-well strategies, assertiveness and social skills training;
problem-solving.

It was computerised and based on cognitive exercises from the interventions and model responses for the therapist. Additionally,
COGPACK software (Marker Software, Mannheim, Germany), a 80 pages of working material for patients were provided. Further
multimedia cognitive rehabilitation software designed for use with details of IPI and case examples are presented elsewhere.37,38 The
individuals with compromised brain functioning. In each session, feasibility of the intervention was tested and confirmed in a pilot
three to six tasks were performed, involving repeated practice of sample of 12 patients.39
exercises for attention, memory and executive functioning.
Patients received performance scores, which were recorded and
referred to in order to reinforce performance progress. Task Supportive counselling
parameters were initially made sufficiently easy for each patient The supportive counselling was designed to provide a minimal
to do well. After session 6, tasks were made more difficult, level of support for individuals who were seeking help and were
according to the next level of difficulty (low to medium, or clearly in need of support as a result of psychiatric symptoms or
medium to severe). concerns relating to functional domains. Basic assessment, basic
psychoeducation about the at-risk mental state and counselling
in a supportive, warm, genuine, empathic and unstructured style
Psychoeducational multifamily groups. In addition, psycho-
were delivered. Supportive counselling was delivered on a one-to-
educational multifamily groups for family members or key
one basis, manual based, regularly supervised and lasted for a
persons were offered. These groups provided information on
maximum of 30 sessions over 12 months.
symptoms, course and treatment of at-risk mental states, as
detailed in a manual.17,36 These sessions aimed to increase the
family’s understanding of the EIPS and to reduce stress and Assessments
interpersonal conflicts.
Face-to-face assessment of the development of the primary
outcomes – subthreshold psychotic symptoms, psychosis and
Procedures and manual. Integrated psychological intervention schizophrenia – were undertaken at each individual treatment
was initially commenced with individual CBT delivered weekly session (maximum of 30 assessments) during the treatment phase
or every 2 weeks, which was then consecutively supplemented and at post-treatment (month 12). During the post-treatment
by cognitive remediation and psychoeducation of family members phase, patients were regularly asked about the primary outcomes
or key persons. Following the assessment and engagement phase, by telephone and by face-to-face interview during the 24-month
and formulation and goal setting, group skills training was offered follow-up. If the telephone interview indicated a deterioration of
to participants, depending on availability of places in the group. symptoms and/or an increased risk of conversion, an additional
While participants were attending the weekly group sessions, the face-to-face interview was conducted. If patients did not attend
frequency of individual sessions was reduced to crisis intervention, assessments, every effort was made to follow them up and to
and only maintained in individuals who were clinically judged to complete assessments with regard to primary outcome variables
have a particularly high risk of developing psychosis or dropping by means of telephone calls and home assessments. If patients
out. During the treatment phase of individual CBT, before or after were not available for interviews, key persons and hospital
the group intervention, CBT sessions were planned to be weekly, admission data were approached to determine conversion status.
with a reduction in their frequency during the termination phase Patients were classified as converters or non-converters by an
towards the end of the overall treatment at 12 months. However, independent consultant psychiatrist or senior clinical psychologist.
the frequency and duration of sessions were intended to be The masking of these independent consultant psychiatrists or
flexible, depending on arrangements made between patients and clinical psychologists was not formally measured.
therapists, as well as being contingent on the mental state of Basic symptom inclusion criteria (Appendix 1) were assessed
individual patients. in a semi-structured interview by a short version of the symptom
The IPI was detailed in a manual of 137 pages36,37 including an list of the ERIraos and the IROAS.27 Inclusion criteria were
overall treatment model, aims of the treatment components and operationally defined as fulfilled if one of the ten basic symptoms
sessions, problem-specific treatment modules, examples of was rated with a severity of at least 1 (corresponding to a mild

24
 Integrated psychological intervention for the prevention of psychosis

severity). A basic symptom total score was calculated by summing (PANSS).42 In accordance with previous definitions8,9 the
the scores of the ten basic symptom items defining the EIPS.15 presence of brief limited intermittent psychotic symptoms or
Genetic risk of schizophrenia as part of the decreased functioning psychosis were operationally defined by cut-off points on PANSS
and risk factor criteria was assessed by the IRAOS.40 Obstetric subscales of 4 or more on hallucinations, 4 or more on delusions
complications were assessed by the respective ERIraos module, and 5 or more on conceptual disorganisation or formal thought
which was modelled on the Obstetric Complications, Scale (OCS).41 disorder. After meeting exit criteria, patients were classified by
The exit criteria to subthreshold psychosis and psychosis an independent consultant psychiatrist or senior clinical
(Appendix DS1) were defined in accordance with definitions used psychologist into one of three categories: (1) subthreshold
by RCTs in the ultra-high-risk population.8-12 The exit criteria to psychotic symptoms (see online Appendix DS1 for definitions);
the subthreshold psychosis syndrome ‘attenuated psychotic (2) DSM-IV psychosis diagnosis:43 schizophrenia/schizophreniform,
symptoms’ were assessed using the symptom list of the ERIraos, schizoaffective disorder, major depression with psychotic features,
and were operationally defined as fulfilled if one of the symptoms bipolar disorder with psychotic features, delusional disorder, brief
was rated as present. The subthreshold psychosis syndrome ‘brief psychotic disorder, brief psychotic disorder not otherwise
limited intermittent psychotic symptoms’ and psychosis criteria specified; or (3) DSM-IV schizophrenia/schizophreniform
were assessed by the Positive and Negative Syndrome Scale disorder diagnosis.43

Assessed with checklist (n = 1597)

7 Did not meet checklist criteria (n = 271)
6
Met checklist criteria (n = 1326)

6
No checklist assessment performed (n = 22) Assessed witih inclusion criteria checklist
7 (n = 1348)

Did not meet EIPS inclusion criteria (n = 1116)

7 Subthreshold psychosis (n = 382)
6
Met EIPS inclusion criteria
(n = 232) Met exclusion criteria (n = 64)
Organic brain disease (n = 5)
Substance dependence (n = 16)
Previous psychotic episode (n = 2)
7 Acute suicidal (n = 4)
6 Treated with antipsychotics (n = 18)
Received other treatment (n = 8)
Eligible for randomisation (n = 168) Lived out of area (n = 11)

Not randomised (n = 40)

7 Refused research participation (n = 22)
6 Refused treatment (n = 15)
Randomised (n = 128) Lost during assessment (n = 2)
Developed psychosis during assessment (n = 1)

6 6
Allocated to IPI (n = 63) Allocated to supportive counselling (n = 65)
Did not receive allocated intervention (n = 2) Did not receive allocated intervention (n = 1)
Attended no session (n = 2) Attended no session (n = 1)
Received allocated intervention (n = 61) Received allocated intervention (n = 64)
Received 450% of the intervention (n = 41) Received 450% of the intervention (n = 42)
Received 550% of the intervention (n = 20) Received 550% of the intervention (n = 22)

6 6
Completed 12-month follow-up (n = 51)
Withdrawn from intervention because of suspicion Completed 12-month follow-up (n = 57)
of organic brain disease (n = 1) Lost to follow-up (n = 8)
Lost to follow-up (n = 11) Moved (n = 3)
Moved (n = 1) Did not return (n = 5)
Did not return (n = 10)

6 6
Completed 24-month follow-up (n = 40) Completed 24-month follow-up (n = 41)
Lost to follow-up (n = 11) Lost to follow-up (n = 16)
Moved (n = 2) Moved (n = 4)
Did not return (n = 9) Did not return (n = 12)

6 6
Analysed (n = 62) Analysed (n = 65)

Fig. 1 CONSORT diagram.

EIPS, early initial prodromal state; IPI, integrated psychological intervention.

25
Bechdolf et al

All assessors were experienced clinical psychologists or Table 2 Sample characteristics ( n = 128)
psychiatrists. They attended a comprehensive workshop lasting
Integrated
several days when the study commenced and yearly throughout psychological Supportive
the study. Reliability checks of the assessments were performed intervention counselling
three times throughout the study with a total number of nine (n = 63) (n = 65)
raters. Agreement with a gold standard rating on absence or
Age, years: mean (s.d.) 25.2 (5.4) 26.8 (6.2)
presence of a symptom from the ERIraos symptom list among
Male, n (%) 39 (61.9) 42 (64.6)
eight raters, who were sufficiently trained in the use of the
Met basic symptoma criteria, n (%) 59 (93.7) 64 (98.5)
schedule, were good to excellent44 (kappa 0.64–0.77). However,
Met decreased functioning and risk
one rater, who was still in need of further training, only achieved
factora criteria, n (%) 14 (22.2) 21(32.3)
a kappa of 0.49 (for symptoms present at time of the interview).
Marital status, n (%)
The reliabilities of the change assessments by the nine raters were
Married/cohabiting 28 (44.4) 24 (36.9)
good to excellent (kappa 0.63-0.87). Living alone/divorced 35 (55.6) 41 (63.1)
Employment status, n (%)
Statistical analysis Full/part time 11 (17.5) 16 (24.6)
Student/training 34 (54.0) 27 (41.5)
Kaplan–Meier survival analysis assessed differences in time to Unemployed/other 18 (28.6) 22 (33.8)
conversion to subthreshold psychotic symptoms between the
Housing status,b n (%)
two treatment arms over the 24-month follow-up using the log- Independent 40 (69.0) 18 (31.0)
rank test. Estimated survival rates were compared at the 12-month Primary family 49 (76.6) 15 (23.4)
and 24-month points on the survival curve using z-tests. Cox Baseline severity of symptomsc
regression was applied to assess whether the effects of treatment Prodromal symptoms (basic
on survival time remained constant when the impact of the basic symptom total score), mean (s.d.) 4.1 (3.1) 5.1 (3.4)
symptom total score at baseline was accounted for. These primary PANSS subscale score, mean (s.d.)
Positive 9.4 (2.9) 9.2 (2.1)
survival analyses were performed on all available follow-up data.
Negative 11.2 (4.1) 11.1 (4.1)
At 12-month and 24-month follow-up, a w2-test was used to General 28.2 (6.4) 28.8 (6.4)
calculate the difference in proportions of patients who developed MADRS score, mean (s.d.) 19.3 (7.8) 18.9 (7.7)
subthreshold psychotic symptoms, psychosis, or schizophreniform/ Global Assessment of Functioning 58.7 (11.0) 60.0 (10.1)
schizophrenia disorders in the two treatments. The numbers
PANSS, Positive and Negative Syndrome Scale; MADRS, Montgomery–Åsberg
needed to treat (NNT) with CBT to prevent one participant Depression Rating Scale.
making a conversion were calculated by the reciprocal of the a. For definitions see Appendix 1.
b. Six people had other living arrangements.
absolute risk reduction.45 Two-tailed tests of significance were c. Symptom data are missing for 0–16 participants.
used in all analyses, with a set to 0.05.

Results number of sessions 15.8 (s.d. = 6.8)) received significantly less

treatment (P50.001) than those in the IPI group (23.7
Enrolment and participant characteristics
(s.d. = 13.1)). After randomisation no patient was withdrawn from
Recruitment took place from January 2001 to January 2004. the study because of suicidal ideation or worsening of depression.
Figure 1 illustrates the flow of participant selection. Of 168 eligible All 128 randomised patients were included in the primary
individuals, 128 help-seeking out-patients in an EIPS were survival analyses. The median follow-up interval for the entire
randomised. Only 15 of the 168 eligible patients (8.9%) refused study period for the 111 participants who did not convert to
to accept the offered interventions, with 25 patients not subthreshold psychosis was 730.0 days (s.d. = 256.6, range 10–
randomised for other reasons (Fig. 1). Table 2 indicates that the 952), while the median interval for the 17 participants who did
randomised patients were substantially symptomatic and convert was 237.0 days (s.d. = 188.7, range 34-664).
functionally compromised, although patients did not score high
on positive psychotic symptoms because these symptoms were
among the exclusion criteria. The two treatment groups were Psychosis incidence and time to conversion
reasonably comparable on sociodemographic, symptom and By the end of the treatment phase, 2 of 63 patients in the IPI
functioning measures at intake (Table 2), with the exception of group and 11 of 65 patients in the supportive counselling group
total basic symptom score, which was slightly higher in the had converted to subthreshold psychosis. During the post-
supportive counselling group. Although any differences between treatment phase, an additional two patients converted in each of
the groups are due to chance alone (since the participants were the treatment groups. The cumulative conversion rates to
randomised to the treatment groups), it was decided to examine subthreshold psychosis at 12 months were 3.2% for IPI and
whether the effects of treatment on time to conversion remained 16.9% for supportive counselling (odds ratio (OR) = 6.21, 95%
constant when the impact of the basic symptom total score at CI 1.32–29.29) and at 24 months 6.3% for IPI and 20% for
baseline was accounted for. supportive counselling (OR = 3.69, 95% CI 1.13–12.01). These
differences were significant (P = 0.008 at 12 months and
Adherence to treatment and follow-up P = 0.019 at 24 months, as indicated by a z-test at each of these
After randomisation, two patients in the IPI group and one in the points) (Fig. 2). The time to conversion for the entire study period
supportive counselling group failed to attend any treatment was significantly shorter for the supportive counselling group than
sessions. There were no statistical differences (w2 = 0.003, the IPI group (IPI: mean 887.1 days, 95% CI 849–925; supportive
P = 0.956) in the number of participants who received less than counselling: mean 784.2 days, 95% CI 702–866; log rank:
50% of the treatment between trial conditions (IPI, 520 sessions: w2 = 5.43, P = 0.020). The effects of treatment on time to
n = 22, 33.8%; supportive counselling, 513 sessions: n = 20, conversion remained statistically significant (P = 0.042) when
31.7%). Patients from the supportive counselling group (mean basic symptom total score at baseline was accounted for in a

26
 Integrated psychological intervention for the prevention of psychosis

risk of developing psychosis is several thousand times higher than

-----------------------------------

-----------------------------------
1.0 – the annual risk in the general population. A transition rate of
P = 0.008
IPI (n = 63)
17% in the first year during supportive treatment is in line with
P = 0.019
a 19% transition rate in the original naturalistic Cologne Early
Proportion of non-converters

0.9 –
Recognition study.15 In accordance with the aim of identifying
an especially early stage of the illness, 12-month transition rates
0.8 – SC (n = 65) to psychosis in the control condition were lower in our EIPS trial
than in RCTs which used ultra-high-risk criteria as inclusion
criteria (17% v. 22–38%).8–12
0.7 –
As regards acceptance of, and adherence to, offered
interventions, our trial is reasonably comparable with the
0.6 – psychological intervention trial in an ultra-high-risk population
by Morrison et al 9 (8.9% v. 2.8% refused treatment). This
contrasts with prevention efforts involving treatment with anti-
0.5 – psychotics in ultra-high-risk individuals, which have proven less
0 6 12 18 24 30 acceptable to patients (refusal rate of 35.9%8) and have
Months relatively low adherence rates (45.2%8 and 54.8%11). The data
on unwanted side-effects go along similar lines. There were no
Fig. 2 Kaplan–Meier estimates of the rate of progression to reports of side-effects in the psychotherapy studies (Morrison
subthreshold psychosis in patients assigned to integrated et al,9 Addington et al10 or our own study), but McGorry and
psychological intervention (IPI, n = 63) or supportive counselling colleagues8 reported some instances of rigour and sedation due
(SC, n = 65). to risperidone treatment. In the McGlashan et al trial11 weight,
Pre-specified z-test comparisons for the difference in the proportions converting to pulse rate and fatigue increased significantly (by 8.8 kg and
subthreshold psychosis at 12 months (P = 0.008) and 24 months (P = 0.019). 9.5 beats/min for weight and pulse rate respectively) in the
olanzapine compared with the placebo group. The acute treatment
effects of the IPI intervention in comparison with supportive
Cox regression model. At 24-month follow-up, significantly fewer counselling were statistically significant, which was not the case
patients in the IPI group than in the supportive counselling group in some trials of ultra-high-risk populations.10,11 Moreover, in
had developed psychosis (3.2% v. 15.4%; w2 = 5.614, d.f. = 1, contrast to the trials in ultra-high-risk populations,8–11,13,14 the
P = 0.018) or schizophrenia/ schizophreniform disorder (1.6% v. conversion rates did not increase substantially after removing
12.3%; P = 0.033). Details of the participants classified as making the specific intervention in the EIPS population. Both findings
conversion are shown in online Table DS1. The NNTs with IPI support the hypothesis that people in an EIPS might be more re-
to prevent one person making the conversion were 8 (95% sponsive to treatment than people in later stages of the prodromal
CI 4.0–8.5) for subthreshold psychotic symptoms, 9 (95% CI phase.20,21
4.6–42.6) for psychosis and 10 (95% CI 2.1–19.3) for
schizophrenia/schizophreniform disorder. The overall conversion
rates did not differ between centres (exact P = 0.785). Methodological considerations
First, the overall sample size doubles those of earlier trials8–12 and
Use of antidepressants the methodological quality of the trial using the Clinical Trial
Assessment Measure46 was high, which strengthens the validity
At intake, 17.5% (n = 11) of the IPI group and 20% (n = 13) of
of the findings. Second, no formal measures of therapists’
the supportive counselling group were being prescribed anti-
adherence to the manual were employed, nor did we use any
depressants. At 12 months, 9.5% of the IPI group and 10.8% of
formal assessments of therapists’ competence. However, we believe
the supportive counselling group and at 24 months, 15.0% of
that the internal validity of the interventions was high, because the
the IPI group and 9.75% of the supportive counselling group were
framework, setting and supervision differed between IPI and
being prescribed antidepressant medication. There were no
supportive counselling, and additionally, both interventions were
significant differences in antidepressant use between treatment
detailed in specific manuals. Third, face-to-face contact with
groups.
therapists within the trial was higher for patients in the IPI group
than for patients receiving supportive counselling. Fourth, since
Discussion
all participants received some sort of treatment (IPI or supportive
counselling) and there was no ‘no treatment’ condition, we cannot
To our knowledge, this is the first trial to evaluate a specific
rule out that participants might have improved without treatment.
prevention strategy in individuals putatively in an EIPS. In
Finally, since IPI covered a variety of psychological strategies, the
accordance with our hypothesis, the incidence of and time to
trial design did not allow assessment of the relative contribution of
conversion to subthreshold psychotic symptoms, psychosis and
the psychological strategies provided.
schizophrenia/schizophreniform disorder during a 12-month
treating period was significantly lower for patients who received
specially designed IPI than for those who were treated with Clinical consequences
supportive counselling. This significant difference was maintained
Despite the limitations mentioned above, the data presented
throughout the 24-month follow-up.
indicate that specifically developed IPI was effective for delaying
the onset of subthreshold, first-episode psychosis and
Comparison with earlier trials in individuals schizophrenia over a 24-month time period. Moreover, the very
at risk of developing first-episode psychosis small numbers of converters after termination of treatment raises
The present study confirms that EIPS criteria define a clinically the likelihood that interventions in the EIPS indeed prevent
symptomatic and functionally compromised population whose psychosis. Integrated psychological therapy was safe, well accepted

27
Bechdolf et al

and tolerated by patients, did not produce unpleasant side-effects (k) decrease in Global Assessment of Functioning score of at least
and might have been helpful in reducing false positives as well. The 30 points (within the past year) and at least one of the following
NNTs of 8 (subthreshold psychotic symptoms) and 9 (psychosis) decreases in functioning and risk factors:
(i) first-degree relative with a lifetime-diagnosis of schizophrenia
for IPI to prevent one conversion are clinically meaningful and
(ii) a schizophrenia-spectrum disorder
contrast with for example, NNTs between 71 and 171 (depending
(iii) pre- or perinatal complications.
on degree of illness) for the treatment of hypertension to prevent
one stroke.1 Thus, IPI has the potential to improve the prognosis
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29
 The British Journal of Psychiatry
1–2. doi: 10.1192/bjp.bp.109.066357

Online supplement

Appendix DS1

Exclusion criteria
(a) Attenuated or brief limited intermittent psychotic symptoms
(b) Present or past diagnosis of a schizophrenic, schizophreniform,
schizoaffective, delusional or bipolar disorder according to DSM-IV
(c) Present or past diagnosis of a brief psychotic disorder according to
DSM-IV with a duration of more than 1 week or within the past 4
weeks regardless of its duration
(d) Diagnosis of delirium, dementia, amnestic or other cognitive disorder,
mental retardation, psychiatric disorders due to a somatic factor or
related to the consumption of psychotropic substances according to
DSM-IV
(e) Alcohol or drug dependence within the past 3 months according to
DSM-IV
(f) Organic brain disease (inflammatory, traumatic, epilepsy, etc.)
(g) Previous treatment with antipsychotics
(h) Acute suicidality
(i) Aged below 17 and above 35 years.

Exit criteria
Subthreshold psychotic symptoms

(a) Attenuated psychotic symptoms: one or more of the following

symptoms appearing several times a week for a period of at least
1 week
and/or
(b) brief limited intermittent psychotic symptoms: one or more of the
following psychotic symptoms for less than 1 week resolving
spontaneously
and/or
(c) psychosis: one or more of the following psychotic symptoms for more
than 1 week.

1
 Table DS1 Details of participants classified as converting to subthreshold psychosis
Time to conversion,
Participant Age, years Gender Entry route Allocation months Probable DSM-IV psychosis diagnosisa

1 19 Male BS SC 5 Schizophrenia/schizophreniform
2 18 Female BS SC 2 Schizophrenia/schizophreniform
3 35 Male BS+DF/R IPT 7 None
4 19 Male BS+DF/R SC 11 Schizophrenia/schizophreniform
5 19 Male BS+DF/R SC 11 Schizophrenia/schizophreniform
6 18 Male BS SC 2 Schizophrenia/schizophreniform
7 24 Male BS SC 3 None
8 22 Male BS SC 3 Psychosis
9 18 Male BS SC 3 Schizophrenia/schizophreniform
10 18 Female BS+DF/R SC 9 None
11 35 Female BS SC 1 Schizophrenia/schizophreniform
12 18 Male BS IPT 11 None
13 20 Male BS SC 8 Schizophrenia/schizophreniform
14 23 Male BS SC 13 None
15 31 Female BS SC 16 Psychosis
16 22 Male BS+DF/R IPT 18 None
17 18 Male BS+DF/R IPT 22 Schizophrenia/schizophreniform

BS, basic symptoms (for definitions see Appendix 1); DF/R, decrease in functioning and risk factors (for definitions see Appendix 1); SC, supportive counselling; IPT, integrated
psychological therapy.
a. None: subthreshold psychotic symptoms (attenuated psychotic symptoms, brief limited psychotic symptoms; see Appendix 1 for definitions); psychosis: DSM-IV
psychotic diagnosis (schizophrenia/schizophreniform, schizoaffective disorder, major depression with psychotic features, bipolar disorder with psychotic features, delusional disorder,
brief psychotic disorder, brief psychotic disorder not otherwise specified); schizophrenia/schizophreniform: probable DSM-IV schizophrenia/schizophreniform disorder diagnosis.

2
Preventing progression to first-episode psychosis in early initial
prodromal states
Andreas Bechdolf, Michael Wagner, Stephan Ruhrmann, Susan Harrigan, Verena Putzfeld, Ralf Pukrop,
Anke Brockhaus-Dumke, Julia Berning, Birgit Janssen, Petra Decker, Ronald Bottlender, Kurt Maurer,
Hans-Jürgen Möller, Wolfgang Gaebel, Heinz Häfner, Wolfgang Maier and Joachim Klosterkötter
BJP 2012, 200:22-29.
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