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Impact of early intervention services on duration of untreated psychosis: Data from the National EDEN prospective cohort study
Schizophrenia Research 159 (2014) 1–6
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Impact of early intervention services on duration of untreated psychosis: Data from the National EDEN prospective cohort study Max Marshall a,⁎, Nusrat Husain a, Natalie Bork a, Imran B. Chaudhry a, Helen Lester b, Linda Everard b, Swaran P. Singh c, Nick Freemantle d, Vimal Sharma e, Peter B. Jones f, David Fowler g, Tim Amos h, Barbara Tomenson a, Max Birchwood b a
School of Medicine, University of Manchester, United Kingdom University of Birmingham, Birmingham, United Kingdom c Health Sciences Research Institute, University of Warwick, Warwick, United Kingdom d Department of Primary Care and Population Health, University College, London, United Kingdom e University of Cheshire, United Kingdom f Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom g School of Medicine, University of East Anglia, United Kingdom h Academic Unit of Psychiatry, University of Bristol, Bristol, United Kingdom b
a r t i c l e
i n f o
Article history: Received 5 December 2013 Received in revised form 5 July 2014 Accepted 10 July 2014 Available online 5 August 2014 Keywords: Early Intervention Service Psychosis Duration of untreated psychosis
a b s t r a c t Objective: This study aimed to determine if the inception of Early Intervention Services (EISs) is followed by an improvement in the prompt treatment of people with first episode psychosis. Method: A prospective cohort study of referrals to new and established EISs was conducted at 1, 2, 3, and 4 years after inception of new EIS. The study was conducted with 14 (seven new and seven established) secondary care EIS within geographically defined catchment areas in England between 2005 and 2009. Participants included 1027 consecutive referrals to EIS aged 14–35 with a first episode of psychosis. Duration of untreated psychosis (DUP) and number of participants treated adequately within 6 months of onset were the main outcome measures. Results: A significant downward trend across yearly cohorts for DUP for new EIS (F1,549 = 8.4, p = 0.004) but not for established EIS (F1,429 = 1.7, p = 0.19) was observed. There was a significant upward trend across cohorts in the proportion of referrals treated within 6 months for new EIS (X2 = 8.0, df = 1, p = 0.005), but not for established EIS (X2 = 0.1, df = 1, p = 0.72). Conclusion: The introduction of new EIS was followed by a reduction in DUP and an increase in the proportion of patients treated within 6 months of onset. These trends were not present in the catchment areas of established services where DUP was initially lower, suggesting that there was no general tendency for DUP to fall over time. Hence, the introduction of an EIS was followed by an improvement in the prompt and proper treatment of first episode psychosis. © 2014 Published by Elsevier B.V.
1. Introduction The duration of untreated psychosis (DUP) is the time from the first psychotic symptom to the initiation of adequate neuroleptic treatment (Norman and Malla, 2001). There are three compelling reasons for shortening DUP. The first is to avoid the social consequences of active psychosis such as homelessness, unemployment, and social isolation ⁎ Corresponding author at: The LANTERN Centre, Vicarage Lane, Fulwood, Preston PR2 8DY, United Kingdom. Tel.: +44 1772 773500; fax: 44 1772 718268. E-mail address: [email protected] (M. Marshall).
http://dx.doi.org/10.1016/j.schres.2014.07.005 0920-9964/© 2014 Published by Elsevier B.V.
(Addington et al., 2002, Bertelsen et al., 2009). The second is to improve prognosis because a shorter DUP is associated with a better recovery across a broad range of outcomes (Marshall et al., 2005, Perkins et al., 2005). The third is to reduce the risk that a person with psychosis will seriously harm himself or other people because this risk is greatest during the untreated period of their first episode, and increases with the length of the episode (Nielssen and Large, 2008, Barrett et al., 2010, Nielssen et al., 2011). It has been proposed that specialist teams for the treatment of early psychosis (known as Early Intervention Services or EISs) could reduce the duration of untreated psychosis by promoting prompt and
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M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6
proper treatment (Bertolote and McGorry, 2005). However, this proposition is difficult to test in a randomized controlled trial as it would require a complex cluster randomized design in which EIS was randomly allocated to localities (Lloyd-Evans et al., 2011). Whilst the proposition has some support from small before and after designs conducted in single localities, a recent systematic review of the limited evidence concluded that “establishing early intervention services probably does not on its own reduce DUP (Lloyd-Evans et al., 2011)”. A unique aspect of the English National Health Service is that EIS looks after all young adults with a first episode of psychosis, following a national policy introduced in 2000 (Department of Health, 2000). In 2003, the English Department of Health set two national targets for EIS: to reduce the median DUP to 3 months, and to minimize the number of people with a DUP of greater than 6 months (Norman and Malla, 2001, Department of Health, 2003). Whilst the policy of establishing EIS was announced in 2000, implementation was initially patchy due to cost and complexity. In 2005, when the National EDEN longitudinal study of people receiving care from EIS started, national coverage was still variable. This afforded an opportunity to observe the effects of introducing new EIS on the duration of untreated psychosis. We hypothesised that over four years the duration of untreated psychosis and the proportion of participants with a DUP of greater than 6 months would fall significantly in the catchment areas of new EIS, whilst the same parameters would remain stable in the catchment areas of established EIS. 2. Methods National EDEN (2005–16) is a longitudinal cohort study of referrals to early intervention services in five socioeconomically diverse sites across England: Birmingham, Cornwall, Cambridgeshire, Norwich, and Lancashire/Cheshire. We chose sites purposively to reflect urban/rural differences. One of our core research objectives for National EDEN was to determine the duration of untreated psychosis in referrals to early intervention services in England (Birchwood et al., 2014). For the present study, we identified, from National EDEN, a prospective cohort of first referrals to EIS at 1, 2, 3, and 4 years after the establishment of new EIS and compared this cohort with a contemporaneous cohort of first referrals to EIS. Fourteen EISs participated at the five sites, each within a defined geographical catchment area, from where they accepted all new cases of first episode psychosis in people aged 14–35. We classified participating EIS into those that had been set up for less than one year when data collection started (new services), and those that had been set up for more than one year when collection started (established services) (see Table 1).
Table 1 New and established Early Intervention Services in National EDEN. Team New Lancashirea Birmingham BENa Birmingham Southa Kings Lynn, Norfolk Birmingham–Solihull Cameo North, Cambridge Cornwalla Established Birmingham Centrala Birmingham Easta East Anglia Norfolka Cameo Southa Wirral West Cheshire East Cheshire a
Catchment area size (100 k pop)
Set up date
Study Entry date
N in study
1,306,000 383,300 392,800 188,600 205,000 311,274 536,000
2005 2005 2005 2007 2006 2007 2005
2006 2005 2006 2007 2007 2008 2006
189 98 79 11 31 23 122
310,000 132,800 633,400 466,911 468,000 260,000 315,000
1995 2002 2003 2002 2005 2004 2005
2005 2005 2005 2005 2007 2007 2007
66 67 146 98 27 18 11
Teams with data for more than 3 years (included in sensitivity analysis).
We approached all referrals accepted by participating EISs from August 2005 to April 2009. However, not all EISs were recruited for the whole period (see Table 1). Our inclusion criteria were the following: aged 14 to 35 and accepted into a participating EIS following a first episode of psychosis. We obtained informed consent from all participants. Research assistants, not directly involved in clinical care, assessed participants at intake to the study and performed 6 and 12-month follow-ups. We evaluated DUP using an internationally accepted standardized definition and methodology (Larsen et al., 1996) that defined the onset of psychosis as one symptom from the positive scale of the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) at a level of 4 or above, or a cluster of symptoms including either delusions, conceptual disorganisation, or hallucinations, with a total score of 7 or more (excluding ‘absent’ scorings). Symptoms had to be present for a period of two weeks or more (unless remission was due to treatment). We defined the end of the period of untreated psychosis as the onset of criterion treatment with antipsychotic medication (Joint Formulary Committee, 2005). In some cases participants never received criterion treatment despite being under the care of an EIS. Some who did not receive criterion treatment recovered nonetheless, so that they were no longer psychotic when assessed at intake to the study or at 6 or 12-month follow-ups. For these participants we added 0, 6, or 12 months to the duration of untreated psychosis depending on the follow-up point at which they were judged to be no longer psychotic. The remainder of the group who never received criterion treatment remained psychotic throughout the study, and their duration of untreated psychosis was increased by 12 months. Diagnosis was established using the OPCRIT (Operational Criteria) computerized diagnostic system. OPCRIT is a 90-item checklist of symptoms rated by a researcher from the participant's clinical case notes. OPCRIT generates diagnoses according to 12 operational diagnostic systems (including ICD 10, DSM-III, and DSM-IIIR). OPCRIT has been used in a wide range of psychiatric research and has proven to be both reliable and valid (McGuffin et al., 1991). 2.1. Statistical analysis We present descriptive statistics for the whole sample and for new and established EISs separately. We compared new and established EISs using chi-squared tests for categorical variables, and t-tests and Mann–Whitney tests for ages, duration between key dates, and logtransformed duration of untreated psychosis. We present medians and geometric means with 95% confidence intervals for duration of untreated psychosis as it is positively skewed and lognormally distributed. Nested one-way analysis of variance was used to estimate the difference between new and established services as well as the difference between individual services within these two groups. We calculated proportions of referrals with DUP less than 6 months by service, by new versus established service, and for the whole group. For comparisons between services and between new and established services we used Fisher's exact test. We investigated whether DUP was stable over time in the catchment areas of established services whilst falling over time in the catchment areas of new services as they became established, by studying duration of untreated psychosis between new and established services across four yearly cohorts, using as baseline for each service the date when the first subject from that service entered the study. Some services were being offered through National EDEN from the beginning and had patients in all 4 yearly sequential cohorts; later services had fewer. Multiple regression was used with log (DUP) as the dependent variable and yearly cohorts, new/established team status, and the interaction of these as the independent variables. Since the interaction term was significant, we used one-way analysis of variance to estimate a linear trend in geometric mean duration of
M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6
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Table 2 Comparison of participants in established and new EISs. Whole group (n = 986)
Established EIS (n = 433)
Sig.a
New EIS (n = 553)
Risk or protective factor
n/N
%
n/N
%
n/N
%
p
Female Ethnic origin: White Asian Black Mixed/other Born in the UK Fluent in English Marital status: Single Married/cohabiting Separated or divorced Living situation: Alone With parents/guardians With partner Other Educated to A level or higher In paid work Ever used drugs Schizophrenia in 1st degree relative
308
31.2
136
31.4
172
31.1
0.95
714 153 71 48 884/972 942
72.4 15.5 7.2 4.9 90.9 95.5
288 85 40 20 374/425 408
66.5 19.6 9.2 4.6 88.0 94.2
426 68 31 28 510/547 534
77.0 12.3 5.6 5.1 93.2 96.6
X2 = 16.7 df = 3 P = 0.001
835 123 28
84.7 12.5 2.8
362 59 12
83.6 13.6 2.8
473 64 16
85.5 11.6 2.9
X2 = 0.9 df = 2 p = 0.63
126 623 104 130 341 185 626/951 91/880
12.8 63.4 10.6 13.2 34.6 18.8 65.8 10.3
54 257 49 71 161 87 263/412 40/379
12.5 59.6 11.4 16.5 37.2 20.1 63.8 10.6
72 366 55 59 180 98 363/539 51/501
13.0 66.3 10.0 10.7 32.5 17.7 67.3 10.2
X2 = 8.3 df = 3 p = 0.040
0.007 0.088
0.14 0.37 0.27 0.91
n = number of patients in the group with the risk or protective factor. N = total number of patients in the group. N = 433 for established teams, and N = 553 for new teams unless otherwise stated. a Comparison used Fisher's exact test for dichotomous variables, and chi-squared test for other variables.
untreated psychosis across the yearly cohorts in new and established services separately. We used logistic regression analysis with DUP less than 6 months as the dependent variable and yearly cohorts, new/established EIS, and the interaction of these as the independent variables. Since the interaction term was significant, the proportion of subjects with DUP less than 6 months in each cohort was compared using the chi-squared test with the test for linear trends across cohorts for new and established teams separately. We based our power calculation on the ability to detect a clinically significant difference of 10% in the number of people treated in less than 6 months in new and established teams. A two-group continuity corrected chi-squared test with a 0.050 two-sided significance level has 80% power to detect the difference between 70% for established teams and 60% for new teams (odds ratio of 1.556) when the sample size in each group is 376. 3. Results 3.1. Participants Over the recruitment period 2097 new patients were incepted into participating EIS. Of these 1027 (49%) were recruited into National EDEN. Women were more common amongst those who did not consent (34% versus 31%) but otherwise there were no significant differences
between those who did not consent and those who did. For the current study, we included 986 participants from the 1027 enrolled in National EDEN. We excluded 14 participants because they were not first episode and had been receiving criterion treatment for psychosis for some years before acceptance into EIS. We excluded an additional 10 who did not appear to have experienced psychosis according to our detailed baseline assessment, and another three who were over the age limit of 35 years at the onset of psychosis. In addition, we excluded six participants transferred from EIS who were not participating in National EDEN and eight for whom no data on duration of untreated psychosis were available. 3.2. Socio-demographic and psychiatric history data The final sample included 308 (31.2%) females and 678 males (see Table 2), with ages ranging from 14 to 35 years (mean = 22.5 years, standard deviation = 4.8 years). The mean age at the onset of prodromal (non-specific) symptoms was 19.8 years (standard deviation = 5.2), and at the onset of psychosis was 21.4 years (standard deviation = 4.9). Majority had an OPCRIT diagnosis in the schizophrenia spectrum (n = 874, 88.6%); 44 (4.5%) had bipolar disorder, and in 68 (6.9%) a diagnosis could not be assigned from the available records. Participants in the new EIS were significantly more likely to be white
Table 3 Comparison of new and established EISs for age and prodrome. Established EIS (n = 433)
Comparisona
New EIS (n = 553)
Mean
sd
n
Mean
sd
n
t
df
p
M–W p
Age accepted by EIS Age at onset of psychosis
22.2 21.3
4.63 4.80
433 433
22.4 21.5
5.02 5.06
553 553
0.9b 0.6
958 984
0.38 0.58
0.67 0.98
Duration of intervals in days Prodromec Duration of untreated psychosis (DUP)
593 300
903 636
414 433
606 325
903 642
537 553
0.2 0.6
949 984
0.83 0.56
0.97 0.25
a b c
Comparison using t-test and Mann–Whitney test. Unequal variance version of the t-test used. No date for the onset of non-specific symptoms so the prodrome cannot be calculated for 35 patients (19 in established teams and 16 in new teams).
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Table 4 Duration of untreated psychosis in days for each EIS. n
Min
Max
Median
Mean
Established EIS Birmingham Central Birmingham East East Anglia Norfolk CAMEO South Wirral West Cheshire East Cheshire All established teams
66 67 146 98 27 18 11 435
0 0 0 0 0 0 5 0
2905 2022 5652 4748 3598 298 783 5652
45 141 102 47 113 73 133 77
237 296 385 257 322 93 261 300
127 to 346 195 to 398 252 to 518 130 to 384 47 to 596 52 to 133 67 to 455 240 to 361
40 85 90 43 69 52 73 64
22 to 72 51 to 142 66 to 124 28 to 66 28 to 165 25 to 109 15 to 347 53 to 78
47 (71.2%) 37 (55.2%) 90 (61.6%) 72 (73.5%) 17 (63.0%) 16 (88.9%) 6 (54.5%) 285 (65.8%)
New EIS Lancashire Birmingham BEN Birmingham South Norfolk Kings Lynn Solihull CAMEO North Cornwall All new teams All teams
189 98 79 11 31 23 122 556 986
0 0 0 0 3 0 0 0 0
5435 4821 1900 1471 2807 857 6185 6185 6185
146 34 141 12 87 110 67 89 82
438 208 307 300 357 200 272 325 314
333 to 544 94 to 321 217 to 397 −18 to 617 144 to 569 100 to 299 141 to 402 271 to 378 274 to 354
133 24 100 15 92 68 57 72 68
103 to 173 15 to 40 66 to 154 1 to 157 45 to 187 29 to 159 40 to 82 60 to 86 60 to 78
100 (52.9%) 76 (77.6%) 43 (54.4%) 7 (63.6%) 19 (61.3%) 13 (56.5%) 82 (67.2%) 340 (61.5%) 625 (63.4%)
and born in the UK than those in the established EIS (see Table 2), but not significantly different in terms of sex, marital status, education (see Table 2), age, or length of prodrome or DUP (see Table 3). 3.3. DUP for new and established EISs Descriptive statistics for DUP for each EIS and for new and established EISs are shown in Table 4. The median DUP was less than 3 months for both new and established EISs (77 days for established EIS and 89 days for new EIS). Overall, the new and established EISs had similar durations of untreated psychosis (F1,12 = 0.27, p = 0.60 for logDUP), although there were significant differences between EISs, and within new and established EIS groups (F12,972 = 5.6, p b 0.001 for logDUP). The percentage of participants with DUP less than 6 months in the various EIS groups ranged from 52.9% at Lancashire to 88.9% at West Cheshire. This difference between EISs was highly significant (X2 = 35.0, df = 13, p = 0.001). However, overall, the new and established EISs did not have significantly different proportions of participants with DUP less than 6 months [63.4% overall, 340 (61.5%) in the new EIS compared with 285 (65.8%) in the established EIS, Fisher's exact p = 0.16]. 3.4. DUP and time since establishment of EIS We hypothesised that there would be a significant downward trend in mean DUP in the new EIS across the annual cohorts, but not in the established EIS. This hypothesis was confirmed. There was a significant interaction effect for logDUP between new/established EIS and linear trends across the yearly cohorts (t = 3.04, p = 0.002), suggesting a significantly different linear trend across the cohorts for new and established EISs. Analysing new and established EISs separately showed that there was a significant downward trend in geometric
95% CI for mean
Geometric mean
95% CI for geometric mean
Number and percentage of patients with DUP under 6 months
mean DUP for new EIS (b = −0.13, 95% confidence interval −0.22 to −0.04, p = 0.004), but no significant linear trend across the four yearly cohorts for DUP in established EIS (b = 0.05, 95% confidence interval −0.03 to 0.13, p = 0.19). Transforming these estimates back from the log scale to the original scale gives a ratio change per year of 0.74 with 95% confidence interval, 0.60 to 0.91 for new EIS, and 1.13, 95% confidence interval 0.94 to 1.36 for established EIS. The cohort geometric means and 95% confidence intervals are shown in Table 5. 3.5. Proportion of participants with DUP less than 6 months and time since establishment of EIS We also hypothesised that there would be a significant upward linear trend across the cohorts with respect to the proportion of patients with DUP less than 6 months for the new EIS, but not for the established EIS. There was a significant interaction between yearly cohort and new/ established EIS (Wald = 5.49, p = 0.019), again suggesting a significantly different linear trend across the cohorts for new and established EISs. Separate analyses showed no significant linear trend for established EIS (X2 = 0.1, df = 1, p = 0.72) and a significant upward trend for new EIS (X2 = 8.0, df = 1, p = 0.005). The number and percentage of patients with DUP less than 6 months for each yearly cohort are shown in Table 6 for new and established teams separately. 3.6. Sensitivity analyses To test the robustness of our findings we carried out three sensitivity analyses. First, we controlled for the fact that six EISs did not contribute at all to the 4th annual cohort by excluding data from participants admitted in the 4th yearly cohort (n = 108) and all the data from the six EISs (Wirral, West and East Cheshire, CAMEO North, Kings Lynn,
Table 5 Duration of untreated psychosis in 4 yearly cohorts since establishment of EIS for new and established EIS teams. Established teams
Within 1 year 1–2 years 2–3 years 3–4 years
New teams Geometric mean DUP in days
95% confidence interval
56.9 57.8 67.9 83.3
39.1 to 82.9 38.4 to 87.0 46.9 to 98.2 53.8 to 128.6
Within 1 year 1–2 years 2–3 years 3–4 years
Geometric mean DUP in days
95% confidence interval
86.7 74.8 57.9 24.5
65.9 to 114.1 56.7 to 98.6 35.3 to 94.6 10.0 to 58.7
M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6 Table 6 Number and percentage of patients with duration of untreated psychosis less than 6 months in 4 yearly cohorts since establishment of EIS for new and established EIS teams. Established teams
Within 1 year (n = 122) 1–2 years (n = 122) 2–3 years (n = 112) 3–4 years (n = 77)
New teams N
%
82 80 73 50
67.2 65.6 65.2 64.9
Within 1 year (n = 214) 1–2 years (n = 229) 2–3 years (n = 79) 3–4 years (n = 31)
N
%
119 143 54 24
55.6 62.4 68.4 77.4
and Solihull) with no data for this cohort (n = 121), leaving data for the first three year cohorts from eight of the fourteen EISs (n = 757). The linear trend for the geometric mean was then non-significant, (b = 0.05, 95%CI − 0.08 to 0.19, p = 0.43) for the established EIS, and b = − 0.09, 95% CI − 0.21 to 0.02, p = 0.11 for the new EIS, i.e. no significant downward trend for either group. However, there remained a significant upward linear trend across the remaining three yearly cohorts with respect to the proportion of participants with DUP less than 6 months for the new EIS (X2 = 4.2, df = 1, p = 0.040), but not for the established EIS (X2 = 0.1, df = 1, p = 0.77). Second, we controlled for differences in DUP between EISs using linear regression for the geometric mean, and logistic regression for the proportion of participants under 6 months. For established EIS, multiple regression with log (DUP) as the dependent variable found that neither EIS nor year cohort was significant, whereas for new EIS, year cohort remained significant even after adjusting for differences between EISs (b = −0.12, t = 2.9, p = 0.003). For established EIS, logistic regression on the proportion of patients with DUP under 6 months found that neither EIS nor year cohort was significant, whereas for new EIS, year cohort was significant when no adjustment was made for differences between EISs (Wald = 7.9, df = 3, p = 0.048), but not when EIS differences were accounted for (Wald = 2.3, df = 1, p = 0.51). Third, we controlled for differences in ethnicity (white vs nonwhite) or place of birth (born in UK or elsewhere) between new and established EISs for all the analyses which tested the relationship between time since establishment of EIS and both length of DUP and proportion of participants with DUP under 6 months. The results were virtually unchanged. 4. Discussion We found that the introduction of new early intervention services was followed by a significant decrease in the duration of untreated psychosis and a significant increase in the proportion of patients treated within six months of the onset of psychosis, in the catchment area of those services over the subsequent four years. These same parameters remained stable in the catchment areas of established early intervention services. On both outcomes, new EIS started from a lower baseline than established EIS, but gradually caught up. Since the EIS in our study had no specific early detection components, the most plausible explanation is that after the introduction of an EIS into a catchment area, people presenting with first episode psychosis in that area receive more prompt and proper treatment. 4.1. Strengths and limitations of the study The main limitation of our study is that it was not randomized, so we cannot rule out an unknown confounding factor associated with both the late introduction of EIS to an area, and a falling rate of DUP in the same area. Other possible confounding factors were a significant difference in DUP length between teams and the fact that not all teams contributed data to all four annual cohorts. However, sensitivity analyses suggest that our findings are largely robust despite these limitations. A further limitation is that nearly 50% of potential participants declined
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to participate. However, our analysis of the limited available data on non-participants suggests that they were similar to the participants. Our study is one of the largest cohort studies of people with first episode psychoses conducted yet. It involves representative samples of first episode patients from defined catchment areas including those not admitted to hospitals. It uses a standardized method of assessing DUP, and it observes the real-world effects of fundamentally transforming clinical practice on a large scale. Our results were not consistent with the findings of a systematic review that concluded that EISs were unlikely to reduce DUP unless they included an intensive public awareness campaign, which our EIS did not (Lloyd-Evans, 2011). However, this conclusion was based on data from two before and after studies that examined DUP following the introduction of a single EIS without a public awareness campaign. In the first study from Ontario, Canada, DUP actually fell from a median of 24.8 weeks to 11.6 weeks over a three-year period following the introduction of an EIS, but the fall was non-significant, suggesting that the study (n = 125) was underpowered (Scholten et al., 2003). The second study, from Copenhagen, was large enough to exclude a clinically significant effect on DUP (n = 578), but had a median DUP (52 weeks) over four times longer than National EDEN (Nordentoft et al., 2008). The authors attributed this very long DUP to differences in measurement methods, but it could also reflect unknown but important differences in the care pathway for first episode psychosis between Denmark and other countries. Our study was not designed or powered to determine precisely what caused the reduction in duration of untreated psychosis. However, on the basis of other research findings it is possible to rule out two explanations. First, it is unlikely that the reduction was caused by earlier detection of people with psychosis in the areas served by new EIS. We know this because the TIPs project has established that earlier detection can only be achieved by a sustained campaign of public education, and none of our participating EISs were engaging in such campaigns (Joa et al., 2008). Nor is it likely that the reduction was caused by EIS encouraging more rapid referrals from primary to secondary care, as a large UK randomized controlled trial (REDIRECT) has shown that even intensive engagement of EIS with primary care does not result in more rapid referrals, largely because referrals are already quite prompt (Lester et al., 2009) We therefore suspect that the explanation lies in the fact that most people in England with a first episode of psychosis have substantial contact with secondary mental health care services before they receive treatment. For example, a recent study in Birmingham found that delay within secondary mental health services accounted for 35% of mean DUP (Nordentoft et al., 2008). We think it likely that the act of setting up EIS within the organizations that provide secondary mental health care has been a catalyst for improvement leading to a more prompt response to first episode psychosis across the whole secondary system of care (Nordentoft et al., 2008). This conclusion contradicts prevailing opinion which asserts that EISs do not affect the duration of untreated psychosis unless they actively seek out “undetected” psychosis in the community through public education campaigns or in-reach into schools and colleges (Brunet et al., 2007; Lloyd-Evans et al., 2011). 4.2. Implications for clinicians and policy makers Since the implementation of EIS in England, new evidence has emerged in favour of the cost-effectiveness of the approach (McCrone et al., 2009), the more favourable illness course of those who receive it (Mihalopoulos, 2009), and the fact that EIS improves the engagement and treatment of young people with first episode psychosis compared to traditional community mental health teams (National Collaborating Centre for Mental Health, 2010). Our study adds to this evidence by suggesting that the introduction of EIS in England may have led to a significant fall in DUP. This is important for both health economies thinking of introducing EIS and also those wondering whether, at a time of international economic recession, to decommission them. It also begs the
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question what further reductions in DUP might be achieved if English EIS were commissioned to actively seek out “undetected” psychosis in the community through public education campaigns or in-reach into schools and colleges (Melle et al., 2004). Ethical approval Ethical approval was given by Suffolk Local Research Ethics Committee, UK. REC reference number: 05/Q0102/44. All participants gave informed consent before taking part. Data sharing No additional data available. Copyright licence The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and sub-licences to exploit all subsidiary rights, as set out in our licence (http://resources.bmj.com/bmj/authors/checklists-forms/ licence-for-publication). Role of funding source This research was funded by the National Institute of Health Research as part of the National EDEN study (National Institute for Health Research Programme Grants for Applied Research PO261680 and RP-PG-0109-10074). MB is part-funded by the National Institute for Health Research through the Collaborations for Leadership in Applied Health Research and Care for Birmingham and Black Country (CLAHRC-BBC) programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The funding source had no role in study design, data collection, analysis, interpretation, or writing of the report. Contributors All authors contributed to the protocol for this work. All authors other than BT and NF participated in the recruitment of participants. MM and BT analysed the data with assistance from NF, LE and NB. All authors contributed to the interpretation of the findings. MM wrote the first draft of the manuscript, which was subsequently edited by all authors who have also approved the final version. All authors had full access to the data (including statistical results and tables) and take responsibility for the integrity of the data and accuracy of the analysis. MM will act as guarantor. Conflict of interest All authors have completed the Unified Competing Interest form at www.icmje.org/ coi_disclosure.pdf (available on request from the corresponding author) and declare support from the National Institute of Health Research for the submitted work. IC is a member of the national expert panel that gives advice to pharmaceutical companies including BMS, Astra Zeneca, Jansen, and Lilly from whom he has received meeting expenses in addition to payment for talks and lectures from BMS, Astra Zeneca, and Jansen. PJ is a member of a scientific advisory board for Roche. There are no other financial relationships with any organizations that might have an interest in the submitted work in the past three years. No spouses, partners, or children have financial relationships that may be relevant to the submitted work. MM, MB, IC, NH and PJ have worked in early intervention services. Acknowledgements We thank all the EIS staff who assisted in the study. We would like to thank Dr James Kirkbride for the help with catchment area populations.
References Addington, J., Van Mastriqt, S., Hutchinson, J., Addington, D., 2002. Pathways to care: help seeking behaviour in first episode psychosis. Acta Psychiatr. Scand. 106, 358–364. Barrett, E.A., Sundet, K., Faerden, A., 2010. Suicidality before and in the early phases of first episode psychosis. Schizophr. Res. 119, 11–17. Bertelsen, M., Jeppesen, P., Petersen, L., 2009. Course of illness in a sample of 265 patients with first-episode psychosis-five-year follow-up of the Danish OPUS trial. Schizophr. Res. 107, 173–178. Bertolote, J., McGorry, P., 2005. Early intervention and recovery for young people with early psychosis: consensus statement. Br. J. Psychiatry Suppl. 48, 116–119. Birchwood, M., Lester, H., McCarthy, L., Jones, P., Fowler, D., Amos, T., Freemantle, N., Sharma, V., Lavis, A., Singh, S., Marshall, M., 2014. The UK National evaluation of the development and impact of early intervention services (The National Eden Studies): study rationale, design and baseline characteristics. Early Interv. Psychiatry 8 (1), 59–67. Brunet, K.B., Lester, M., Thornhill, H.K., 2007. Delays in mental health services and duration of untreated psychosis. Psychiatr. Bull. 31, 408–410. The NHS Plan: A Summary. Department of Health, London. Improvement, Expansion and Reform: The Next 3 Years — Priorities and Planning Framework 2003–2006. Department of Health, London. Joa, I., Johannessen, J.O., Auestad, B., Friis, S., McGlashan, T., Melle, I., Opjordsmoen, S., Simonsen, E., Vaglum, P., Larsen, T.K., 2008. The key to reducing duration of untreated first psychosis: information campaigns. Schizophr. Bull. 34 (3), 466–472. Joint Formulary Committee, 2005. British National Formulary, 49 ed. BMJ Group and Pharmaceutical Press, London. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. Larsen, T.K., McGlashan, T.H., Moe, L.C., 1996. First-episode schizophrenia: I. Early course parameters. Schizophr. Bull. 22, 241–256. Lester, H., Birchwood, M., Freemantle, N., Michall, M., Tait, L., 2009. REDIRECT: cluster randomised controlled trial of GP training in first-episode psychosis. Br. J. Gen. Pract. 59 (563), e183–e190. Lloyd-Evans, B., Crosby, M., Stockton, S., Pilling, S., Hobbs, L., Hinton, M., Johnson, S., 2011. Initiatives to shorten duration of untreated psychosis: systematic review. Br. J. Psychiatry 198, 256–263. Marshall, M., Lewis, S., Lockwood, A., Drake, R., Jones, P., Croudace, T., 2005. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients. Arch. Gen. Psychiatry 62, 975–983. McCrone, P., Knapp, M., Dhanasiri, S., 2009. Economic impact of services for first-episode psychosis: a decision model approach. Early Interv. Psychiatry 3, 266–273. McGuffin, P., Farmer, A., Harvey, I., 1991. A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system. Arch. Gen. Psychiatry 48, 764–770. Melle, I., Larsen, T.K., Haahr, U., Friis, S., Johannessen, J.O., Opjordsmoen, S., Simonsen, E., Rund, B.R., Vaglum, P., McGlashan, T., 2004. Reducing the duration of untreated firstepisode psychosis: effects on clinical presentation. Arch. Gen. Psychiatry 61, 143–150. Mihalopoulos, C., 2009. Why invest in early psychosis intervention services? Early Interv. Psychiatry 3, 237–238. National Collaborating Centre for Mental Health, 2010. Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. The British Psychological Society and the Royal College of Psychiatrists (Report No CG 82). Nielssen, O., Large, M., 2008. Rates of homicide during the first episode of psychosis and after treatment: a systematic review and meta-analysis. Schizophr. Bull. 36, 702–712. Nielssen, O., Yee, N., Millard, M., Large, M., 2011. Comparison of first-episode and previously treated persons with psychosis found NGMI for a violent offense. Psychiatr. Serv. 62, 759–764. Nordentoft, M., Thorup, A., Petersen, L., Ohlenschlaeger, J., Christensen, T.O., Krarup, G., Jorgensen, P., Jeppesen, P., 2008. Does a detection team shorten duration of untreated psychosis? Early Interv. Psychiatry 2 (1), 22–26. Norman, R.M., Malla, A.K., 2001. Duration of untreated psychosis: a critical examination of the concept and its importance. Psychol. Med. 31, 381–400. Perkins, D.O., Gu, H., Boteva, K., Lieberman, J.A., 2005. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am. J. Psychiatry 162, 1785–1804. Scholten, D., Malla, A., Norman, R., McLean, T.S., McIntosh, E.M., McDonald, C.L., Eliasziw, M., Speechley, K.N., 2003. Removing barriers to treatment of first episode psychotic disorders. Can. J. Psychiatr. 48 (8), 561–565.
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Impact of early intervention services on duration of untreated psychosis: Data from the National EDEN prospective cohort study Max Marshall a,⁎, Nusrat Husain a, Natalie Bork a, Imran B. Chaudhry a, Helen Lester b, Linda Everard b, Swaran P. Singh c, Nick Freemantle d, Vimal Sharma e, Peter B. Jones f, David Fowler g, Tim Amos h, Barbara Tomenson a, Max Birchwood b a
School of Medicine, University of Manchester, United Kingdom University of Birmingham, Birmingham, United Kingdom c Health Sciences Research Institute, University of Warwick, Warwick, United Kingdom d Department of Primary Care and Population Health, University College, London, United Kingdom e University of Cheshire, United Kingdom f Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom g School of Medicine, University of East Anglia, United Kingdom h Academic Unit of Psychiatry, University of Bristol, Bristol, United Kingdom b
a r t i c l e
i n f o
Article history: Received 5 December 2013 Received in revised form 5 July 2014 Accepted 10 July 2014 Available online 5 August 2014 Keywords: Early Intervention Service Psychosis Duration of untreated psychosis
a b s t r a c t Objective: This study aimed to determine if the inception of Early Intervention Services (EISs) is followed by an improvement in the prompt treatment of people with first episode psychosis. Method: A prospective cohort study of referrals to new and established EISs was conducted at 1, 2, 3, and 4 years after inception of new EIS. The study was conducted with 14 (seven new and seven established) secondary care EIS within geographically defined catchment areas in England between 2005 and 2009. Participants included 1027 consecutive referrals to EIS aged 14–35 with a first episode of psychosis. Duration of untreated psychosis (DUP) and number of participants treated adequately within 6 months of onset were the main outcome measures. Results: A significant downward trend across yearly cohorts for DUP for new EIS (F1,549 = 8.4, p = 0.004) but not for established EIS (F1,429 = 1.7, p = 0.19) was observed. There was a significant upward trend across cohorts in the proportion of referrals treated within 6 months for new EIS (X2 = 8.0, df = 1, p = 0.005), but not for established EIS (X2 = 0.1, df = 1, p = 0.72). Conclusion: The introduction of new EIS was followed by a reduction in DUP and an increase in the proportion of patients treated within 6 months of onset. These trends were not present in the catchment areas of established services where DUP was initially lower, suggesting that there was no general tendency for DUP to fall over time. Hence, the introduction of an EIS was followed by an improvement in the prompt and proper treatment of first episode psychosis. © 2014 Published by Elsevier B.V.
1. Introduction The duration of untreated psychosis (DUP) is the time from the first psychotic symptom to the initiation of adequate neuroleptic treatment (Norman and Malla, 2001). There are three compelling reasons for shortening DUP. The first is to avoid the social consequences of active psychosis such as homelessness, unemployment, and social isolation ⁎ Corresponding author at: The LANTERN Centre, Vicarage Lane, Fulwood, Preston PR2 8DY, United Kingdom. Tel.: +44 1772 773500; fax: 44 1772 718268. E-mail address: [email protected] (M. Marshall).
http://dx.doi.org/10.1016/j.schres.2014.07.005 0920-9964/© 2014 Published by Elsevier B.V.
(Addington et al., 2002, Bertelsen et al., 2009). The second is to improve prognosis because a shorter DUP is associated with a better recovery across a broad range of outcomes (Marshall et al., 2005, Perkins et al., 2005). The third is to reduce the risk that a person with psychosis will seriously harm himself or other people because this risk is greatest during the untreated period of their first episode, and increases with the length of the episode (Nielssen and Large, 2008, Barrett et al., 2010, Nielssen et al., 2011). It has been proposed that specialist teams for the treatment of early psychosis (known as Early Intervention Services or EISs) could reduce the duration of untreated psychosis by promoting prompt and
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M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6
proper treatment (Bertolote and McGorry, 2005). However, this proposition is difficult to test in a randomized controlled trial as it would require a complex cluster randomized design in which EIS was randomly allocated to localities (Lloyd-Evans et al., 2011). Whilst the proposition has some support from small before and after designs conducted in single localities, a recent systematic review of the limited evidence concluded that “establishing early intervention services probably does not on its own reduce DUP (Lloyd-Evans et al., 2011)”. A unique aspect of the English National Health Service is that EIS looks after all young adults with a first episode of psychosis, following a national policy introduced in 2000 (Department of Health, 2000). In 2003, the English Department of Health set two national targets for EIS: to reduce the median DUP to 3 months, and to minimize the number of people with a DUP of greater than 6 months (Norman and Malla, 2001, Department of Health, 2003). Whilst the policy of establishing EIS was announced in 2000, implementation was initially patchy due to cost and complexity. In 2005, when the National EDEN longitudinal study of people receiving care from EIS started, national coverage was still variable. This afforded an opportunity to observe the effects of introducing new EIS on the duration of untreated psychosis. We hypothesised that over four years the duration of untreated psychosis and the proportion of participants with a DUP of greater than 6 months would fall significantly in the catchment areas of new EIS, whilst the same parameters would remain stable in the catchment areas of established EIS. 2. Methods National EDEN (2005–16) is a longitudinal cohort study of referrals to early intervention services in five socioeconomically diverse sites across England: Birmingham, Cornwall, Cambridgeshire, Norwich, and Lancashire/Cheshire. We chose sites purposively to reflect urban/rural differences. One of our core research objectives for National EDEN was to determine the duration of untreated psychosis in referrals to early intervention services in England (Birchwood et al., 2014). For the present study, we identified, from National EDEN, a prospective cohort of first referrals to EIS at 1, 2, 3, and 4 years after the establishment of new EIS and compared this cohort with a contemporaneous cohort of first referrals to EIS. Fourteen EISs participated at the five sites, each within a defined geographical catchment area, from where they accepted all new cases of first episode psychosis in people aged 14–35. We classified participating EIS into those that had been set up for less than one year when data collection started (new services), and those that had been set up for more than one year when collection started (established services) (see Table 1).
Table 1 New and established Early Intervention Services in National EDEN. Team New Lancashirea Birmingham BENa Birmingham Southa Kings Lynn, Norfolk Birmingham–Solihull Cameo North, Cambridge Cornwalla Established Birmingham Centrala Birmingham Easta East Anglia Norfolka Cameo Southa Wirral West Cheshire East Cheshire a
Catchment area size (100 k pop)
Set up date
Study Entry date
N in study
1,306,000 383,300 392,800 188,600 205,000 311,274 536,000
2005 2005 2005 2007 2006 2007 2005
2006 2005 2006 2007 2007 2008 2006
189 98 79 11 31 23 122
310,000 132,800 633,400 466,911 468,000 260,000 315,000
1995 2002 2003 2002 2005 2004 2005
2005 2005 2005 2005 2007 2007 2007
66 67 146 98 27 18 11
Teams with data for more than 3 years (included in sensitivity analysis).
We approached all referrals accepted by participating EISs from August 2005 to April 2009. However, not all EISs were recruited for the whole period (see Table 1). Our inclusion criteria were the following: aged 14 to 35 and accepted into a participating EIS following a first episode of psychosis. We obtained informed consent from all participants. Research assistants, not directly involved in clinical care, assessed participants at intake to the study and performed 6 and 12-month follow-ups. We evaluated DUP using an internationally accepted standardized definition and methodology (Larsen et al., 1996) that defined the onset of psychosis as one symptom from the positive scale of the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) at a level of 4 or above, or a cluster of symptoms including either delusions, conceptual disorganisation, or hallucinations, with a total score of 7 or more (excluding ‘absent’ scorings). Symptoms had to be present for a period of two weeks or more (unless remission was due to treatment). We defined the end of the period of untreated psychosis as the onset of criterion treatment with antipsychotic medication (Joint Formulary Committee, 2005). In some cases participants never received criterion treatment despite being under the care of an EIS. Some who did not receive criterion treatment recovered nonetheless, so that they were no longer psychotic when assessed at intake to the study or at 6 or 12-month follow-ups. For these participants we added 0, 6, or 12 months to the duration of untreated psychosis depending on the follow-up point at which they were judged to be no longer psychotic. The remainder of the group who never received criterion treatment remained psychotic throughout the study, and their duration of untreated psychosis was increased by 12 months. Diagnosis was established using the OPCRIT (Operational Criteria) computerized diagnostic system. OPCRIT is a 90-item checklist of symptoms rated by a researcher from the participant's clinical case notes. OPCRIT generates diagnoses according to 12 operational diagnostic systems (including ICD 10, DSM-III, and DSM-IIIR). OPCRIT has been used in a wide range of psychiatric research and has proven to be both reliable and valid (McGuffin et al., 1991). 2.1. Statistical analysis We present descriptive statistics for the whole sample and for new and established EISs separately. We compared new and established EISs using chi-squared tests for categorical variables, and t-tests and Mann–Whitney tests for ages, duration between key dates, and logtransformed duration of untreated psychosis. We present medians and geometric means with 95% confidence intervals for duration of untreated psychosis as it is positively skewed and lognormally distributed. Nested one-way analysis of variance was used to estimate the difference between new and established services as well as the difference between individual services within these two groups. We calculated proportions of referrals with DUP less than 6 months by service, by new versus established service, and for the whole group. For comparisons between services and between new and established services we used Fisher's exact test. We investigated whether DUP was stable over time in the catchment areas of established services whilst falling over time in the catchment areas of new services as they became established, by studying duration of untreated psychosis between new and established services across four yearly cohorts, using as baseline for each service the date when the first subject from that service entered the study. Some services were being offered through National EDEN from the beginning and had patients in all 4 yearly sequential cohorts; later services had fewer. Multiple regression was used with log (DUP) as the dependent variable and yearly cohorts, new/established team status, and the interaction of these as the independent variables. Since the interaction term was significant, we used one-way analysis of variance to estimate a linear trend in geometric mean duration of
M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6
3
Table 2 Comparison of participants in established and new EISs. Whole group (n = 986)
Established EIS (n = 433)
Sig.a
New EIS (n = 553)
Risk or protective factor
n/N
%
n/N
%
n/N
%
p
Female Ethnic origin: White Asian Black Mixed/other Born in the UK Fluent in English Marital status: Single Married/cohabiting Separated or divorced Living situation: Alone With parents/guardians With partner Other Educated to A level or higher In paid work Ever used drugs Schizophrenia in 1st degree relative
308
31.2
136
31.4
172
31.1
0.95
714 153 71 48 884/972 942
72.4 15.5 7.2 4.9 90.9 95.5
288 85 40 20 374/425 408
66.5 19.6 9.2 4.6 88.0 94.2
426 68 31 28 510/547 534
77.0 12.3 5.6 5.1 93.2 96.6
X2 = 16.7 df = 3 P = 0.001
835 123 28
84.7 12.5 2.8
362 59 12
83.6 13.6 2.8
473 64 16
85.5 11.6 2.9
X2 = 0.9 df = 2 p = 0.63
126 623 104 130 341 185 626/951 91/880
12.8 63.4 10.6 13.2 34.6 18.8 65.8 10.3
54 257 49 71 161 87 263/412 40/379
12.5 59.6 11.4 16.5 37.2 20.1 63.8 10.6
72 366 55 59 180 98 363/539 51/501
13.0 66.3 10.0 10.7 32.5 17.7 67.3 10.2
X2 = 8.3 df = 3 p = 0.040
0.007 0.088
0.14 0.37 0.27 0.91
n = number of patients in the group with the risk or protective factor. N = total number of patients in the group. N = 433 for established teams, and N = 553 for new teams unless otherwise stated. a Comparison used Fisher's exact test for dichotomous variables, and chi-squared test for other variables.
untreated psychosis across the yearly cohorts in new and established services separately. We used logistic regression analysis with DUP less than 6 months as the dependent variable and yearly cohorts, new/established EIS, and the interaction of these as the independent variables. Since the interaction term was significant, the proportion of subjects with DUP less than 6 months in each cohort was compared using the chi-squared test with the test for linear trends across cohorts for new and established teams separately. We based our power calculation on the ability to detect a clinically significant difference of 10% in the number of people treated in less than 6 months in new and established teams. A two-group continuity corrected chi-squared test with a 0.050 two-sided significance level has 80% power to detect the difference between 70% for established teams and 60% for new teams (odds ratio of 1.556) when the sample size in each group is 376. 3. Results 3.1. Participants Over the recruitment period 2097 new patients were incepted into participating EIS. Of these 1027 (49%) were recruited into National EDEN. Women were more common amongst those who did not consent (34% versus 31%) but otherwise there were no significant differences
between those who did not consent and those who did. For the current study, we included 986 participants from the 1027 enrolled in National EDEN. We excluded 14 participants because they were not first episode and had been receiving criterion treatment for psychosis for some years before acceptance into EIS. We excluded an additional 10 who did not appear to have experienced psychosis according to our detailed baseline assessment, and another three who were over the age limit of 35 years at the onset of psychosis. In addition, we excluded six participants transferred from EIS who were not participating in National EDEN and eight for whom no data on duration of untreated psychosis were available. 3.2. Socio-demographic and psychiatric history data The final sample included 308 (31.2%) females and 678 males (see Table 2), with ages ranging from 14 to 35 years (mean = 22.5 years, standard deviation = 4.8 years). The mean age at the onset of prodromal (non-specific) symptoms was 19.8 years (standard deviation = 5.2), and at the onset of psychosis was 21.4 years (standard deviation = 4.9). Majority had an OPCRIT diagnosis in the schizophrenia spectrum (n = 874, 88.6%); 44 (4.5%) had bipolar disorder, and in 68 (6.9%) a diagnosis could not be assigned from the available records. Participants in the new EIS were significantly more likely to be white
Table 3 Comparison of new and established EISs for age and prodrome. Established EIS (n = 433)
Comparisona
New EIS (n = 553)
Mean
sd
n
Mean
sd
n
t
df
p
M–W p
Age accepted by EIS Age at onset of psychosis
22.2 21.3
4.63 4.80
433 433
22.4 21.5
5.02 5.06
553 553
0.9b 0.6
958 984
0.38 0.58
0.67 0.98
Duration of intervals in days Prodromec Duration of untreated psychosis (DUP)
593 300
903 636
414 433
606 325
903 642
537 553
0.2 0.6
949 984
0.83 0.56
0.97 0.25
a b c
Comparison using t-test and Mann–Whitney test. Unequal variance version of the t-test used. No date for the onset of non-specific symptoms so the prodrome cannot be calculated for 35 patients (19 in established teams and 16 in new teams).
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M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6
Table 4 Duration of untreated psychosis in days for each EIS. n
Min
Max
Median
Mean
Established EIS Birmingham Central Birmingham East East Anglia Norfolk CAMEO South Wirral West Cheshire East Cheshire All established teams
66 67 146 98 27 18 11 435
0 0 0 0 0 0 5 0
2905 2022 5652 4748 3598 298 783 5652
45 141 102 47 113 73 133 77
237 296 385 257 322 93 261 300
127 to 346 195 to 398 252 to 518 130 to 384 47 to 596 52 to 133 67 to 455 240 to 361
40 85 90 43 69 52 73 64
22 to 72 51 to 142 66 to 124 28 to 66 28 to 165 25 to 109 15 to 347 53 to 78
47 (71.2%) 37 (55.2%) 90 (61.6%) 72 (73.5%) 17 (63.0%) 16 (88.9%) 6 (54.5%) 285 (65.8%)
New EIS Lancashire Birmingham BEN Birmingham South Norfolk Kings Lynn Solihull CAMEO North Cornwall All new teams All teams
189 98 79 11 31 23 122 556 986
0 0 0 0 3 0 0 0 0
5435 4821 1900 1471 2807 857 6185 6185 6185
146 34 141 12 87 110 67 89 82
438 208 307 300 357 200 272 325 314
333 to 544 94 to 321 217 to 397 −18 to 617 144 to 569 100 to 299 141 to 402 271 to 378 274 to 354
133 24 100 15 92 68 57 72 68
103 to 173 15 to 40 66 to 154 1 to 157 45 to 187 29 to 159 40 to 82 60 to 86 60 to 78
100 (52.9%) 76 (77.6%) 43 (54.4%) 7 (63.6%) 19 (61.3%) 13 (56.5%) 82 (67.2%) 340 (61.5%) 625 (63.4%)
and born in the UK than those in the established EIS (see Table 2), but not significantly different in terms of sex, marital status, education (see Table 2), age, or length of prodrome or DUP (see Table 3). 3.3. DUP for new and established EISs Descriptive statistics for DUP for each EIS and for new and established EISs are shown in Table 4. The median DUP was less than 3 months for both new and established EISs (77 days for established EIS and 89 days for new EIS). Overall, the new and established EISs had similar durations of untreated psychosis (F1,12 = 0.27, p = 0.60 for logDUP), although there were significant differences between EISs, and within new and established EIS groups (F12,972 = 5.6, p b 0.001 for logDUP). The percentage of participants with DUP less than 6 months in the various EIS groups ranged from 52.9% at Lancashire to 88.9% at West Cheshire. This difference between EISs was highly significant (X2 = 35.0, df = 13, p = 0.001). However, overall, the new and established EISs did not have significantly different proportions of participants with DUP less than 6 months [63.4% overall, 340 (61.5%) in the new EIS compared with 285 (65.8%) in the established EIS, Fisher's exact p = 0.16]. 3.4. DUP and time since establishment of EIS We hypothesised that there would be a significant downward trend in mean DUP in the new EIS across the annual cohorts, but not in the established EIS. This hypothesis was confirmed. There was a significant interaction effect for logDUP between new/established EIS and linear trends across the yearly cohorts (t = 3.04, p = 0.002), suggesting a significantly different linear trend across the cohorts for new and established EISs. Analysing new and established EISs separately showed that there was a significant downward trend in geometric
95% CI for mean
Geometric mean
95% CI for geometric mean
Number and percentage of patients with DUP under 6 months
mean DUP for new EIS (b = −0.13, 95% confidence interval −0.22 to −0.04, p = 0.004), but no significant linear trend across the four yearly cohorts for DUP in established EIS (b = 0.05, 95% confidence interval −0.03 to 0.13, p = 0.19). Transforming these estimates back from the log scale to the original scale gives a ratio change per year of 0.74 with 95% confidence interval, 0.60 to 0.91 for new EIS, and 1.13, 95% confidence interval 0.94 to 1.36 for established EIS. The cohort geometric means and 95% confidence intervals are shown in Table 5. 3.5. Proportion of participants with DUP less than 6 months and time since establishment of EIS We also hypothesised that there would be a significant upward linear trend across the cohorts with respect to the proportion of patients with DUP less than 6 months for the new EIS, but not for the established EIS. There was a significant interaction between yearly cohort and new/ established EIS (Wald = 5.49, p = 0.019), again suggesting a significantly different linear trend across the cohorts for new and established EISs. Separate analyses showed no significant linear trend for established EIS (X2 = 0.1, df = 1, p = 0.72) and a significant upward trend for new EIS (X2 = 8.0, df = 1, p = 0.005). The number and percentage of patients with DUP less than 6 months for each yearly cohort are shown in Table 6 for new and established teams separately. 3.6. Sensitivity analyses To test the robustness of our findings we carried out three sensitivity analyses. First, we controlled for the fact that six EISs did not contribute at all to the 4th annual cohort by excluding data from participants admitted in the 4th yearly cohort (n = 108) and all the data from the six EISs (Wirral, West and East Cheshire, CAMEO North, Kings Lynn,
Table 5 Duration of untreated psychosis in 4 yearly cohorts since establishment of EIS for new and established EIS teams. Established teams
Within 1 year 1–2 years 2–3 years 3–4 years
New teams Geometric mean DUP in days
95% confidence interval
56.9 57.8 67.9 83.3
39.1 to 82.9 38.4 to 87.0 46.9 to 98.2 53.8 to 128.6
Within 1 year 1–2 years 2–3 years 3–4 years
Geometric mean DUP in days
95% confidence interval
86.7 74.8 57.9 24.5
65.9 to 114.1 56.7 to 98.6 35.3 to 94.6 10.0 to 58.7
M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6 Table 6 Number and percentage of patients with duration of untreated psychosis less than 6 months in 4 yearly cohorts since establishment of EIS for new and established EIS teams. Established teams
Within 1 year (n = 122) 1–2 years (n = 122) 2–3 years (n = 112) 3–4 years (n = 77)
New teams N
%
82 80 73 50
67.2 65.6 65.2 64.9
Within 1 year (n = 214) 1–2 years (n = 229) 2–3 years (n = 79) 3–4 years (n = 31)
N
%
119 143 54 24
55.6 62.4 68.4 77.4
and Solihull) with no data for this cohort (n = 121), leaving data for the first three year cohorts from eight of the fourteen EISs (n = 757). The linear trend for the geometric mean was then non-significant, (b = 0.05, 95%CI − 0.08 to 0.19, p = 0.43) for the established EIS, and b = − 0.09, 95% CI − 0.21 to 0.02, p = 0.11 for the new EIS, i.e. no significant downward trend for either group. However, there remained a significant upward linear trend across the remaining three yearly cohorts with respect to the proportion of participants with DUP less than 6 months for the new EIS (X2 = 4.2, df = 1, p = 0.040), but not for the established EIS (X2 = 0.1, df = 1, p = 0.77). Second, we controlled for differences in DUP between EISs using linear regression for the geometric mean, and logistic regression for the proportion of participants under 6 months. For established EIS, multiple regression with log (DUP) as the dependent variable found that neither EIS nor year cohort was significant, whereas for new EIS, year cohort remained significant even after adjusting for differences between EISs (b = −0.12, t = 2.9, p = 0.003). For established EIS, logistic regression on the proportion of patients with DUP under 6 months found that neither EIS nor year cohort was significant, whereas for new EIS, year cohort was significant when no adjustment was made for differences between EISs (Wald = 7.9, df = 3, p = 0.048), but not when EIS differences were accounted for (Wald = 2.3, df = 1, p = 0.51). Third, we controlled for differences in ethnicity (white vs nonwhite) or place of birth (born in UK or elsewhere) between new and established EISs for all the analyses which tested the relationship between time since establishment of EIS and both length of DUP and proportion of participants with DUP under 6 months. The results were virtually unchanged. 4. Discussion We found that the introduction of new early intervention services was followed by a significant decrease in the duration of untreated psychosis and a significant increase in the proportion of patients treated within six months of the onset of psychosis, in the catchment area of those services over the subsequent four years. These same parameters remained stable in the catchment areas of established early intervention services. On both outcomes, new EIS started from a lower baseline than established EIS, but gradually caught up. Since the EIS in our study had no specific early detection components, the most plausible explanation is that after the introduction of an EIS into a catchment area, people presenting with first episode psychosis in that area receive more prompt and proper treatment. 4.1. Strengths and limitations of the study The main limitation of our study is that it was not randomized, so we cannot rule out an unknown confounding factor associated with both the late introduction of EIS to an area, and a falling rate of DUP in the same area. Other possible confounding factors were a significant difference in DUP length between teams and the fact that not all teams contributed data to all four annual cohorts. However, sensitivity analyses suggest that our findings are largely robust despite these limitations. A further limitation is that nearly 50% of potential participants declined
5
to participate. However, our analysis of the limited available data on non-participants suggests that they were similar to the participants. Our study is one of the largest cohort studies of people with first episode psychoses conducted yet. It involves representative samples of first episode patients from defined catchment areas including those not admitted to hospitals. It uses a standardized method of assessing DUP, and it observes the real-world effects of fundamentally transforming clinical practice on a large scale. Our results were not consistent with the findings of a systematic review that concluded that EISs were unlikely to reduce DUP unless they included an intensive public awareness campaign, which our EIS did not (Lloyd-Evans, 2011). However, this conclusion was based on data from two before and after studies that examined DUP following the introduction of a single EIS without a public awareness campaign. In the first study from Ontario, Canada, DUP actually fell from a median of 24.8 weeks to 11.6 weeks over a three-year period following the introduction of an EIS, but the fall was non-significant, suggesting that the study (n = 125) was underpowered (Scholten et al., 2003). The second study, from Copenhagen, was large enough to exclude a clinically significant effect on DUP (n = 578), but had a median DUP (52 weeks) over four times longer than National EDEN (Nordentoft et al., 2008). The authors attributed this very long DUP to differences in measurement methods, but it could also reflect unknown but important differences in the care pathway for first episode psychosis between Denmark and other countries. Our study was not designed or powered to determine precisely what caused the reduction in duration of untreated psychosis. However, on the basis of other research findings it is possible to rule out two explanations. First, it is unlikely that the reduction was caused by earlier detection of people with psychosis in the areas served by new EIS. We know this because the TIPs project has established that earlier detection can only be achieved by a sustained campaign of public education, and none of our participating EISs were engaging in such campaigns (Joa et al., 2008). Nor is it likely that the reduction was caused by EIS encouraging more rapid referrals from primary to secondary care, as a large UK randomized controlled trial (REDIRECT) has shown that even intensive engagement of EIS with primary care does not result in more rapid referrals, largely because referrals are already quite prompt (Lester et al., 2009) We therefore suspect that the explanation lies in the fact that most people in England with a first episode of psychosis have substantial contact with secondary mental health care services before they receive treatment. For example, a recent study in Birmingham found that delay within secondary mental health services accounted for 35% of mean DUP (Nordentoft et al., 2008). We think it likely that the act of setting up EIS within the organizations that provide secondary mental health care has been a catalyst for improvement leading to a more prompt response to first episode psychosis across the whole secondary system of care (Nordentoft et al., 2008). This conclusion contradicts prevailing opinion which asserts that EISs do not affect the duration of untreated psychosis unless they actively seek out “undetected” psychosis in the community through public education campaigns or in-reach into schools and colleges (Brunet et al., 2007; Lloyd-Evans et al., 2011). 4.2. Implications for clinicians and policy makers Since the implementation of EIS in England, new evidence has emerged in favour of the cost-effectiveness of the approach (McCrone et al., 2009), the more favourable illness course of those who receive it (Mihalopoulos, 2009), and the fact that EIS improves the engagement and treatment of young people with first episode psychosis compared to traditional community mental health teams (National Collaborating Centre for Mental Health, 2010). Our study adds to this evidence by suggesting that the introduction of EIS in England may have led to a significant fall in DUP. This is important for both health economies thinking of introducing EIS and also those wondering whether, at a time of international economic recession, to decommission them. It also begs the
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M. Marshall et al. / Schizophrenia Research 159 (2014) 1–6
question what further reductions in DUP might be achieved if English EIS were commissioned to actively seek out “undetected” psychosis in the community through public education campaigns or in-reach into schools and colleges (Melle et al., 2004). Ethical approval Ethical approval was given by Suffolk Local Research Ethics Committee, UK. REC reference number: 05/Q0102/44. All participants gave informed consent before taking part. Data sharing No additional data available. Copyright licence The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and sub-licences to exploit all subsidiary rights, as set out in our licence (http://resources.bmj.com/bmj/authors/checklists-forms/ licence-for-publication). Role of funding source This research was funded by the National Institute of Health Research as part of the National EDEN study (National Institute for Health Research Programme Grants for Applied Research PO261680 and RP-PG-0109-10074). MB is part-funded by the National Institute for Health Research through the Collaborations for Leadership in Applied Health Research and Care for Birmingham and Black Country (CLAHRC-BBC) programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The funding source had no role in study design, data collection, analysis, interpretation, or writing of the report. Contributors All authors contributed to the protocol for this work. All authors other than BT and NF participated in the recruitment of participants. MM and BT analysed the data with assistance from NF, LE and NB. All authors contributed to the interpretation of the findings. MM wrote the first draft of the manuscript, which was subsequently edited by all authors who have also approved the final version. All authors had full access to the data (including statistical results and tables) and take responsibility for the integrity of the data and accuracy of the analysis. MM will act as guarantor. Conflict of interest All authors have completed the Unified Competing Interest form at www.icmje.org/ coi_disclosure.pdf (available on request from the corresponding author) and declare support from the National Institute of Health Research for the submitted work. IC is a member of the national expert panel that gives advice to pharmaceutical companies including BMS, Astra Zeneca, Jansen, and Lilly from whom he has received meeting expenses in addition to payment for talks and lectures from BMS, Astra Zeneca, and Jansen. PJ is a member of a scientific advisory board for Roche. There are no other financial relationships with any organizations that might have an interest in the submitted work in the past three years. No spouses, partners, or children have financial relationships that may be relevant to the submitted work. MM, MB, IC, NH and PJ have worked in early intervention services. Acknowledgements We thank all the EIS staff who assisted in the study. We would like to thank Dr James Kirkbride for the help with catchment area populations.
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