Treatment delay and response rate in firstepisode psychosis

Wunderink A, Nienhuis FJ, Sytema S, Wiersma D. Treatment delay andresponse rate in first episode psychosis.

Objective: There is no consistent evidence of long duration ofuntreated psychosis (DUP) predicting long time to response(TTR) in first psychosis. This study aims to investigate thepredictors of DUP and TTR in a first episode patientpopulation.Method: An epidemiologically representative sample of 157 non-affective first psychotic episode patients was interviewed and followed-up for at least half a year.Results: The mean DUP was 46 weeks, the median 31 days. LongDUP was associated with being unemployed before treatment andmale gender. Short DUP, having a job, and living with a partner beforetreatment predicted early response.Conclusion: Early intervention likely improves short-term treatmentresponse in first episode psychosis. The best strategy to reduce DUPprobably is to direct attention to the substantial number of patientswho do not engage in regular treatment.

A. Wunderink, F. J. Nienhuis,S. Sytema, D. WiersmaDepartment of Psychiatry, University Medical CenterGroningen, University of Groningen, Groningen, TheNetherlands

Key words: psychotic disorders; schizophrenia; earlydiagnosis

A. Wunderink MD, Department of Psychiatry, UniversityMedical Center Groningen, University of Groningen,PO Box 30.001, 9700 RB Groningen, The Netherlands.E-mail: a.wunderink@med.umcg.nl

Accepted for publication September 28, 2005

Significant outcomes

• Longer DUP is associated with longer time to treatment response in first episode psychosis.• Being employed and living with a partner before treatment are associated with early treatment

response, controlling for DUP and other posited predictors.

Limitations

• The study sample is not representative for patients with an age at onset of psychosis before 18 yearsof age.

• Non-participants differed from the study sample regarding educational level (lower), vocationalstatus (more unemployed) and DUP (longer). They are less adherent to mental health care.

Introduction

Early intervention in psychotic disorders hasbecome a major focus in modern mental healthcare (1, 2). A lengthy delay between the onset ofpsychotic symptoms and the start of antipsychotictreatment is a common finding in first episode

studies. Studies from a variety of countries provideestimates of time between onset of psychosis andinitiation of treatment (duration of untreatedpsychosis, or DUP) – the means of which varybetween 22 weeks to over 150 weeks, and themedians between 4 and 26 weeks (3–5). For DUPthe median is a more appropriate measure of

Acta Psychiatr Scand 2006: 113: 332–339All rights reservedDOI: 10.1111/j.1600-0447.2005.00685.x

Copyright � 2005 Blackwell Munksgaard

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central tendency than the mean, because of itsmarked positively skewed distribution. Long DUPwas shown to predict longer time to response(TTR) by a number of studies (6–8), but not all (9,10). This inconsistency might be because of theskewed distribution of DUP, suggesting the appro-priateness of transformations or nonparametricanalyses. Some studies did not apply these (11).Selective sampling of patients and confoundingeffects by potential predictors of treatmentresponse might also account for contradictoryfindings. It is important to control for variablesthat may determine DUP and that have been foundin the past to predict treatment outcome. Gender,length of the prodromal period, age at onset ofpsychosis, premorbid social functioning, drugabuse and urban living environment have beenposited as confounders of an association betweenDUP and outcome (6, 12). The associationbetween posited predictors and DUP was incon-sistently demonstrated (11, 13–16). The disen-tanglement of the potentially complex relationbetween DUP, TTR and conceivable confoundersis an important issue because, if DUP is causallyrelated to treatment response, it may be one of thefew factors amenable to intervention.

Aims of the study

The aim of this study was to investigate thepredictors of DUP and the effect of DUP on initialtreatment response in an epidemiologically repre-sentative cohort of first psychotic episode patients,controlling for potential confounders.

Material and methods

Setting

All patients referred for the first time to mentalhealth care during a 15-month period because of afirst episode of non-affective psychosis werescreened for eligibility. The participating mentalhealth care organizations, including the Depart-ment of Psychiatry of the University MedicalCenter Groningen, cover the north-eastern partand an area in the south-west of the Netherlands,constituting a catchment area of 3.1 millioninhabitants. Communities in this area rangedfrom deprived to prosperous and from rural tourban populations. The publicly funded mentalhealth care organizations were catchment areabased. Patients were referred by general practi-tioners to out-patient departments. The treatmentprogramme for psychotic disorders included pref-erential prescription of second-generation anti-

psychotics at low dosages and individualpsychosocial and family treatment. All patientsentering the study gave written informed consent.Data concerning non-participants have been gath-ered anonymously for the purpose of bias testing.

Study design and procedures

Patients were recruited in the context of a rand-omized clinical trial on targeted vs. maintenancemedication strategies in first psychotic episodepatients. Clinicians of seven regional mentalhealth services were asked to bring all firstpsychotic episode patients to the attention of theresearch team immediately after first contact.Members of the research team asked patients togive informed consent as soon as they were able todecide about this. Research psychiatrists inter-viewed the patients to establish diagnoses using acomputerized version of the Schedules for ClinicalAssessment in Neuropsychiatry (SCAN) (17). Thesections on depression, mania, psychosis, alcoholand substance abuse were completed. The SCANinterview covered the duration of the entire episodeincluding prodromal symptoms. All patients weretreated with antipsychotics from first contact andwere followed up until they showed treatmentresponse. Response of the acute symptomatologywithin 6 months after starting antipsychotic treat-ment was a prerequisite for entering the medicationstrategy trial. The first assessment was completedfollowing response. If no response occurred duringthe first 6 months of antipsychotic treatment, theassessment was completed after this observationperiod.

Subjects

Inclusion criteria consisted of: suffering from a firstepisode of psychosis, SCAN diagnosis matchingDSM-IV schizophrenia, schizophreniform disor-der, schizoaffective disorder, brief psychotic disor-der, delusional disorder or psychotic disorder nototherwise specified (18); age 18–45 years; living inthe catchment area of one of the seven participa-ting mental health care organizations; being treat-ment-naıve (defined as not having receivedprevious antipsychotic medication above or equal-ling 1 mg haloperidol equivalents daily for morethan 3 months); command of the Dutch language;having an estimated IQ-score above 70; under-standing the nature of the study and being able togive informed consent. The research team screenedall patients referred to it from 1 October 2001through 31 December 2002 for eligibility. From atotal number of 378 patients who were screened

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257 patients were eligible. Of these 257 patients 157(61%) gave informed consent; 98 patients were notincluded because they refused treatment and/orassessment or did not show up after first contact.Two patients committed suicide. At least 44 non-participating patients did not establish regularcontacts with mental health services. Non-partici-pants differed significantly from included patientsin having a lower educational level [44.3% of non-participants (n ¼ 79) vs. 24.8% of includedpatients (n ¼ 157) had completed only primaryschool, 35.4% of non-participants vs. 58.0% ofincluded patients completed secondary school and20.3% of non-participants vs. 17.2% of includedpatients completed high school; Pearson v2 ¼11.904, d.f. ¼ 2, P ¼ 0.003], being less oftenemployed [31.0% of non-participants (n ¼ 100)vs. 43.9% of included patients (n ¼ 157) did have aregular job, Fisher’s exact test, P ¼ 0.049], andshowing a longer DUP [37.8% of non-participants(n ¼ 90) vs. 24.8% of included patients (n ¼ 157)had a DUP of longer than 6 months, 30.0% ofnon-participants vs. 46.5% of included patientshad a DUP of between 1 and 6 months, and 32.2%of non-participants vs. 28.7% of included patientshad a DUP of <1 month; Pearson v2 ¼ 7.327,d.f. ¼ 2, P ¼ 0.026]. There were no differencesbetween participants and non-participants regard-ing gender, age at first contact, marital status,living situation and illicit drug use. The anony-mous enquiry suggested that treatment responseoccurred less frequently in the non-participantgroup.

Measurements

The assessments included DUP, TTR and conceiv-able predictors: age at onset of psychosis, durationof prodromal signs, familial loading with schizo-phrenia, living and housing conditions, level ofeducation, pretreatment social functioning, level ofurbanicity and drug abuse. Relevant questionsfrom the Interview for the Retrospective Assess-ment Of Schizophrenia (IRAOS) (19) were used toassess sociodemographic characteristics and detailson the history of illness.The level of social functioning disabilities in the

month preceding referral was evaluated with theGroningen Social Disability Schedule (GSDS) (20).With this instrument role functioning in sevenareas is rated, such as self-care, housekeeping,family contacts, occupational functioning. Thetotal score was used (range 0–21, higher scoremeans more disability). DUP was defined as thetime between the onset of the first positivesymptom and the actual start of antipsychotic

treatment. Any delay of actual antipsychotictreatment after first contact (because of initialcompliance problems) was taken into account. Theonset of the first positive symptom was assessed bymeans of the SCAN interview. The SCAN proce-dure implied the assessment of the onset of eachpositive psychotic symptom separately. The onsetof the prodromal phase was defined as the onset ofany persisting psychiatric symptom other thanpositive psychotic symptoms, leading up to thepsychotic episode. Duration of the prodromalphase was calculated from this date to the onsetof the first positive symptom. The onset of the firstprodromal sign or symptom was assessed inde-pendently with the relevant questions from theIRAOS interview and the SCAN interview. In caseof conflicting data, an attempt was made toreconcile the two by acquiring additional data.TTR was defined as the time between the start ofantipsychotic treatment (minimal daily dosage ofat least 1 mg haloperidol equivalents) and treat-ment response. Treatment response was defined bytwo consecutive criteria: clinical improvement ofthe patient to a stable non-florid psychotic state asjudged by the clinician, subsequently and inde-pendently confirmed by positive and negativesyndrome scale (PANSS) positive symptom sub-scale rating, allowing for at most one item rating of4 (moderate) (21).

Training and reliability

The diagnostic SCAN interview was administeredby psychiatrists who were formally trained by aWHO Centre for Training and Research. Boostersessions were part of the study. Training includedlive patient interviews. All other scales wereadministered by other members of the researchteam. Formal training for these scales and inter-views was provided at an investigator meeting,supplemented by written training materials. Train-ing for the PANSS and GSDS included rating of avideotaped interview, followed by discussion andreview of ratings. Regular booster meetings wereorganized to maintain interrater reliability forboth scales. Reliability of the GSDS was estab-lished by 12 raters all rating the same 11 subjects.We used another 12 subjects, all rated by 11 raters,to establish the reliability of the PANSS. Wecalculated weighted kappas for each GSDS item.The square weighted kappa-scores ranged from0.55 to 0.88 for each GSDS item, with a mean of0.67. The two-way mixed model intraclass corre-lation coefficient (ICC) was used to assess thereliability of the PANSS scales. The ICC for thePANSS subscale of positive symptoms was 0.84

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and for the subscale of negative symptoms was0.83. Reliability scores between 0.41 and 0.60 aregenerally considered as moderate and scores above0.60 as good (22).

Statistical procedures

Analyses were carried out with the statisticalpackage spss (version 12.0.2; SPSS Inc., Chicago,IL, USA). First bivariate relationships were ana-lysed between DUP, TTR and conceivable orknown predictors of both treatment delay andoutcome in schizophrenia spectrum psychoses:gender, age at onset of psychosis, having a firstdegree relative with schizophrenia, educationallevel, housing with others, sharing life with apartner, urban living conditions, duration of pro-dromal signs, having a regular job, pretreatmentsocial functioning, alcohol and drug abuse. Weused nonparametric methods (the Mann–Whitneytest and the Kruskal–Wallis test for independentsamples and Spearman correlations) as both DUPand TTR had skewed distributions.Because the dependent variables in our analyses

(DUP and TTR) were time-to-event data, Coxregression analyses were applied. There were bydefinition no censored cases in the Cox regressionanalysis with DUP as the dependent variable.Censored cases in the Cox regression analysis withTTR being the dependent variable were defined asthose cases that did not respond within theobservation period (6 months after start of anti-psychotic treatment). Only nine of the 157 caseswere censored (5.7%).To examine if there were any robust determi-

nants of DUP controlling for other associatedfactors, variables showing significant relationshipswith either DUP or TTR were entered as covari-ates into a Cox regression analysis, with DUP asthe dependent variable. To explore the effects ofDUP on initial treatment response a Cox regres-sion analysis was carried out with TTR as thedependent variable and log transformed DUPadded as an independent variable.

Results

Characteristics of the included patients are shownin Table 1. Age at onset of psychosis rangedbetween 11.7 and 43.1 years of age. In males themean age at onset was significantly lower than themean age at onset in females [24.3 years (SD ¼6.0) and 28.0 years (SD ¼ 7.5) respectively, P ¼0.004]. DUP ranged between 1.0 and 1065 weeks.The mean DUP was 54.8 weeks in males (SD ¼121.4, median 8.7 weeks) and 24.4 weeks in

females (SD ¼ 79.8, median 4.4 weeks). Of 157subjects nine subjects (5.7%) did not show treat-ment response within 6 months from initiation ofantipsychotic treatment. Mean and median TTR aspresented in Table 1 were calculated for theremaining 148 subjects, who responded within26 weeks. Minimum TTR was 1 week.

Correlates of DUP and TTR

A nonparametric bivariate analysis revealed thatthe following variables: gender, age at onset ofpsychosis, pretreatment social functioning, havinga regular job, and – as expected – a diagnosis ofschizophrenia, were significantly related to DUP.Measures of association with DUP and TTR areshown in Table 2.However, because of the design of the study, the

study sample with its age range between 18 and45 years is not representative for subjects with anage at onset of psychosis before 18 years of age.For example, a subject experiencing the firstpsychotic symptoms at age 15, would only beincluded if the first contact with mental health carewas at 18 years of age or later (giving a long DUP

Table 1. Demographic and diagnostic characteristics of the sample, averages (SD),median and percentages (n ¼ 157)

Cohort characteristics n (%)*

Male gender 113 (72)Duration of prodrome: weeks, mean (SD) [median]� 85.7 (163.6) [17.1]Age at onset psychosis: years, mean (SD) [median] 25.3 (6.6) [23.1]DUP: weeks, mean (SD) [median] 46.3 (111.9) [4.4]TTR: weeks, mean (SD) [median]� 11.0 (7.4) [8.7]Married or cohabiting 22 (14.0)Housing alone� 52 (33.3)Primary school 39 (24.8)Secondary school 91 (58.0)High school, university 27 (17.2)Regular job before treatment 69 (43.9)Very urban >2500 households/km2 12 (7.6)Urban 1500–2500 37 (23.6)Intermediate 1000–1500 27 (17.2)Rural 500–1000 49 (31.2)Very rural 0–500 32 (20.4)Schizophrenia 79 (50.3)Schizophreniform disorder 31 (19.7)Schizoaffective disorder 8 (5.1)Delusional disorder 19 (12.1)Brief psychotic disorder 3 (1.9)Psychotic disorder NOS 17 (10.8)Alcohol dependence or abuse 25 (15.9)Cannabis dependence or abuse 40 (25.5)Other dependence or abuse 11 (7.0)Alcohol and cannabis dependence or abuse 12 (7.6)Any dependence or abuse 56 (35.7)

*Unless otherwise indicated numbers and percentages are presented.�n ¼ 156, one missing case.�n ¼ 148, excluding nine censored cases not responding within 6 months oftreatment.

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of 3 years). Therefore the association between theage at onset of psychosis and DUP was biased. Toexamine the bivariate association in a non-biasedsample, we repeated the bivariate analysis exclu-ding the 11 subjects who were younger than18 years at onset of psychosis. The association ofage at onset of psychosis with DUP still remainedsignificant (rs ¼ ).190, P ¼ 0.022), as well as itsassociation with TTR (rs ¼ ).228, P ¼ 0.006).DUP and TTR were moderately but significantlyinterrelated (rs ¼ 0.29; P < 0.001).Variables showing a significant relationship with

DUP were also significantly associated with TTR.Only one variable not significantly associated withDUP did show a significant relationship with TTR:sharing life with a partner.

Independent predictors of DUP

All significant variables, with the exception of thevariable �schizophrenia diagnosis�, were entered aspredictors into a Cox regression analysis with DUPas the dependent variable. The variable �schizo-phrenia diagnosis� was excluded from the analysisbecause a diagnosis of schizophrenia implies bydefinition a DUP of 6 months or more (subjectswere diagnostically assessed soon after first con-tact). We also had to deal with the interdependencydescribed above between age at onset and DUP.We decided to perform two analyses: first weanalysed the total sample without the variable �ageat onset of psychosis� (model 1 in Table 3). Second,we performed an analysis on that part of thesample not biased for age at onset by excluding the11 subjects with an age at onset before 18 years ofage. In that Cox regression analysis we includedage at onset (model 2 in Table 3).

Model 1 showed that having a regular jobremained as the only significant predictor ofDUP. Patients employed before treatment had ashorter DUP than unemployed patients. Model 2shows that age at onset was not significantlyrelated to DUP whereas gender and having a jobnow both reached significance.

Independent predictors of TTR

The variables associated with TTR in the bivariateanalysis, with the exception of age at onset, werethen entered into a Cox regression analysis withTTR as the dependent variable. We entered theindependent variables in three blocks. This hierar-chical method was chosen to see whether DUP

Table 2. Nonparametric bivariate analyses of conceivable predictors of DUP and TTR

Conceivable predictor n

Association with DUP Association with TTR

Statistic P-value Statistic P-value

Gender 157 M-W Z-score )2.409 0.016 M-W Z-score )2.009 0.045First degree relative with schizophrenia 157 M-W Z-score ).351 0.726 M-W Z-score ).441 0.659Duration of prodrome 156 rs 0.118 0.144 rs 0.087 0.283Age at onset psychosis 157 rs ).263 0.001 rs ).266 0.001DUP 157 rs 0.290 0.000Pretreatment social functioning (GSDS) 157 rs 0.258 0.001 rs 0.246 0.002Sharing life with a partner 157 M-W Z-score )1.441 0.150 M-W Z-score )3.533 0.000Housing alone 156 M-W Z-score ).749 0.454 M-W Z-score ).026 0.979Level of education 157 K-W v2 d.f. ¼ 2 0.685 0.710 K-W v2 d.f. ¼ 2 4.065 0.131Regular job before treatment 157 M-W Z-score )2.187 0.029 M-W Z-score )3.071 0.002Urban environment 157 K-W v2 d.f. ¼ 4 7.962 0.093 K-W v2 d.f. ¼ 4 8.390 0.078Schizophrenia diagnosis 157 M-W Z-score )6.579 0.000 M-W Z-score )4.344 0.000Any dependence or abuse 157 M-W Z-score )1.272 0.203 M-W Z-score ).776 0.438

DUP, duration of untreated psychosis; TTR, time to response; M-W, Mann–Whitney statistic; rs, Spearman's rho; GSDS, Groningen Social Disability Scale; K-W, Kruskal–Wallisstatistic.

Table 3. Cox regression analysis of predictors of duration of untreated psychosis(DUP)

Predictor d.f.Significantvalue

Hazardratio

95% CI for Exp(B)

Lower Upper

Model 1 in total sample (n ¼ 157)Female gender* 1 0.074 1.421 0.967 2.090Sharing life with partner * 1 0.275 1.307 0.808 2.114Having a regular job * 1 0.031 1.453 1.035 2.039GSDS social functioningtotal score

1 0.288 0.976 0.934 1.020

Model 2 in adjusted sample (n ¼ 146)�Female gender* 1 0.016 1.661 1.100 2.509Sharing life with partner * 1 0.606 1.139 0.695 1.865Having a regular job * 1 0.015 1.613 1.097 2.371GSDS social functioningtotal score

1 0.251 0.974 0.932 1.091

Age at onset of psychosis 1 0.796 0.996 0.970 1.024

*Dichotomous variable, the opposite category is the reference.�Adjusted sample only represents subjects with age at onset of psychosis above18 years of age.

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adds to the prediction of TTR in addition to otherpredictors. The latter were entered in the firstblock, including: gender, living with a partner,having a regular job and the GSDS total score.When in addition DUP (log transformed) wasadded to the model in the second block, the overallchi-square of the model significantly improved(v2 ¼ 8.76, d.f. ¼ 1, P ¼ 0.003). The model wasnot further improved by adding in the third blockall interactions of DUP with each of the otherexplanatory variables in the model (v2 ¼ 2.3,d.f. ¼ 4, P ¼ 0.681). Therefore these interactionsare not included in the final model presented inTable 4. DUP appeared to be more stronglyrelated to TTR than the other variables. Thehazard ratio of DUP without including the othervariables in the analysis (HR ¼ 0.787; P ¼ 0.001)was almost the same as when adding DUP afterincluding them (HR ¼ 0.794, P ¼ 0.003).To examine the predictive power of age at onset

regarding TTR, the Cox regression was repeatedwith the same independent variables, and age atonset added as an independent variable in the firstblock, in the adjusted sample. The results werenot different: age at onset did not significantlyadd to the model predicting TTR (not shown inTable 4).

Discussion

Determinants of DUP

We found a median DUP of 31 days, which isrelatively short compared with other studies (23,24). This might be partly explained by the longerDUP of non-participants. But more plausibly arelatively short DUP might be the merit of theDutch mental health system. The latter is charac-terized by a relatively quick referral by generalpractitioners of patients with a first episodepsychosis to mental health care, and an easyaccess to it (25).

In the present study only having a regular joband female gender remained as significant predic-tors of shorter DUP. The association with voca-tional functioning before treatment was found insome other studies (26, 27) and the association withgender as well (27, 28). What determines DUPapart from employment and gender remains poorlyunderstood. Probably many factors, both illnessrelated and environmental, interact and finallyresult in engaging in treatment. Drake et al. (13)suggested that concern of others is the key factor tobring a patient into treatment. As having a regularjob likely implies concern of others in case ofpsychotic behaviour, this view is consistent withour results.

Predictors of early treatment response

The main findings of the present study are thatshorter DUP, being employed in a regular job andhaving a partner predict shorter time to treatmentresponse. These results are in agreement with otherstudies that have examined the relationshipbetween DUP and early treatment response (7,26, 28). However, some studies did not replicatethis association, which might be because of selec-tion bias. For example, in the study by Ho et al. (9)the sampling was limited to first admissions ofpatients with schizophrenia or a schizophreniaspectrum disorder during a time frame of the last5 years. Such a sample will discard all rapidlyresponding cases and mild cases that can bemanaged on an out-patient base (6). In modernmental health care in-patient treatment is restrictedto the most severe cases. Therefore chronic patientswill be overrepresented.A strength of the present study is that we

prospectively included patients with a first psy-chotic episode, both out-patients and first admis-sions, from a described catchment area.

Limitations

Of 257 subjects meeting criteria 157 subjects wereincluded. The 100 or 39% non-participants differedfrom the included patients in having lower educa-tion, being less often employed and showing longerDUP. Their inclusion would probably have streng-thened the association of longer DUP with a longerTTR, as the non-participants have longer DUPand are less prone to reach treatment response.Longer DUP in not included subjects was alsoreported elsewhere (24). A relatively large propor-tion of at least 44% of the non-participants did notestablish any regular treatment contacts withmental health services. By implication the included

Table 4. Cox regression analysis of predictors of time to response (TTR)

Predictor d.f.Significantvalue

Hazardratio

95% CI for Exp(B)

Lower Upper

Female gender* 1 0.415 1.171 0.801 1.710Sharing life with partner* 1 0.015 1.856 1.125 3.063Having a regular job* 1 0.004 1.687 1.181 2.410GSDS social functioningtotal score

1 0.442 0.984 0.945 1.025

DUP (log transformed) 1 0.003 0.794 0.683 0.923

*Dichotomous variable, the opposite category is the reference.

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subjects can be regarded as representative of firstpsychotic episode patients who engage in regulartreatment.We assessed social functioning during the month

before entering treatment. This measure might beconsidered as an outcome of DUP instead of apossible predictor. However, some indicators ofprognostic factors have to be derived from baselineassessments because there is no way to assess themprospectively: Verdoux et al. (29) used highestGlobal Assessment of Functioning (GAF) scoresregarding the year before admission as an index ofsocial functioning in their analysis of factorsdetermining DUP; and Drake et al. (13) derivedindices from the Social Functioning Scale (30) andPANSS measured at baseline as possible determi-nants of DUP. Because of its retrospective nature,assessment of DUP is less accurate in long DUPranges, the error increasing with time. However, themajority of patients in our sample were recent onset(median DUP 31 days), causing no problems toassess the precise date of onset of positive symp-toms in most cases. As an index of morbidity beforethe presence of psychotic symptoms we used theduration of prodromal symptoms. Because of theinsidious development of prodromal symptoms, thereliability of the assessment of the time of onset ofthe prodromal phase is doubtful. The onset ofprodromal symptoms was independently assessedwith SCAN and IRAOS, with the patient and aninformant as the sources of information. In case ofconflicting data, we acquired additional informa-tion and used the most plausible date of onset.Another limitation of the present study is its

focus on early response, which is restricted tosymptomatic recovery speed (TTR). As DUP isalso related to the domain of symptoms, anassociation is quite likely. Increasingly, researchersfocus their attention on quality of life and relatedfunctional outcome domains. The impact of out-come determinants including DUP on communityfunctioning might be different from their impact onsymptomatic recovery. These outcome domains arenot dealt with in the present study. A finallimitation has already been mentioned: thesample was not representative of subjects with anage at onset before 18 years of age. This limits thevalidity of the finding that age of onset of psychosiswas unrelated to DUP to patients with an age atonset of psychosis after the age of 18.To conclude, DUP has an independent and

robust deferring effect on early treatment response.In addition to shorter DUP also having a regularjob and living with a partner before treatmentpredict early treatment response. Vocational func-tioning and having a partner relationship may

indicate a greater resilience of patients and bettercoping skills associated with a better prognosis.

Implications for intervention

These results add to the evidence that earlyintervention improves short-term outcome in firstepisode psychosis. Even in this study populationcharacterized by a relatively short DUP thisassociation is maintained. One might question thefeasibility and relevance of a further reduction ofthe DUP within the Dutch mental health system.Much effort to shorten this period will probablygain little effect. Instead of directing efforts atfinding cases of undetected first episode patients,resources are probably more effectively spent onthose first episode patients who are detected at theentrances of mental health care, but who do notengage in regular treatment. In the present studythese patients comprise 44 of 257 patients or 17%of the first contact incidence.

Declaration of interest

Zorgonderzoek Nederland Medische Wetenschap-pen (DO945-01-001), Stichting Steun V.C.V.G.Z(Arnhem), Stichting Dienstbetoon (Soesterberg),Eli Lilly Nederland B.V.

References

1. Larsen TK, Friis S, Haahr U et al. Early detection andintervention in first-episode schizophrenia: a criticalreview. Acta Psychiatr Scand 2001;103:323–334.

2. Carbone S, Harrigan S, McGorry PD, Curry C, Elkins K.Duration of untreated psychosis and 12-month outcome infirst-episode psychosis: the impact of treatment approach.Acta Psychiatr Scand 1999;100:96–104.

3. McGlashan TH. Duration of untreated psychosis in first-episode schizophrenia: marker or determinant of course?Biol Psychiatry 1999;46:899–907.

4. Norman RM,Malla AK. Duration of untreated psychosis: acritical examination of the concept and its importance.Psychol Med 2001;31:381–400.

5. Norman RM, Malla AK, Verdi MB, Hassall LD, Fazekas C.Understanding delay in treatment for first-episode psy-chosis. Psychol Med 2004;34:255–266.

6. Malla AK, Norman RM, Manchanda R et al. One yearoutcome in first episode psychosis: influence of DUP andother predictors. Schizophr Res 2002;54:231–242.

7. Perkins DO, Lieberman JA, Gu HB et al. Predictors ofantipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreni-form disorders. Br J Psychiatry 2004;185:18–24.

8. Robinson DG, Woerner MG, Alvir JM et al. Predictors oftreatment response from a first episode of schizophrenia orschizoaffective disorder. Am J Psychiatry 1999;156:544–549.

9. Ho BC, Andreasen NC, Flaum M, Nopoulos P, Miller D.Untreated initial psychosis: its relation to quality of life

Wunderink et al.

338

and symptom remission in first-episode schizophrenia. AmJ Psychiatry 2000;157:808–815.

10. Craig TJ, Bromet EJ, Fennig S, Tanenberg-Karant M,Lavelle J, Galambos N. Is there an association betweenduration of untreated psychosis and 24-month clinicaloutcome in a first-admission series? Am J Psychiatry2000;157:60–66.

11. Norman RM, Lewis SW, Marshall M. Duration ofuntreated psychosis and its relationship to clinical out-come. Br J Psychiatry Suppl 2005;48:s19–s23.

12. Van Os J. Does the urban environment cause psychosis? BrJ Psychiatry 2004;184:287–288.

13. Drake RJ, Haley CJ, Akhtar S, Lewis SW. Causes andconsequences of duration of untreated psychosis in schi-zophrenia. Br J Psychiatry 2000;177:511–515.

14. Lambert M, Conus P, Lubman DI et al. The impact of sub-stance use disorders on clinical outcome in 643 patientswith first-episode psychosis. Acta Psychiatr Scand2005;112:141–148.

15. Larsen TK, Moe LC, Vibe-Hansen L, Johannessen JO. Pre-morbid functioning vs. duration of untreated psychosis in1 year outcome in first-episode psychosis. Schizophr Res2000;45:1–9.

16. Larsen TK, Johannessen JO, Opjordsmoen S. First-episodeschizophrenia with long duration of untreated psychosis.Pathways to care. Br J Psychiatry Suppl 1998;172:45–52.

17. World Health Organisation. Schedules for clinical assess-ment in neuropsychiatry. Geneva: World Health Organi-sation, 1992.

18. American Psychiatric Association. Diagnostic and statis-tical manual of mental disorders: DSM-IV. Washington,DC: American Psychiatric Association, 1994.

19. Hafner H, Riecher-Rossler A, Hambrecht M et al. Iraos – anInstrument for the Assessment of Onset and Early Courseof Schizophrenia. Schizophr Res 1992;6:209–223.

20. Wiersma D, De Jong A, Kraaijkamp HJM, Ormel J. GSDS II,the Groningen social disabilities schedule, 2nd version.

Groningen: Department of Psychiatry, RijksuniversiteitGroningen, 1990.

21. Kay S, Fishbein A, Opler L. The positive and negativesyndrome scale (PANSS) for schizophrenia. Schizophr Bull1987;13:261–275.

22. Landis JR, Koch GG. The measurement of observer agree-ment for categorical data. Biometrics 1977;33:159–174.

23. Lieberman JA, Perkins D, Belger A et al. The early stages ofschizophrenia: speculations on pathogenesis, pathophysi-ology, and therapeutic approaches. Biol Psychiatry2001;50:884–897.

24. Friis S, Melle I, Larsen TK et al. Does duration ofuntreated psychosis bias study samples of first-episodepsychosis? Acta Psychiatr Scand 2004;110:286–291.

25. Wiersma D, Kluiter H, Pijl YJ, Sytema S. Mental healthcare in the Netherlands. Int J Ment Health 2002;31:50–65.

26. Kalla O, Aaltonen J, Wahlstrom J, Lehtinen V, Garcia CI,Gonzalez DC. Duration of untreated psychosis and itscorrelates in first-episode psychosis in Finland and Spain.Acta Psychiatr Scand 2002;106:265–275.

27. Larsen TK, McGlashan TH, Moe LC. First-episode schizo-phrenia: I. Early course parameters. Schizophr Bull1996;22:241–256.

28. Loebel AD, Lieberman JA, Alvir JM, Mayerhoff DI, GeislerSH, Szymanski SR. Duration of psychosis and outcome infirst-episode schizophrenia. Am J Psychiatry1992;149:1183–1188.

29. Verdoux H, Liraud F, Bergey C, Assens F, Abalan F, Van OsJ. Is the association between duration of untreated psy-chosis and outcome confounded? A two year follow-upstudy of first-admitted patients. Schizophr Res2001;49:231–241.

30. Birchwood M, Smith J, Cochrane R, Wetton S, Copestake S.The Social Functioning Scale – the development and val-idation of a new scale of social-adjustment for use in familyintervention programs with schizophrenic patients. Br JPsychiatry 1990;157:853–859.

Treatment delay in first episode psychosis

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