Introduction
Schizophrenia remains a devastating disorder, often emerging during the final neurobiological push toward mature human brain structure and function. The consequence of its expression at this critical juncture is all too often an ablation of capacities for productivity, creativity and relatedness that lasts for the entire adult lifespan. Given the resistance of this disorder to ameliorative treatments, the last two decades have seen an emerging interest in prevention through early detection (ED) and intervention (McGlashan & Johannessen, Reference McGlashan and Johannessen1996; McGorry et al. Reference McGorry, Johanessen, Lewis, Birchwood, Malla, Nordentoft, Addington and Yung2010).
One of the first preventive strategies to become popular targets the initial emergence of psychosis and attempts to identify and treat this ‘first episode’ as early as possible, i.e. to reduce the duration of untreated psychosis (DUP). Two meta-analytical reviews document a significant correlation between reduced or shorter DUP and better outcome (Marshall et al. Reference Marshall, Lewis, Lockwood, Drake, Jones and Croudace2005; Perkins et al. Reference Perkins, Gu, Boteva and Lieberman2005). However, as noted in a prior communication (Melle et al. Reference Melle, Larsen, Haahr, Friis, Johannesen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2008), while the significance of this correlation is clear, the underlying direction is not (McGlashan, Reference McGlashan1999). We do not know whether untreated psychosis generates poorer prognosis or whether persons who are at risk for a poor prognosis enter treatment via pathways generating longer DUP (Bosanac et al. Reference Bosanac, Patton and Castle2010). The only way of disentangling the causal direction is to manipulate the DUP and then measure the outcome. Delaying treatment through a randomized clinical trial would be unethical in acute first episode psychosis. The best possible way to isolate the influence of DUP at this point is through a quasi-experimental ‘service-systems’ design intended to reduce DUP in one healthcare area (experimental) but not in another (control) and to track the outcomes of the ED versus no-ED groups.
The early Treatment and Intervention in Psychosis (TIPS) investigation used this design to study whether DUP could be reduced and, if so, what effect it would have upon the course of the disorder (Johannessen et al. Reference Johannessen, McGlashan, Larsen, Horneland, Joa, Mardal, Kvebaek, Friis, Melle, Opjordsmoen, Simonsen, Ulrik and Vaglum2001). A comprehensive ED system based on low-threshold psychosis-detecting teams and public information campaigns was created in one area (ED area). First-episode patients from this area were compared with first-episode patients from a parallel area without ED (no-ED area). The chosen areas had nearly indistinguishable sociodemographic and treatment service characteristics. Both ran equivalent 2-year comprehensive first-episode treatment programmes consisting of antipsychotic medication, assertively oriented individual out-patient treatment and psycho-educational family work.
The study was designed to test the following core hypotheses: (1) ED programmes can reduce DUP; (2) reducing DUP will be related to a comparative reduction in positive and negative symptoms displayed at the beginning of the first treatment; (3) the initial ED area versus no-ED area differences in these variables will be maintained for the first 2 years of standardized treatment, indicating ED-related secondary prevention.
The TIPS study of 2 years confirmed all of these hypotheses except for positive symptoms, where the two groups had nearly identical levels from 3 months and beyond (Melle et al. Reference Melle, Haahr, Friis, Hustoft, Johannessen, Larsen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2005, Reference Melle, Johannesen, Friis, Haahr, Joa, Larsen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2006, Reference Melle, Larsen, Haahr, Friis, Johannesen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2008; Larsen et al. Reference Larsen, Melle, Auestad, Friis, Haahr, Johannessen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2006). This report tests the additional hypothesis that the initial ED/no-ED differences will have a long-term effect. The 5-year follow-up aims to test whether the 2-year advantage in outcome of the ED group survives beyond the cessation of the standardized study treatment. This would suggest that ED and treatment has a lasting effect on outcome of first episode psychosis that is significantly independent of ongoing treatment.
Method
Setting
Four Scandinavian specialized psychiatric healthcare service sectors or areas participated in the study. The ED sectors were located in Rogaland County on the west coast of Norway, which is divided into a north and a south healthcare sector. The ED sectors had a total population of 370 000 inhabitants. The control (no-ED) sectors were located at Ullevaal healthcare sector in Oslo, Norway and Roskilde mid-sector in Denmark. The combined population for the control sites was 295 000 inhabitants. The four sectors were regarded as similar since they had no differences in age and gender distribution, mean income levels and unemployment rates. All four sectors are mainly urban or suburban, but in the no-ED sector 96% lived in urban areas compared with 84% in the ED sector (for details, see Melle et al. Reference Melle, Haahr, Friis, Hustoft, Johannessen, Larsen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2005, Reference Melle, Larsen, Haahr, Friis, Johannesen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2008). All sectors served all possible cases with first episode psychosis since the participant treatment systems were catchment area-based, publicly funded and organized within national healthcare systems.
During 1997–2000 all cases with possible psychosis were referred to the healthcare system, rapidly assessed and, if meeting intake criteria, were offered treatment within the public healthcare systems either at out-patients' clinics or hospital wards. All four sites utilized the same treatment algorithm during the first 2 years, consisting of three elements: antipsychotic medication; supportive individual psychotherapy at least once per week; multi-family psycho-education groups twice per month. After 2 years the study treatment package was terminated, but sectorized psychiatric care was available, which included individual psychotherapy, medication and hospitalization if necessary.
In the ED sector an elaborate system for ED of psychosis was established using information campaigns about the signs and symptoms of psychosis, its treatment and phone numbers to call for rapid evaluation. The campaigns were directed at the general population, general practitioners, schools and primary health providers (for details, see Johannessen et al. Reference Johannessen, McGlashan, Larsen, Horneland, Joa, Mardal, Kvebaek, Friis, Melle, Opjordsmoen, Simonsen, Ulrik and Vaglum2001; Melle et al. Reference Melle, Haahr, Friis, Hustoft, Johannessen, Larsen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2005; Joa et al. Reference Joa, Johannessen, Auestad, Friis, McGlashan, Melle, Opjordsmoen, Simonsen, Vaglum and Larsen2008).
Participants
The study included all patients with a first episode psychosis who came for treatment in one of the four catchment areas from 1 January 1997 to 31 December 2000. Inclusion criteria were as follows: living in one of the four healthcare sectors; aged 18–65 years; meeting the DSM-IV criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder (core), brief psychotic episode, delusional disorder, affective psychosis with mood-incongruent features or psychotic disorder not otherwise specified; being actively psychotic, as measured by a Positive and Negative Syndrome Scale (PANSS) score of ⩾4 on at least one of the positive subscale items, 1 (delusions), 3 (hallucinatory behaviour), 5 (grandiosity) or 6 (suspiciousness/persecution) or general subscale item 9 (unusual thought content) for at least 7 days; not having received previous adequate treatment for psychosis (defined as antipsychotic medication >3.5 haloperidol equivalents for >12 weeks or until remission of the psychotic symptoms); having no neurological or endocrine disorders with relationship to the psychosis; having no contraindications to antipsychotic medication; speaking a Scandinavian language; having an IQ score >70; being willing and able to give informed consent.
Baseline sample
Power analysis estimated the need for 300 patients in order to ascertain clinically significant outcome differences between ED and no-ED sites (Friis et al. Reference Friis, Larsen, Melle, Opjordsmoen, Johannessen, Haahr, Simonsen, Rund, Vaglum and McGlashan2003). Over 4 years of recruitment, we identified 179 patients from the ED area and 194 from the no-ED area. Informed consent was obtained from 281 patients; 141 in the ED area and 140 in the no-ED area. The refuser rate was thus 24%. Patients who did not enter the study had significantly longer DUP than patients who entered [median 26 weeks (range 0–936 weeks) and 10 weeks (range 0–1196 weeks), respectively; p<0.001]. This finding was replicated in both areas when they were examined separately. No other significant differences between patients who did and did not enter the study were found (for details, see Friis et al. Reference Friis, Larsen, Melle, Opjordsmoen, Johannessen, Haahr, Simonsen, Rund, Vaglum and McGlashan2003.) The sample was reassessed at 3 months, 1, 2 and 5 years after intake.
Follow-up sample
At the 5-year follow-up, 13 patients (5%) of the original 281 had died and we collected complete datasets for 195 cases of the 268 who were still alive (73%). Out of the 76 cases, we lacked data on 28 who refused, 36 who did not show up, nine who could not be found and three who had incomplete datasets. Compared with the group with complete data, the 89 (33%) cases with no PANSS scores at 5-year follow-up were generally more symptomatic at earlier follow-up points. For example, they had higher scores on drug abuse at 2 years (1.70 v. 1.38, p=0.047), more severe PANSS general symptoms at 3 months (29.2 v. 25.5, p=0.007), higher PANSS total scores at 3 months (56.4 v. 50.4, p=0.018), higher PANSS depressive scores at 3 months (10.5 v. 9.2, p=0.011), higher PANSS excitative scores both at 3 months (7.9 v. 6.7, p=0.009) and 1 year (7.7 v. 6.5, p=0.024). No additional significant differences for PANSS or global assessment functioning (GAF) scores at baseline, 3 months, 1 or 2 years were found and there were also no differences for age, gender distribution, pre-morbid adjustment, drug or alcohol use at baseline, 1 or 2 years, suicidality before or at baseline or at 1 or 2 years, DUP or the proportion of patients with core schizophrenia spectrum disorder at baseline and 1 or 2 years.
Overall, however, subjects dropping out of the study were more symptomatic. For most variables, this tendency was the same for both ED and no-ED patients. However, while the ED patients who were lost at 5 years had a slightly lower level of negative symptoms at 2 years (PANSS negative component score 14.8 v. 15.7), the no-ED sites lost patients with higher levels of negative symptoms (22.1 v. 18.3). The tendency to lose more high negative symptom no-ED patients is close to statistically significant (F=3.54, degrees of freedom=1, p=0.06 for the interaction). Therefore, we used linear mixed effect modelling as the statistical method when we compared ED with no-ED groups. For details see the section regarding statistics.
At baseline and at follow-up it is noteworthy that the ED group was younger, more often of Nordic origin, had shorter DUP and more substance abuse (Table 1).
Table 1. Baseline demographic and clinical characteristics of early versus usual detected first episode psychosis patients
After a complete description of the study to the subjects, written informed consent was obtained. The regional ethical research committees approved the study.
Assessments
The assessment teams at all sites consisted of clinically experienced and trained research personnel. The Structured Clinical Interview for the DSM-IV Axis I disorders was used for diagnostic purposes (First et al. Reference First, Spitzer, Gibbon and Williams1995). Pre-morbid functioning was measured by the Premorbid Adjustment Scale (PAS), which describes four pre-morbid periods in life: childhood (<12 years); early adolescence (12–15 years); late adolescence (16–18 years); adulthood (>18 years) (Cannon-Spoor et al. Reference Cannon-Spoor, Potkin and Wyatt1982). Previous analyses identified two pre-morbid dimensions: (a) social, consisting of the PAS items social isolation and peer relationships; (b) academic, containing school performance and school adaptation. Two parameters for each dimension were rated, childhood level of adjustment and degree of change of level of adjustment over post-childhood developmental phases (for details about this modification, see Larsen et al. Reference Larsen, Friis, Haahr, Johannessen, Melle, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2004; Haahr et al. Reference Haahr, Friis, Larsen, Melle, Johannesen, Opjordsmoen, Simonsen, Rund, Vaglum and McGlashan2008). Symptom levels were measured by means of the PANSS (Kay et al. Reference Kay, Fiszbein and Opler1987). Symptom domains are represented by the corresponding PANSS components (positive, negative, excitement, cognitive and depressive) (Bentsen et al. Reference Bentsen, Munkvold and Notland1996). The cognitive factor consists of the PANSS items P2: Conceptual disorganization, N5: Abstract thinking and G10: Disorientation and does not represent a full neuropsychological testing. Global functioning was measured by the GAF scale (DSM-IV) and the scores were split into symptom (GAFs) and function (GAFf) scores to improve psychometric properties (Pedersen et al. Reference Pedersen, Hagtvedt and Karterud2007). Quality of life was measured with the Lehman Quality of Life Interview, brief version (Lehman, Reference Lehman1988). Misuse of alcohol and drugs was measured by the Drake Scale (Drake et al. Reference Drake, Osher, Noordsy, Hurlbut, Teague and Beaudett1990). If patients abused drugs, we would initiate a longer period (>4 weeks) of drug-free observation (mostly involuntarily) before a diagnostic conclusion was made. The DUP was measured as the time from onset of psychosis until the start of adequate treatment (for details, see Melle et al. Reference Melle, Haahr, Friis, Hustoft, Johannessen, Larsen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2005).
After 3 months, we repeated PANSS and GAF measurements. At 1-, 2- and 5-year follow-ups, all assessments were repeated including the Structured Clinical Interview for DSM-IV. For each follow-up, a separate summary interview was conducted, in which we gathered information regarding three different outcome domains: (1) psychosis course: time to remission, duration and number of relapses and remission status at follow-up; (2) treatment utilization as weeks of participation for hospitalizations, individual supportive psychotherapy (at least weekly sessions), family work and use of antipsychotic medication; (3) participation in working activities.
The definition of stable remission was at least 2 months with no positive symptoms defined as a rating <4 on specific PANSS items. The definition of relapse was that the patient had a score >3 on the PANSS items for >1 week. Patients who were psychotic at follow-up, but not continuously psychotic, were labelled as being in relapse (for details, see Friis et al. Reference Friis, Larsen, Melle, Opjordsmoen, Johannessen, Haahr, Simonsen, Rund, Vaglum and McGlashan2003).
Assessment reliability
All major baseline assessments such as diagnosis, PANSS, GAF, drug abuse and DUP underwent tests of intra- and inter-site reliability with satisfactory results. Raters trained in reliability for DUP and PANSS made assessments of remission and relapse at follow-up.
Regarding reliability for the follow-up, 31 vignettes were randomly selected from 1 and 2 years follow-up and rated by two experienced psychiatrists on the following variables: diagnosis; GAFs; GAFf; alcohol and drug use scores. For all dimensions, the reliability was clearly satisfactory. For diagnosis, κ=0.81, for the other dimension intra-class correlations (ICCs) (1.1), GAFf=0.86; GAFs=0.91, alcohol use=0.75 and illicit drug use=0.86. No new reliability tests were carried out at 5 years since the same raters did the assessments.
Statistical method
Statistical analyses were conducted with the use of SPSS 15.0 (SPSS Inc., USA) and R 2.9.0 (R Development Core Team, 2005). All tests are two-tailed with a level of significance of 0.05. For the bivariate group comparisons, the p values are corrected for multiple testing. Non-significant findings are marked n.s. For skewed data, we used non-parametric tests or transformed the variable in order to achieve normal distribution; DUP was substituted in the linear mixed-effects and regression models with ln (DUP +1).
To account for missing data and confounding variables, we used a linear mixed model, which has been the recommended method for repeated measures (Pinheiro & Bates, Reference Pinheiro and Bates2000). As opposed to performing t tests for the 5-year data only, a longitudinal approach, which utilizes data for a longer period, will generally have more power. The linear mixed-effects model is strongly recommended and a standard way to handle the dependencies of the longitudinal data at hand and the model with maximum likelihood estimation has the advantage of coping with drop-outs in an efficient way (Gueorguieva & Krystal, Reference Gueorguieva and Krystal2004). To fit the linear mixed-effects models, baseline scores were excluded since all symptom measures had a clear non-linearity during the first months of treatment. Otherwise, the average time trends seem fairly linear. We used a random intercept model with expected score at month j conditional on individual i:
with β0 being the main level, β1 the deviation from the main level for group ED=1, β2 the average level change per month and β3 the deviation from the average level change for group ED=1. The b 0i is the random intercept term for individual i. The covariates represent the variables age, gender, ethnicity (i.e. being Nordic or not), change in pre-morbid academic performance, DUP (log transformed) and substance abuse or not at baseline. The main focus in the analysis was on the estimates of the β1 term, which represents a difference in level between the two groups in the linear predicting time trends. In order to ascertain that group differences are not caused by possible confounding variables, we first fitted models with the covariates only. Then the two terms representing group differences were included and checked for significant improvement (likelihood ratio test). For the negative, depressive and cognitive factors in the PANSS and for symptom and functioning GAF scores, the improvement was significant. Except for GAFs, the group×time interaction term β3 was non-significant and the models were refit without this term.
Results
Treatment utilization data revealed no statistically significant differences between the groups regarding participation in psychotherapy or use of medication (Table 2). However, the ED group was more often hospitalized during year 5 and had more weeks in hospital during all 5 years of follow-up.
Table 2. Functional status at 5-year follow-up of early versus usual detected first episode psychosis patients
PANSS, Positive and Negative Syndrome Scale; GAF, global assessment of functioning.
A large majority of the patients were in stable remission at follow-up and most of these had been in remission for the whole of the previous year (no-ED 62 of 68; ED 61 of 74). Only a small proportion of the patients (10% in the no-ED group and 12% in the ED group) were continuously psychotic. No significant differences between the groups were found on this variable. The same goes for total duration of psychosis during all 5 years and total number of relapses.
No difference between the groups was found regarding participation in work. Overall, approximately 25% of patients worked >20 h per week. The ED group had more contacts with friends; 76% saw friends more than twice per month compared with 59% in the no-ED group.
Regarding levels of symptoms, the ED group had better scores for PANSS cognitive and depressive components.
The linear mixed-effects modelling indicates that the outcome was significantly better for the ED group compared with the no-ED group for the negative, depressive and cognitive component scores in the PANSS. Figs. 1–3 show average values at 0, 3, 12, 24 and 60 months. The lines show lapse at 3–60 months as estimated by the linear mixed effects model.
Fig. 1. Linear mixed-effects models for Positive and Negative Syndrome Scale negative component for early versus usual detected first episode psychosis patients over the 5-year period. ○, average values for no-early detection (ED) group; ×, average values for the ED group at 0, 3, 12, 24 and 60 months. Lines indicate lapse at 3 and 60 months as estimated by the linear mixed effects model: – – –, no-ED group; –––––, ED group.
Fig. 2. Linear mixed-effects models for the Positive and Negative Syndrome Scale depressive component for early versus usual detected first episode psychosis patients over the 5-year period.
Fig. 3. Linear mixed-effects models for the Positive and Negative Syndrome Scale cognitive component for early versus usual detected first episode psychosis patients over the 5-year period.
Similar profiles were found for the GAF social functioning scores (not reported in the figures).
Discussion
This is the first study showing that ED may have a positive impact on long-term outcome, i.e. 5 years. We have already shown in the TIPS study that ED is clinically beneficial, since patients from the ED sector enter treatment with a lower level of symptoms (Melle et al. Reference Melle, Haahr, Friis, Hustoft, Johannessen, Larsen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2005), less suicidality (Melle et al. Reference Melle, Johannesen, Friis, Haahr, Joa, Larsen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2006) and shorter total duration of their first episode (Larsen et al. Reference Larsen, Melle, Friis, Joa, Johannessen, Opjordsmoen, Simonsen, Vaglum and McGlashan2007). We have also reported previously that the ED group had a persistently lower level of negative symptoms throughout the first 2 years of follow-up (Melle et al. Reference Melle, Larsen, Haahr, Friis, Johannesen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2008). That finding has now been extended to 5 years. Furthermore, the difference at 5 years is significant for depressive and cognitive component symptoms in addition to negative symptoms. We also see an effect on social functioning since ED patients have more contact with friends.
Both groups were provided with the same treatment package consisting of antipsychotic medication, supportive psychotherapy and multi-family groups focusing on psycho-educational approaches. Treatment utilization for medication and psychotherapy was the same. The ED group had more hospitalizations despite the fact that they did not have more relapses or a greater total time as psychotic. This discrepancy, in turn, suggests that hospitalization may be more policy driven than psychopathology driven, thus rendering it less valid as a treatment-related dependent variable.
The null hypothesis of this study is that the ED/no-ED differences seen at 2 years would not be extended to 5 years after the cessation of the study treatment package. That hypothesis has been disconfirmed. Our results stand in contrast with those of the recently completed and published 5-year follow-up of the OPUS study in Denmark (Bertelsen et al. Reference Bertelsen, Jeppesen, Petersen, Thorup, Ohlenschlaeger, le Quach, Christensen, Krarup, Jorgensen and Nordentoft2008). There, first episode psychotic patients were openly randomized to intensive versus standard treatment. No attempt was made to treat either sample earlier and, in fact, the median DUP for each sample was around 1 year. In contrast, even the no-ED group of the TIPS study had a considerably shorter DUP (median=4 months) than the OPUS sample.
The TIPS study also differed from the OPUS study in that the same treatment package was applied to both ED and no-ED samples. TIPS was designed to test whether different timing of the same treatment makes a difference in outcome, whereas OPUS was designed to test whether similar timing of different treatments makes a difference in outcome.
Both studies found that their unique manipulations did make a significant difference in outcome 2 years after intake (Petersen et al. Reference Petersen, Jeppesen, Thorup, Abel, Ohlenschlaeger, Christensen, Krarup, Jorgensen and Nordentoft2005; Melle et al. Reference Melle, Larsen, Haahr, Friis, Johannesen, Opjordsmoen, Rund, Simonsen, Vaglum and McGlashan2008). For TIPS, however, this difference continued to the 5-year follow-up, whereas for OPUS the difference did not (Bertelsen et al. Reference Bertelsen, Jeppesen, Petersen, Thorup, Ohlenschlaeger, le Quach, Christensen, Krarup, Jorgensen and Nordentoft2008). The prima facie interpretation of these contrasting findings between OPUS and TIPS is that the (earlier) timing of treatment has a lasting effect on course but that the complexity and intensity of the treatment does not, at least when treatment initiation is as late as in the OPUS study.
Strengths and limitations
Our study has several strengths. First, the sample is large and from a well-defined catchment area. We assume that nearly every first episode case has been identified and we regard our sample as being highly representative. Second, our sample is from Scandinavia, in which all healthcare is free and provided by the State. Third, we report outcome results from an early detected sample. The study also had a number of limitations. Although the sample was large, 24% refused to participate at baseline and we were able to collect full datasets at 5-year follow-up for only 68% of the original sample.
It certainly can be argued that the drop-out and refuser rate may threaten the validity of the findings. However, the refusers had a longer DUP than the participants and the no-ED drop-outs had a higher level of negative symptoms than the ED drop-outs. If attrition might have affected our results, it would be in the direction of reducing the ED/no-ED difference. Consequently, the loss of patients due to refusal and drop-out seems to have reduced the chance of finding significant differences in outcome between ED and no-ED patients. Therefore, we think that our results represent an underestimate rather than an overestimate of the true differences. However, since our study has a quasi-experimental design it is difficult to rule out selection biases. We believe our study needs to be replicated in order to strengthen our findings.
Possible mechanisms
Overall, our study could not disconfirm the hypothesis that the 2-year differences between ED and no-ED first episode samples would be carried forward to 5 years. The mechanism(s) by which this ED and/or intervention advantage is generated and maintained is unknown. The finding, nevertheless, raises the question/hypothesis that earlier recognition and/or treatment of psychosis somehow prevents or at least slows the neurobiological processes leading to greater severity and chronicity of psychosis. The nature of these processes remain largely unknown (McGlashan & Hoffman, Reference McGlashan and Hoffman2000) and they require further theoretical elaboration and empirical testing. Our results, however, do suggest that these processes can be influenced with the earlier application of existing interventions, the result being lasting secondary prevention of psychotic deficits.
To our knowledge, a 5-year follow-up of differences in the outcome of earlier treatment of first episode psychosis has never been reported. Our findings clearly require further follow-up to determine the permanence of these differences. They also require replication by independent investigators. In the meantime, however, our findings continue to suggest that the timing of illness detection and illness treatment has a powerfully mutative effect on the development and/or expression of psychotic psychopathology.
Acknowledgments
Supported by the Norwegian National Research Council (no. 133897/320 and no. 154642/320), the Norwegian Department of Health and Social Affairs, the National Council for Mental Health/Health and Rehabilitation (no. 1997/41 and no. 2002/306), Rogaland County and Oslo County (Drs Vaglum, Johannessen, Friis, Larsen, Melle, Opjordsmoen). Also funded by the Theodore and Vada Stanley Foundation, the Regional Health Research Foundation for Eastern Region, Denmark; Roskilde County, Denmark, Helsefonden Lundbeck Pharma, Eli Lilly and Janssen-Cilag Pharmaceuticals (Drs Simonsen and Haahr). Also supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Distinguished Investigator Award and NIMH grant MH-01654 (Dr McGlashan) and a NARSAD Young Investigator Award (Dr Larsen).
Declaration of Interest
Melle, Larsen and Joa have received a speaker's fee from Jansen Cilag. Simonsen has received a speaker's fee from Boehringer Ingelheim, Eli Lilly and Bristol–Myers Squibb. Haahr has received a speaker's fee from Bristol–Myers Squibb. Opjordsmoen has received a speaker's fee from Bristol–Myers Squibb, has been a member of a Nordic expert group concerning antipsychotics sponsored by Janssen Cilag and is currently PI for an investigation sponsored by Janssen Cilag.
