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Predictors of recovery in first episode psychosis: The OPUS cohort at 10 year follow-up
Schizophrenia Research, 1, 150, pages 163 - 168
Recovery, the optimal goal in treatment, is the attainment of both symptomatic and functional remission over a sustained period of time. Identification of factors that promote recovery can help develop interventions that facilitate good outcomes for people with first episode psychosis.
To examine long-term outcomes within a cohort of people with first episode psychosis in relation to symptom remission, functioning and recovery, 10 years after diagnosis.
The study had a prospective design. Participants from the OPUS trial (1998–2000) (n = 496) completed a series of interviews and questionnaires to measure current levels of psychopathology and social/vocational functioning, ten years after diagnosis. Predictors of recovery were identified using socio-demographic and clinical characteristics collected at baseline.
A total of 304 participants were interviewed, giving a follow-up rate of 61%. A total of 42 people (14%) met the criteria for symptomatic and psychosocial recovery at 10 years. A multivariable binary logistic regression analysis indicated that baseline predictors accounted for 22% of the variance of full recovery. Lower severity of negative symptoms at baseline (Odds Ratio (OR) 0.53, 95% confidence interval CI 0.36–0.78, p < 0.001) and earlier age of diagnosis (OR 0.92, 95% CI 0.86–0.99, p < 0.05) predicted better rates of recovery at 10 years.
Results of this study indicated that negative symptoms could play a central role in the process of recovery from schizophrenia. A challenge for clinicians and researchers is to understand the mechanisms behind negative symptoms and develop interventions that can prevent or ameliorate these symptoms in order to promote recovery.
Keywords: Recovery, First episode psychosis, Long-term prognosis, Schizophrenia.
Recovery, the optimal goal in treatment, is often conceptualized as the attainment of both symptomatic and functional remission over a sustained period of time ( Liberman and Kopelowicz, 2005 ). The identification of predictors for recovery can directly inform clinical practice. Factors which are modifiable and associated with good outcomes can be targeted or enhanced to promote greater rates on recovery. Furthermore, identification of predictors of recovery can increase the understanding of the underlying pathophysiology of the illness ( Emsley et al., 2008 ).
Rates of recovery within first episode psychosis have varied between 10 and 25%, dependent on diagnosis composition and length of follow-up period (Harrison et al, 2001, Robinson et al, 2004, Harrow et al, 2005, San et al, 2007, Bertelsen et al, 2009, Wunderink et al, 2009, and Henry et al, 2010). A recent systematic review of over 50 naturalistic studies found the median rate that meet recovery criteria for schizophrenia was 13.5% ( Jaaskelainen et al., 2012 ).
Studies into predictors of recovery in first episode psychosis have consistently found better pre-morbid functioning (Petersen et al, 2008, Bobes et al, 2009, Wunderink et al, 2009, and Albert et al, 2011) lower levels of psychopathology at baseline and shorter duration of untreated psychosis (DUP) (Jeppesen et al, 2008, Wunderink et al, 2009, Chang et al, 2012a, and Verma et al, 2012) have been associated with higher rates of recovery. Other factors that have been associated with recovery include better cognition and less depressive symptoms at baseline (Bobes et al, 2009 and Faber et al, 2011), higher levels of education at baseline (Chang et al, 2012b and Verma et al, 2012), early response to treatment (Verma et al, 2012 and Schennach et al, 2012), the timing of onset of psychosis, no substance abuse at baseline, and adherence to medication (Leung and Chue, 2000, Ascher-Svanum et al, 2006, Petersen et al, 2008, Novick et al, 2009, Albert et al, 2011, and Verma et al, 2012). Some studies have indicated females may achieve higher rates of recovery ( Leung and Chue, 2000 ) although this finding does not appear too robust ( Jaaskelainen et al., 2012 ).
Many studies identifying predictors of recovery within first episode psychosis have a number of methodological limitations such as sampling bias, small sample sizes; relatively short follow-up periods, significant attrition and the lack of standardization in the definition and measurement of recovery ( Menezes et al., 2006 ). These problems may compromise the validity and generalizability of findings. Furthermore, there are still relatively few prospective studies that have systematically applied a structured definition for recovery and investigated long-term outcomes within this population.
The following study attempted to address the methodological weaknesses of previous longitudinal studies within FEP cohorts and applied universally recognized definitions of remission and recovery to investigate long-term outcomes. Specifically, the study examined rates of symptom remission and recovery and identified baseline predictors of recovery, within a representative cohort of people with first episode psychosis, 10 years after diagnosis.
2. Materials and method
A sample of 496 people with first episode psychosis recruited as part of the OPUS trial (1998–2000) was included in the study. At the time of inclusion participants were between 18 and 45 years old, and had a diagnosis within the schizophrenia spectrum disorder (F20–29). Those people with a schizotypal disorder (F21) were excluded since the study was concerned with people that had experienced psychotic symptoms. Participants had not received more than 12 weeks of anti-psychotic medication. A full description of the sample characteristics have been published previously (Petersen et al, 2005 and Bertelsen et al, 2008).
2.2. Study design and measures
The design of the study was prospective in nature, where information on symptoms and functioning had been collected at baseline, 1 year, 2 years, and 5 years. All participants from the OPUS trial were invited to participate in the 10 year follow-up. Current psychiatric diagnosis was determined using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN, Version 2.1)( Wing et al., 1998 ). The Schedules for Positive and Negative Symptoms (SAPS/SANS) was used to evaluate the type and severity of positive and negative symptoms ( Andreasen et al., 2005 ). Course of illness over the past two years was determined using Life Chart Schedules ( World Health Organization, 1992 ).
Level of functioning was evaluated by the Global Assessment of Functioning scale (GAF) ( American Psychiatric Association, 1994 ). The split version of the scale of the GAF scale was used, where functioning (GAF-F) and symptoms (GAF-S) were evaluated separately ( Pedersen et al., 2007 ). The scores on both scales ranged from 1 to 100, with a higher score representing better functioning or fewer symptoms. Pre-morbid functioning at baseline was assessed using the pre-morbid adjustment scale (PAS) ( Cannon-Spoor et al., 1982 ). DUP was assessed at baseline using the Interview for Retrospective Assessment of Onset of Schizophrenia—IRAOS ( Hafner et al., 1992 ). Data on days of hospitalization and number of contacts with psychiatric services was obtained from the Danish Psychiatric Central Research Register ( Mors et al., 2011 ) whilst information on the number of days in supported housing was collected using a national database constructed by Nordentoft and colleagues ( Nordentoft et al., 2012 ).
2.3. Definitions of symptom remission, functional recovery, full recovery and institutionalization
Symptom remission was defined as the display of minimal–mild positive and negative symptoms on the global scores for SAPS and SANS for at least 6 months ( Andreasen et al., 2005 ). Functional recovery was defined as currently engaged in work/study, a GAF-F score over 60, and no psychiatric hospitalizations or living in supported accommodation for the past two years ( Albert et al., 2011 ). Full recovery was defined as the stable remission of both negative and positive symptoms, no psychiatric admissions to hospital or living in supported accommodation for the past two years, currently engaged in work or study and a GAF/PSP score of over 60 ( Liberman and Kopelowicz, 2005 ). Institutionalization was defined as living in supported accommodation or hospital for at least 50% of the time in the past two years and having significant psychotic symptoms as rated by SAPS ( Albert et al., 2011 ).
2.4. Statistical analysis
Analyses were made with the statistical package SPSS 19.0 ( Pallant, 2010 ). Differences in socio-demographic and clinical variables for participators/non-participators and those recovered/non-recovered were calculated using Student's t-test for continuous variables and the Pearson chi-square test for categorical variables. A non-parametric test (Mann–Whitney U test) was applied to DUP as it had a positively skewed distribution. Where appropriate DUP was log transformed (adding a slight error term in the case of DUP equal to zero).
Binary logistic regression was used to identify predictors of recovery at 10 years. All predictors that were found to be statistically significant (p < 0.05) from the univariable analysis were included in the multivariable analysis model. Variables included in the multivariable model were checked that they did not excessively correlate with each other or violate the assumptions of collinearity. A composite score for positive and negative dimensions was calculated from global scores on SAPS and SANS ( Arndt et al., 1995 ). For ease of analysis with binary regression social contact was dichotomized as either adequate (minimum of one contact a week with friend or family) or inadequate (no contacts with family or friends in a week). Scores for pre-morbid social and academic functioning (PAS) were multiplied by a factor of 10 to assist in the interpretation of the results.
A total of 304 participants were interviewed at 10 year follow-up. Participants were on average 26 years old, 55% were men and 80% had a schizophrenia diagnosis (F20) at baseline. Comparison between participators and non-participators revealed no statistically significant differences on a range of baseline characteristics including psychiatric diagnosis, sex distribution, positive and negative symptoms, educational level, DUP, pre-morbid social/academic functioning or psychiatric admissions in the past two years. Participators scored higher on global functioning (GAF-F) (mean = 41.20, S.D. = 11.97) than non-participators (mean = 37.55, S.D. = 13.68, t (483) = 2.98, p = 0.003) at baseline and participators were younger (mean age. = 26.18 years, S.D. = 6.33) than non-participators at baseline (mean. = 27.59, S.D. = 6.66, t (492) = 2.37, p = 0.018). Fig. 1 delineates the flow of participants in the OPUS cohort. An overall follow-up rate of 61% was attained at 10 year follow-up. After adjusting for participants that were either deceased (n = 33) or emigrated (n = 18) at 10 years, the follow-up rate is nearly 70% within the contactable sample.
3.1. Rates of recovery
Fig. 2 provides an overview of the rates of symptom remission, recovery and institutionalization for follow-up at 2 years, 5 years and 10 years. Results from the 10 year follow-up revealed that 7% (n = 22) of the sample were institutionalized, 39% (n = 119) achieved both sustained positive and negative symptom remission and 14% were recovered. A total of 20% (n = 60) were functionally recovered. For those that achieved full recovery, 64% had not taken any medication for psychiatric problems within the last two years.
Overall the rates of symptom remission and full recovery for 2 years, 5 years and 10 years appear to be stable, although it was not the same people who achieved recovery at each follow-up. At 2 year follow-up, only 34% of those recovered achieved recovery at 5 years. For those recovered at 5 years, only 45% achieved recovery at 10 years. Furthermore, examination of illness course for the entire 10 year period revealed that 64% of participants achieved sustained symptom remission at least once in the past 10 years and nearly 30% of participants achieved full recovery at some time during the past 10 years. Comparison of recovered and non-recovered participants revealed no differences in sex, age or medication compliance. Results are summarized in Table 1 .
15 people (6%) in the not recovered group were not prescribed medication but were actively psychotic.
3.2. Univariable and multivariable analysis of predictors of recovery
Table 2 contains the results for the binary logistic regression analyses. Results from the univariable analysis revealed a number of baseline characteristics were significantly associated with recovery at 10 years. The multivariable analysis revealed the model explained 22% of the variance of full recovery at 10 years (pseudo r2 = 0.22, X2 (7, N = 277) = 35.60, p < 0.001). Younger age of inclusion into the trial (OR 0.92, 95% CI 0.86–0.99, p < 0.05) and lower negative symptoms at baseline significantly predicted recovery (OR 0.53, 95% CI 0.36–0.78, p < 0.001).
OR exp (B)
CI for exp (B) 95%
OR exp (B)
CI for exp (B) 95%
|Social function (10) (PAS)||0.78 (0.64–0.94)||0.010||0.93 (0.74–1.18)||0.572|
|Academic function (10)
|0.78 (0.64–0.95)||0.012||0.91 (0.71–1.15)||0.399|
|Completed high school||2.68 (1.38–5.21)||0.003||2.10 (0.92–4.78)||0.076|
|Living independently||1.68 (0.76–3.69)||0.199||–||–|
|Working prior to diagnosis||1.12 (0.90–1.46)||0.284||–||–|
|Social contact (weekly)||3.64 (1.67–7.91)||0.001||1.44 (0.59–3.56)||0.322|
|GAF-F function||1.02 (1.00–1.05)||0.051||1.00 (0.97–1.03)||0.979|
|GAF-S symptoms||1.00 (0.97–1.04)||0.898||–||–|
|Psychotic dimension||1.08 (0.84–1.38)||0.571||–||–|
|Disorganized dimension||0.88 (0.61–1.28)||0.498||–||–|
|Negative dimension||0.56 (0.41–0.76)||< 0.001||0.53 (0.36–0.78)||0.001|
|Substance dependence||1.27 (0.64–2.52)||0.502||–||–|
|Schizophrenia diagnosis (F20)||0.60 (0.29–1.26)||0.180||–||–|
|Schizoaffective diagnosis (F25)||4.92 (1.49–16.31)||0.009||3.55 (0.77–16.29)||0.103|
|Age included in trial||0.94 (0.88–0.99)||0.035||0.92 (0.86–0.99)||0.037|
Variables in bold are statistical significant predictors of recovery, DUP—duration of untreated psychosis, PAS—pre-morbid social adjustment, GAF—Global Assessment of Functioning.
A subsequent multivariable analysis of predictors of recovery at one year after diagnosis revealed that functioning at one year follow-up (GAF-F) (OR 1.04, p < 0.05) and negative symptoms at one year follow-up (OR 0.37, p < 0.01) predicted recovery at 10 years. Furthermore, negative symptoms at one year follow-up independently predicted recovery at 10 years after controlling for baseline factors (OR 0.49, 95% CI 0.25–0.98, p < 0.05) including baseline negative symptoms.
4.1. Rates of recovery
This study examined outcomes and identified predictors of recovery within a cohort of people with first episode psychosis, 10 years after diagnosis. Rates of remission and recovery were comparable with other FEP studies although lower than some studies (Lambert et al, 2008, Wunderink et al, 2009, and Henry et al, 2010). The most probable explanation for this lower rate of recovery was the higher proportion of people with a schizophrenia diagnosis in this study compared to those other studies. A schizophrenia diagnosis is often associated with poorer outcomes compared to other diagnoses within the schizophrenia spectrum (Harrison et al, 2001 and Lang et al, 2012). A recent meta-analysis examining levels of recovery within schizophrenia using naturalistic studies found a median recovery rate of 13.5%, which is very similar to the rate found in the OPUS cohort ( Jaaskelainen et al., 2012 ).
Whilst only 14% met criteria for full recovery at ten year follow-up, nearly a third of the cohort achieved full recovery at some time over the ten year follow-up. Harrow et al. (2005) found similar pattern in a long-term follow-up study for people with FEP, where roughly 40% achieved recovery at least once over a period of 15 years ( Harrow et al., 2005 ). It appears people move in and out of recovery over time and future treatment could focus on helping people both attain and maintain recovery.
A relatively small number of people achieved recovery (14%) although 35% of the cohort (n = 109) meet the criteria for both sustained symptom remission and adequate social and daily living skills, but were not engaged in work or study. Thus, not working or studying was a primary reason for not fulfilling the recovery criteria at 10 year follow-up. Clinical trials have shown Individual Placement Support (IPS) is an effective intervention to help people with FEP to return to work (Bond et al, 2008 and Campbell et al, 2011). Improving access to this evidence based intervention may facilitate the process of gaining employment within this FEP population.
4.2. Predictors of recovery
Results from the univariable analysis revealed that younger age at inclusion, lower levels of negative symptoms, completion of high school, adequate social contacts, schizoaffective diagnosis and better pre-morbid social and academic functioning all increased the chance of recovery at 10 year follow-up. DUP was not a significant predictor of recovery. A number of these factors became non-significant when entered into a multivariate model, indicating a degree of interdependence.
Younger age at the inclusion in the OPUS trial was associated with recovery at 10 year follow-up. Specifically, each year a person was older and received a schizophrenia spectrum disorder diagnosis and commenced treatment, their chances of recovery were reduced by roughly 8%.
Thus, if a person first received a diagnosis at 26 years of age they would have a 30% less chance of recovery at 10 years than someone who was 22 years and received a diagnosis.
Whilst early onset of psychosis is usually associated with poorer outcomes (Hollis, 2000, Rabinowitz et al, 2006, and Schennach-Wolff et al, 2009), these early onset studies typically include participants that are much younger (mean age = 17 years) ( Rabinowitz et al., 2006 ) compared to participants in the current study (mean age = 26 years). Thus, the OPUS cohort is representative of adult onset psychosis, where many participants achieved a number of social, educational and vocational milestones before becoming psychiatrically ill. Baseline characteristics of OPUS participants revealed that nearly a third (n = 97, 32%) had completed high school before receiving a diagnosis/treatment. Completion of high school, adequate social contact and good pre-morbid social functioning were all significant predictors for recovery in the univariable analysis, with completion of high school bordering on significance in the multivariable analysis (p = 0.076).
Reframing the results with this perspective, adults who developed psychosis may have a foundation of vocational and social skills and with suitable treatment these individuals maintain or re-establish important vocational and social relationships, thereby assisting the process of recovery.
Two recent studies (Amminger et al, 2011 and Verma et al, 2012) within FEP cohorts found that younger age predicted higher rates of recovery. Both research groups suggested that treatment was successful in helping people with FEP to maintain links with schools and friends, thereby facilitating the achievement academic and social milestones despite their illness. These findings also provide evidence for interventions that target young people with first episode psychosis can positively impact on long-term outcomes.
Despite this finding that younger age predicted recovery in this study, these results should be viewed with a degree of caution given that there was a significant difference in age between the participators and non-participators at 10 year follow-up.
The second significant predictor of recovery from the multivariable analysis was lower baseline negative symptoms. For each point a person increased on the negative symptom scale (0–5) the chance of recovery at 10 years reduced by roughly 45%. Negative symptoms are concerned with the loss or reduction or certain normal functions or behaviors such as impairment of affect, emotion, social interaction, purpose and motivation.
Several other studies have identified higher levels of negative symptoms are directly associated with poorer functioning and clinical outcomes for people with first episode psychosis (Milev et al, 2005, White et al, 2009, Henry et al, 2010, Lambert et al, 2010, Alvarez-Jimenez et al, 2011, Alvarez-Jimenez et al, 2012, Rabinowitz et al, 2012, and Strauss et al, 2012).
Currently, there are a few documented treatments for negative symptoms. Pharmacological interventions have so far failed to demonstrate a clear effect on negative symptoms (Alphs, 2006 and Erhart et al, 2006). A review of cognitive behavioral interventions demonstrated a moderate effect on negative symptoms although further studies are required ( Wykes et al., 2008 ). Cognitive remediation (CR) has been shown to have a small but significant effect on reducing negative symptoms ( Pfammatter et al., 2006 ). A recent clinical study suggested a combination of CBT and CR may also be effective reducing negative symptoms ( Klingberg et al., 2011 ). Despite, a number of promising psychosocial interventions for the treatment of negative symptoms, further RCT's are required to establish their efficacy.
Other researchers have focussed on factors that can prevent the formation of negative symptoms. Several studies have found longer DUP (Verdoux et al, 2001, Norman et al, 2001, Perkins et al, 2005, and Boonstra et al, 2012) to be associated with higher levels of negative symptoms. Currently, the hypothesis that shortening DUP will lead to a reduction of negative symptoms and potentially improve rates of long-term recovery is speculative. A recent Norwegian study found that a reduction of DUP was associated with a reduction in negative symptoms and significant gains in rates of employment ( Melle et al., 2008 ) although further studies are required.
Importantly from a treatment perspective, this study found that not only baseline negative symptoms predicted recovery but negative symptoms at 1 year follow-up also predicted recovery, independent of baseline characteristics. Thus, interventions that focus on the prevention of the formation and/or reduction of negative symptoms after diagnosis may have the potential to impact positively on long-term outcomes.
4.3. Study limitations
Whilst this study is one of the largest long-term follow-up cohorts within first episode psychosis, it still only interviewed 68% of the contactable sample, or 61% of the original sample. Thus, the long-term outcomes for over a third of the original sample are unknown. Whilst there were few systematic differences between the participators and non-participators, participators were younger, better functioning and displayed lower symptoms at baseline than non-participators. Thus, the results showed must be viewed with caution and may over represent good outcomes within this cohort. Use of Danish national registers which contain near complete information on demographic data such as psychiatric contacts and income could supplement clinical data to provide an overview of functioning.
Secondly, data from the OPUS trial is based on RCT and therefore it is likely that differences in treatment within the first two years influenced outcomes. Furthermore, no detailed information about the treatment participants received in remaining 8 years was available, so it was not possible to evaluate how treatment impacted on recovery.
Thirdly, the multivariable analysis provided information about association but not causality between variables. Furthermore, the analysis did not capture the complexity of relationships between different variables, such as how DUP may impact on negative symptoms which may mediate functional outcomes. A number of variables in the regression analysis were interdependent making it difficult to isolate the precise impact of each variable on recovery.
Finally, whilst the study collected information on a range of socio-demographic and clinical variables, no baseline information was collected on cognitive functioning. Recent studies have demonstrated that cognitive performance is an important predictor of functional outcome within FEP, although further studies are required (Allott et al, 2011 and Faber et al, 2011).
Modest rates of recovery at 10 year follow-up were achieved, highlighting the need to develop more effective interventions to improve prognosis in first episode psychosis. Evidence based interventions that promote re-integration into the workforce may improve rates of recovery.
The early identification and treatment of adult onset psychosis may facilitate social and vocational relationships and thereby assist in the process of recovery. Negative symptoms could play a central role in long-term outcomes within first episode psychosis. Current interventions for these symptoms appear to relatively ineffective and future research should focus on the systematic measurement and treatment of negative psychopathology as a potential way to promote recovery.
Role of funding source
The funding sources had no influence on the analyses or the presentation of the results.
MN, OM and SFA conceived the study. MN rose the funding. SFA drafted the first manuscript. CRH, SFA conducted the analysis and interpretation of results. All authors critically revised the manuscript and approved the version submitted for publication.
Conflict of interest
All authors declare they have no conflict of interest.
The project received unconditional grants from the Lundbeck, University of Copenhagen, Trygfonden, and Midt-Jylland research fund.
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