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The prognostic significance of early remission of positive symptoms in first treated psychosis
Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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The prognostic significance of early remission of positive symptoms in first treated psychosis Ross M.G. Norman a,b,n,1, Rahul Manchanda a,b, Deborah Windell b a
Department of Psychiatry, University of Western Ontario, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9 Prevention and Early Intervention Program for Psychoses (PEPP), London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9
b
art ic l e i nf o
a b s t r a c t
Article history: Received 16 July 2013 Received in revised form 13 March 2014 Accepted 2 April 2014
Objectives: We examine the relationship between achieving remission of positive symptoms within 3 months in first episode psychosis and outcomes 5 years later. Methods: Time to remission of positive symptoms, other early characteristics and 5 year outcomes were assessed in a prospective study of 132 patients being treated for the first time for a psychotic disorder. Results: Just under 60% of patients showed remission of positive symptoms within 3 months. In comparison to later remitters, they showed lower levels of positive symptoms, greater likelihood of competitive employment and less likelihood of collecting a disability pension at 5 years. Conclusions: Earlier remission of positive symptoms may have prognostic significance for longer term outcomes. & 2014 Published by Elsevier Ireland Ltd.
Keywords: Schizophrenia Outcomes Prognosis Functioning Employment Disability
1. Introduction One of the most obvious and earliest signs of response to treatment of psychotic disorders is reduction of positive symptoms. Time to remission of positive symptoms has frequently been used as an important indicator of treatment outcome for patients with a psychotic disorder (Lieberman et al., 1993; Ho et al., 2000; Perkins et al., 2004; Malla et al., 2006; Wade et al., 2006). A recent and detailed examination of positive symptom remission in first episode psychosis (Simonsen et al., 2010), used severity criteria similar to those recommended by the Remission in Schizophrenia Working Group (Andreasen et al., 2005), and reported that 56% of patients showed remission of positive symptoms within 3 months of treatment (which they considered early remission), while by 2 year follow-up 16% of patients had never met criteria for remission of positive symptoms for 1 week. Those patients showing early remission were more likely to be single, have a schizophrenia related diagnosis, and have a shorter
n Correspondence to: Department of Psychiatry, University of Western Ontario, A2-643, London Health Sciences Centre-VH, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9. Tel.: þ 1 519 685 8500x75493; fax: þ1 519 667 6657. E-mail address: [email protected] (R.M.G. Norman). 1 Department of Epidemiology & Biostatistics, University of Western Ontario, A2-643, London Health Sciences Centre-VH, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9.
duration of untreated psychosis (DUP) and higher levels of negative symptoms. While early remission of positive symptoms is desirable in itself, there has been little prospective investigation of the role of time to such remission in predicting longer term outcomes. Prospective research on previously untreated patients would be particularly important in addressing this issue. Alvarez-Jimenez, et al. (2011) reported that shorter time to remission of psychosis discriminated first episode patients with a single psychotic episode from those with relapses over a 7.5 year follow-up (AlvarezJimenez et al., 2011). In a subsequent paper (Alvarez-Jimenez et al., 2012), they did not find remission of positive symptoms by 8 weeks or 6 months of follow-up to predict functional and social recovery at 7.5 year follow-up, but no duration criteria were applied in the identification of positive symptom remission. Other studies examining the relationship between initial remission and subsequent course have not focused on remission of positive symptoms and/or have not used follow-ups of greater than two years (e.g., Chang et al., 2009; Cassidy et al., 2010a). In the current study, we report data from a prospective study examining the implications of speed of remission of positive symptoms for symptom and functioning outcomes at 5 years. Our primary purpose is to test the hypothesis that earlier remission of psychotic symptoms is associated with better symptom and functioning outcomes at 5year follow-up. The data also permit further examination of the earlier findings regarding the factors that predict remission of positive symptoms.
http://dx.doi.org/10.1016/j.psychres.2014.04.006 0165-1781/& 2014 Published by Elsevier Ireland Ltd.
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i
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2. Method 2.1. Sample Participants were recruited from successive admissions to the Prevention and Early Intervention Program for Psychoses (PEPP) in London, Canada. Patients had a psychotic disorder for which they had not previously received treatment. A total of 188 participants provided informed consent as approved by the Western University Ethics Board for Health Sciences Research. The treatment program in PEPP includes pharmacological and psychosocial intervention for individuals with psychotic disorders (for details see Malla et al., 2003 or www.PEPP.ca). PEPP is primarily intended to treat non-affective psychotic disorders. The treatment program emphasizes continuity of care and an assertive case management model designed to address the needs of a younger population who have not received previous treatment or whose previous treatment did not exceed 30 days. At the end of 2years of treatment, a detailed review of each patient is carried out and he or she usually graduates to a less intensive stepped-down form of care within PEPP. 2.2. Measures and procedures 2.2.1. Early characteristics Onset and treatment delay were identified using a structured interview (Norman and Malla, 2002), administered to patients and at least one collateral source. Age of onset was the age at which clear symptoms of psychosis emerged. DUP was the period of length of time between onset of psychotic symptoms and initiation of treatment as measured in weeks. Level of symptoms at time of presentation for treatment were assessed with reference to the month prior to admission using the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 1984), and the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1983), concerning the month prior to admission. Diagnosis is based on the Structured Clinical Interview for DSM-IV (First et al., 1995). The Premorbid Adjustment Scale (PAS; Cannon-Spoor et al., 1982) was completed using information provided by patients and family. It was completed for developmental periods prior to the onset of symptoms. Parallel to the procedures used by Simonsen et al. (2010), change scores for the social and academic domain were calculated between the last premorbid developmental period and childhood (Simonsen et al., 2010). Adherence to early treatment was assessed by each patient's primary clinician using a 5-point rating scale ranging from 0-not taking medication to 4-taking medication as prescribed, 75–100% of time. This measure has been found to correlate highly with pill count assessments (Cassidy et al., 2010b). The mean score at 2, 3, 6 and 12 months was used as an index of early adherence. 2.2.2. Outcomes Course of psychotic symptoms during 5 years was assessed using a relapseremission chart as part of a modified Life Chart Schedule (Susser et al., 2000). Assessments based on interviews with patients, clinicians and review of case notes, provided a detailed longitudinal assessment of positive symptoms, and allowed charting on a weekly basis of whether the patient had global ratings of less than 3 on items of the SAPS, corresponding to recommended severity criteria for remission of positive symptoms (Andreasen et al., 2005). Consistent with Simonsen et al. (2010) we used two alternate duration criteria for remission of positive symptoms, 1 week and 6 months. The Global Assessment of Functioning (GAF; American Psychiatric Association, 1994) was completed at the end of the fifth year. In addition, two pragmatic measures of functional outcome were available. These were the number of weeks of full-time competitive employment and weeks on a disability pension during the final 2 years of follow-up. Level of positive and negative symptoms was assessed at the end of the fifth year using the SAPS and SANS. All assessments were completed by trained and highly experienced research associates. The intra-class correlations between raters on all relevant assessments were at least 0.80.
3. Results One hundred thirty-two individuals (70.2%) completed the 5year follow-up. Of these, 102 were male and 108 had a diagnosis of a core schizophrenia spectrum disorder (schizophrenia, schizoaffective or schizophreniform disorders). The vast majority (82.6%) were single with just under half (48.5%) not having completed high school at the time of entering treatment. There were no significant differences between those retained and not retained in early characteristics. The mean DUP was 73.7 weeks.
Table 1 Time to initial remission of positive symptoms. Time
At least 1 week remission [n/(%)]
At least 6 months remission [n/(%)]
Month 1 Month 2 Month 3 Months 4–24 Years 3–5 Never remitted
39 26 13 29 12 13
39 25 13 30 10 15
(29.5) (19.7) (9.8) (21.2) (9.1) (9.8)
(29.5) (18.9) (9.8) (22.7) (7.6) (11.4)
DUP was positively skewed and a log10 transformation was effective in approximating a normal distribution. Table 1 provides a classification of the length of time taken to meet criteria for positive symptom remission with duration of at least 1 week or 6 months. Following the precedent of Simonson, et al., those who achieved initial remission within 3 months were considered early remitters, and those who remitted subsequently were later remitters. Results are very similar to those reported by Simonsen et al. (2010) who found 56.9% of their sample meeting remission criteria of 1 week duration within 3 months and 83.6% having experienced remission by 2 years. Of the 119 patients showing a 1 week remission of positive symptoms, 113 (95%) maintained remission for at least 6 months. Of the 6 patients whose initial remission was less than 6 months, 4 subsequently had a 6 month remission and 2 did not. Length of time to a 6 month remission for all patients is reported in the second column of Table 2. Given the high correspondence between 1 week and 6 month duration criteria (recommended by Andreasen et al. (2005)), we carried out subsequent analyses using 6 months duration. Table 2 summarizes early characteristics associated with remission status. There was no significant relationship of remission status to sex, marital status, age of onset, initial symptom levels or social premorbid adjustment. Having a core schizophrenia diagnosis was associated with remission status (χ2 ¼8.05; d.f. ¼2; po 0.05), reflecting a lower proportion of early remitters among individuals with a core schizophrenia diagnosis (Z¼2.7; p o0.05). There was also a difference between remission groups in adherence to medication (F¼5.84; d.f. ¼ 2,113; p o0.01), duration of untreated psychosis (F¼ 4.97; d.f. ¼ 2,129; p o0.01), and deterioration of academic premorbid adjustment (F¼6.71; d.f. ¼2,121; po 0.01). When these variables were entered into a logistic regression to predict whether or not an individual was an early remitter, only presence of a schizophrenia spectrum diagnosis was independently associated with remission status. Table 3 summarizes data on prognostic significance of early remission for symptoms at 5 years. In order to avoid confounding the differences in symptomatology that are intrinsic to nonremission with outcomes, the relevant data do not include patients who had not remitted by the fourth year of follow-up. Early remitters had significantly lower levels of positive symptoms at 5 years (t¼2.79; p o0.01), higher levels of functioning as assessed by the GAF (t ¼2.74; p o0.01), and more weeks of competitive employment (t ¼2.12; p o0.05). There was also evidence of a borderline significance of early remitters having lower levels of negative symptoms (t¼1.70; p ¼0.09) and fewer weeks on a disability pension (t¼1.77; p ¼0.08).
4. Discussion Our data concerning the proportion of patients showing remission of positive symptoms within 3 months and those showing later remission or no remission by 2 years, are remarkably similar to those
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i
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Table 2 Relationship of time to remission to presenting characteristics. Early remission
Later remission
Non-remission
Diagnosisn Core schizophrenia Not core schizophrenia
57 20
38 2
13 2
Gender Male Female
55 22
34 6
13 2
Marital status Single Married/stable relationship Separated/divorced
62 12 3
34 5 1
13 1 1
Age of onset Mean (S.D.) Median Initial SAPS global – mean (S.D.) Initial SANS global – mean (S.D.) Adherencen/mean (S.D.)nn Change in social PAS – mean (S.D.) Change in academic PAS – mean (S.D.)nn Weeks DUP – mean (S.D.)nn
24.5 (7.9) 22.0 10.5 (3.3) 12.0 (5.2) 3.9 (0.31) 0.05 (0.23) 0.11 (0.17) 52.3 (107.9)
22.4 (7.9) 20.9 9.8 (3.8) 11.2 (4.8) 3.7 (0.68) 0.10 (0.20) 0.19 (0.18) 75.4 (81.7)
23.6 (10.0) 19.5 10.1 (3.0) 12.8 (3.9) 3.3 (0.91) 0.15 (0.25) 0.27 (0.20) 120.2 (159.4)
n
po 0.05. p o0.01.
nn
Table 3 Outcomes for early versus later remitters.
SAPS global – mean (S.D.)nn SANS global – mean (S.D.) GAF – mean (S.D.)nn Weeks of disability pension Weeks competitive employmentn n
Early remission
Late remission
1.1 4.6 67.7 31.2 38.0
2.3 5.9 58.6 48.1 21.6
(1.8) (4.0) (16.0) (45.6) (42.3)
(3.0) (3.6) (14.7) (49.9) (32.6)
po 0.05. p o0.01.
nn
reported in first episode patients by Simonsen, et al. (2010). In addition, our findings regarding the role of schizophrenia spectrum diagnosis, DUP, adherence and change in premorbid function as predictors of likelihood of early remission parallel theirs and/or others (Loebel et al., 1992; McGorry et al., 1996; Perkins et al., 2004; Malla et al., 2006). Initial treatment of psychotic disorders is often focused on reduction of positive symptoms, but there has been little research on the prognostic significance of the length of time to resolution of such symptoms. Those studies that have been completed have generally had follow-ups of not more than 2 years and/or focused on joint remission or positive and negative symptoms (e.g., Cassidy et al., 2010a; Chang et al., 2013), and there is evidence suggesting that the prognostic significance of indicators of early response may fade with longer follow-up (Levine and Leucht, 2012). Our findings indicate that achieving remission of positive symptoms within 3 months of initiation of treatment is related to longer term outcomes, including level of symptoms at 5 years, GAF scores, amount of competitive employment, and use of a disability pension. Our findings do contrast with a recent report by AlvarezJimenez et al. (2012) who found that having achieved remission of positive symptoms by either eight weeks or 6 months of treatment in an early intervention program did not predict functional recovery at a 7.5 year follow-up (Alvarez-Jimenez et al., 2012). The primary differences between the study designs were that the remission criteria in the Alvarez-Jimenez et al.'s
(2012) study did not include the 6 months duration. There are also differences in the index of functioning. Alvarez-Jimenez et al. (2012) used ratings on the Quality of Life Scale (Heinrichs et al., 1984) as opposed to the GAF and the objective indicators of weeks of competitive employment and disability pension. The strengths of the current study include the use of a consistent protocol which assesses the time of remission of positive symptoms and inclusion of objective indicators related to employment and use of disability as indicators of functioning at follow-up. There are, however, limitations. Although our focus is on timing of remission of positive symptoms, there is evidence that negative symptoms have implications for psychosocial functioning (Milev et al., 2005). Future studies on long-term implications of time to remission would be strengthened by separate examination of timing of remission of positive and negative symptoms. In addition, the current data are derived from patients in a treatment program primarily treating non-affective psychotic disorders and findings may not generalize to a more diverse clinical sample. Furthermore, there were substantially more men than women in our sample. There is, however, increasing evidence that incidence of schizophrenia spectrum disorders is greater for males than females, particularly at younger ages (Abel et al., 2010), and it is not unusual to have a preponderance of males in first episode samples (Crumlish et al., 2009; Wunderink et al., 2009). In addition, within the current sample, sex was not significantly related to time of remission or outcomes at follow-up. Our data do not establish a causal relationship. It is possible that shorter time to remission is a marker for a less pernicious course of illness. On the other hand, there is evidence that increased periods of untreated psychosis may compromise recovery (Marshall et al., 2005; Perkins et al., 2005) and longer delay in remission after initiation of treatment might compound this effect. At the very least, it appears that efforts to bring about prompt remission of positive symptoms may be justified not just by the suffering intrinsic to such an experience. While we would certainly not disagree with Alvarez-Jimenez et al. (2012) conclusions that we need to deliver interventions directed at functional recovery as early as possible and not assume that symptom remission leads to such recovery, our data do provide evidence that quicker remission of positive symptoms is related to longer term symptom and functional outcomes.
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i
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Acknowledgments The authors wish to acknowledge the support and co-operation from staff and clients of the Prevention and Early Intervention Program for Psychoses in London, Ontario, Canada. References Abel, K.M., Drake, R., Goldstein, J.M., 2010. Sex differences in schizophrenia. International Review of Psychiatry 22, 417–428. Alvarez-Jimenez, M., Gleeson, J.F., Henry, L.P., Harrigan, S.M., Harris, M.G., Amminger, G.P., Killackey, E., Yung, A.R., Herrman, H., Jackson, H.J., McGorry, P.D., 2011. Prediction of a single psychotic episode: a 7.5-year, prospective study in firstepisode psychosis. Schizophrenia Research 125, 236–246. Alvarez-Jimenez, M., Gleeson, J.F., Henry, L.P., Harrigan, S.M., Harris, M.G., Killackey, E., Bendall, S., Amminger, G.P., Yung, A.R., Herrman, H., Jackson, H.J., McGorry, P. D., 2012. Road to full recovery: longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years. Psychological Medicine 42, 595–606. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association, Washington, DC. Andreasen, N.C., 1983. Scale for the Assessment of Negative Symptoms. University of Iowa Press, Iowa City, IA. Andreasen, N.C., 1984. Scale for the Assessment of Positive Symptoms. University of Iowa, Iowa City, IA. Andreasen, N.C., Carpenter Jr., W.T., Kane, J.M., Lasser, R.A., Marder, S.R., Weinberger, D.R., 2005. Remission in schizophrenia: proposed criteria and rationale for consensus. American Journal of Psychiatry 162, 441–449. Cannon-Spoor, H.E., Potkin, S.G., Wyatt, R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophrenia Bulletin 8, 470–484. Cassidy, C.M., Norman, R., Manchanda, R., Schmitz, N., Malla, A., 2010a. Testing definitions of symptom remission in first-episode psychosis for prediction of functional outcome at 2 years. Schizophrenia Bulletin 36, 1001–1008. Cassidy, C.M., Rabinovitch, M., Schmitz, N., Joober, R., Malla, A., 2010b. A comparison study of multiple measures of adherence to antipsychotic medication in first-episode psychosis. Journal of Clinical Pharmacology 30, 64–67. Chang, W.C., Chan, T.C., Chen, E.S., Hui, C.L., Wong, G.H., Chan, S.K., Lee, E.H., Chen, E. Y., 2013. The concurrent and predictive validity of symptomatic remission criteria in first-episode schizophrenia. Schizophrenia Research 143, 107–115. Chang, Y.M., Wang, J.K., Chiu, S.N., Lin, M.T., Wu, E.T., Chen, C.A., Huang, S.C., Chen, Y. S., Chang, C.I., Chiu, I.S., Lin, J.L., Lai, L.P., Wu, M.H., 2009. Clinical spectrum and long-term outcome of Ebstein's anomaly based on a 26-year experience in an Asian cohort. European Journal of Pediatrics 168, 685–690. Crumlish, N., Whitty, P., Clarke, M., Browne, S., Kamali, M., Gervin, M., McTigue, O., Kinsella, A., Waddington, J.L., Larkin, C., O’Callaghan, E., 2009. Beyond the critical period: longitudinal study of 8-year outcome in first-episode nonaffective psychosis. British Journal of Psychiatry 194, 18–24. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B., 1995. Structured Clinical Interview of DSM-IV Axis 1 (SCID-1) Disorders: Clinical Version. Biometrics Research Department; New York State Psychiatric Institute, New York. Heinrichs, D.W., Hanlon, T.E., Carpenter Jr., W.T., 1984. The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bulletin 10, 388–398.
Ho, B.C., Andreasen, N.C., Flaum, M., Nopoulos, P., Miller, D., 2000. Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia. American Journal of Psychiatry 157, 808–815. Levine, S.Z., Leucht, S., 2012. Early symptom response to antipsychotic medication as a marker of subsequent symptom change: an eighteen-month follow-up study of recent episode schizophrenia. Schizophrenia Research 141, 168–172. Lieberman, J., Jody, D., Geisler, S., Alvir, J., Loebel, A., Szymanski, S., Woerner, M., Borenstein, M., 1993. Time course and biologic correlates of treatment response in first-episode schizophrenia. Archives of General Psychiatry 50, 369–376. Loebel, A.D., Lieberman, J.A., Alvir, J.M., Mayerhoff, D.I., Geisler, S.H., Szymanski, S.R., 1992. Duration of psychosis and outcome in first-episode schizophrenia. American Journal of Psychiatry 149, 1183–1188. Malla, A., Norman, R., McLean, T., Scholten, D., Townsend, L., 2003. A Canadian programme for early intervention in non-affective psychotic disorders. Australia and New Zealand Journal of Psychiatry 37, 407–413. Malla, A., Norman, R., Schmitz, N., Manchanda, R., Bechard-Evans, L., Takhar, J., Harricharan, R., 2006. Predictors of rate and time to remission in first-episode psychosis: a two-year outcome study. Psychological Medicine 36, 649–658. 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: a systematic review. Archives of General Psychiatry 62, 975–983. McGorry, P.D., Edwards, J., Mihalopoulos, C., Harrigan, S.M., Jackson, H.J., 1996. EPPIC: an evolving system of early detection and optimal management. Schizophrenia Bulletin 22, 305–326. Milev, P., Ho, B.C., Arndt, S., Andreasen, N.C., 2005. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry 162, 495–506. Norman, R.M.G., Malla, A.K., 2002. Course of Onset and Relapse Schedule: Interview and Coding Instruction Guide, 1st ed. Prevention and Early Intervention Program for Psychoses, London, Ontario. Perkins, D., Lieberman, J., Gu, H., Tohen, M., McEvoy, J., Green, A., Zipursky, R., Strakowski, S., Sharma, T., Kahn, R., Gur, R., Tollefson, G., 2004. Predictors of antipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreniform disorders. British Journal of Psychiatry 185, 18–24. 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. American Journal of Psychiatry 162, 1785–1804. Simonsen, E., Friis, S., Opjordsmoen, S., Mortensen, E.L., Haahr, U., Melle, I., Joa, I., Johannessen, J.O., Larsen, T.K., Rossberg, J.I., Rund, B.R., Vaglum, P., McGlashan, T.H., 2010. Early identification of non-remission in first-episode psychosis in a two-year outcome study. Acta Psychiatrica Scandinavica 122, 375–383. Susser, E., Finnerty, M., Mojtabai, R., Yale, S., Conover, S., Goetz, R., Amador, X., 2000. Reliability of the life chart schedule for assessment of the long-term course of schizophrenia. Schizophrenia Research 42, 67–77. Wade, D., Harrigan, S., Edwards, J., Burgess, P.M., Whelan, G., McGorry, P.D., 2006. Substance misuse in first-episode psychosis: 15-month prospective follow-up study. British Journal of Psychiatry 189, 229–234. Wunderink, L., Sytema, S., Nienhuis, F.J., Wiersma, D., 2009. Clinical recovery in first-episode psychosis. Schizophrenia Bulletin 35, 362–369.
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
The prognostic significance of early remission of positive symptoms in first treated psychosis Ross M.G. Norman a,b,n,1, Rahul Manchanda a,b, Deborah Windell b a
Department of Psychiatry, University of Western Ontario, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9 Prevention and Early Intervention Program for Psychoses (PEPP), London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9
b
art ic l e i nf o
a b s t r a c t
Article history: Received 16 July 2013 Received in revised form 13 March 2014 Accepted 2 April 2014
Objectives: We examine the relationship between achieving remission of positive symptoms within 3 months in first episode psychosis and outcomes 5 years later. Methods: Time to remission of positive symptoms, other early characteristics and 5 year outcomes were assessed in a prospective study of 132 patients being treated for the first time for a psychotic disorder. Results: Just under 60% of patients showed remission of positive symptoms within 3 months. In comparison to later remitters, they showed lower levels of positive symptoms, greater likelihood of competitive employment and less likelihood of collecting a disability pension at 5 years. Conclusions: Earlier remission of positive symptoms may have prognostic significance for longer term outcomes. & 2014 Published by Elsevier Ireland Ltd.
Keywords: Schizophrenia Outcomes Prognosis Functioning Employment Disability
1. Introduction One of the most obvious and earliest signs of response to treatment of psychotic disorders is reduction of positive symptoms. Time to remission of positive symptoms has frequently been used as an important indicator of treatment outcome for patients with a psychotic disorder (Lieberman et al., 1993; Ho et al., 2000; Perkins et al., 2004; Malla et al., 2006; Wade et al., 2006). A recent and detailed examination of positive symptom remission in first episode psychosis (Simonsen et al., 2010), used severity criteria similar to those recommended by the Remission in Schizophrenia Working Group (Andreasen et al., 2005), and reported that 56% of patients showed remission of positive symptoms within 3 months of treatment (which they considered early remission), while by 2 year follow-up 16% of patients had never met criteria for remission of positive symptoms for 1 week. Those patients showing early remission were more likely to be single, have a schizophrenia related diagnosis, and have a shorter
n Correspondence to: Department of Psychiatry, University of Western Ontario, A2-643, London Health Sciences Centre-VH, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9. Tel.: þ 1 519 685 8500x75493; fax: þ1 519 667 6657. E-mail address: [email protected] (R.M.G. Norman). 1 Department of Epidemiology & Biostatistics, University of Western Ontario, A2-643, London Health Sciences Centre-VH, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9.
duration of untreated psychosis (DUP) and higher levels of negative symptoms. While early remission of positive symptoms is desirable in itself, there has been little prospective investigation of the role of time to such remission in predicting longer term outcomes. Prospective research on previously untreated patients would be particularly important in addressing this issue. Alvarez-Jimenez, et al. (2011) reported that shorter time to remission of psychosis discriminated first episode patients with a single psychotic episode from those with relapses over a 7.5 year follow-up (AlvarezJimenez et al., 2011). In a subsequent paper (Alvarez-Jimenez et al., 2012), they did not find remission of positive symptoms by 8 weeks or 6 months of follow-up to predict functional and social recovery at 7.5 year follow-up, but no duration criteria were applied in the identification of positive symptom remission. Other studies examining the relationship between initial remission and subsequent course have not focused on remission of positive symptoms and/or have not used follow-ups of greater than two years (e.g., Chang et al., 2009; Cassidy et al., 2010a). In the current study, we report data from a prospective study examining the implications of speed of remission of positive symptoms for symptom and functioning outcomes at 5 years. Our primary purpose is to test the hypothesis that earlier remission of psychotic symptoms is associated with better symptom and functioning outcomes at 5year follow-up. The data also permit further examination of the earlier findings regarding the factors that predict remission of positive symptoms.
http://dx.doi.org/10.1016/j.psychres.2014.04.006 0165-1781/& 2014 Published by Elsevier Ireland Ltd.
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i
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2. Method 2.1. Sample Participants were recruited from successive admissions to the Prevention and Early Intervention Program for Psychoses (PEPP) in London, Canada. Patients had a psychotic disorder for which they had not previously received treatment. A total of 188 participants provided informed consent as approved by the Western University Ethics Board for Health Sciences Research. The treatment program in PEPP includes pharmacological and psychosocial intervention for individuals with psychotic disorders (for details see Malla et al., 2003 or www.PEPP.ca). PEPP is primarily intended to treat non-affective psychotic disorders. The treatment program emphasizes continuity of care and an assertive case management model designed to address the needs of a younger population who have not received previous treatment or whose previous treatment did not exceed 30 days. At the end of 2years of treatment, a detailed review of each patient is carried out and he or she usually graduates to a less intensive stepped-down form of care within PEPP. 2.2. Measures and procedures 2.2.1. Early characteristics Onset and treatment delay were identified using a structured interview (Norman and Malla, 2002), administered to patients and at least one collateral source. Age of onset was the age at which clear symptoms of psychosis emerged. DUP was the period of length of time between onset of psychotic symptoms and initiation of treatment as measured in weeks. Level of symptoms at time of presentation for treatment were assessed with reference to the month prior to admission using the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 1984), and the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1983), concerning the month prior to admission. Diagnosis is based on the Structured Clinical Interview for DSM-IV (First et al., 1995). The Premorbid Adjustment Scale (PAS; Cannon-Spoor et al., 1982) was completed using information provided by patients and family. It was completed for developmental periods prior to the onset of symptoms. Parallel to the procedures used by Simonsen et al. (2010), change scores for the social and academic domain were calculated between the last premorbid developmental period and childhood (Simonsen et al., 2010). Adherence to early treatment was assessed by each patient's primary clinician using a 5-point rating scale ranging from 0-not taking medication to 4-taking medication as prescribed, 75–100% of time. This measure has been found to correlate highly with pill count assessments (Cassidy et al., 2010b). The mean score at 2, 3, 6 and 12 months was used as an index of early adherence. 2.2.2. Outcomes Course of psychotic symptoms during 5 years was assessed using a relapseremission chart as part of a modified Life Chart Schedule (Susser et al., 2000). Assessments based on interviews with patients, clinicians and review of case notes, provided a detailed longitudinal assessment of positive symptoms, and allowed charting on a weekly basis of whether the patient had global ratings of less than 3 on items of the SAPS, corresponding to recommended severity criteria for remission of positive symptoms (Andreasen et al., 2005). Consistent with Simonsen et al. (2010) we used two alternate duration criteria for remission of positive symptoms, 1 week and 6 months. The Global Assessment of Functioning (GAF; American Psychiatric Association, 1994) was completed at the end of the fifth year. In addition, two pragmatic measures of functional outcome were available. These were the number of weeks of full-time competitive employment and weeks on a disability pension during the final 2 years of follow-up. Level of positive and negative symptoms was assessed at the end of the fifth year using the SAPS and SANS. All assessments were completed by trained and highly experienced research associates. The intra-class correlations between raters on all relevant assessments were at least 0.80.
3. Results One hundred thirty-two individuals (70.2%) completed the 5year follow-up. Of these, 102 were male and 108 had a diagnosis of a core schizophrenia spectrum disorder (schizophrenia, schizoaffective or schizophreniform disorders). The vast majority (82.6%) were single with just under half (48.5%) not having completed high school at the time of entering treatment. There were no significant differences between those retained and not retained in early characteristics. The mean DUP was 73.7 weeks.
Table 1 Time to initial remission of positive symptoms. Time
At least 1 week remission [n/(%)]
At least 6 months remission [n/(%)]
Month 1 Month 2 Month 3 Months 4–24 Years 3–5 Never remitted
39 26 13 29 12 13
39 25 13 30 10 15
(29.5) (19.7) (9.8) (21.2) (9.1) (9.8)
(29.5) (18.9) (9.8) (22.7) (7.6) (11.4)
DUP was positively skewed and a log10 transformation was effective in approximating a normal distribution. Table 1 provides a classification of the length of time taken to meet criteria for positive symptom remission with duration of at least 1 week or 6 months. Following the precedent of Simonson, et al., those who achieved initial remission within 3 months were considered early remitters, and those who remitted subsequently were later remitters. Results are very similar to those reported by Simonsen et al. (2010) who found 56.9% of their sample meeting remission criteria of 1 week duration within 3 months and 83.6% having experienced remission by 2 years. Of the 119 patients showing a 1 week remission of positive symptoms, 113 (95%) maintained remission for at least 6 months. Of the 6 patients whose initial remission was less than 6 months, 4 subsequently had a 6 month remission and 2 did not. Length of time to a 6 month remission for all patients is reported in the second column of Table 2. Given the high correspondence between 1 week and 6 month duration criteria (recommended by Andreasen et al. (2005)), we carried out subsequent analyses using 6 months duration. Table 2 summarizes early characteristics associated with remission status. There was no significant relationship of remission status to sex, marital status, age of onset, initial symptom levels or social premorbid adjustment. Having a core schizophrenia diagnosis was associated with remission status (χ2 ¼8.05; d.f. ¼2; po 0.05), reflecting a lower proportion of early remitters among individuals with a core schizophrenia diagnosis (Z¼2.7; p o0.05). There was also a difference between remission groups in adherence to medication (F¼5.84; d.f. ¼ 2,113; p o0.01), duration of untreated psychosis (F¼ 4.97; d.f. ¼ 2,129; p o0.01), and deterioration of academic premorbid adjustment (F¼6.71; d.f. ¼2,121; po 0.01). When these variables were entered into a logistic regression to predict whether or not an individual was an early remitter, only presence of a schizophrenia spectrum diagnosis was independently associated with remission status. Table 3 summarizes data on prognostic significance of early remission for symptoms at 5 years. In order to avoid confounding the differences in symptomatology that are intrinsic to nonremission with outcomes, the relevant data do not include patients who had not remitted by the fourth year of follow-up. Early remitters had significantly lower levels of positive symptoms at 5 years (t¼2.79; p o0.01), higher levels of functioning as assessed by the GAF (t ¼2.74; p o0.01), and more weeks of competitive employment (t ¼2.12; p o0.05). There was also evidence of a borderline significance of early remitters having lower levels of negative symptoms (t¼1.70; p ¼0.09) and fewer weeks on a disability pension (t¼1.77; p ¼0.08).
4. Discussion Our data concerning the proportion of patients showing remission of positive symptoms within 3 months and those showing later remission or no remission by 2 years, are remarkably similar to those
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i
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Table 2 Relationship of time to remission to presenting characteristics. Early remission
Later remission
Non-remission
Diagnosisn Core schizophrenia Not core schizophrenia
57 20
38 2
13 2
Gender Male Female
55 22
34 6
13 2
Marital status Single Married/stable relationship Separated/divorced
62 12 3
34 5 1
13 1 1
Age of onset Mean (S.D.) Median Initial SAPS global – mean (S.D.) Initial SANS global – mean (S.D.) Adherencen/mean (S.D.)nn Change in social PAS – mean (S.D.) Change in academic PAS – mean (S.D.)nn Weeks DUP – mean (S.D.)nn
24.5 (7.9) 22.0 10.5 (3.3) 12.0 (5.2) 3.9 (0.31) 0.05 (0.23) 0.11 (0.17) 52.3 (107.9)
22.4 (7.9) 20.9 9.8 (3.8) 11.2 (4.8) 3.7 (0.68) 0.10 (0.20) 0.19 (0.18) 75.4 (81.7)
23.6 (10.0) 19.5 10.1 (3.0) 12.8 (3.9) 3.3 (0.91) 0.15 (0.25) 0.27 (0.20) 120.2 (159.4)
n
po 0.05. p o0.01.
nn
Table 3 Outcomes for early versus later remitters.
SAPS global – mean (S.D.)nn SANS global – mean (S.D.) GAF – mean (S.D.)nn Weeks of disability pension Weeks competitive employmentn n
Early remission
Late remission
1.1 4.6 67.7 31.2 38.0
2.3 5.9 58.6 48.1 21.6
(1.8) (4.0) (16.0) (45.6) (42.3)
(3.0) (3.6) (14.7) (49.9) (32.6)
po 0.05. p o0.01.
nn
reported in first episode patients by Simonsen, et al. (2010). In addition, our findings regarding the role of schizophrenia spectrum diagnosis, DUP, adherence and change in premorbid function as predictors of likelihood of early remission parallel theirs and/or others (Loebel et al., 1992; McGorry et al., 1996; Perkins et al., 2004; Malla et al., 2006). Initial treatment of psychotic disorders is often focused on reduction of positive symptoms, but there has been little research on the prognostic significance of the length of time to resolution of such symptoms. Those studies that have been completed have generally had follow-ups of not more than 2 years and/or focused on joint remission or positive and negative symptoms (e.g., Cassidy et al., 2010a; Chang et al., 2013), and there is evidence suggesting that the prognostic significance of indicators of early response may fade with longer follow-up (Levine and Leucht, 2012). Our findings indicate that achieving remission of positive symptoms within 3 months of initiation of treatment is related to longer term outcomes, including level of symptoms at 5 years, GAF scores, amount of competitive employment, and use of a disability pension. Our findings do contrast with a recent report by AlvarezJimenez et al. (2012) who found that having achieved remission of positive symptoms by either eight weeks or 6 months of treatment in an early intervention program did not predict functional recovery at a 7.5 year follow-up (Alvarez-Jimenez et al., 2012). The primary differences between the study designs were that the remission criteria in the Alvarez-Jimenez et al.'s
(2012) study did not include the 6 months duration. There are also differences in the index of functioning. Alvarez-Jimenez et al. (2012) used ratings on the Quality of Life Scale (Heinrichs et al., 1984) as opposed to the GAF and the objective indicators of weeks of competitive employment and disability pension. The strengths of the current study include the use of a consistent protocol which assesses the time of remission of positive symptoms and inclusion of objective indicators related to employment and use of disability as indicators of functioning at follow-up. There are, however, limitations. Although our focus is on timing of remission of positive symptoms, there is evidence that negative symptoms have implications for psychosocial functioning (Milev et al., 2005). Future studies on long-term implications of time to remission would be strengthened by separate examination of timing of remission of positive and negative symptoms. In addition, the current data are derived from patients in a treatment program primarily treating non-affective psychotic disorders and findings may not generalize to a more diverse clinical sample. Furthermore, there were substantially more men than women in our sample. There is, however, increasing evidence that incidence of schizophrenia spectrum disorders is greater for males than females, particularly at younger ages (Abel et al., 2010), and it is not unusual to have a preponderance of males in first episode samples (Crumlish et al., 2009; Wunderink et al., 2009). In addition, within the current sample, sex was not significantly related to time of remission or outcomes at follow-up. Our data do not establish a causal relationship. It is possible that shorter time to remission is a marker for a less pernicious course of illness. On the other hand, there is evidence that increased periods of untreated psychosis may compromise recovery (Marshall et al., 2005; Perkins et al., 2005) and longer delay in remission after initiation of treatment might compound this effect. At the very least, it appears that efforts to bring about prompt remission of positive symptoms may be justified not just by the suffering intrinsic to such an experience. While we would certainly not disagree with Alvarez-Jimenez et al. (2012) conclusions that we need to deliver interventions directed at functional recovery as early as possible and not assume that symptom remission leads to such recovery, our data do provide evidence that quicker remission of positive symptoms is related to longer term symptom and functional outcomes.
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i
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Acknowledgments The authors wish to acknowledge the support and co-operation from staff and clients of the Prevention and Early Intervention Program for Psychoses in London, Ontario, Canada. References Abel, K.M., Drake, R., Goldstein, J.M., 2010. Sex differences in schizophrenia. International Review of Psychiatry 22, 417–428. Alvarez-Jimenez, M., Gleeson, J.F., Henry, L.P., Harrigan, S.M., Harris, M.G., Amminger, G.P., Killackey, E., Yung, A.R., Herrman, H., Jackson, H.J., McGorry, P.D., 2011. Prediction of a single psychotic episode: a 7.5-year, prospective study in firstepisode psychosis. Schizophrenia Research 125, 236–246. Alvarez-Jimenez, M., Gleeson, J.F., Henry, L.P., Harrigan, S.M., Harris, M.G., Killackey, E., Bendall, S., Amminger, G.P., Yung, A.R., Herrman, H., Jackson, H.J., McGorry, P. D., 2012. Road to full recovery: longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years. Psychological Medicine 42, 595–606. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association, Washington, DC. Andreasen, N.C., 1983. Scale for the Assessment of Negative Symptoms. University of Iowa Press, Iowa City, IA. Andreasen, N.C., 1984. Scale for the Assessment of Positive Symptoms. University of Iowa, Iowa City, IA. Andreasen, N.C., Carpenter Jr., W.T., Kane, J.M., Lasser, R.A., Marder, S.R., Weinberger, D.R., 2005. Remission in schizophrenia: proposed criteria and rationale for consensus. American Journal of Psychiatry 162, 441–449. Cannon-Spoor, H.E., Potkin, S.G., Wyatt, R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophrenia Bulletin 8, 470–484. Cassidy, C.M., Norman, R., Manchanda, R., Schmitz, N., Malla, A., 2010a. Testing definitions of symptom remission in first-episode psychosis for prediction of functional outcome at 2 years. Schizophrenia Bulletin 36, 1001–1008. Cassidy, C.M., Rabinovitch, M., Schmitz, N., Joober, R., Malla, A., 2010b. A comparison study of multiple measures of adherence to antipsychotic medication in first-episode psychosis. Journal of Clinical Pharmacology 30, 64–67. Chang, W.C., Chan, T.C., Chen, E.S., Hui, C.L., Wong, G.H., Chan, S.K., Lee, E.H., Chen, E. Y., 2013. The concurrent and predictive validity of symptomatic remission criteria in first-episode schizophrenia. Schizophrenia Research 143, 107–115. Chang, Y.M., Wang, J.K., Chiu, S.N., Lin, M.T., Wu, E.T., Chen, C.A., Huang, S.C., Chen, Y. S., Chang, C.I., Chiu, I.S., Lin, J.L., Lai, L.P., Wu, M.H., 2009. Clinical spectrum and long-term outcome of Ebstein's anomaly based on a 26-year experience in an Asian cohort. European Journal of Pediatrics 168, 685–690. Crumlish, N., Whitty, P., Clarke, M., Browne, S., Kamali, M., Gervin, M., McTigue, O., Kinsella, A., Waddington, J.L., Larkin, C., O’Callaghan, E., 2009. Beyond the critical period: longitudinal study of 8-year outcome in first-episode nonaffective psychosis. British Journal of Psychiatry 194, 18–24. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B., 1995. Structured Clinical Interview of DSM-IV Axis 1 (SCID-1) Disorders: Clinical Version. Biometrics Research Department; New York State Psychiatric Institute, New York. Heinrichs, D.W., Hanlon, T.E., Carpenter Jr., W.T., 1984. The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bulletin 10, 388–398.
Ho, B.C., Andreasen, N.C., Flaum, M., Nopoulos, P., Miller, D., 2000. Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia. American Journal of Psychiatry 157, 808–815. Levine, S.Z., Leucht, S., 2012. Early symptom response to antipsychotic medication as a marker of subsequent symptom change: an eighteen-month follow-up study of recent episode schizophrenia. Schizophrenia Research 141, 168–172. Lieberman, J., Jody, D., Geisler, S., Alvir, J., Loebel, A., Szymanski, S., Woerner, M., Borenstein, M., 1993. Time course and biologic correlates of treatment response in first-episode schizophrenia. Archives of General Psychiatry 50, 369–376. Loebel, A.D., Lieberman, J.A., Alvir, J.M., Mayerhoff, D.I., Geisler, S.H., Szymanski, S.R., 1992. Duration of psychosis and outcome in first-episode schizophrenia. American Journal of Psychiatry 149, 1183–1188. Malla, A., Norman, R., McLean, T., Scholten, D., Townsend, L., 2003. A Canadian programme for early intervention in non-affective psychotic disorders. Australia and New Zealand Journal of Psychiatry 37, 407–413. Malla, A., Norman, R., Schmitz, N., Manchanda, R., Bechard-Evans, L., Takhar, J., Harricharan, R., 2006. Predictors of rate and time to remission in first-episode psychosis: a two-year outcome study. Psychological Medicine 36, 649–658. 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: a systematic review. Archives of General Psychiatry 62, 975–983. McGorry, P.D., Edwards, J., Mihalopoulos, C., Harrigan, S.M., Jackson, H.J., 1996. EPPIC: an evolving system of early detection and optimal management. Schizophrenia Bulletin 22, 305–326. Milev, P., Ho, B.C., Arndt, S., Andreasen, N.C., 2005. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry 162, 495–506. Norman, R.M.G., Malla, A.K., 2002. Course of Onset and Relapse Schedule: Interview and Coding Instruction Guide, 1st ed. Prevention and Early Intervention Program for Psychoses, London, Ontario. Perkins, D., Lieberman, J., Gu, H., Tohen, M., McEvoy, J., Green, A., Zipursky, R., Strakowski, S., Sharma, T., Kahn, R., Gur, R., Tollefson, G., 2004. Predictors of antipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreniform disorders. British Journal of Psychiatry 185, 18–24. 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. American Journal of Psychiatry 162, 1785–1804. Simonsen, E., Friis, S., Opjordsmoen, S., Mortensen, E.L., Haahr, U., Melle, I., Joa, I., Johannessen, J.O., Larsen, T.K., Rossberg, J.I., Rund, B.R., Vaglum, P., McGlashan, T.H., 2010. Early identification of non-remission in first-episode psychosis in a two-year outcome study. Acta Psychiatrica Scandinavica 122, 375–383. Susser, E., Finnerty, M., Mojtabai, R., Yale, S., Conover, S., Goetz, R., Amador, X., 2000. Reliability of the life chart schedule for assessment of the long-term course of schizophrenia. Schizophrenia Research 42, 67–77. Wade, D., Harrigan, S., Edwards, J., Burgess, P.M., Whelan, G., McGorry, P.D., 2006. Substance misuse in first-episode psychosis: 15-month prospective follow-up study. British Journal of Psychiatry 189, 229–234. Wunderink, L., Sytema, S., Nienhuis, F.J., Wiersma, D., 2009. Clinical recovery in first-episode psychosis. Schizophrenia Bulletin 35, 362–369.
Please cite this article as: Norman, R.M.G., et al., The prognostic significance of early remission of positive symptoms in first treated psychosis. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.04.006i