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Impacts of duration of untreated psychosis on cognition and negative symptoms in first-episode schizophrenia: a 3-year prospective follow-up study

  • W. C. Chang (a1), C. L. M. Hui (a1), J. Y. M. Tang (a1), G. H. Y. Wong (a1), S. K. W. Chan (a1), E. H. M. Lee (a1) and E. Y. H. Chen (a1)...

Cognitive impairment is a core feature of schizophrenia. Its relationship with duration of untreated psychosis (DUP), a potentially malleable prognostic factor, has been less studied, with inconsistent findings being observed in the literature. Previous research investigating such a relationship was mostly cross-sectional and none of those prospective studies had a follow-up duration beyond 2 years.


A total of 93 Hong Kong Chinese aged 18 to 55 years presenting with first-episode schizophrenia-spectrum disorder were studied. DUP and pre-morbid adjustment were measured using a structured interview incorporating multiple sources of information. Psychopathological evaluation was administered at intake, after clinical stabilization of the first psychotic episode, and at 12, 24 and 36 months. Cognitive functions were measured at clinical stabilization, and at 12, 24 and 36 months.


DUP exerted differential effects on various cognitive domains, with memory deficits being the most related to DUP even when potential confounders including pre-morbid adjustment and sex were adjusted. Prolonged DUP was associated with more severe impairment in visual memory at clinical stabilization and verbal memory at 24 and 36 months. Further, patients with a long DUP were found to have worse outcomes on negative symptoms at 36 months. The effects of DUP on verbal memory remained significant even when negative symptoms were taken into consideration.


Our findings provided further supportive evidence that delayed treatment to first-episode psychosis is associated with poorer cognitive and clinical outcomes. In addition, DUP may specifically affect memory function and its adverse impact on verbal memory may only become evident at a later stage of the recovery process.

Corresponding author
*Address for correspondence: W. C. Chang, Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. (Email:
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Addington, J, van Mastrigt, S, Addington, D (2004). Duration of untreated psychosis: impact on 2-year outcome. Psychological Medicine 34, 277284.
Albus, M, Hubmann, W, Scherer, J, Dreikorn, B, Hecht, S, Sobizack, N, Mohr, F (2002). A prospective 2-year follow-up study of neurocognitive functioning in patients with first-episode schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 252, 262267.
Amminger, GP, Edwards, J, Brewer, WJ, Harrigan, S, McGorry, PD (2002). Duration of untreated psychosis and cognitive deterioration in first-episode schizophrenia. Schizophrenia Research 54, 223230.
APA (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, revised. American Psychiatric Association: Washington, DC.
Bangalore, SS, Goradia, DD, Nutche, J, Diwadkar, VA, Prasad, KMR, Keshavan, MS (2009). Untreated illness duration correlates with gray matter loss in first-episode psychoses. NeuroReport 20, 729734.
Barnes, TRE, Leeson, VC, Mutsatsa, H, Watt, HC, Hutton, S, Joyce, EM (2008). Duration of untreated psychosis and social function: 1-year follow-up study of first-episode schizophrenia. British Journal of Psychiatry 193, 203209.
Boonstra, G, Cahn, W, Schnack, HG, Hulshoff-Pol, HE, Minerhoud, TC, Kahn, RS, van Haren, NEM (2011). Duration of untreated illness in schizophrenia is not associated with 5-year brain volume change. Schizophrenia Research 132, 8490.
Cahn, W, Rais, M, Stigter, FP, van Haren, NEM, Caspers, E, Hulshoff Pol, HE, Xu, Z, Schnack, HG, Kahn, RS (2009). Psychosis and brain volume changes during the first five years of schizophrenia. European Neurospsychopharmacology 19, 147151.
Cannon-Spoor, HE, Potkin, SG, Wyatt, RJ (1982). Measurement of premorbid adjustment in chronic schizophrenia. Schizophrenia Bulletin 8, 470484.
Cassidy, CM, Norman, R, Manchanda, R, Schmitz, N, Malla, A (2010). Testing definitions of symptom remission in first-episode psychosis for prediction of functional outcome at 2 years. Schizophrenia Bulletin 36, 10011008.
Castle, D, Sham, P, Murray, R (1998). Differences in distribution of ages of onset in males and females with schizophrenia. Schizophrenia Research 33, 179183.
Chang, WC, Chan, SSM, Chung, DWS (2009). Diagnostic stability of functional psychosis: a systematic review. Hong Kong Journal of Psychiatry 19, 3041.
Chang, WC, Hui, CLM, Tang, JYM, Wong, GHY, Lam, MML, Chan, SKW, Chen, EYH (2011). Persistent negative symptoms in first-episode schizophrenia: a prospective three-year follow-up study. Schizophrenia Research 133, 2228.
Chen, EYH, Hui, CLM, Dunn, ELW, Miao, MYK, Yeung, WS, Wong, CK, Chan, WF, Tang, WN (2005). A prospective 3-year longitudinal study of cognitive predictors of relapse in first-episode schizophrenic patients. Schizophrenia Research 77, 99104.
Chen, EYH, Lam, LCW, Chen, RYL, Nguyen, DGH (1996). Negative symptoms, neurological signs and neuropsychological impairments in 204 Hong Kong Chinese patients with schizophrenia. British Journal of Psychiatry 168, 227233.
Clarke, M, Whitty, P, Browne, S, McTigue, O, Kamali, M, Gervin, M, Kinsella, A, Waddington, JL, Larkin, C, O'Callaghan, E (2006). Untreated illness and outcome of psychosis. British Journal of Psychiatry 189, 235240.
Ebdrup, BH, Glenthoj, B, Rasmussen, H, Aggernaes, B, Langkilde, AR, Paulson, OB, Lublin, H, Skimminge, A, Baare, W (2010). Hippocampal and caudate volume reductions in antipsychotic-naïve first-episode schizophrenia. Journal of Psychiatry and Neuroscience 35, 95104.
Edwards, J, Harrigan, SM, McGorry, PD, Amminger, GP (2002). Correspondence: Norman & Malla (2001) reviewed the literature on duration of untreated psychosis (DUP) and outcome in schizophrenia. Psychological Medicine 32, 563564.
Elvevag, B, Goldberg, TE (2000). Cognitive impairment in schizophrenia is the core of the disorder. Critical Reviews in Neurobiology 14, 121.
Gold, S, Arndt, S, Nopoulos, P, Leary, DS, Andreasen, N (1999). Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia. American Journal of Psychiatry 153, 13421348.
Goldberg, TE, Burdick, KE, McCormack, J, Napolitano, B, Patel, RC, Sevy, SM, Goldman, R, Lencz, T, Malhotra, AK, Kane, JM, Robinson, DG (2009). Lack of an inverse relationship between duration of untreated psychosis and cognitive function in first-episode schizophrenia. Schizophrenia Research 107, 262266.
Goldberg, TE, Goldman, RS, Burdick, KE, Malhotra, AK, Lencz, T, Patel, RC, Woerner, MG, Schooler, NR, Kane, JM, Robinson, DG (2007). Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Archives of General Psychiatry 64, 11151122.
Green, MF, Kern, RS, Braff, DL, Mintz, J (2000). Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophrenia Bulletin 26, 119136.
Häfner, H, Riecher-Rossler, A, Hambrecht, M, Maurer, K, Meissner, S, Schmidtke, A, Fätkenheuer, B, Löffler, W, an der Heiden, W (1992). IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophrenia Research 6, 209223.
Häfner, H, Riecher-Rössler, A, An der Heiden, W, Maurer, K, Fätkenheuer, B, Löffler, W (1993). Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia. Psychological Medicine 23, 925940.
Harrigan, SM, McGorry, PD, Krstev, H (2003). Does treatment delay in first-episode psychosis really matter? Psychological Medicine 33, 97110.
Harris, MG, Henry, LP, Harrigan, SM, Purcell, R, Schwartz, OS, Farrelly, SE, Prosser, AL, Jackson, HJ, McGorry, PD (2005). The relationship between duration of untreated psychosis and outcome: an eight-year prospective study. Schizophrenia Research 79, 8593.
Harvey, PD, Koren, D, Reichenberg, A, Bowie, CR (2006). Negative symptoms and cognitive deficits: what is the nature of their relationship? Schizophrenia Bulletin 32, 250258.
Ho, BC, Alicata, D, Ward, J, Moser, DJ, O'Leary, DS, Arndt, S, Andreasen, NC (2003). Untreated initial psychosis: relation to cognitive deficits and brain morphology in first-episode schizophrenia. American Journal of Psychiatry 160, 142148.
Hoff, AL, Sakuma, MR, Heydebrand, G, Csernansky, J, DeLisi, LE (2000). Lack of association between duration of untreated illness and severity of cognitive and structural brain deficits at the first episode of schizophrenia. American Journal of Psychiatry 157, 18241828.
Hong Kong Psychological Society (1989 a). The Wechsler Adult Intelligence Scale-Revised (Cantonese version). Hong Kong Psychological Society: Hong Kong.
Hong Kong Psychological Society (1989 b). The Wechsler Memory Scale-Revised (Cantonese version). Hong Kong Psychological Society: Hong Kong.
Jeppesen, P, Petersen, L, Thorup, A, Abel, MB, Ohlenschlaeger, J, Christensen, TO, Krarup, G, Jorgensen, P, Nordentoft, M (2008). The association between pre-morbid adjustment, duration of untreated psychosis and outcome in first-episode psychosis. Psychological Medicine 38, 11571166.
Joyce, E, Hutton, S, Mutsatsa, S, Gibbins, H, Webb, E, Paul, S, Robbins, T, Barnes, T (2002). Executive dysfunction in first-episode schizophrenia and relationship to duration of untreated psychosis: the West London Study. British Journal of Psychiatry 181 (Suppl. 43), 3844.
Kay, SR, Opler, LA, Fiszbein, A (1987). Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.
Keshavan, MS, Haas, GL, Kahn, CE, Aguilar, E, Dick, EL, Schooler, NR, Sweeny, JA, Pettegrew, JW (1998). Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? Journal of Psychiatric Research 32, 161167.
Lappin, JM, Morgan, K, Morgan, C, Hutchison, G, Chitnis, X, Suckling, J, Fearon, P, McGuire, PK, Jones, PB, Leff, J, Murray, RM, Dazzan, P (2006). Gray matter abnormalities associated with duration of untreated psychosis. Schizophrenia Research 83, 145153.
Lappin, JM, Morgan, KD, Morgan, C, Dazzan, P, Reichenberg, A, Zanelli, JW, Fearon, P, Jones, PB, Lloyd, T, Tarrant, J, Farrant, A, Leff, J, Murray, RM (2007). Duration of untreated psychosis and neuropsychological function in first episode psychosis. Schizophrenia Research 95, 103110.
Malla, AK, Bodnar, M, Joober, R, Lepage, M (2011). Duration of untreated psychosis is associated with orbito-frontal grey matter volume reductions in first episode psychosis. Schizophrenia Research 125, 1320.
Malla, AK, Norman, RMG, Takhar, J, Manchanda, R, Townsend, L, Scholten, D, Haricharan, R (2004). Can patients at risk for persistent negative symptoms be identified during their first episode of psychosis? Journal of Nervous and Mental Disease 192, 455463.
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, 975983.
McGlashan, TH (1999). Duration of untreated psychosis in first-episode schizophrenia: marker or determinant of course? Biological Psychiatry 46, 899907.
Melle, I, Larsen, TK, Haahr, U, Friis, S, Johannessen, JO, Opjordsmoen, S, Simonsen, E, Rund, BR, Vaglum, P, McGlashan, T (2008). Prevention of negative symptom psychopathologies in first-episode schizophrenia: two-year effects of reducing the duration of untreated psychosis. Archives of General Psychiatry 65, 634640.
Mesholam-Gately, RI, Giuliano, AJ, Goff, KP, Faraone, SV, Seidman, LJ (2009). Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology 23, 315336.
Mortimer, AM, McKenna, PJ, Lund, CE, Mannuzza, S (1989). Rating of negative symptoms using the High Royds Evaluation of Negativity (HEN) Scale. British Journal of Psychiatry 155 (Suppl. 7), 8992.
Nelson, HE (1976). A modified card sorting test sensitive to frontal lobe defects. Cortex 12, 313324.
Norman, RMG, Townsend, L, Malla, AK (2001). Duration of untreated psychosis and cognitive functioning in first-episode patients. British Journal of Psychiatry 179, 340345.
Oosthuizen, P, Emsley, RA, Keyter, N, Niehaus, DJH, Koen, L (2005). Duration of untreated psychosis and outcome in first-episode psychosis: perspective from a developing country. Acta Psychiatrica Scandinavica 111, 214219.
Penttila, M, Jaaskelainen, E, Haapea, M, Tanskanen, P, Veijola, J, Ridler, K, Murray, GK, Barnes, A, Jones, PB, Isohanni, M, Koponen, H, Miettunen, J (2010). Association between duration of untreated psychosis and brain morphology in schizophrenia within the Northern Finland 1966 Birth Cohort. Schizophrenia Research 123, 145152.
Perkins, DO, Gu, H, Boteva, K, Lieberman, J (2005). Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. American Journal of Psychiatry 162, 17851804.
Rund, BR, Melle, I, Friis, S, Johannessen, JO, Larsen, TK, Midboe, LJ, Opjordsmoen, S, Simonsen, E, Vaglum, P, McGlashan, T (2007). The course of neurocognitive functioning in first-episode psychosis and its relation to premorbid adjustment, duration of untreated psychosis, and relapse. Schizophrenia Research 91, 132140.
Scully, PJ, Coakley, G, Kinsella, A, Waddington, JL (1997). Psychopathology, executive (frontal) and general cognitive impairment in relation to duration of initially untreated versus subsequently treated psychosis in chronic schizophrenia. Psychological Medicine 27, 13031310.
Silverstein, ML, Mavrolefteros, G, Close, D (2002). Premorbid adjustment and neuropsychological performance in schizophrenia. Schizophrenia Bulletin 28, 157165.
So, E, Kam, I, Leung, CM, Chung, D, Liu, Z, Fong, S (2003). The Chinese-bilingual SCID-I/P Project: Stage 1: reliability for mood disorders and schizophrenia. Hong Kong Journal of Psychiatry 13, 718.
Townsend, LA, Norman, RMG, Malla, AK, Rychlo, AD, Ahmed, RR (2002). Changes in cognitive functioning following comprehensive treatment for first episode patients with schizophrenia spectrum disorders. Psychiatry Research 113, 6981.
Tulving, E, Markowitsch, HJ (1998). Episodic and declarative memory: role of the hippocampus. Hippocampus 8, 198204.
Ucok, A, Polat, A, Genc, A, Cakir, STN (2004). Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia. Journal of Psychiatric Research 38, 163168.
Wyatt, R (1991). Neuroleptics and the natural course of schizophrenia. Schizophrenia Bulletin 17, 325351.
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