The duration of untreated illness (DUI), meaning the latency to the pharmacological treatment, has been increasingly investigated in the last decade as a predictor of outcome across different psychiatric conditions, particularly in psychotic disorders. DUI is essentially computed by subtracting the age of onset of a specific disorder from the age at which the first adequate pharmacological treatment is administered. Assessment of the latency to treatment represents one of the first steps in planning early interventions. This review examines the role of the DUI in psychotic and affective disorders, focusing on neuropathological, epidemiologic, clinical and prognostic factors related to a longer latency to treatment. Through a Medline and Cochrane Library search, relevant studies up to June 2011 and other pertinent articles including meta-analyses, randomized controlled trials, naturalistic studies and clinical reviews were identified. Converging evidence indicates that a prolonged DUI negatively influences the outcome of first-episode psychosis and schizophrenia in different ways, and increasing data point toward a similar conclusion in affective disorders. Even though methodological limitations related to investigation of the DUI need to be considered, research and interventions aimed to reduce latency to treatments are object of increasing implementation worldwide. The assessment of the DUI represents one of the most important parameters to consider in this perspective, in order to quantify different latency to treatment in specific disorders and to plan related, targeted interventions.

Breitborde NJK, Srihari VH, Woods SW: Review of the operational definition for first-episode psychosis. Early Interv Psychiatry 2009;3:259–265.
Compton MT, Carter T, Bergner E, Franz L, Stewart T, Trotman H, McGlashan TH, McGorry PD: Defining, operationalizing, and measuring the duration of untreated psychosis: advances, limitations and future directions. Early Interv Psychiatry 2007;1:236–250.
Dell’Osso B, Altamura AC: Duration of untreated psychosis and duration of untreated illness: new vistas. CNS Spectr 2010;15:238–246.
Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T: Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry 2005;62:975–983.
Perkins DO, Gu H, Boteva K, Lieberman JA: Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 2005;162:1785–1804.
McGlashan T: Duration of untreated psychosis in first-episode schizophrenia: marker or determinant of course? Biol Psychiatry 1999;46:899–907.
Barnes TR, Hutton SB, Chapman MJ, Mutsatsa S, Puri BK, Joyce EM: West London first-episode study of schizophrenia. Clinical correlates of duration of untreated psychosis. Br J Psychiatry 2000;177:207–211.
Penttilä M, Jääskeläinen E, Haapea M, Tanskanen P, Veijola J, Ridler K, Murray GK, Barnes A, Jones PB, Isohanni M, Koponen H, Miettunen J: Association between duration of untreated psychosis and brain morphology in schizophrenia within the Northern Finland 1966 Birth Cohort. Schizophr Res 2010;123:145–152.
Goldberg TE, Burdick KE, McCormack J, Napolitano B, Patel RC, Sevy SM, Goldman R, Lencz T, Malhotra AK, Kane JM, Robinson DG: Lack of an inverse relationship between duration of untreated psychosis and cognitive function in first episode schizophrenia. Schizophr Res 2009;107:262–266.
Altamura AC, Bobo WV, Meltzer HY: Factors affecting outcome in schizophrenia and their relevance for psychopharmacological treatment. Int Clin Psychopharmacol 2007;22:249–267.
Häfner H, Löffler W, Maurer K, Hambrecht M, van der Heiden W: Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatr Scand 1999;100:105–118.
Large M, Nielssen O, Slade T, Harris A: Measurement and reporting of the duration of untreated psychosis. Early Interv Psychiatry 2008;2:201–211.
Jeppesen P, Petersen L, Thorup A, Abel MB, Øhlenschlaeger J, Christensen TØ, Krarup G, Jørgensen P, Nordentoft M: The association between pre-morbid adjustment, duration of untreated psychosis and outcome in first-episode psychosis. Psychol Med 2008;38:1157–1166.
Schimmelmann BG, Huber CG, Lambert M, Cotton S, McGorry PD, Conud P: Impact of duration of untreated psychosis on pre-treatment, baseline, and outcome characteristics in an epidemiological first-episode psychosis cohort. J Psychiatr Res 2008;42:982–990.
Ghaemi SN, Boiman EE, Goodwin FK: Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry 2000;61:804–808.
Kohn R, Safena S, Levav I, Saraceno B: The treatment gap in mental health care. Bull World Health Organ 2004;11:858–866.
Freidl M, Piralic Spitzl S, Aigner M: How depressive symptoms correlate with stigma perception of mental illness. Int Rev Psychiatry 2008;20:510–514.
Franz L, Carter T, Leiner AS, Bergner E, Thompson NJ, Compton MT: Stigma and treatment delay in first-episode psychosis: a grounded theory study. Early Interv Psychiatry 2010;4:47–56.
O’Callaghan E, Turner N, Renwick L, Jackson D, Sutton M, Foley SD, McWilliams S, Behan C, Fetherstone A, Kinsella A: First episode psychosis and the trail to secondary care: help-seeking and health-system delays. Soc Psychiatry Psychiatr Epidemiol 2010;45:381–391.
Altamura AC, Dell’Osso B, Berlin HA, Buoli M, Bassetti R, Mundo E: Duration of untreated illness and suicide in bipolar disorder: a naturalistic study. Eur Arch Psychiatry Clin Neurosci 2010;260:385–389.
Craig TJ, Bromet EJ, Fennig S, Tanenberg-Karant M, Lavelle J, Galambos N: Is there an association between duration of untreated psychosis and 24-month clinical outcome in a first-admission series? Am J Psychiatry 2000;157:60–66.
Altamura AC, Santini A, Salvadori D, Mundo E: Duration of untreated illness in panic disorder: a poor outcome risk factor? Neuropsychiatr Dis Treat 2005;1:345–347.
Wagner R, Silove D, Marnane C, Rouen D: Delays in referral of patients with social phobia, panic disorder and generalized anxiety disorder attending a specialist anxiety clinic. J Anxiety Disord 2006;20:363–371.
Altamura AC, Dell’Osso B, D’Urso N, Russo M, Fumagalli S, Mundo E: Duration of untreated illness as a predictor of treatment response and clinical course in generalized anxiety disorder. CNS Spectr 2008;13:415–422.
Dell’Osso B, Buoli M, Hollander E, Altamura AC: Duration of untreated illness as a predictor of treatment response and remission in obsessive-compulsive disorder. World J Biol Psychiatry 2010;11:59–65.
Singh SP: Outcome measures in early psychosis; relevance of duration of untreated psychosis. Br J Psychiatry 2007;50:s58–s63.
Olney JW, Farber NB: Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995;52:998–1007.
Coyle JT: The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 1996;3:241–253.
Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E: The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry 2008;165:1015–1023.
Salisbury DF, Kuroki N, Kasai K, Shenton ME, McCarley RW: Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch Gen Psychiatry 2007;64:521–529.
Lawrie SM, McIntosh AM, Hall J, Johnstone EC: Brain structure and function changes during the development of schizophrenia: the evidence from studies of subjects at increased genetic risk. Schizophr Bull 2008;34:330–340.
Hulshoff Pol HE, Kahn RS: What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull 2008;34:354–366.
Cahn W, Rais M, Stigter FP, van Haren NE, Caspers E, Hulshoff Pol HE, Xu Z, Schnack HG, Kahn RS: Psychosis and brain volume changes during the first five years of schizophrenia. Eur Neuropsychopharmacol 2009;19:147–151.
Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol HE, Kahn RS: Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp 2009;30:3719–3735.
Vita A, De Peri L, Sacchetti E: Gray matter, white matter, brain and intracranial volumes in first-episode bipolar disorder: a meta-analysis of magnetic resonance imaging studies. Bipolar Disord 2009;11:807–814.
Pittenger C, Duman RS: Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008;33:88–109.
Lopez-Larson M, Breeze JL, Kennedy DN, Hodge SM, Tang L, Moore C, Giuliano AJ, Makris N, Caviness VS, Frazier JA: Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements. Brain Imaging Behav 2010;4:220–231.
Chan WY, Yang GL, Chia MY, Woon PS, Lee J, Keefe R, Sitoh YY, Nowinski WL, Sim K: Cortical and subcortical white matter abnormalities in adults with remitted first-episode mania revealed by Tract-Based Spatial Statistics. Bipolar Disord 2010;12:383–389.
Bora E, Fornito A, Yücel M, Pantelis C: Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biol Psychiatry 2010;67:1097–1105.
Salvadore G, Drevets WC, Henter ID, Zarate CA, Manji HK: Early intervention in bipolar disorder. 2. Therapeutics. Early Interv Psychiatry 2008;2:136–146.
Dell’Osso B, Buoli B, Baldwin DS, Altamura AC: Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efficacy. Hum Psychopharmacol 2010;25:17–29.
Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, López-Solà M, Hernández-Ribas R, Deus J, Alonso P, Yücel M, Pantelis C, Menchon JM, Cardoner N: Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch Gen Psychiatry 2009;66:1189–1200.
Duran FL, Hoexter MQ, Valente AA Jr, Miguel EC, Busatto GF: Association between symptom severity and internal capsule volume in obsessive-compulsive disorder. Neurosci Lett 2009;452:68–71.
Nitschke JB, Sarinopoulos I, Oathes DJ, Johnstone T, Whalen PJ, Davidson RJ, Kalin NH: Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am J Psychiatry 2009;166:302–310.
Altamura AC, Buoli M, Albano A, Dell’Osso B: Age at onset and latency to treatment (duration of untreated illness) in patients with mood and anxiety disorders: a naturalistic study. Int Clin Psychopharmacol 2010;25:172–179.
Harris MG, Henry LP, Harrigan SM, Purcell R, Schwartz OS, Farrelly SE, Prosser AL, Jackson HJ, McGorry PD: The relationship between duration of untreated psychosis and outcome: an eight-year prospective study. Schizophr Res 2005;79:85–93.
Altamura AC, Bassetti R, Sassella F, Salvatori D, Mundo E: Duration of untreated psychosis as a predictor of outcome in first-episode schizophrenia: a retrospective study. Schizophr Res 2001;52:29–36.
Altamura AC, Bassetti R, Bignotti S, Pioli R, Mundo E: Clinical variables related to suicide attempts in schizophrenic patients: a retrospective study. Schizophr Res 2003;60:47–55.
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: Duration of untreated psychosis and neuropsychological function in first episode psychosis. Schizophr Res 2007;95:103–110.
Melle I, Larsen TK, Haahr U, Friis S, Johannesen JO, Opjordsmoen S, Rund BR, Simonsen E, Vaglum P, McGlashan T: Prevention of negative symptom psychopathologies in first-episode schizophrenia: two-year effects of reducing the duration of untreated psychosis. Arch Gen Psychiatry 2008;65:634–640.
Jibson MD, Glick ID, Tandon RT: Schizophrenia and other psychotic disorders. Focus 2004;2:17–30.
Clarke M, Whitty P, Browne S, Mc Tigue O, Kinsella A, Waddington JL, Larkin C, O’Callaghan E: Suicidality in first episode psychosis. Schizophr Res 2006;86:221–225.
Barrett EA, Sundet K, Faerden A, Nesvåg R, Agartz I, Fosse R, Mork E, Steen NE, Andreassen OA, Melle I: Suicidality before and in the early phases of first episode psychosis. Schizophr Res 2010;119:11–17.
Altamura AC, Dell’Osso B, Mundo E, Dell’Osso L: Duration of untreated illness in major depressive disorder: a naturalistic study. Int J Clin Pract 2007;61:1697–1700.
Gormley N, O’Leary D, Costello F: First admissions for depression: is the ‘no-treatment interval’ a critical predictor of time to remission? J Affect Disord 1999;54:49–54.
de Diego-Adelino J, Portella MJ, Puidgemont D, Pérez-Egea R, Alvarez E, Pérez V: A short duration of untreated illness (DUI) improves response outcomes in first-depressive episodes. J Affect Disord 2010;120:221–225.
Altamura AC, Dell’Osso B, Vismara S, Mundo E: May duration of untreated illness influence the long-term course of major depressive disorder? Eur Psychiatry 2008;23:92–96.
Okuda A, Suzuki T, Kishi T, Yamanouchi Y, Umeda K, Haitoh H, Hashimoto S, Ozaki N, Iwata N: Duration of untreated illness and antidepressant fluvoxamine response in major depressive disorder. Psychiatry Clin Neurosci 2010;64:268–273.
Marchall M, Rathbone J: Early intervention in psychosis. Cochrane Database Syst Rev 2006;4:CD004718.
Francey SM, Nelson B, Thompson A, Parker AG, Kerr M, Macneil C, Fraser R, Hughes F, Crisp K, Harrigan S, Wood SJ, Berk M, McGorry PD: Who needs antipsychotic medication in the earliest stages of psychosis? A reconsideration of benefits, risks, neurobiology and ethics in the era of early intervention. Schizophr Res 2010;119:1–10.
Liu P, Parker AG, Hetrick SE, Callahan P, de Silva S, Purcell R: An evidence map of interventions across premorbid, ultra-high risk and first episode phases of psychosis. Schizophr Res 2010;123:37–44.
Yung AR, Nelson B, Thompson AD, Wood SJ: Should a ‘Risk Syndrome for Psychosis’ be included in the DSMV? Schizophr Res 2010;120:7–15.
Larson MK, Walker EF, Compton MT: Early signs, diagnosis and therapeutic of the prodromal phase of schizophrenia and related psychotic disorders. Expert Rev Neurother 2010;10:1347–1359.
Piontkewitz Y, Arad M, Weiner I: Risperidone administered during asymptomatic period of adolescence prevents the emergence of brain structural pathology and behavioral abnormalities in an animal model of schizophrenia. Schizophr Bull 2011;37:1257–1269.
Josiassen RC, Shaughnessy RA, Filymer DM, Donohue AM, Kacso M, Finkel N, Curtis J, Audino B, Skuban N: Early intervention with second generation antipsychotics in first-episode psychosis: results of an 8-week naturalistic study. Early Interv Psychiatry 2010;4:57–63.
Meulenbeek P, Willemse G, Smit F, van Balkom A, Spinhoven P, Cuijpers P: Early intervention in panic: pragmatic randomised controlled trial. Br J Psychiatry 2010;196:326–331.
Meulenbeek P, Spinhoven P, Smit F, van Balkom A, Cuijpers P: Cognitive mediation of panic reduction during an early intervention for panic. Acta Psychiatr Scand 2010;122:20–29.
Roberts NP, Kitchiner NJ, Bisson JL: Early psychological interventions to treat acute traumatic stress symptoms. Cochrane Database Syst Rev 2010;3:CD007944.
Minde K, Roy J, Bezonsky R, Hashemi A: The effectiveness of CBT in 3- to 7-year-old anxious children: preliminary data. J Can Acad Child Adolesc Psychiatry 2010;19:109–115.
Neil AL, Christensen H: Australian school-based prevention and early intervention programs for anxiety and depression: a systematic review. Med J Aust 2007;186:305–308.
Christensen H, Pallister E, Smale S, Hickie IB, Calear AL: Community-based prevention programs for anxiety and depression in youth: a systematic review. J Prim Prev 2010;31:139–170.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.