Duration of untreated illness (DUI) and schizophrenia sub-types: A collaborative study between the universities of Milan and Moscow

Abstract

Background:

Several studies show an association between a long duration of untreated illness (DUI) and poor outcome in schizophrenic patients. DUI, in turn, may be influenced by different variables including specific illness-related factors as well as access to local psychiatric services.

Aims:

The purposes of the present study were to detect differences in terms of DUI among schizophrenics coming from different geographic areas and to evaluate differences in DUI across diagnostic sub-types.

Method:

One hundred and twenty-five (125) schizophrenic patients of the Psychiatric Clinic of Milan (n = 51) and Moscow (n = 74) were enrolled. SCID-I was administered to all patients and information about DUI was obtained by consulting clinical charts and health system databases, and by means of clinical interviews with patients and their relatives. DUI was defined as the time between the onset of illness and the administration of the first antipsychotic drug. One-way analyses of variance (ANOVAs) were performed to find eventual differences in terms of DUI across diagnostic sub-types.

Results:

Italian patients showed a longer DUI (M = 4.14 years, SD = 4.95) than Russians (M = 1.16 years, SD = 1.43) (F = 24.03, p < .001). DUI was found to be longer in paranoid schizophrenics (M = 3.47 years, SD = 4.19) compared to catatonic patients (M = 0.96 years, SD = 0.94) (F = 3.56, p = .016).

Conclusions:

The results of the present study suggest that the different schizophrenic sub-types may differ in terms of DUI, likely due to different clinical severity and social functioning. Studies with larger samples are needed to confirm the data of the present study.

Keywords

Schizophrenia duration of untreated illness (DUI)diagnostic sub-types

Introduction

Several studies have investigated the duration of untreated illness (DUI) – defined as the time elapsing between the onset of an illness and the first adequate pharmacological treatment – as a predictor of outcome and clinical course across different psychiatric disorders (Compton et al., 2007). In the case of schizophrenia, the term DUI is frequently substituted with DUP (duration of untreated psychosis), which refers to the time between the onset of psychotic symptoms and the start of pharmacological treatment (Dell’Osso & Altamura, 2010). Negative symptoms like withdrawal or apathy can be present in the prodomal phases of the illness (Cornblatt et al., 2012; Häfner, Löffler, Maurer, Hambrecht & an der Heiden, 1999); however, positive symptoms (delusions, hallucinations, disorganization) are necessary to make a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria (APA, 2000) and the terms DUI and DUP may be viewed as interchangeable in this perspective.

Of note, increasing evidence has shown a variable association between DUI and poor outcome in schizophrenia (Altamura, Buoli & Serati, 2011; Keshavan & Amirsadri, 2007). For instance, patients with a longer DUI showed poorer treatment response and worse social functioning compared to schizophrenics with a short latency to treatment (Marshall et al., 2005; Owens, Johnstone, Miller, Macmillan & Crow, 2010; Simonsen et al., 2007). The reasons for poor outcome in schizophrenic patients with long DUI are debated. According to one hypothesis, prolonged DUI is responsible for social deficits and cognitive impairment, with rehabilitation programmes having little effect (Drake, Haley, Akhtar & Lewis, 2000). On the other hand, some authors state that poor response to pharmacological treatments could be due to brain changes and immunological abnormalities associated with long DUI (Altamura, Buoli et al., 2010). Of note, an association between prolonged DUI and decreased temporal volume has been reported by numerous studies (Takahashi et al., 2007; Velakoulis et al., 2002). In addition, differences in the levels of some cytokines (e.g. IL-2 and IL-6) among short- and long-DUI patients have also been reported (Akiyama, 1999; Lin et al., 1998; Liu et al., 2012; Müller et al., 2002). However, the mechanisms underlying the putative biological modifications associated with long DUI have not been clarified yet. One toxicity model suggests that N-methyl-D-aspartic acid receptor hypo-functioning may induce symptoms and produce glutamatergically mediated excitotoxic damage in neurons at the same time (Coyle, 1996). Alternatively, prolonged stress, including that resulting from untreated illness, may activate the hypothalamic–pituitary–adrenal (HPA) axis, leading to greater gluco-corticoid secretion which, in turn, may contribute to neuronal damage (Altamura, Bobo & Meltzer, 2007).

In light of a negative effect of DUI on schizophrenia outcome, prevention programmes are actually the most appropriate strategy to prevent the risks associated with a long DUI and to ameliorate outcome for schizophrenics (Dell’Osso & Altamura, 2010). Of note, early intervention programmes, including promotion of early help-seeking, have shown to produce better outcomes than routine management (Yung et al., 2007). Several data show that the effectiveness of these programmes depends, among other factors, on the health care system of patient’s country (Schaffner, Schimmelmann, Niedersteberg & Schultze-Lutter, 2012).

To date, few studies have investigated inter-country differences in clinical variables of schizophrenic patients (Vandiver, 1998). A recent observational cross-sectional survey reported differences in terms of DUI and severity of illness between Mediterranean (Italy, Spain and Greece) and north Europe countries (Germany), with the former showing longer DUI and minor severity of symptoms compared to the latter (Papageorgiou, Cañas, Zink & Rossi, 2011). In addition, specific studies aimed to quantify DUI across schizophrenic diagnostic sub-types are lacking, according to the authors’ knowledge. However, a very recent study found a longer DUP in patients showing predominantly positive symptoms (Malla, Bodnar, Joober & Lepage, 2011).

The present study was therefore conducted with two main objectives. The first purpose was to compare clinical variables with particular attention to DUI in a sample of schizophrenics from two different countries (Italy and Russia). The second aim was to assess eventual differences in relation to the latency to treatment across the diagnostic schizophrenic sub-types.

Methods

One hundred and twenty-five (125) patients attending the Department of Psychiatry of the University of Milan (n = 51) and Moscow (n = 74) were included in the study. All patients had to be diagnosed as schizophrenic according to DSM-IV-TR (APA, 2000) and after the administration of the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I; First, Spitzer, Gibbon & Williams, 1997). Patients gave their written informed consent to be interviewed and to have the clinical information included in their charts. The assessment of DUI was based on the clinical information derived from the diagnostic interview and on all additional information provided by patients and close family members. DUI was defined as the time between the onset of symptoms satisfying the criteria for schizophrenia diagnosis (APA, 2000) and the prescription of the first antipsychotic (Altamura, Camuri et al., 2010). Patients treated with psychotherapy without the prescription of an antipsychotic as well as subjects at ultra-high risk for psychosis (Yung & Nelson, 2011) were excluded. Descriptive analyses of the whole sample were performed.

The sample was then divided in two groups according to country, and χ² tests and one-way analyses of variance (ANOVAs) were performed to compare, respectively, dichotomous and continuous variables between Italian and Russian patients.

Finally, one-way ANOVAs with post-hoc tests and χ² tests were performed to compare variables, and in particular DUI, across the different diagnostic schizophrenic sub-types.

For all the analyses, the level of statistical significance was set at .05. SPSS for Windows (version 19.0) was used as the statistical program.

Results

Clinical and demographic variables of the whole sample are described in Table 1. The whole sample showed a mean DUI of 2.37 years (SD = 3.64) and the diagnostic sub-types were distributed as follows: paranoid 24.0%; disorganized 45.0%; undifferentiated 25.6%; catatonic 14.4%.

Table 1.

Demographic and clinical variables of the whole sample and of the two groups divided according to the country.

Variables		Total sample (N = 125)	Milan (n = 51)	Moscow (n = 74)
Gender	Male	69 (55.2)	33 (64.7)	36 (48.6)
	Female	56 (44.8)	18 (35.3)	38 (51.4)
Age^a		33.29 (±10.85)	36.76 (±12.14)	30.89 (±9.22)
Age at onset		24.18 (±7.75)	23.22 (±5.97)	24.84 (±8.74)
Age at first treatment		26.55 (±8.33)	27.35 (±7.35)	25.99 (±8.95)
Diagnosis(sub-types)^b	Paranoid	30 (24.0)	19 (37.3)	11 (14.9)
	Disorganized	45 (36.0)	14 (27.5)	31 (41.9)
	Undifferentiated	32 (25.6)	17 (33.3)	15 (20.3)
	Catatonic	18 (14.4)	1 (1.9)	17 (22.9)
Duration of untreated illness (years)^c		2.37 (±3.64)	4.14 (±4.95)	1.16 (±1.43)
Duration of illness (years)^d		9.11 (±8.04)	13.55 (±10.94)	6.05 (±2.14)

F = 9.44, p = .003; ^bχ² = 19.33, df = 3, p < .001, φ = 0.39; ^cF = 24.04, p < .001; ^dF = 33.00, p < .001.

Note: Standard deviations for continuous variables and percentages for dichotomic ones are reported in parentheses.

Italian patients did not differ from Russians in terms of gender distribution (χ² = 3.15, df = 1, p = .1), age at onset (F = 1.33, p = .25) and age at first pharmacological treatment (F = 0.80, p = .37). However, Italian patients were older (F = 9.44, p = .003) and had a longer DUI (F = 24.04, p < .001) and duration of illness (F = 33.0, p < .001) compared to Russian patients. In addition, paranoid schizophrenics were more frequent in the Italian sample, while catatonic schizophrenics were more frequent in the Russian sample (χ² = 19.33, df = 3, p < .001, φ = 0.39) (Table 1).

The diagnostic sub-types did not differ in terms of gender distribution (χ² = 1.36, df = 3, p = .69), age at first pharmacological treatment (F = 1.25, p = .30) and duration of illness (F = 1.39, p = .25), but they showed a different age at onset (F = 3.47, p = .018) and DUI (F = 3.56, p = .016). Of note, paranoid schizophrenics showed a longer DUI compared to the disorganized (LSD test: p = .021) and catatonic ones (LSD test: p = .018) (Figure 1).

Figure 1.

Duration of untreated illness (DUI) across the different diagnostic sub-types.

In addition, undifferentiated and paranoid schizophrenics showed an earlier age at onset compared to the catatonic ones (F = 3.47, p = .018; LSD: paranoid vs catatonic p = .009 and undifferentiated vs catatonic p = .003). This result was further confirmed by Bonferroni’s post-hoc tests (paranoid vs catatonic p = .05 and undifferentiated vs catatonic p = .016) (Table 2 and Figure 2).

Table 2.

Clinical variables of the diagnostic schizophrenic sub-types for the whole sample.

Variables		Paranoid (n = 30)	Disorganized (n = 45)	Undifferentiated (n = 32)	Catatonic (n = 18)
Gender	Male	15 (50.0)	24 (53.3)	18 (56.3)	12 (66.7)
	Female	15 (50.0)	21 (46.7)	14 (43.7)	6 (33.3)
Age at onset^a		23.00 (±7.63)	24.44 (±7.23)	22.19 (±6.87)	29.00 (±9.10)
Age at first treatment		26.47 (±8.97)	25.98 (±7.16)	25.51 (±8.47)	29.96 (±9.48)
Duration of untreated illness (years)^b		3.47 (±4.19)	1.53 (±2.00)	3.32 (±5.11)	0.96 (±0.94)
Duration of illness (years)		10.73 (±9.37)	8.31 (±7.02)	10.19 (±9.69)	6.50 (±2.68)

F = 3.47, p = .018; ^bF = 3.56, p = .016.

Note: Standard deviations for continuous variables and percentages for dichotomic ones are reported in parentheses.

Figure 2.

Age at onset of illness across the different diagnostic sub-types.

Discussion

The first result of the present study is that in our total sample mean DUI was more than two years. In spite of providing further confirmation of the significant latency to treatment in schizophrenia, the mean DUI appeared shorter (M = 2.37 years, SD = 3.64) than that reported in other studies (Boonstra et al., 2011; Keshavan et al., 2003); perhaps this is related to the second level of care and nationwide catchment area of the Milan and Moscow clinics. Of note, DUI was significantly shorter in Russian patients compared to Italians. This difference can be explained in light of the different target population of the two clinics: in the Russian department, there was a specific focus on prodromal or first-episode patients. A shorter DUI might be viewed as evidence of the efficacy of prevention policies such as the institution of specific first-episode psychiatric facilities, as shown by a relatively recent study (Lindgren, Falk Hogstedt & Cullberg, 2006). In addition, a very recent study showed that DUI is variable across European countries, probably for differences in clinical presentation of schizophrenia and in the organization of mental health services (Papageorgiou et al., 2011). Finally, cultural factors such as family attitudes towards psychotic manifestations can contribute to delay help-seeking in schizophrenic patients (Wylan & Mintz, 1976).

The study sample showed a different diagnostic sub-type distribution between Russia and Italy, with the catatonic sub-type more frequent in the Russian sample. Country differences in the frequency of catatonia presentation have been reported by another study comparing admissions in India and Wales (Chalasani, Healy & Morriss, 2005). In this study, catatonic patients were more frequent in India than Wales, but the authors could not identify whether the demographic factors of the two samples or environmental/cultural factors were responsible for this difference (Chalasani et al., 2005). It is debated whether inter-country differences in the diagnosis of catatonic schizophrenia depend on environmental factors (e.g. rate of urbanization, income) or whether the phenomenon is a bias of the current diagnostic classifications (Stompe, Ortwein-Swoboda, Ritter, Marquart & Schanda, 2005).

Another interesting result of the present study is represented by the different DUIs found across the diagnostic sub-types. Catatonic schizophrenics had the shortest DUI, while the paranoid patients had the longest. This result might be explained by the different clinical presentation of the two sub-types (Kleinhaus et al., 2012). Catatonic schizophrenia is the most severe sub-type of the illness and the severity of symptoms accounts for early hospitalization and help-seeking (Lykouras, Oulis, Daskalopoulou, Psarros & Christodoulou, 2001). In contrast, the suspiciousness and the frequent high level of functioning of paranoid schizophrenics – particularly over the first years of illness – might likely explain the delay in their diagnosis and treatment (Xiang et al., 2011).

Limitations

Some methodological limitations in the context of the present study should be kept into account. First, the retrospective assessment of DUI necessitated trust in the reliability of the patient and other available information sources (e.g. relatives); in this regard, information about the onset of schizophrenia may not have been precise in some cases. Furthermore, according to some authrs, DUI is defined as the time between onset of prodromal symptoms and any appropriate treatment (Esterberg & Compton, 2012). Second, the reported results refer to psychiatric patients seeking treatment and their value might not be representative of the entire schizophrenic population (Altamura, Camuri et al., 2010). In addition, in our sample residual schizophrenics were lacking as these patients are normally hospitalized in rehabilitative structures for chronic patients. Finally, mental health services are different between countries and the presented findings might not be extended to countries that have systems dissimilar to Italy and Russia. These results are therefore preliminary and general population studies with multi-centre, larger samples are required to confirm the present data.

Footnotes

Acknowledgements

Special appreciation goes to our Russian colleagues for participating in the present collaborative project.

Declaration of conflicting interest

Drs Buoli, Dell’Osso, Yuliya, Gurovich, Movina, Dorodnova, Shmuckler do not have any affiliation with or financial interest in any organization that might pose a conflict of interest with the present article. Prof. A. Carlo Altamura is a Merck consultant, Astra Zeneca consultant, Sanofi-Aventis speaker bureau, Lilly speaker bureau, Pfizer speaker bureau and Roche consultant.

Contributions

All authors contributed to the development of the present paper. Dr Buoli performed statistical analysis and wrote the paper. Dr Dell’Osso and Prof. Altamura supervised the project. Drs Zaytseva, Gurovich, Movina, Dorodnova and Shmuckler provided the data from Moscow Research Institute of Psychiatry.

References

Akiyama

(1999). Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophrenia Research, 37, 97–106.

Altamura

A. C.

Bobo

W. V.

Meltzer

H. Y.

(2007). Factors affecting outcome in schizophrenia and their relevance for psychopharmacological treatment. International Clinical Psychopharmacology, 22, 249–267.

Altamura

A. C.

Buoli

Albano

Dell’Osso

(2010). Age at onset and latency to treatment (duration of untreated illness) in patients with mood and anxiety disorders: A naturalistic study. International Clinical Psychopharmacology, 25, 172–179.

Altamura

A. C.

Buoli

Serati

(2011). Duration of illness and duration of untreated illness in relation to drug response in psychiatric disorders. Neuropsychiatry, 1, 81–90.

Altamura

A. C.

Camuri

Dell’Osso

(2010). [Understanding the role of the duration of untreated illness in psychiatric disorders: A narrative review]. Rivista di Psichiatria, 45, 197–208.

APA (American Psychiatric Association). (2000). Diagnostic and statistical manual of mental disorders, 4th edn, text revision. Washington, DC: APA.

Boonstra

Cahn

Schnack

H. G.

Hulshoff Pol

H. E.

Minderhoud

T. C.

Kahn

R. S.

van Haren

N. E.

(2011). Duration of untreated illness in schizophrenia is not associated with 5-year brain volume change. Schizophrenia Research, 132, 84–90.

Chalasani

Healy

Morriss

(2005). Presentation and frequency of catatonia in new admissions to two acute psychiatric admission units in India and Wales. Psychological Medicine, 35, 1667–1675.

Compton

M. T.

Carter

Bergner

Franz

Stewart

Trotman

… McGorry

P. D.

(2007). Defining, operationalizing, and measuring the duration of untreated psychosis: Advances, limitations, and future directions. Early Intervention in Psychiatry, 1, 236–250.

10.

Cornblatt

B. A.

Carrión

R. E.

Addington

Seidman

Walker

E. F.

Cannon

T. D.

… Lencz

(2012). Risk factors for psychosis: Impaired social and role functioning. Schizophrenia Bulletin, 38(6):1247–1257.

11.

Coyle

J. T.

(1996). The glutamatergic dysfunction hypothesis for schizophrenia. Harvard Review of Psychiatry, 3, 241–253.

12.

Dell’Osso

Altamura

A. C.

(2010). Duration of untreated psychosis and duration of untreated illness: New vistas. CNS Spectrums, 15, 238–246.

13.

Drake

R. J.

Haley

C. J.

Akhtar

Lewis

S. W.

(2000). Causes and consequences of duration of untreated psychosis in schizophrenia. British Journal of Psychiatry, 177, 511–515.

14.

Esterberg

Compton

(2012). Family history of psychosis negatively impacts age at onset, negative symptoms, and duration of untreated illness and psychosis in first-episode psychosis patients. Psychiatry Research, 197, 23–28.

15.

First

M. B.

Spitzer

R. L.

Gibbon

Williams

J. B. W.

(1997). Structured clinical interview for DSM-IV Axis I (SCID-I), clinician version. Washington, DC: American Psychiatric Press.

16.

Häfner

Löffler

Maurer

Hambrecht

an der Heiden

(1999). Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatrica Scandinavica, 100, 105–118.

17.

Keshavan

M. S.

Amirsadri

(2007). Early intervention in schizophrenia: Current and future perspectives. Current Psychiatry Reports, 9, 325–328.

18.

Keshavan

M. S.

Haas

Miewald

Montrose

D. M.

Reddy

Schooler

N. R.

Sweeney

J. A.

(2003). Prolonged untreated illness duration from prodromal onset predicts outcome in first episode psychoses. Schizophrenia Bulletin, 29, 757–769.

19.

Kleinhaus

Harlap

Perrin

M. C.

Manor

Weiser

Harkavy-Friedman

J. M.

… Malaspina

(2012). Catatonic schizophrenia: A cohort prospective study. Schizophrenia Bulletin, 38(2):331–337.

20.

Lin

Kenis

Bignotti

Tura

G. J.

De Jong

Bosmans

… Maes

(1998). The inflammatory response system in treatment-resistant schizophrenia: Increased serum interleukin-6. Schizophrenia Research, 32, 9–15.

21.

Lindgren

Falk Hogstedt

Cullberg

(2006). Outpatient vs. comprehensive first-episode psychosis services: A 5-year follow-up of Soteria Nacka. Nordic Journal of Psychiatry, 60, 405–409.

22.

Liu

Kang

Liang

Xiu

Chen

… Zhang

X. Y.

(2012). Lower serum interleukin-2 levels in schizophrenic patients with tardive dyskinesia. Psychiatry Research, 198, 329–331.

23.

Lykouras

Oulis

Daskalopoulou

Psarros

Christodoulou

G. N.

(2001). Clinical subtypes of schizophrenic disorders: A cluster analytic study. Psychopathology, 34, 23–28.

24.

Malla

A. K.

Bodnar

Joober

Lepage

(2011). Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis. Schizophrenia Research, 125, 13–20.

25.

Marshall

Lewis

Lockwood

Drake

Jones

Croudace

(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.

26.

Müller

Riedel

Scheppach

Brandstätter

Sokullu

Krampe

Schwarz

M.J.

(2002). Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. American Journal of Psychiatry, 159, 1029–1034.

27.

Owens

D. C.

Johnstone

E. C.

Miller

Macmillan

J. F.

Crow

T. J.

(2010). Duration of untreated illness and outcome in schizophrenia: Test of predictions in relation to relapse risk. British Journal of Psychiatry, 196, 296–301.

28.

Papageorgiou

Cañas

Zink

Rossi

(2011). Country differences in patient characteristics and treatment in schizophrenia: Data from a physician-based survey in Europe. European Psychiatry, 26, 17–28.

29.

Schaffner

Schimmelmann

B. G.

Niedersteberg

Schultze-Lutter

(2012). [Pathways-to-Care for First-Episode psychotic patients: An overview of international studies]. Fortschritte der Neurologie-Psychiatrie, 80, 72–78.

30.

Simonsen

Friis

Haahr

Johannessen

J. O.

Larsen

T. K.

Melle

… McGlashan

(2007). Clinical epidemiologic first-episode psychosis: 1-year outcome and predictors. Acta Psychiatrica Scandinavica, 116, 54–61.

31.

Stompe

Ortwein-Swoboda

Ritter

Marquart

Schanda

(2005). The impact of diagnostic criteria on the prevalence of schizophrenic subtypes. Comprehensive Psychiatry, 46, 433–439.

32.

Takahashi

Suzuki

Tanino

Zhou

S.Y.

Hagino

Niu

… Kurachi

(2007). Volume reduction of the left planum temporale gray matter associated with long duration of untreated psychosis in schizophrenia: A preliminary report. Psychiatry Research, 154, 209–219.

33.

Vandiver

V. L.

(1998). Quality of life, gender and schizophrenia: A cross-national survey in Canada, Cuba, and USA. Community Mental Health Journal, 34, 501–511.

34.

Velakoulis

Wood

S. J.

Smith

D. J.

Soulsby

Brewer

Leeton

… Pantelis

(2002). Increased duration of illness is associated with reduced volume in right medial temporal/anterior cingulate grey matter in patients with chronic schizophrenia. Schizophrenia Research, 57, 43–49.

35.

Wylan

Mintz

(1976). Ethnic differences in family attitudes towards psychotic manifestations, with implications for treatment programmes. International Journal of Social Psychiatry, 22, 86–95.

36.

Xiang

Y. T.

Wang

C. Y.

Chiu

H. F.

Weng

Y. Z.

Q. J.

Chan

S. S.

… Ungvari

G. S.

(2011). Socio-demographic and clinical profiles of paranoid and nonparanoid schizophrenia: A prospective, multicenter study in China. Perspectives in Psychiatric Care, 47, 126–130.

37.

Yung

A. R.

Killackey

Hetrick

S.E.

Parker

A.G.

Schultze-Lutter

Klosterkoetter-Lutter

Mcgorry

P.D.

(2007). The prevention of schizophrenia. International Review of Psychiatry, 19, 633–646.

38.

Yung

A. R.

Nelson

(2011). Young people at ultra high risk for psychosis: A research update. Early Intervention in Psychiatry, 5, 52–57.