Duration of untreated psychosis: Impact of the definition of treatment onset on its predictive value over three years of treatment

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Abstract

Background

While reduction of DUP (Duration of Untreated Psychosis) is a key goal in early intervention strategies, the predictive value of DUP on outcome has been questioned. We planned this study in order to explore the impact of three different definition of “treatment initiation” on the predictive value of DUP on outcome in an early psychosis sample.

Methods

221 early psychosis patients aged 18–35 were followed-up prospectively over 36 months. DUP was measured using three definitions for treatment onset: Initiation of antipsychotic medication (DUP1); engagement in a specialized programme (DUP2) and combination of engagement in a specialized programme and adherence to medication (DUP3).

Results

10% of patients never reached criteria for DUP3 and therefore were never adequately treated over the 36-month period of care. While DUP1 and DUP2 had a limited predictive value on outcome, DUP3, based on a more restrictive definition for treatment onset, was a better predictor of positive and negative symptoms, as well as functional outcome at 12, 24 and 36 months. Globally, DUP3 explained 2 to 5 times more of the variance than DUP1 and DUP2, with effect sizes falling in the medium range according to Cohen.

Conclusions

The limited predictive value of DUP on outcome in previous studies may be linked to problems of definitions that do not take adherence to treatment into account. While they need replication, our results suggest effort to reduce DUP should continue and aim both at early detection and development of engagement strategies.

Introduction

Delay between psychosis onset and exposure to appropriate treatment or duration of untreated psychosis (DUP), has been identified as a key target in programs specialized in the treatment of the early phase of psychotic disorders, based on the rationale that it’s reduction should have an impact on the course of symptoms and functioning (Melle et al., 2008). While numerous papers have indeed shown DUP to be significantly associated with clinical and social outcomes (Malla et al., 2014, Marshall et al., 2005), this possible correlation was modest and has been a matter of an intense controversy (Craig et al., 2000, Harrigan et al., 2003, Ho and Andreasen, 2001).

Various factors may explain the contradictory nature of results in this domain and the only modest association found between DUP and outcomes in first episode psychosis (FEP) patients. First, in an extensive review, it has been suggested that considerable variability exists in the definition of both onset and endpoint of DUP (Compton et al., 2007). In particular, the literature reveals significant differences between studies regarding the definition of treatment onset, hence “end” of DUP. In a previous paper, we reported that while considerable attention has been paid to the assessment of psychosis onset, resulting in a certain degree of consensus regarding its definition, this is not true for criteria applied to define the end of DUP: definitions applied ranged from “start of medication” to “hospitalization” and “entry to a specialized program”, and were therefore based on many different conceptual levels (Polari et al., 2009). Second, when definition of DUP's end is based on medication, various definitions have been considered, ranging from “initiation of medication”, “start of any form of treatment”, or “initiation of adequate treatment”, to “time of first effective treatment” (Norman and Malla, 2001, Polari et al., 2009). Thirdly, when end of DUP is based on exposure to a certain level of medication, the definition of “adequate treatment” can be the matter of important debate, some authors requiring 12 weeks of medication (Loebel et al., 1992) while 3 weeks were sufficient for others (Larsen et al., 1996). Globally, in a review of 16 FEP studies, Norman and Malla (2001) found that definition applied to identify initiation of treatment varied greatly. Fourthly, patients' adherence to the prescribed medication has not been taken into consideration in the majority of studies (Norman and Malla, 2001). Considering the high rate of non adherence to treatment in FEP patients, it is therefore likely that DUP may have been considered finished for many patients while they actually did not receive any adequate medication yet.

In this context, it can be argued that such a lack of consistency in definition could be one of the critical factors that so far limited the conclusiveness of studies exploring consequences of DUP (Polari et al., 2009). Indeed, when applying 3 possible definitions for treatment onset in a FEP sample, we confirmed that estimation of DUP could vary greatly, which in turn could significantly influence the measurement of its impact on outcome variables.

Considering that the existence or not of a correlation between DUP and outcome is critical when choosing strategies that should be applied in specialized programs for the early phase of psychosis, we designed the current study in order to compare different definitions of DUP in their ability to predict outcome in FEP patients. Our hypothesis was that when defining beginning of treatment in a restrictive manner on the basis of both engagement in a specialized program and adherence to adequate medication according to current guidelines, DUP would be significantly correlated to outcome. Considering some patients may never adhere to treatment despite our efforts (Lambert et al., 2010) our secondary aim was to characterize patients who never met these restrictive criteria and could never be engaged into effective treatment within the 3-years of our program and therefore remained in a phase of “untreated psychosis”.

Section snippets

Procedure and participants

TIPP (Treatment and early Intervention in Psychosis Program), a specialized early psychosis program, was launched in 2004 at the Department of Psychiatry CHUV, in Lausanne, Switzerland (Baumann et al., 2013). Entry criteria to the program are: (I) age between 18 and 35; (II) residing in the catchment area (Lausanne and surroundings; population about 300′000); (III) meeting threshold criteria for psychosis, as defined by the ‘Psychosis threshold’ subscale of the Comprehensive Assessment of At

Results

Descriptive statistics for the three DUP are presented in Table 1. While DUP1 and DUP2 values did not vary over the time, DUP3 values could increase significantly during the follow-up (Z = −8.823, p < .001) considering the substantial number of patients who became adherent to medication only after a few weeks to months in treatment. It is worth noting that 9.1% patients never became adherent to medication, and therefore never met the definition of end of DUP3 (Fig. 1). The most restrictive

Discussion

To the best of our knowledge, this is the first prospective study in EP patients examining the impact of DUP on clinical and functional outcomes according to several definitions of treatment initiation.

Firstly, our results clearly show that defining end of DUP either on the basis of the date of “initiation of an antipsychotic medication” (DUP1) or on that of “entry to a specialized program” (DUP2) erroneously suggest that DUP has come to an end, since at each of these time points, an important

Conclusion

Despite these limitations, our study showed that when defined on the basis of engagement in a specialized treatment and adherence to medication, DUP is a significant predictor of outcome. While other studies based on a similar definition are needed in order to confirm our findings, these results suggest that early intervention and identification strategies are justified. They also suggest that additional effort should be put in the development of strategies facilitating engagement and adherence

Conflicts of interest

None.

Funding source

Swiss National Science Foundation (#320030_122419 to P.C.); National Center of Competence in Research (NCCR) “SYNAPSY — The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (no. 51AU40_125759 to LA); This study was based on institutional funding. There was no role of the funding sources in the study design, analysis and interpretation of data, writing of the manuscript or decision to submit the manuscript.

Contribution

PG, LA and PC, contributed to the conception and design of the study.

LA and PB contributed to the acquisition of the data.

PG contributed to data analysis and interpretation of the data.

PG, LA, AP and PC drafted the manuscript.

PG, PB, JE, PP and PC were involved in the critical revision of the manuscript.

All authors have given final approval of the version to be published.

Acknowledgements

We wish to thank the case managers from the Tipp Program for their invaluable work for collecting this data over the years. We also express our gratitude to all patients for their enduring participation. The authors have declared that there are no conflicts of interest in relation to the subject of the study.

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