Medium term follow-up of a randomized controlled trial of interventions for young people at ultra high risk of psychosis

Abstract

Valid criteria to identify young people who are believed to be at ultra high risk (UHR) of developing a psychotic episode were developed over the last decade. The first randomized controlled trial of treatment in a UHR cohort indicated that specific pharmacotherapy and psychotherapy delayed onset of disorder, and possibly reduced incidence. This paper reports results of follow-up of that trial.

41 of the 59 (69.5%) participants in the original study agreed to follow-up. No differences were found in transition rate, level of symptomatology or functioning between participants who received a combination of psychological treatment and anti-psychotic medication compared to those who received supportive therapy alone. A significant proportion of both treatment groups reported moderate levels of psychiatric morbidity and a continuing need and desire for care at this follow-up. Low levels of hospitalisation were noted for those who did progress to psychosis.

Conclusions that can be drawn from this exploratory study are limited by the relatively small number of participants in the original study and the failure to follow-up the entire cohort. Although participants may have been treated too briefly to result in enduring positive effects, there appear to have been some cost savings in inpatient mental health treatment required after the end of the trial for individuals in both treatment groups who developed psychosis.

Introduction

Clinical research into the onset phase of psychotic disorders has been conducted for over a decade (Yung et al., 2004a) following speculation that full-blown psychosis might be prevented if appropriate treatment is provided as the illness is developing (Meares, 1959, Sullivan, 1927, reprinted 1994). Additionally, as Häfner et al. (1995) suggested that the level of disability that develops during the early phase of psychotic illness creates a ceiling for recovery, very early intervention might minimise the impact of an episode on functioning if it does eventuate. Therefore, the potential benefits of pre-psychotic intervention are considerable.

Reliable criteria to identify young people at incipient or ‘ultra high’ risk (UHR) of developing a psychotic disorder were developed at the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne, Australia (McGorry et al., 2003, Phillips et al., 2002, Yung et al., 1996, Yung et al., 2004a). Approximately 40% of young people who meet UHR criteria develop a full-blown psychosis despite the provision of supportive psychotherapy and, where appropriate, anti-depressant or anxiolytic medication (Yung et al., 2003, Yung et al., 2004b) — much higher than the risk rate attributed to family history of illness alone or the annual population risk (Jablensky, 2000). Other centres have subsequently adopted these UHR criteria and have reported comparable transition rates (Cadenhead, 2002, Larsen, 2002, Mason et al., 2004, McGlashan et al., 2003, Miller et al., 2003, Morrison et al., 2004).

Three clinical trials have been conducted to evaluate the efficacy of a range of treatment approaches in reducing the transition rate to psychosis. The first randomized trial, conducted at the PACE Clinic between October 1996 and January 1999, compared the outcome of UHR participants who received a combination of up to 2 mg risperidone plus cognitively oriented psychotherapy (Specific Preventive Intervention: SPI, n = 31) with participants who received supportive psychotherapy only (Needs Based Intervention: NBI, n = 28) (McGorry et al., 2002). In this randomized controlled trial, study participants and clinicians were not blind to treatment but research interviewers were. Treatment was provided for six months with follow-up six months later.

When analyzed by intention-to-treat, significantly more people in the NBI group developed a psychotic episode by the end of the treatment phase than the SPI group. This difference was no longer evident at the second follow-up point due to the progression to psychosis of some SPI participants following treatment cessation. Importantly, SPI group members who were fully adherent to anti-psychotic medication were significantly less likely to develop psychosis over the entire follow-up period than NBI group members. The higher transition rate in the NBI group could not be accounted for by the use of SSRI medication, nor did SSRI medication appear to have any protective influence. Members of both groups reported symptom improvement at the end of the follow-up phase. Despite design limitations which have been noted (McGorry et al., 2002), this study provided the first evidence that it might be possible to at least delay, and in some cases perhaps even avert, the progression to psychotic disorder in young people deemed to be at ‘ultra’ high risk.

Two other clinical trials with UHR cohorts have been conducted. The PRIME (Prevention through Risk Identification Management and Education) North America study compared 12-months treatment with an antipsychotic (olanzapine, 5–15 mg daily) with 12-months of placebo treatment (McGlashan et al., 2003). At the end of the treatment phase, 16% of the olanzapine group had converted to psychosis compared to 38% of the placebo group, a trend level difference, and the olanzapine group reported greater improvement in level of positive psychotic symptoms than the placebo group (McGlashan et al., 2006). After a second 12 month period when neither group received treatment, the conversion-to-psychosis rate remained the same between the groups. A trial based at Early Detection and Intervention Evaluation (EDIE) in Manchester, United Kingdom reported that only 6% of UHR participants who received cognitive therapy (CT) for six months developed a psychotic disorder compared to 22% of individuals who did not receive any active psychological or medical treatment (Morrison et al., 2004). This difference remained significant after another six months when no treatment was provided, suggesting that CT significantly reduced the likelihood of developing psychosis.

These three studies suggest a role for both psychological and pharmacological approaches in the treatment of young people who meet UHR criteria. However, all of these studies have had follow-up periods of only six or 12 months after the cessation of treatment. The aim of the current exploratory study is to determine transition rates to psychosis and to compare levels of psychopathology, general functioning and treatment sought for mental health problems between the treatment groups in the PACE trial three to four years after recruitment.