Randomized, Double-Blind Trial of Olanzapine Versus Placebo in Patients Prodromally Symptomatic for Psychosis

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
American Journal of Psychiatry (Impact Factor: 12.3). 06/2006; 163(5):790-9. DOI: 10.1176/appi.ajp.163.5.790
Source: PubMed


This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia.
This randomized trial occurred at four North American clinics in the Prevention Through Risk Identification, Management, and Education project. Outpatients received olanzapine (5-15 mg/day, N=31) or placebo (N=29) during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period. Efficacy measures included the conversion-to-psychosis rate and Scale of Prodromal Symptoms scores.
During the treatment year, 16.1% of olanzapine patients and 37.9% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The hazard of conversion among placebo patients was about 2.5 times that among olanzapine-treated patients, which also approached significance. In the follow-up year, the conversion rate did not differ significantly between groups. During treatment, the mean score for prodromal positive symptoms improved more in the olanzapine group than in the placebo group, and the mixed-model repeated-measures least-squares mean score showed significantly greater improvement between weeks 8 and 28 with olanzapine. The olanzapine patients gained significantly more weight (mean=8.79 kg, SD=9.05, versus mean=0.30 kg, SD=4.24).
A significant treatment difference in the conversion-to-psychosis rate was not demonstrated. However, these results may be influenced by low power. The nearly significant differences suggest that olanzapine might reduce the conversion rate and delay onset of psychosis. Olanzapine was efficacious for positive prodromal symptoms but induced weight gain. Further treatment research in this phase of illness is warranted.

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Available from: A. Preda, Oct 08, 2015
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    • "For those at the highest end of the risk spectrum, early commencement of preventive treatments may win time in combatting the pathophysiological processes associated with psychosis onset (de Koning et al. 2009; Pasternak et al. 2012). In contrast, for those in the low-risk group, reliable risk estimation will prevent the potentially stigmatizing consequences of a psychiatric diagnosis and exposure to potentially harmful effects of pharmacological and other interventions (McGlashan et al. 2006). Clinical assessments alone for determination of transition risk to psychosis are problematic due to the fluctuating course of symptoms in high-risk individuals (Ruhrmann et al. 2010a). "
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    ABSTRACT: The concept of indicated prevention has proliferated in psychiatry, and accumulating evidence suggests that it may indeed be possible to prevent or delay the onset of a first episode of psychosis though adequate interventions in individuals deemed at clinical high risk (CHR) for such an event. One challenge undermining these efforts is the relatively poor predictive accuracy of clinical assessments used in practice for CHR individuals, often leading to diagnostic and therapeutic uncertainty reflected in clinical guidelines promoting a 'watch and wait' approach to CHR patients. Using data from published studies, and employing predictive models based on the odds-ratio form of Bayes' rule, we simulated scenarios where clinical interview, neurocognitive testing, structural magnetic resonance imaging and electrophysiology are part of the initial assessment process of a CHR individual (extended diagnostic approach). Our findings indicate that for most at-risk patients, at least three of these assessments are necessary to arrive at a clinically meaningful differentiation into high- intermediate-, and low-risk groups. In particular, patients with equivocal results in the initial assessments require additional diagnostic testing to produce an accurate risk profile forming part of the comprehensive initial assessment. The findings may inform future research into reliable identification and personalized therapeutic targeting of CHR patients, to prevent transition to full-blown psychosis.
    Journal of Neural Transmission 10/2014; 122(1). DOI:10.1007/s00702-014-1325-9 · 2.40 Impact Factor
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    • "Unlike other trials, this study also reported a significant improvement in negative symptoms. However, a randomised, double-blind, placebo-controlled study of olanzapine reported no beneficial effects on functioning over placebo, despite significant improvement in positive symptoms (Woods et al., 2003; McGlashan et al., 2006). "
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    ABSTRACT: Background: Transition to psychotic disorder has been the traditional outcome of interest for research in the at-risk mental state (ARMS). However, there is growing recognition that individuals with ARMS may function poorly regardless of whether they develop psychosis. We aimed to review the literature to determine whether there are specific factors associated with, or predictive of, functional impairment in the ARMS population. Method: An electronic database search of MEDLINE, PsycINFO and Embase from inception until May 2014 was conducted using keyword search terms synonymous with the at-risk mental state and functioning. Eligible studies were original peer-reviewed English language research articles with populations that met validated at-risk diagnostic criteria and examined the cross-sectional or longitudinal association between any variable and a measure of functioning. Results: Seventy-two eligible studies were identified. Negative symptoms and neurocognitive impairment were associated with poor functioning in cross-sectional studies. Negative and disorganised symptoms, neurocognitive deficits and poor functioning at baseline were predictive of poor functional outcome in longitudinal studies. Positive symptoms were unrelated to functioning in both cross-sectional and longitudinal studies. Functional disability was persistent and resistant to current treatments. Conclusions: Negative and disorganised symptoms and cognitive deficits pre-date frank psychotic symptoms and are risk factors for poor functioning. This is consistent with a subgroup of ARMS individuals potentially having neurodevelopmental schizophrenia. Treatments aimed at improving functioning must be considered a priority on par with preventing transition to psychosis in the development of future interventions in the ARMS group.
    Schizophrenia Research 09/2014; 159(2-3). DOI:10.1016/j.schres.2014.09.012 · 3.92 Impact Factor
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    • "In North America, the Prevention through Risk Identification Management and Education (PRIME) study compared the transition rates of a 12-month treatment with olanzapine (5–15 mg daily) or placebo.66 At the end of the treatment phase, 16% of the UHR individuals treated with olanzapine and 38% of the placebo group converted to psychosis, but the difference between transition rates did not reach statistical significance.66 "
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    ABSTRACT: In the last few decades, substantial research has focused on the possibility of early detection and prevention of the first psychotic episode in young individuals at risk of developing this mental disturbance; however, unresolved clinical and ethical issues still call for further investigations. New perspectives and opportunities may come from the identification of selective psychopathological and instrumental markers linking the appearance of subtle psychotic symptoms with the clinical outcome of specific mental pathologies. Furthermore, empirically derived algorithms and risk staging models should facilitate the identification of targeted prevention therapies, possibly improving the efficacy of well-tolerated therapeutic approaches, such as psychological interventions and natural compound supplementations. To date, the collected evidence on the efficacy and tolerability of pharmacological prevention therapies raises more doubts than hopes. A very early detection of risk and appropriate symptomatic pattern classifications may provide a chance to better match prevention strategies with the development of psychosis.
    Therapeutics and Clinical Risk Management 03/2014; 10(1):241-253. DOI:10.2147/TCRM.S55770 · 1.47 Impact Factor
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