early intervention studies…

  1. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms.
    by McGorry PD, Yung AR, Phillips LJ, Yuen HP, Francey S, Cosgrave EM, Germano D, Bravin J, McDonald T, Blair A, Adlard S, and Jackson H.
    Arch Gen Psychiatry. 2002 59(10):921-8.

      BACKGROUND: Most disability produced by psychotic illnesses, especially schizophrenia, develops during the prepsychotic period, creating a case for intervention during this period. However, only recently has it been possible to engage people in treatment during this phase.
      METHODS: A randomized controlled trial compared 2 interventions in 59 patients at incipient risk of progression to first-episode psychosis. We termed this group ultra-high risk to emphasize the enhanced risk vs conventional genetic high-risk studies. Needs-based intervention was compared with specific preventive intervention comprising low-dose risperidone therapy (mean dosage, 1.3 mg/d) and cognitive behavior therapy. Treatment was provided for 6 months, after which all patients were offered ongoing needs-based intervention. Assessments were performed at baseline, 6 months, and 12 months.
      RESULTS: By the end of treatment, 10 of 28 people who received needs-based intervention progressed to first-episode psychosis vs 3 of 31 from the specific preventive intervention group (P=.03). After 6-month follow-up, another 3 people in the specific preventive intervention group became psychotic, and with intention-to-treat analysis, the difference was no longer significant (P=.24). However, for risperidone therapy-adherent patients in the specific preventive intervention group, protection against progression extended for 6 months after cessation of risperidone use.
      CONCLUSIONS: More specific pharmacotherapy and psychotherapy reduces the risk of early transition to psychosis in young people at ultra-high risk, although their relative contributions could not be determined. This represents at least delay in onset (prevalence reduction), and possibly some reduction in incidence.
  2. Randomised controlled trial of early detection and cognitive therapy for preventing transition to psychosis in high-risk individuals. Study design and interim analysis of transition rate and psychological risk factors.
    by Morrison AP, Bentall RP, French P, Walford L, Kilcommons A, Knight A, Kreutz M, and Lewis SW.
    British Journal of Psychiatry Supplement 2002 43:s78-84.
      BACKGROUND: There is interest in the possibility of indicated prevention of psychosis. There is a strong case for using psychological approaches to prevent transition to psychosis in high-risk patients.
      AIMS: To identify individuals at high risk of transition to psychosis, and psychological characteristics relevant to the development of psychosis in this group.
      METHOD: The design of a randomised controlled trial of cognitive therapy for the prevention of psychosis in people at high risk (meeting operational criteria of brief or attenuated psychotic symptoms, or first-degree family history with functional decline) is outlined. The first patients recruited are compared with non-patient samples on cognitive and personality factors; an interim analysis of transition rate is reported.
      RESULTS: Cases (n = 31) were recruited mainly from primary care. Of the 23 high-risk patients monitored for 6-12 months, 5 (22%) made the transition to psychosis. The high-risk group scored significantly higher than non-patients on measures of schizotypy, metacognitive beliefs and dysfunctional self-schemas (sociotropy).
      CONCLUSIONS: The findings validate the methods of identifying individuals at high risk of experiencing a psychotic episode. Compared with non-patient controls, the cases showed dysfunctional metacognitive beliefs and self-schemas.
    Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial.
    by Morrison AP, French P, Walford L, Lewis SW, Kilcommons A, Green J, Parker S, and Bentall RP.
    British Journal of Psychiatry . 2004 185:291-7.

      BACKGROUND: Advances in the ability to identify people at high risk of developing psychosis have generated interest in the possibility of preventing psychosis.
      AIMS: To evaluate the efficacy of cognitive therapy for the prevention of transition to psychosis.
      METHOD: A randomised controlled trial compared cognitive therapy with treatment as usual in 58 patients at ultra-high risk of developing a first episode of psychosis. Therapy was provided over 6 months, and all patients were monitored on a monthly basis for 12 months.
      RESULTS: Logistic regression demonstrated that cognitive therapy significantly reduced the likelihood of making progression to psychosis as defined on the Positive and Negative Syndrome Scale over 12 months. In addition, it significantly reduced the likelihood of being prescribed antipsychotic medication and of meeting criteria for a DSM-IV diagnosis of a psychotic disorder. Analysis of covariance showed that the intervention also significantly improved positive symptoms of psychosis in this population over the 12-month period
      CONCLUSIONS: Cognitive therapy appears to be an acceptable and efficacious intervention for people at high risk of developing psychosis.
    Three-year follow-up of a randomized controlled trial of cognitive therapy for the prevention of psychosis in people at ultrahigh risk.
    by Morrison AP, French P, Parker S, Roberts M, Stevens H, Bentall RP, and Lewis SW.
    Schizophrenia Bulletin. 2007 33(3):682-7.
    [full text online]
      There have been recent advances in the ability to identify people at high risk of developing psychosis. This has led to interest in the possibility of preventing the development of psychosis. A randomized controlled trial compared cognitive therapy (CT) over 6 months with monthly monitoring in 58 patients meeting criteria for ultrahigh risk of developing a first episode of psychosis. Participants were followed up over a 3-year period. Logistic regression demonstrated that CT significantly reduced likelihood of being prescribed antipsychotic medication over a 3-year period, but it did not affect transition to psychosis defined using the Positive and Negative Syndrome Scale (PANSS) or probable Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis. However, exploratory analyses revealed that CT significantly reduced the likelihood of making progression to psychosis as defined on the PANSS over 3 years after controlling for baseline cognitive factors. Follow-up rate at 3 years was 47%. There appear to be enduring benefits of CT over the long term, suggesting that it is an efficacious intervention for people at high risk of developing psychosis.
    Effects of cognitive therapy on the longitudinal development of psychotic experiences in people at high risk of developing psychosis.
    by French P, Shryane N, Bentall RP, Lewis SW, and Morrison AP.
    British Journal of Psychiatry Supplement  2007 51:s82-7.
      BACKGROUND: There have been recent advances in the identification of people at high risk of psychosis and psychological treatments have shown promise for prevention.
      AIMS: To compare the longitudinal course of psychotic experiences and emotional dysfunction in high-risk participants receiving cognitive therapy with those receiving treatment as usual.
      METHOD: Data from a recent randomised controlled trial of cognitive therapy for people at risk of developing psychosis were utilised to examine three different statistical models that were based on 432 measurements of psychotic experiences and 421 of emotional dysfunction (anxiety-depression) contributed by 57 participants across the 13 measurement occasions (monthly monitoring for a year).
      RESULTS: Psychotic experiences and emotional dysfunction were correlated and decreased significantly over the course of the study, with most improvement in the early months. The reduction in positive symptoms, but not emotional dysfunction, was enhanced by allocation to cognitive therapy.
      CONCLUSIONS: Psychotic experiences and emotional dysfunction appear to interact in people at risk of developing psychosis. There appears to be a specific benefit of cognitive therapy.
  3. Transition rates from schizotypal disorder to psychotic disorder for first-contact patients included in the OPUS trial.
    A randomized clinical trial of integrated treatment and standard treatment.
    by Nordentoft M, Thorup A, Petersen L, Ohlenschlaeger J, Melau M, Christensen TØ, Krarup G, Jørgensen P, and Jeppesen P.
    Schizophrenia Research. 2006 83(1):29-40.
      BACKGROUND: Only a few randomized clinical trials have tested the effect on transition rates of intervention programs for patients with sub-threshold psychosis-like symptoms.
      AIM: To examine whether integrated treatment reduced transition to psychosis for first-contact patients diagnosed with schizotypal disorder.
      METHODS: Seventy-nine patients were randomized to integrated treatment or standard treatment. Survival analysis with multivariate Cox-regression was used to identify factors determinant for transition to psychotic disorder.
      RESULTS: In the multivariate model, male gender increased risk for transition to psychotic disorder (relative risk=4.47, (confidence interval 1.30-15.33)), while integrated treatment reduced the risk (relative risk=0.36 (confidence interval 0.16-0.85)). At two-year follow-up, the proportion diagnosed with a psychotic disorder was 25.0% for patients randomized to integrated treatment compared to 48.3% for patients randomized to standard treatment.
      CONCLUSION: Integrated treatment postponed or inhibited onset of psychosis in significantly more cases than standard treatment.
  4. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.
    by by McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, Hawkins KA, Hoffman RE, Preda A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, and Breier A.
    American Journal of Psychiatry. 2006 163(5):790-9.
    [full text online]
      OBJECTIVE: This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia.
      METHOD: 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.
      RESULTS: 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).
      CONCLUSIONS: 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.
  5. Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: study design and baseline characteristics. .
    by Phillips LJ, Nelson B, Yuen HP, Francey SM, Simmons M, Stanford C, Ross M, Kelly D, Baker K, Conus P, Amminger P, Trumpler F, Yun Y, Lim M, McNab C, Yung AR, McGorry PD.
    Aust N Z J Psychiatry. 2009 43(9):818-29.
      OBJECTIVE: Intervention during the pre-psychotic period of illness holds the potential of delaying or even preventing the onset of a full-threshold disorder, or at least of reducing the impact of such a disorder if it does develop. The first step in realizing this aim was achieved more than 10 years ago with the development and validation of criteria for the identification of young people at ultra-high risk (UHR) of psychosis. Results of three clinical trials have been published that provide mixed support for the effectiveness of psychological and pharmacological interventions in preventing the onset of psychotic disorder.
      METHOD:The present paper describes a fourth study that has now been undertaken in which young people who met UHR criteria were randomized to one of three treatment groups: cognitive therapy plus risperidone (CogTher + Risp: n = 43); cognitive therapy plus placebo (CogTher + Placebo: n = 44); and supportive counselling + placebo (Supp + Placebo; n = 28). A fourth group of young people who did not agree to randomization were also followed up (monitoring: n = 78). Baseline characteristics of participants are provided.
      RESULTS AND CONCLUSION: The present study improves on the previous studies because treatment was provided for 12 months and the independent contributions of psychological and pharmacological treatments in preventing transition to psychosis in the UHR cohort and on levels of psychopathology and functioning can be directly compared. Issues associated with recruitment and randomization are discussed.
    Randomized controlled trial of interventions for young people at ultra high risk for psychosis: 6-month analysis.
    by Yung AR, Phillips LJ, Nelson B, Francey SM, PanYuen H, Simmons MB, Ross ML, Kelly D, Baker K, Amminger GP, Berger G, Thompson AD, Thampi A, and McGorry PD.
    Journal of Clinical Psychiatry. 2011 72(4):430-40.
      OBJECTIVE: Cognitive therapy and/or low-dose antipsychotic administered during the prodromal phase of schizophrenia may prevent or delay the onset of full-blown illness. However, it is unclear which of these treatments are most effective, how long treatment should be given, and whether effects will be sustained over a prolonged period.
      METHOD: In order to examine these issues, we conducted a randomized controlled trial of cognitive therapy + risperidone; cognitive therapy + placebo; and supportive therapy + placebo in young people at ultra high risk for developing a psychotic disorder (that is, putatively prodromal). The main outcome was transition to psychotic disorder, with level of symptoms and functioning the secondary outcomes. This article reports the interim 6-month follow-up results. The study was conducted from August 2000 to May 2007.
      RESULTS: Of a possible 464 eligible ultra high risk individuals, 115 were recruited to the randomized controlled trial (cognitive therapy + risperidone, n = 43; cognitive therapy + placebo, n = 44; and supportive therapy + placebo, n = 28). An additional 78 individuals agreed to follow-up assessments but not to randomization ("monitoring group," n = 78). At 6 months, 8 of the 115 participants (7.0%) and 4 of the monitoring group (5.1%) had developed psychotic disorder. There were no significant differences between the 3 randomized groups (log rank test, P = .92) or between all 4 groups (log rank test, P = .93). There was also no difference between the 4 groups in secondary measures, with all groups showing a reduction in symptoms and increased functioning.
      CONCLUSIONS: Rates of transition to psychosis were lower than expected, particularly in the control supportive therapy + placebo group. This may have accounted for the negative finding, as the sample was therefore underpowered to find any difference between groups. Alternatively, it may be that all treatments were equally effective or equally ineffective at 6 months.
  6. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial.
    by Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, and Berger GE.
    Archives of General Psychiatry. 2010 67(2):146-54.
    [full text on-line]
      CONTEXT: The use of antipsychotic medication for the prevention of psychotic disorders is controversial. Long-chain omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) may be beneficial in a range of psychiatric conditions, including schizophrenia. Given that omega-3 PUFAs are generally beneficial to health and without clinically relevant adverse effects, their preventive use in psychosis merits investigation.
      OBJECTIVE: To determine whether omega-3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis.
      DESIGN: Randomized, double-blind, placebo-controlled trial conducted between 2004 and 2007.
      SETTING: Psychosis detection unit of a large public hospital in Vienna, Austria.
      PARTICIPANTS: Eighty-one individuals at ultra-high risk of psychotic disorder.
      INTERVENTIONS: A 12-week intervention period of 1.2-g/d omega-3 PUFA or placebo was followed by a 40-week monitoring period; the total study period was 12 months.
      MAIN OUTCOME MEASURES: The primary outcome measure was transition to psychotic disorder. Secondary outcomes included symptomatic and functional changes. The ratio of omega-6 to omega-3 fatty acids in erythrocytes was used to index pretreatment vs posttreatment fatty acid composition.
      RESULTS: Seventy-six of 81 participants (93.8%) completed the intervention. By study’s end (12 months), 2 of 41 individuals (4.9%) in the omega-3 group and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder (P = .007). The difference between the groups in the cumulative risk of progression to full-threshold psychosis was 22.6% (95% confidence interval, 4.8-40.4). omega-3 Polyunsaturated fatty acids also significantly reduced positive symptoms (P = .01), negative symptoms (P = .02), and general symptoms (P = .01) and improved functioning (P = .002) compared with placebo. The incidence of adverse effects did not differ between the treatment groups.
      CONCLUSIONS: Long-chain omega-3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states. Trial Registration clinicaltrials.gov Identifier: NCT00396643.