Lead Investigator: Luis Farhat, University of São Paulo (USP)
Title of Proposal Research: An evaluation of lack early of improvement and later non-response in early-onset schizophrenia: a systematic review and meta-analysis of randomized controlled trials.
Vivli Data Request: 9966
Funding Source: None
Potential Conflicts of Interest: Dr. Polanczyk reports: I served as a speaker and / or consultant to Aché, Abbott, Aspen, Medice, Novo Nordisk and Takeda. I also receive authorship royalties from Manole Editora, a publisher from Brazil who publishes several relevant Psychiatry textbooks in my country.
In case any additional relationships or affiliations with commercial interests arise, we will declare them in any subsequent publication.
Summary of the Proposed Research:
Schizophrenia is a serious psychiatric condition. While there is considerable interpersonal variability, individuals who live with this condition generally experience psychosocial impairments (for example, difficulties to maintain relationships, employment, and independent living) and, on average, have a reduced life expectancy by 13-15 years. Studies indicate that between 2 and 10 per 1,000 persons live with schizophrenia, and around 8% are estimated to have early-onset schizophrenia (EOS), that is when schizophrenia onsets in children or adolescents under 18 years of age.
EOS represents a more severe form of schizophrenia and manifests at a critical stage of development, disrupting age-related milestones, such as independent living, vocational training, and social integration. In this context, proper treatment of EOS is paramount. Clinical practice guidelines such as those from the UK National Institute for Health & Care Excellence (NICE) recommend that antipsychotics should be adopted in the treatment of acute episodes of schizophrenia in children and adolescents. Antipsychotics are believed to affect the symptoms of schizophrenia by reducing dopamine signalling in the brain (Dopamine is a neurotransmitter, that is a chemical that conveys information in our brain).
Because clinicians are unable to predict treatment outcomes in schizophrenia, routine clinical practice involves trying the available antipsychotics until a patient shows benefit. NICE recommends that practitioners should trial antipsychotics for 6 to 8 weeks before switching to another medicine. However, the evidence justifying this specific duration of treatment is unclear. Because there are important safety concerns around antipsychotics in children and adolescents, minimizing unnecessary exposure to such medications (for example in patients who are unlikely to benefit from them) may be a sensible strategy to maximize risk-benefits trade-offs of antipsychotics in EOS.
A previous meta-analysis (that is, study combining results from several similar studies), of mostly adult studies, demonstrated that lack of early improvement predicted a later non-response at the end of the study. However, as children and adolescents are not ‘small adults’, corresponding evidence that is directly applicable to them is needed.
In children and adolescents, three previous randomized controlled trials (RCTs) have examined whether lack of early improvement predicts later non-response. Overall, their findings indicate that most benefits occur early in the treatment (during the first 2 weeks) and lack of early improvement may predict later non-response, but a wider review of all evidence is required to inform treatment recommendations in routine clinical practice.
This study aims to address this gap by conducting a meta-analysis of randomized controlled trials (RCTs) examining antipsychotics for the treatment of schizophrenia in children and adolescents. We aim to generate evidence that may help inform practitioners about the duration of antipsychotic treatment in EOS in their routine practice. If individuals who do not improve early are demonstrated to be likely non-responders at the end of the antipsychotic trial, practitioners could consider switching the patient to a different antipsychotic earlier instead of waiting for the whole recommended 6-8 weeks.
Requested Studies:
Bagadia, V. N., Shah, L. P., Abhyankar, R. R. (1980) A double-blind controlled trial of loxapine and trifluoperazine in adolescent schizophrenia. Curr Ther Res Clin Exp 27(6 II): 886–896
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Bagadia_1980
Findling, R. L., Cavus, I., Pappadopulos, E., Vanderburg, D. G., Schwartz, J. H., Gundapaneni, B. K., DelBello, M. P. (2013) Ziprasidone in adolescents with schizophrenia: results from a placebo-controlled efficacy and long-term open-extension study. J Child Adolesc Psychopharmacol 23(8): 531–544. doi: 10.1089/cap.2012.0068
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Findling_2013
Findling, R. L., Landbloom, R. P., Mackle, M., Pallozzi, W., Braat, S., Hundt, C., Wamboldt, M. Z., Mathews, M. (2015) Safety and Efficacy from an 8 Week Double-Blind Trial and a 26 Week Open-Label Extension of Asenapine in Adolescents with Schizophrenia. J Child Adolesc Psychopharmacol 25(5): 384–396. doi: 10.1089/cap.2015.0027
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Findling_2015
Kumra, S., Frazier, J. A., Jacobsen, L. K., McKenna, K., Gordon, C. T., Lenane, M. C., Hamburger, S. D., Smith, A. K., Albus, K. E., Alaghaband-Rad, J., Rapoport, J. L. (1996) Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry 53(12): 1090–1097
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Kumra_1996
Pagsberg, A. K., et al. (2017) Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial. Lancet Psychiatry 4(8):605-618.
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Pagsberg_2017
Shaw, P., Sporn, A., Gogtay, N., Overman, G. P., Greenstein, D., Gochman, P., Tossell, J. W., Lenane, M., Rapoport, J. L. (2006) Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 63(7): 721–730
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Shaw_2006
Sikich, L., Hamer, R. M., Bashford, R. A., Sheitman, B. B., Lieberman, J. A. (2004) A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology 29(1): 133–145
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Sikich_2004
Sikich L, Frazier JA, McClellan J., Findling, R. L., Vitiello, B., Ritz, L., Ambler, D., Puglia, M., Maloney, A. E., Michael, E., De Jong, S., Slifka, K., Noyes, N., Hlastala, S., Pierson, L., McNamara, N. K., Delporto-Bedoya, D., Anderson, R., Hamer, R. M., Lieberman, J. A. (2008) Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 165(11): 1420–1431. doi: 10.1176/appi.ajp.2008.08050756
Data Contributor: I WILL BRING MY OWN
Sponsor ID: Sikich_2008
A Randomized, Double-Blind, Placebo-Controlled Clinical Study of the Efficacy and Safety of Risperidone for the Treatment of Schizophrenia in Adolescents
Data Contributor: Johnson & Johnson
Study ID: NCT00088075
Sponsor ID: CR003370
The Efficacy and Safety of Risperidone in Adolescents With Schizophrenia: a Comparison of Two Dose Ranges of Risperidone
Data Contributor: Johnson & Johnson
Study ID: NCT00034749
Sponsor ID: CR003361
A Randomized, Multicenter, Double-Blind, Weight-Based, Fixed-Dose, Parallel-Group, Placebo-Controlled Study of the Efficacy and Safety of Extended Release Paliperidone for the Treatment of Schizophrenia in Adolescent Subjects, 12 to 17 Years of Age
Data Contributor: Johnson & Johnson
Study ID: NCT00518323
Sponsor ID: CR002368
A Randomized, Multicenter, Double-Blind, Active-Controlled, Flexible-Dose, Parallel-Group Study of the Efficacy and Safety of Extended Release Paliperidone for the Treatment of Symptoms of Schizophrenia in Adolescent Subjects, 12 to 17 Years of Age
Data Contributor: Johnson & Johnson
Study ID: NCT01009047
Sponsor ID: CR016675
Olanzapine Versus Placebo in the Treatment of Adolescents With Schizophrenia
Data Contributor: Lilly
Study ID: NCT00051298
Sponsor ID: 4066
Aripiprazole in Adolescents With Schizophrenia
Data Contributor: Otsuka Pharmaceuticals
Study ID: NCT00102063
Sponsor ID: 31-03-239