Effective treatment of schizophrenia in youth
: a study about how children and adolescents are treated with antipsychotics, which medications are most effective as first-line treatment and which are most effective for treatment-resistant schizophrenia

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Aim Our work builds on recent findings that (a) it is possible to devise algorithms for structured, focused and not timely treatment of schizophrenia (Agid et al, 2011) and (b) while prescribed later than it should be, Clozapine is the most effective antipsychotic treatment for adult treatment-resistant schizophrenia (Howes et al., 2012). However, there is no algorithm-based treatment for early onset schizophrenia, but rather generic, overly lengthy and non-specific guidelines (NICE 2012 and NICE 2013) and there is insufficient similar research in relation to, and therefore the use of, Clozapine treatment for treatment-resistant early onset schizophrenia. Hence our work aims to investigate the use of antipsychotics for early onset schizophrenia, and develop an hypothesis regarding a structured treatment to be tested prospectively like some studies did for adult schizophrenia (Agid et al, 2011) to reach clear, concise, algorithmic recommendations and become a solid basis for clinicians to make decisions for effective first-line treatment of early onset schizophrenia and effective treatment of treatment-resistant schizophrenia, hence having our study be a significant stepping stone towards the development of clinical decision making tools for the effective treatment of early onset schizophrenia. 
Hypotheses Firstly, there are antipsychotics to prescribe for early onset schizophrenia, which are more effective than others and have manageable side effects. Secondly, Clozapine is the most effective antipsychotic for treatment-resistant early onset schizophrenia and is not sufficiently used due to unfounded concerns with regards to its side effects. 
Methods Following a period of comprehensive review of available studies on the use of antipsychotics in children and adolescents, which we describe in chapters 1 and 2, we concluded we could not engage in a time limited (within the number of years we had set out to conduct our study) prospective study since doctors would not straight away engage in prospective studies to prescribe specific medications. This is because doctors follow guidelines (NICE 2012, NICE 2013) that are focused on the risks related to prescribing antipsychotics emphasizing what patient-dependent side effects to avoid when considering prescription and are therefore generic, unclear and ineffectively large citing many possible antipsychotic drugs. We instead opted to perform retrospective statistical analysis of two long-term treatments datasets documented with sufficient consistency over long periods to credibly be able to recommend future studies to engage in very specific prospective studies such as the algorithm-based approach to first-episode schizophrenia by Agid (Agid et al, 2011). Those long-term treatment datasets were: 1. The prescription collection records in a nation-wide unbiased population demographic and clinical dataset of youth with psychosis who were prescribed with Clozapine. 2. The electronic records of 100 patients at the South London and Maudsley NHS Foundation Trust’s child and adolescent psychiatry services which we studied over 2 years. This was a population prescribed antipsychotics as part of their routine inpatient treatment, with data collected at baseline before antipsychotics switch / initiation and 3, 6 and 12 months thereafter. One-way ANOVA Power analysis was completed to ascertain appropriateness of the sample analyzed in the above-mentioned 2-year study. 
Results
1. The whole body of literature on the use of antipsychotics for early onset schizophrenia highlights the need for further evidence in relation to efficacy and safety. 
2. In the study we conducted with a 100-patient sample, which findings we ratified by performing a power analysis, we found that: A. Olanzapine was the most effective antipsychotic and patients prescribed with it were less likely to discontinue treatment, however it also resulted in the highest proportion of side effects; and B. Clozapine was the least prescribed antipsychotic (less than 0.5% of the sample) and only for one third of those with poor treatment response from Olanzapine. The antipsychotics examined were generally well tolerated. However, the overall rate of side effects was low suggesting that many side effects are either missed or not recorded in routine settings. 
3. Clozapine is the most effective antipsychotic for patients with treatment-resistant early onset schizophrenia. Strict routine monitoring of its impact during treatment can provide an adequate level of comfort in its use. 
Conclusions
1. All antipsychotics routinely prescribed to inpatients are associated with improvement in terms of global function. 
2. Olanzapine showed evidence for efficacy superiority, suggesting that olanzapine should be considered as first line medication. This statistically significant fact was ratified by other studies completed in the year after the completion of our study (Zhu et al., 2017). 
3. Clozapine is the most effective antipsychotic for patients with treatment-resistant early onset schizophrenia. Tools for its monitored prescription (such as blood measurement tools for youth) should serve as effective decision-making tools for clinicians wanting to use Clozapine more often and earlier in treatment.
Date of Award1 May 2020
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorDavid Taylor (Supervisor) & Sophia Frangou (Supervisor)

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