Missing data were noted for each outcome.
When dropout was not reported, we contacted the authors. For both primary and secondary outcomes reporting data for completers as well as controlling for dropout for example, imputed using regression methods , we used the latter. Subgroup analyses were conducted for different doses of antipsychotic medication, where more than one dose was compared with placebo. Because children, adolescents and young adults previously unexposed to antipsychotics may be particularly vulnerable to weight gain associated with antipsychotic use [ 36 ], we also conducted subgroup analyses for FEP and subsequent acute episode groups.
FEP and subsequent acute episode groups were defined as reported by the trial authors. Statistical heterogeneity was assessed by visual inspection of forest plots, by performing the Chi 2 test assessing the p value , and by calculating the I 2 statistic [ 37 , 38 ], which describes the percentage of observed heterogeneity that would not be expected by chance.
If the p value was less than 0. Meta-analyses were conducted using RevMan [ 39 ]. Confidence in the results was assessed using the GRADE method [ 40 ], which is a structured assessment of the quality of evidence attending to the following factors: 1 risk of bias; 2 inconsistency; 3 indirectness; 4 imprecision; and 5 publication bias. This review was conducted as part of a clinical guideline for the management of psychosis and schizophrenia in children, adolescents and young adults which identified potentially relevant citations, for which papers were retrieved.
Of these, were not relevant and were excluded. The most common reason for exclusion was that the study was conducted in an adult population and included no-one under the age of 18 years. Thirty studies were excluded from this review with reasons Appendix C in S1 File.
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Two studies [ 41 , 42 ] were not published in English and were identified via an included systematic review of antipsychotic medication for childhood-onset schizophrenia [ 22 ]. Nine trials await assessment six trials were not published in English, and three trials reported insufficient information in a conference abstract to make an assessment, see Appendix D in S1 File and four ongoing trials were identified Appendix E in S1 File.
Therefore, 27 randomised controlled trials reported in 52 published papers were included in this systematic review and meta-analysis Fig. Nineteen included pharmacological trials assigned participants. Table 1 contains the characteristics of included pharmacological trials. Comparisons included seven placebo controlled trials and 12 head-to-head trials.
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The median length of treatment was 8 weeks range 4 to 52 with only two trials reporting long-term follow-up assessments at [ 43 ] and weeks [ 44 ]. We conducted meta-analysis for seven pharmacological comparisons. Antipsychotic drugs that were compared with a placebo included quetiapine [ 45 ], aripiprazole [ 46 ], risperidone [ 47 ], paliperidone [ 48 ], amisulpride [ 49 ], olanzapine [ 50 ] and haloperidol [ 51 ].
The median of the mean ages was None of these trials were conducted in FEP. Relapse and anxiety were not measured in any trials of antipsychotic medication compared with placebo. Additionally, head-to-head comparisons included risperidone compared with olanzapine [ 44 , 52 — 56 ], haloperidol [ 22 , 53 ], quetiapine [ 55 , 57 , 58 ], and chlorpromazine [ 22 ]; and olanzapine compared with quetiapine [ 55 , 57 , 59 ] and haloperidol [ 43 , 53 ].
Subgroup analyses were conducted for FEP and subsequent acute episode groups. Relapse and anxiety were not measured in any of the included head-to-head trials. Eight included psychological trials assigned participants with a median sample size of 64 range 30 to The median length of treatment across trials was 22 weeks range 10 to 65 and all trials except one [ 60 ] conducted follow-up assessments, with a median follow-up of 78 weeks range 26 to All participants were either currently experiencing FEP or a subsequent acute episode of psychosis or schizophrenia, apart from two trials that were specifically designed to test a relapse prevention strategy following remission from first psychotic episode [ 61 , 62 ].
Table 2 contains the characteristics of included psychological trials. We conducted meta-analysis for five psychological comparisons. Psychological interventions included arts therapy, CBT and family interventions. Three of eight included trials were conducted in a specialist Early Psychosis Prevention and Intervention Centre EPPIC in Australia, which offers a highly comprehensive service to people aged 15 to 25 years with emerging psychotic disorders [ 62 , 66 , 67 ].
Appendix F in S1 File provides a detailed description of the psychological interventions used in the included trials. Relapse was measured using the BPRS. Psychosocial functioning and anxiety were not measured in any of the psychological trials. We rated risk of bias for each trial Appendix G in S1 File using the Cochrane risk of bias tool [ 27 ]. Nine out of 19 included pharmacological trials employed adequate methods of sequence generation, however the risk of bias due to inadequate allocation concealment was unclear in 17 trials. Lack of blinding of assessors created a high risk of bias for some outcomes in two studies and for 12 studies this was unclear.
Five studies were at high risk of bias because participants or staff were not blind and for 11 studies this was unclear. There was a high risk of bias due to incomplete outcome data for 15 included trials and only two trials were clearly free of attrition bias.
Only nine studies were clearly free of selective outcome reporting; seven trials did not report all outcomes and for two trials data were not reported in sufficient detail to be included in meta-analysis. It was unclear whether three trials reported all outcomes.
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Four out of eight included psychological trials were considered to have employed adequate methods of sequence generation, however the risk of bias owing to poor allocation concealment was unclear for all trials. There was a high risk of bias due to incomplete outcome data for four trials, and for one trial this was unclear. Four trials were at a high risk of selective outcome reporting, and for three of these trials, no data could be extracted for any outcomes.
We analysed psychotic symptoms, relapse, global state, psychosocial functioning, depression, weight and discontinuation of treatment. Summary of effects for all comparisons and all outcomes can be found in Appendix H in S1 File. A meta-analysis of antipsychotic medications compared to placebo was conducted because of the small number of trials and participants, and therefore lack of statistical power, for any single antipsychotic compared to placebo.
Six of seven placebo-controlled trials reported data for at least one outcome in sufficient detail to be included in this meta-analysis [ 45 — 50 ].
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Eleven of twelve head-to-head trials reported data for at least one outcome to be included in meta-analysis [ 22 , 43 , 52 — 59 ]. We analysed nine trials comparing two antipsychotics and three trials comparing three antipsychotics. Subgroup analyses were conducted for FEP and subsequent acute episodes of schizophrenia. However, the effect of treatment was relatively small compared with change over time, even in the absence of intervention.
In one trial, PANSS scores fell approximately 20 points in the placebo group [ 45 ], constituting a minimum clinically important difference of greater than 15 PANSS points as estimated by Hermes et al. The difference between post-treatment mean scores between groups was approximately eight points, and in another trial, the difference between placebo and antipsychotic treated groups was approximately nine points [ 48 ].
These differences are small and do not meet this threshold. Psychosocial functioning was not measured in trials of olanzapine compared with haloperidol, and depression was not measured in trials of risperidone compared with haloperidol. In very low quality evidence there were no further significant effects on weight or leaving the study early due to side effects, between antipsychotics in head-to-head trials. Five of eight included psychological trials reported data for at least one outcome in sufficient detail to be included in an analysis [ 61 , 62 , 65 — 67 ], however the comparators used in these trials were considered to be too different to combine in a meta-analysis and so single pairwise comparisons were conducted.
At 33 weeks post-treatment, there was low quality evidence that time to relapse was significantly extended by Time to relapse was not reported at weeks follow-up.
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No differential effects between groups were found for depression or leaving the study early for any reason. Anxiety and global state were not measured in this trial. Symptoms, relapse, global state, psychosocial functioning and anxiety were not measured in this trial. Relapse, depression, global state and anxiety were not measured by this trial. The primary outcome in this trial was suicidality; however symptom and global state data were also collected, but not reported in sufficient detail to be included in an analysis.
Relapse, depression, anxiety and psychosocial functioning were not measured in this trial. Global state, psychosocial functioning, depression, anxiety and numbers of participants leaving the study early for any reason were not measured by this trial. This is the first systematic review and meta-analysis of pharmacological and psychological treatments for children, adolescents and young adults with psychosis and schizophrenia. The data set on antipsychotics includes 19 trials, with participants with a median mean age of Low quality evidence suggests small effects for antipsychotic medication on positive and negative symptoms, depression and psychosocial functioning and a large effect on global state, but also a medium effect on weight gain which increased quickly, especially over the first six weeks of treatment, with a median of the mean change in weight across antipsychotic treated participants of 1.
We note that in these trials the placebo groups improved substantially, with antipsychotics adding relatively small additional benefit.
mikamepas.tk Head-to-head trials of antipsychotics showed medium to large differential effects on weight gain with olanzapine. However, most head-to-head trials of antipsychotics were underpowered and the evidence was very low quality, making any comparisons between individual antipsychotics unreliable. The data set for psychological treatments amounted to eight trials, including participants. Disappointingly, there were no psychological treatment trials for children or young people under 18 years of age reporting data in a sufficient format to be included in an analysis; but for young people under 25 years old, we found some low quality evidence that combining family interventions with individual CBT had a strong, statistically significant effect on extending time to relapse, although there were no differences in relapse rate.
No significant beneficial effects were found for psychological interventions for psychotic symptoms or for depression. It was not possible to meta-analyse data from any of the psychological treatment trials, largely because of variation in controls, and we found no other statistically significant effects.
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