An evaluation of lack of early improvement and later non-response in early-onset schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

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.