The effect of antipsychotics on first episode psychosis: a systematic review
Systematic review
|Published
The purpose of this systematic review is to investigate the effect of antipsychotic treatment compared to placebo or non-pharmacological treatments on people with first episode psychosis.
Key message
Studies investigating the effect of antipsychotics have mainly been conducted on people with multiple previous psychosis episodes and not young people with first episode psychosis. The purpose of this systematic review is to investigate the effect of antipsychotic treatment compared to placebo or non-pharmacological treatments on people with first episode psychosis.
We searched for randomized controlled trials in six scientific databases. Two researchers independently screened the references, evaluated risk of bias, extracted data, and assessed the quality of the evidence using the GRADE approach.
We included three RCTs. All studies compared antipsychotics with cognitive behavioural therapy or other psychosocial interventions. The studies measured psychosis symptoms and social functioning. None of the studies measured relapse.
There were small to no differences in the effect estimates between comparison groups and we have very low confidence in the results included in this report.
Based on the evidence in this report it is uncertain whether the effect of antipsychotics is different from the effect of non-pharmacological interventions, either given alone or in combination with placebo, in relation to psychosis symptoms and social functioning in people with first episode psychosis.
Summary
Introduction
The term psychosis or psychotic episode is used to describe a mental state where it is difficult to distinguish between what is and is not real. Antipsychotics are currently used as the primary treatment for psychosis, including first episode psychosis (FEP). Studies investigating the effect of antipsychotics have mainly been performed on people with several previous psychoses and not people with FEP. Therefore, evidence is lacking on whether the treatment effect may be different for the latter group. Long-term treatment with antipsychotics for people with FEP is common, but both the long-term and short-term effects for this group are unclear. People with FEP are often younger, have not received treatment before and may be more prone to side effects from pharmacological treatment. It is unclear whether there are other and better treatment options for people with FEP than with antipsychotics.
Objective
The objective of this systematic review was to investigate the effect of antipsychotics compared with placebo or non-pharmacological interventions in people with FEP.
Method
We developed a systematic review using procedures as described in the Norwegian Institute of Public Health's method book for summarized research and in a peer-reviewed protocol. To identify relevant studies, a librarian searched six international literature databases, such as MEDLINE, EMBASE, and PsycINFO, in June 2021. We also conducted a search using the «knowledge graph» in MAG (Microsoft Academic Graph) to identify studies with similar contents. We checked the reference lists for all studies that were read in full text, as well as studies with adjacent themes. We included randomized controlled trials examining the effects of antipsychotics compared to placebo or non-pharmacological interventions in people with FEP. Relevant outcomes were:
- Psychosis symptoms measured with validated assessment tools such as the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS)
- Relapse measured as the study authors defined it or as aggravation of mental condition that required treatment.
- Functional change in social relationships or work/education
Two researchers independently selected relevant studies and evaluated risk of bias for each outcome in the included studies, using the Cochrane risk of bias tool 2.0 (RoB 2).
Furthermore, two researchers independently extracted relevant data and the results were summarized in text and tables. We calculated effect estimates for relevant outcomes reported in the included studies and performed a meta-analysis across two studies. We described the majority of the results from each study separately, as it was not possible to combine them in meta-analyses. We assessed the quality of the evidence using the GRADE approach.
Results
The literature search identified 4283 references (after duplicate removal) plus 802 references identified via MAG. We included three RCTs in this systematic review, one from Australia and two from the UK. The studies were published in 2018 and 2020. All studies compared antipsychotics with cognitive behavioral therapy or other psychosocial interventions, where two studies included a third comparison group combining antipsychotics and the non-pharmacological intervention. The studies had relatively few participants (<100) who were mainly adolescents or young adults. All participants received "early interventions for psychosis" either as part of child and adolescent psychiatry or specialized mental health services, and the interventions took place in these settings. The studies measured psychosis symptoms and social functioning, as well as other outcomes that were not relevant for our problem. None of the studies measured relapse.
We assessed the overall risk of bias in two of the studies to be high and in one study to be unclear. The main reason for the assessment of high risk was a lack of blinding of participants and personnel, insufficient information about treatment group changes, and high attrition. It was not reported when during the intervention period group changes were made. No information on reason for study discontinuation or whether those who dropped out are different from those who continued their participation was given. A study was considered to have unclear risk when the protocol was published after study initiation, hence we do not know whether the reported results or interventions were in accordance with a pre-specified plan.
The studies measured psychotic symptoms and social functioning. None of the studies measured relapse. There were small to no differences in the effect estimates between comparison groups and we have very low confidence in the results (Table 2).
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Table 2: |
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Outcome |
Anticipated absolute effects (SMD or MD, 95% CI) AP vs. PI |
N studies (participants) |
Quality of the evidence (GRADE) |
|
|
Control (PI) |
Intervention (AP) |
|||
|
Psychotic symptoms (6 months after start of intervention, measured with PANSS* and BPRS**) |
- |
Mean score was 0.17 standard deviations higher (0.46 lower to 0.8 higher) |
2 (100) |
⨁◯◯◯ VERY LOW a-e |
|
Social functioning (6 months after start of intervention, measured with SOFAS***) |
Mean score was 61.7 |
Mean score was 0.08 higher (0.11 lower to 0.26 higher) |
1 (70) |
⨁◯◯◯ VERY LOW c,d,e |
|
Outcome |
Anticipated absolute effects (MD, 95% CI) AP + PI vs. PI |
N studies (participants) |
Quality of the evidence (GRADE) |
|
|
Control (PI) |
Intervention (AP + PI) |
|||
|
Psychotic symptoms (6 months after start of intervention, measured with PANSS*) |
Mean score was 59.8 |
Mean score was 2.2 higher (7.9 lower to 12.3 higher) |
1 (33) |
⨁◯◯◯ VERY LOW a,b,d,e |
|
Outcome |
Anticipated absolute effects (MD, 95% CI) AP vs. CBT |
N studies (participants) |
Quality of the evidence (GRADE) |
|
|
Control (CBT) |
Intervention (AP) |
|||
|
Psychotic symptoms (6 months after start of intervention, measured with PANSS*) |
Mean score was 60.5 |
Mean score was 0.59 higher (6.46 lower to 7.64 higher) |
1 (44) |
⨁◯◯◯ VERY LOW a,b,d,e |
|
Outcome |
Anticipated absolute effects (MD, 95% CI) AP + CBT vs. CBT |
N studies (participants) |
Quality of the evidence (GRADE) |
|
|
Control (CBT) |
Intervention (AP + CBT) |
|||
|
Psychotic symptoms (6 months after start of intervention, measured with PANSS*) |
Mean score was 60.5 |
Mean score was 6.73 lower (13.12 lower to 0.34 lower) |
1 (44) |
⨁◯◯◯ VERY LOW a,b,d,e |
*PANSS: 30-210 (Higher score equals more symptoms), **BPRS: 18-126 (Higher score equals more symptoms),
***SOFAS: 1-100 (Higher score equals better functioning)
Abbreviations: AP: Antipsychotics, CBT: Cognitive behavioural therapy, CI: Confidence interval, MD: Mean difference, SMD: Standardized mean difference
Explanations
a) Downgraded one level due to risk of bias: Deviations from planned interventions
b) Downgraded one level due to risk of bias: Attrition/lack of outcome measurements
c) Downgraded one level due to risk of bias: Lack of pre-published project plan ahead of study initiation for one study
d) Downgraded one level due to precision: Wide confidence intervals and small study sample
e) Downgraded one level due to indirectness: The study population differ from the target population
Discussion
The evidence comparing the use of antipsychotic medication with placebo or non-pharmacological treatments in people with FEP is very scarce. Due to very low quality of the evidence for all outcomes, the findings’ potential to inform decision making processes is greatly limited.
The findings from this systematic review highlight that there is a need for well-designed and larger randomized controlled trails of high methodological quality that investigate the effect of antipsychotic treatment compared to placebo or non-pharmacological treatments in people with FEP.
Conclusion
Based on the evidence in this report it is uncertain whether the effect of antipsychotics is different from the effect of non-pharmacological interventions, either given alone or in combination with placebo, in relation to psychosis symptoms and social functioning in people with first episode psychosis.
