Thirty countries, one algorithm
STUDY: McCutcheon RA et al, Lancet Psychiatry 2025;12:384–94
STUDY TYPE: Consensus guideline (umbrella review, expert survey, lived experience focus groups)
FUNDING: Wellcome Trust; National Institute for Health and Care Research
Background
Most schizophrenia treatment guidelines are country-specific, lengthy, and vague on what to do when a medication isn’t working. INTEGRATE, developed by experts from 30 countries, fills that gap with a concise, step-by-step algorithm covering the full arc of treatment — from first episode to clozapine.
The Method
The guideline was built using an umbrella review of existing meta-analyses, two iterative expert surveys (70 respondents from all UN regions), and lived experience focus groups. Statements endorsed by over 70% of respondents were incorporated. The result is a consensus algorithm accompanied by a free digital tool.
Key Treatment Recommendations
- For first-episode psychosis, start low — aripiprazole 5 mg is the default if there’s no stated preference — reassess after one week, and escalate based on response.
- If two antipsychotics fail at adequate doses, move to clozapine promptly; delay worsens outcomes. Target a clozapine plasma level of at least 350 ng/mL; if positive symptoms persist after 12 weeks, push toward 550 ng/mL.
- For negative symptoms, consider cariprazine or aripiprazole.
- For cognitive and functional impairments, cognitive remediation therapy.
Side Effects
- Akathisia: try dose reduction first, then adjunctive propranolol 10 mg three times daily or mirtazapine 15 mg.
- Metabolic monitoring — BMI, waist circumference, blood pressure, HbA1c, fasting glucose, lipids — should start at baseline and be repeated weekly for six weeks, then at three months, then annually.
- Co-start metformin with clozapine and with any antipsychotic carrying a high metabolic burden.
- The guidelines also endorse GLP-1 receptor agonists for antipsychotic-related weight gain when other measures fail.
Practice Implications
- The digital tool is useful: plug in your patient’s current medications, symptoms, and side effects and it walks you through the algorithm in real time.
- I agree with the guidelines, though xanomeline-trospium (Cobenfy) might be first line if this was a U.S. guidelines (this antipsychotic is the safest long-term, but is not available in many countries)
- Another difference: I often recommend vitamin B6 instead for side effects. It equaled propranolol in a head-to-head trial, and also treats hyperprolactinemia, tremor, and may improve overall symptoms and reduce the risk of tardive dyskinesia. Some avoid it because high doses carry a risk of neuropathy, but new research suggests we can avoid this by using the active form, and the active form can be given in lower doses. Here’s my guide to antipsychotic side effects.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Which antipsychotic do you start with in schizophrenia?
- How do you manage side effects?
