Closing the Gap in Schizophrenia Care: Insights From the INTEGRATE Guidelines

The newly published International Guidelines for Algorithmic Treatment (INTEGRATE) represent an international effort to standardize schizophrenia care. They were developed through a global collaboration of experts from all United Nations (UN) regions, beginning at the 2023 Schizophrenia International Research Society (SIRS) meeting in Toronto, Ontario, Canada, where leaders called for a globally applicable, algorithmic guideline. Between July and September 2023, the team conducted an umbrella review to ensure the guideline was grounded in the most comprehensive evidence available.

A draft questionnaire, informed by the umbrella review, was refined through steering committee input and focus groups of individuals with lived experience of schizophrenia, spanning diverse ages, ethnicities, genders, and illness stages. From February to March 2024, 70 experts from 30 countries across all UN regions participated in a consensus survey; items endorsed by 70% or more were incorporated into the guideline. A draft algorithm was presented at the April 2024 SIRS workshop with over 250 participants and revised following additional surveys and focus group feedback. By mid-2024, the group had produced a stepwise, consensus-driven guideline, paired with a digital decision support tool, focused on pharmacologic treatment and side effect management. The INTEGRATE guidelines were published in May 2025, designed to harmonize pharmacologic care for schizophrenia across diverse health care systems.¹

The INTEGRATE guidelines for schizophrenia provide a structured, reproducible approach to schizophrenia care, with application internationally across practice settings and health systems.² Of course, INTEGRATE is not the first attempt to codify schizophrenia treatment. National bodies such as the American Psychiatric Association, the United Kingdom’s National Institute for Health and Care Excellence, and the Canadian Schizophrenia Guidelines have all produced guidelines that shape practice within their respective contexts.^3-5 The INTEGRATE guidelines represent the most recent iteration of evidence-based practice with an explicitly international perspective, deliberately crafted to be agnostic toward any single nation’s health care infrastructure. By doing so, it provides clinicians worldwide with a common language and algorithm that can transcend regional practice patterns. This universality is critical in psychiatry, where treatment disparities remain stark both domestically and internationally.

Schizophrenia remains one of the most disabling psychiatric disorders worldwide, and its treatment landscape continues to face 2 major challenges. First, therapeutic options remain limited, as most interventions still rely on dopamine antagonists with only modest impact on negative and cognitive symptoms. Second, even when effective treatments exist, they are inconsistently applied: Clozapine remains underutilized, long-acting injectables (LAIs) are too often reserved as last resorts, and metabolic comorbidities are frequently undermonitored or inadequately addressed. The INTEGRATE project was designed to close these gaps by convening international experts and conducting an umbrella review, essentially a review of reviews, that synthesizes evidence across existing systematic reviews and meta-analyses. This approach, commonly used in the development of treatment guidelines, ensures that recommendations are grounded in the most comprehensive and rigorously evaluated body of evidence available.

Core Components of the INTEGRATE Algorithm

At its foundation, the INTEGRATE algorithm emphasizes a structured approach to treatment initiation and monitoring. For patients with first-episode psychosis, clinicians are advised to start low, titrate quickly, and reassess response at weekly intervals during the first month. This early vigilance is paired with comprehensive baseline investigations, including hemoglobin A1C, lipid profile, prolactin, liver and renal panels, complete blood count, and electrocardiogram. Additional monitoring parameters such as weight, body mass index, waist circumference, and blood pressure checks are recommended each week for the first 6 weeks. These assessments are then repeated at 3 months and annually thereafter, creating a rhythm of monitoring that is far more explicit than what is typically seen in US outpatient practice, where cardiometabolic tracking is often deprioritized once acute stabilization is achieved.

Perhaps the most distinctive feature of INTEGRATE is its emphasis on proactive metabolic cotreatment. Metformin is recommended at the time of initiation for agents with high metabolic risk, such as olanzapine or clozapine, rather than reactive introduction after weight gain has occurred. Glucagon-like peptide-1 receptor agonists, such as semaglutide or liraglutide, are also explicitly included for patients with established obesity or rapid weight gain, reflecting the accumulating evidence for their benefit in antipsychotic-associated metabolic dysfunction. By embedding these strategies into the algorithm, the guidelines reframe cardiometabolic care not as optional or secondary but as a standard component of psychiatric management.

Treatment response is approached with a strict timeline. If there is no clinically meaningful improvement after 4 weeks at a therapeutic dose, clinicians are advised to switch to an antipsychotic with a different pharmacologic profile. After 2 failed trials, clozapine should be initiated, coprescribed with metformin for metabolic protection. Importantly, the guidelines emphasize achieving therapeutic plasma levels, targeting at least 350 ng/mL and considering up to 550 ng/mL before pursuing augmentation strategies. This creates a clear expectation for early and decisive movement toward clozapine, in contrast to the hesitancy that often characterizes real-world practice.

The algorithm also integrates domain-specific treatment strategies. For negative symptoms, clinicians are encouraged to consider dose reduction within the therapeutic range, switching to partial agonists, such as cariprazine or aripiprazole, or using low-dose amisulpride. For patients experiencing hyperprolactinemia, a switch to a partial agonist or the addition of low-dose aripiprazole is recommended. In cases of tardive dyskinesia, the algorithm explicitly incorporates the use of VMAT2 inhibitors. These targeted recommendations reflect a broader shift toward tailoring treatment not only to diagnostic categories but also to specific symptom domains that drive disability.

A particularly important cultural shift embedded in INTEGRATE is the reframing of LAIs. Rather than reserving LAIs for cases of nonadherence, the guidelines recommend clinicians introduce LAIs as a routine, evidence-based option that reduces relapse risk and improves long-term outcomes that once oral tolerability is established. By making LAIs part of the early treatment conversation, INTEGRATE challenges the stigma that has historically surrounded their use and positions them as a proactive tool rather than a punitive measure.

Finally, INTEGRATE provides structured guidance on discontinuation of antipsychotic therapy, a topic often marked by uncertainty. For patients who have remained symptom free for at least 2 years, tapering is considered possible, but only if done gradually over a minimum of 6 months with close clinical monitoring. This recommendation acknowledges both the clinical desire to minimize unnecessary medication exposure and the substantial risks associated with abrupt or premature discontinuation.

How INTEGRATE Differs From Typical US Practice

Although much of the algorithm will feel familiar to American clinicians, 3 areas stand out as departures worth highlighting (Table). Additionally, the guidelines deemphasize the traditional first-generation antipsychotic (FGA)/second-generation antipsychotic (SGA) distinction, recommending neuroscience nomenclature with drug selection based on receptor profile and side effect burden. Although this is already implicit in many US prescribers’ decision-making, the explicit dismissal of FGA/SGA categories represents a philosophical shift.

TABLE. How INTEGRATE Guidelines Differ From Typical US Practice

Exploring the Clinical Implications for US Practice

Adopting the INTEGRATE framework in the United States would require a series of important cultural and clinical shifts. Perhaps the most immediate involves rethinking prevention. Too often, US psychiatry waits until metabolic complications emerge before acting, introducing metformin or lifestyle counseling only after weight gain has occurred. INTEGRATE challenges this reactive model by embedding metabolic protection at the outset, treating it not as an adjunctive step but as a fundamental part of antipsychotic prescribing. Framed this way, the guidelines force us to confront the reality that the premature mortality associated with schizophrenia is driven primarily by cardiovascular disease, not psychosis itself.

Equally significant is the reframing of LAIs. In the US, LAIs are still stigmatized as punitive interventions, reserved for patients labeled as nonadherent. INTEGRATE positions them instead as a routine, proactive option to be discussed early in treatment, long before adherence problems surface. This approach has the potential to normalize LAIs, reduce relapse rates, and build patient trust by framing injectables as a tool for long-term stability rather than a marker of treatment failure.

Another critical implication lies in the use of plasma drug levels. Outside of clozapine, antipsychotic levels are rarely obtained in US outpatient psychiatry, despite their use in distinguishing true treatment resistance from pseudoresistance due to subtherapeutic exposure. By embedding plasma level testing into the algorithm, INTEGRATE provides a mechanism for avoiding premature polypharmacy, misclassification of nonresponse, and the unnecessary escalation of treatment strategies.

Finally, the guidelines underscore the need for psychiatry to operate in a more integrated manner with other fields of medicine. By explicitly embedding cardiometabolic management into schizophrenia care, INTEGRATE makes it clear that psychiatrists cannot afford to view physical health as “outside our lane.” Instead, psychiatric providers must take an active role in initiating cardiometabolic interventions and collaborating with primary care and endocrinology. In doing so, we shift from a fragmented system, where psychiatric and medical care are siloed, to care integration, where patients receive care that addresses both their mental and physical health risks in tandem.

Concluding Thoughts

Guidelines do not exist to replace clinical judgment, nor do they constrain the art of psychiatry. Their purpose is to act as a backstop, a structure that ensures patients receive care grounded in the best available evidence, even when practice environments are variable and resources uneven. The success of the Johns Hopkins central line checklist demonstrates that even highly skilled experts benefit from structured approaches that safeguard against omission and variability. The INTEGRATE guidelines extend that same logic to schizophrenia: They provide an algorithmic framework that supports clinicians in translating knowledge into consistent, high-quality care.

As psychiatric prescribing becomes increasingly diverse, with physician associates, nurse practitioners, and early-career psychiatrists taking on central roles in treatment, guidelines such as INTEGRATE offer a critical safety net. They help ensure that patients with schizophrenia are not left vulnerable to gaps in implementation or the idiosyncrasies of individual practice styles.

Schizophrenia will remain a condition marked by limited pharmacologic innovation and profound clinical challenges. Yet by committing to structured, reproducible care, we can narrow the gap between what is possible in theory and what is delivered in practice. The lesson from INTEGRATE is clear: When we align our treatments with evidence and apply them consistently, we give our patients not only better odds of recovery but also a health care system worthy of their trust.

Dr Asbach is a psychiatric physician associate and serves as associate director of interventional psychiatry at DENT Neurologic Institute in Amherst, New York. Dr Roque is a clinical associate professor in the Hahn School of Nursing and Health Science at the University of San Diego in California.

References

1. McCutcheon RA, Pillinger T, Varvari I, et al; INTEGRATE Advisory Group. INTEGRATE: international guidelines for the algorithmic treatment of schizophrenia. Lancet Psychiatry. 2025;12(5):384-394.

2. Hasan A, Correll CU, Miyamoto S, et al. INTEGRATE: an international guideline and algorithm for the treatment of adults with schizophrenia. Lancet Psychiatry. 2025;12(5):389-406.

3. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872.

4. Psychosis and schizophrenia in adults: prevention and management. National Institute for Health and Care Excellence. February 12, 2014. Accessed September 3, 2025. https://www.nice.org.uk/guidance/cg178

5. Remington G, Addington D, Honer W, et al. Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatry. 2017;62(9):604-616.