A rationale for staging is the promise that early intervention can prevent or delay progression to more severe and treatment-resistant stages, where only symptom amelioration may be possible [7,8]. Existing evidence demonstrates that patients in earlier stages of illness, such as those experiencing first-episode psychosis or mild to moderate symptoms, show better treatment responses and require less aggressive treatments [9]. Delays in effective treatment may lead to relapses, contributing to decreased responsiveness to future treatments, negative social and occupational consequences, as well as personal and economic challenges, all of which collectively contributing to a poorer overall prognosis. Each relapse further compromises the patient’s capacity to fully recover after each relapse, progressively lowering baseline function until an eventual plateau is reached (Fig. 1) [10]. Therefore, timely initiation and consistent use of effective medication is critical for relapse prevention and maintaining the highest possible baseline functioning.

By identifying and intervening during the early phases, clinicians can capitalize on neuroplasticity and minimize the accumulation of psychosocial (e.g., suicide, forensic history, loss of employment, loss of societal standing, loss of social networks) and biological toxicities (i.e., treatment resistance).

Stage-based models usually describe a progression from asymptomatic high-risk states (stage 0) through mild or moderate subthreshold symptoms (stage 1), full threshold first psychotic episodes (stage 2), recurrent illness such as relapses (stage 3), and severe and unremitting chronic state (stage 4). Some models further subdivide stages. This allows for more precise tailoring of interventions to the individual’s clinical and functional status [11,12].

Stage-based care is not limited to schizophrenia but is relevant across transdiagnostic psychiatry, where early intervention can similarly prevent progression to chronic stages in other psychiatric disorders [7,13]. In treatment-resistant schizophrenia (TRS), staging helps identify when to escalate or step up treatment, such as initiating clozapine, and when to consider alternative or adjunctive treatments [14]. The stage-based approach is guided by the following principles [10]:

• Early intervention: prompt identification and treatment of symptoms, ideally during the prodromal or first-episode phase, to reduce the duration of untreated psychosis [15,16] and improve long-term outcomes.

• Stage-specific care: interventions are tailored to the specific needs and risks associated with each stage. For example, psychosocial support and cognitive behavioral therapy may be emphasized in early prodromal stages, while antipsychotic medications are recommended for full-threshold symptoms.

• Stepped care: treatment intensity is adjusted based on response, with more intensive or specialized interventions offered for those who do not adequately respond to first line treatments.

TRS affects approximately one-third of individuals with schizophrenia [5]. TRS is defined as inadequate symptom response to at least two adequate trials of non-clozapine antipsychotic medications, including first-, second-, and third-generation antipsychotics [17]. Importantly, most patients with TRS (84%) exhibit resistance from the onset of illness rather than developing over time, suggesting the need for early identification and intervention [18]. This early resistance seen even during the first psychotic episode may reflect a distinct neurobiological subtype. Clinically, TRS is heterogeneous [19] and characterized by an earlier age of onset, more severe symptoms, and poorer functional outcomes compared to treatment-responsive schizophrenia [20]. Biologically, TRS patients often have greater familial aggregation and genetic loading [21], with a pathophysiology less driven by dopaminergic dysfunction [22]. These factors contribute to the distinct profile of TRS and the limitations of conventional antipsychotic treatments. When the patient history is unclear, after ruling out medical etiologies and substance use, the most efficient way to confirm TRS is through a trial with a long-acting injectable (LAI) antipsychotic, ensuring adequate dose, duration, and particularly adherence [23].

Clozapine is the only antipsychotic with robust evidence for superior effectiveness in TRS [24]. Studies have shown that approximately 50% of TRS patients respond positively to clozapine, with improvements in positive and negative symptoms, as well as overall functioning [5]. Unlike other antipsychotics, clozapine has a broad-spectrum profile, effectively reducing suicidality [25] and aggression [26,27] independent of its antipsychotic effects. Meta-analyses confirm clozapine’s superiority in symptom reduction and relapse prevention, as well as in lowering all-cause mortality [28]. The American Psychiatric Association’s (APA) latest guidelines recommend clozapine as the treatment of choice for TRS, suicidality, and aggression, emphasizing its role as a foundational treatment option, not a last resort. Clinicians are encouraged to prioritize clozapine for individuals experiencing treatment-resistant first episodes, for patients with chronic schizophrenia and poor illness course, and patients with forensic histories due to aggression or suicidality. In addition, those with comorbid substance use disorders [29], catatonic features, or sensitivity to extrapyramidal symptoms, including established tardive dyskinesia, should also be considered good candidates for early clozapine intervention [24,25,30,31].

Despite its proven efficacy, clozapine is often prescribed late in the illness course. Delays in initiation contribute to accumulating psychosocial toxicity as noted earlier, including job loss, disrupted education, legal problems, damage to reputation, and increased suicide risk. Prolonged, untreated, or inadequately treated psychosis may lead to “end-stage” brain disease characterized by poor cognitive and functional outcomes. Moreover, delayed clozapine use is associated with increased polypharmacy, more relapses that can induce increased treatment non-response and hospitalizations, and higher mortality (Table 1) [28,32-34]. These consequences underscore the critical importance of timely clozapine initiation and routine use to maximize long-term benefits. Ineffective treatment given over long periods of time is still ineffective even if given with great sincerity. The Optimizing Treatment with Clozapine in Treatment-Resistant Schizophrenia trial demonstrated no added benefit to a switch to another dopamine blocking agent such as olanzapine before transitioning to clozapine [35,36]. Assuming that cases of treatment resistance are at least somewhat unresponsive to dopamine blockade, per definition, it is only logical to consider clozapine the treatment of choice and not a third-line treatment. A recent nationwide database study reported that switching to clozapine after a first psychotic relapse was associated with the lowest risk of subsequent relapse, whereas switching to another non-clozapine antipsychotic was nearly as ineffective as discontinuation [37,38]. These findings challenge current treatment algorithms and support earlier initiation of clozapine to improve clinical outcomes.

Clozapine, given its numerous medical side effect profile, requires careful management but can be safely managed through a structured, multidisciplinary team-based approach. Clozapine FDA black box warnings include severe neutropenia (formerly agranulocytosis), seizures, myocarditis and cardiomyopathy, and orthostatic hypotension/bradycardia/syncope. Additional concerns include metabolic syndrome including weight gain, constipation potentially progressing to bowel obstruction, and sialorrhea which may lead to aspiration pneumonia. Adhering to blood monitoring protocols and proactively addressing side effects are critical to mitigate these risks [39].

The landscape of clozapine safety management evolved in 2025 with the publication of two landmark international consensus guidelines that have the potential to reshape and harmonize monitoring approaches. The Global Delphi guideline [40] on absolute neutrophil count (ANC) and adverse drug reaction (ADR) monitoring represents a paradigm shift from neutropenia-focused monitoring to comprehensive, evidence-based, and clinically-informed approach. It recommends discontinuing routine ANC monitoring after 2 years (discussed further in the subsequent section) and introduces a systematic checklist for ADR monitoring every 3 months. This checklist covers metabolic syndrome, constipation, sialorrhea, sleep apnea, and many others. The guideline promotes a collaborative approach between primary care and psychiatric providers while emphasizing shared decision making and patient participation in clinical management.

Complementing this broader monitoring approach, new multidisciplinary consensus guidelines for clozapine-associated myocarditis (CAM) [41] provide the first standardized framework for preventing, detecting, and managing CAM. They establish clear diagnostic criteria adapted from cardio-oncology guidelines and emphasize preventive strategies, such as slower titration starting at 12.5 mg and mandatory weekly monitoring of high-sensitivity troponin and C-reactive protein levels during the first 4 weeks (with some suggesting extension to 8 weeks). They also outline a structured, risk-stratified framework for high-risk populations and provide a systematic approach for safely rechallenging patients after CAM.

Together, these guidelines advance clozapine management by balancing safety with accessibility, potentially improving outcomes for many with TRS who could benefit from this life-saving medication. Population-based management approaches, including systematic mechanisms to ensure annual metabolic labs and frequent weight monitoring, can help mitigate long-term metabolic complications. Effective risk management involves collaboration among psychiatrists, nurses, pharmacists, and primary care providers to ensure safe medication titration, continuous monitoring, and comprehensive patient education. The specific composition of the clinical team should be adapted to local service structures and workforce capacity.

Clinically, practice should shift toward routinely offering a time-limited trial of clozapine early and to all patients with residual symptoms rather than reserving it as a last resort treatment. This approach aims to prevent progression to irreversible disability and optimize functional recovery. Early and routine clozapine use, when indicated clinically, combined with proactive side effect management, represents ideal practice in schizophrenia care [42].

Since FDA approval, clozapine has required regular blood work to monitor neutropenia risk, implemented through a mandatory Risk Evaluation and Mitigation Strategy (REMS) in the United States. Under REMS regulations, prescribers required certification, ANC had to be reported to an online registry, and pharmacies were required to verify ANC results before dispensing medication. Although intended for patient safety, REMS created substantial barriers for both clinicians and patients. Following safety data scrutinization and advocacy efforts from grassroot groups such as “Angry Moms,” [43] which secured wide congressional support, the FDA removed the clozapine REMS in February 2025, completely ceasing operations by June 2025 in the US [44].

This regulatory change is anticipated to improve patient access by reducing administrative barriers and minimizing disruptions associated with delayed laboratory testing or ANC reporting. However, regular blood monitoring still remains essential. The removal of REMS provides greater flexibility, enabling consideration of less frequent ANC monitoring schedules such as those recommended by the Global Delphi [40] and European guidelines [45]. The Global Delphi expert consensus statement recommends weekly ANC monitoring for the first 18 weeks, monthly monitoring until the 2-year mark, and discontinuation of ANC monitoring thereafter, although it still advises performing complete blood count with differential annually to screen for hematological malignancies. The European guidelines propose weekly ANC monitoring for the initial 18 weeks, monthly until the 1-year mark, quarterly from 1 to 2 years, and then annually thereafter. Both sets of guidelines suggest extended monitoring intervals compared to the traditional frequency, which involves weekly monitoring for the first 6 months, bi-weekly monitoring for the next 6 months, and monthly thereafter (Fig. 2). This adjustment is based on evidence indicating the highest risk period for agranulocytosis occurs during the initial 18 weeks, after which the risk significantly decreases, eventually approaching the lower risk levels similar to other antipsychotics.

It is important to note that despite these updated evidence-based recommendations, the current FDA-approved prescribing information (package insert) still advises adherence to the traditional monitoring frequency. Therefore, transitioning to less frequent ANC monitoring requires careful discussion via a collaborative, shared decision-making and informed consent process among patients, caregivers, and healthcare providers. This dialogue should comprehensively address the potential risks and benefits associated with adopting newer monitoring protocols, ultimately supporting personalized decisions that align with individual patient circumstances, preferences, and treatment goals. The informed consent discussion needs to be documented in the medical record.

In addition, innovative ANC monitoring methods, such as fingerstick tests using point-of-care devices, offer greater convenience and patient comfort compared to arm-based venipuncture, which could further facilitate wider adoption of clozapine [46,47].

Individuals with schizophrenia face a substantially reduced life expectancy, ranging from 10 to 25 years less than that of the general population. This excess mortality is driven primarily by cardiovascular disease, cancer, and pneumonia, rather than by the psychiatric illness itself [1,48]. Contributing factors include poor lifestyle habits, iatrogenic morbidity, notably AIWG, delayed diagnosis and treatment of medical conditions, high rates of suicide and accidents, and illicit drug use [2,49-51]. The interplay of these factors calls for proactive medical management as a critical part of schizophrenia care.

AIWG is a well-recognized and common side effect of antipsychotic medications, with the greatest risk seen with agents such as clozapine and olanzapine. Weight gain often occurs rapidly in the early months of treatment and can lead to metabolic syndrome, insulin resistance, type 2 diabetes, and cardiovascular complications. Effective management strategies are essential to minimize both short- and long-term health risks [52-54].

In general, clinicians should initially select antipsychotics with a favorable metabolic profile, such as aripiprazole, lurasidone, or ziprasidone. However, once the need for clozapine is established, prompt and guideline-concordant monitoring of weight and metabolic parameters becomes even more important to identify and address emerging metabolic disturbances [52]. The Global Delphi guideline [40] recommends measuring weight, waist circumference, HgA1c, lipid panel, fasting glucose at baseline. Subsequently, weight and waist circumference should be monitored weekly for the first 18 weeks, then monthly up to 2 years, and thereafter every 3 months. Metabolic laboratory tests are recommended at baseline and then every 6 to 12 months.

Randomized controlled trials indicate that combination of lifestyle intervention and metformin is effective for reducing AIWG including for patients who require metabolically high-risk antipsychotics (olanzapine, clozapine) [55]. Lifestyle interventions alone, such as dietary modifications, nutritional guidance, and increased physical activity, are typically insufficient to prevent rapid weight gain, especially during the initial months of clozapine treatment. Metformin, generally well-tolerated, should be considered early to mitigate weight gain, particularly in high-risk individuals [56]. According to the 2024 international expert consensus guidelines, developed through systematic review and Delphi validation [57], metformin is now recommended from the outset concurrently when initiating high-risk antipsychotics, such as clozapine or olanzapine, to prevent AIWG. This demonstrates the shift to preventive and early intervention strategies. Other adjunctive medications to blunt weight gain, such as topiramate, may also be considered.

The arrival of GLP-1 agonists has advanced treatment options for AIWG. These agents have demonstrated superior weight loss effects compared to other available medications and are increasingly considered for patients who do not achieve adequate weight loss with metformin and lifestyle interventions. Beyond weight reduction, GLP-1 agonists improve glycemic control and may have additional benefits for other conditions such as obstructive sleep apnea and substance use disorders.

A 2024 meta-analysis by Bak et al. [58] reported significant weight loss with liraglutide (approximately 4.7 kg greater than controls) and promising results with exenatide. Recent studies from 2025 have validated the effectiveness of semaglutide for AIWG: the Clozapine Obesity and Semaglutide Treatment (COaST) trial demonstrated substantial weight reduction (approximately 14%) in clozapine-treated patients without worsening psychiatric symptoms [59]. Similarly, a feasibility study by Heald et al. [60] observed notable metabolic and weight improvements in patients with schizophrenia. Both studies reported that semaglutide is well-tolerated and its gastrointestinal side effects are manageable. Evidence supporting the use of more potent dual GLP-1 agonists like tirzepatide for AIWG is currently limited, although one case report showed high effectiveness in fully reversing clozapine-induced weight gain and the importance of continued maintenance treatment to sustain weight loss [61]. At a minimum, clinicians are encouraged to familiarize themselves with GLP-1 agonists, as these agents could potentially reshape the standard of schizophrenia care, working with the medical treatment team to advocate for their use if indicated. However, important questions remain regarding long-term safety, cost-effectiveness, and the ideal timing for initiating treatment, including whether earlier, preventative use (even at lower doses) could offer clinical benefit, and further research is needed.

Despite advances in psychopharmacology and psychosocial interventions, outcomes for many people with schizophrenia remain inadequate. Recent longitudinal data from the aforementioned Suffolk County Study tracking 311 patients over 25 years indicate that the most common long-term outcomes are neither remission nor functional recovery, with Black individuals having even worse outcomes compared to their white counterparts [3,4]. These disparities reveal systemic inequities, including unequal access to high-quality care and evidence-based treatments. Moreover, older patients, who often face accumulating medical and social challenges, are especially vulnerable and underserved by current healthcare systems. The gap between research evidence and clinical practice, compounded by stigma and fragmented care, hinders progress. In addition, negative and cognitive symptoms of schizophrenia, for which effective treatments are limited, contribute to poor functional outcomes, and dopamine-blocking antipsychotics further exacerbate these symptoms, complicating treatment efforts [62-65].

Several non-biological factors contribute to suboptimal outcomes in schizophrenia. Prolonged duration of untreated psychosis is a major predictor of worse long-term outcomes, as time spent in active psychosis increases the risk of functional decline and treatment resistance [15,16]. Poor access to and engagement in ongoing treatment further exacerbate these risks, with many individuals facing barriers such as inadequate insurance, transportation difficulties, and lack of social support. Social determinants of health, including poverty, housing instability, and substance use, play a critical role in prognosis. Short of a cure, social interventions often have a greater impact on outcomes than molecular advances for managing chronic diseases [66-68]. In addition, substandard psychiatric care and comorbid medical disorders often go unrecognized or undertreated, leading to preventable morbidity and mortality. State-level variation in clozapine initiation highlights the need for more uniform [69], accessible paths to this mission-critical medication. Widespread underuse of clozapine contributes directly to treatment failures, increasing rates of homelessness and incarceration in people with schizophrenia.

Recent years have seen promising innovations in schizophrenia care. Third-generation antipsychotics and LAIs antipsychotics with extended dosing intervals provide improved adherence and reduced relapse risk. Novel cholinergic agents, such as the muscarinic agonist xanomeline/trospium (KarXT) [70], represent a shift away from traditional dopamine D2 receptor blockade pharmacology, providing a hope for patients, although it remains unclear how it compares to clozapine in terms of effectiveness for treatment-resistance due the lack of head-to-head trials. Furthermore, VMAT-2 inhibitors (e.g., valbenazine, deutetrabenazine) have been approved as first-line treatment for tardive dyskinesia, potentially reducing the stigma associated with visible symptoms of the condition. It is important to note that there are currently no disease-modifying antipsychotic treatments and no approved medications targeting negative and cognitive symptoms of schizophrenia. Increased investment in psychiatric clinical trials is warranted [71,72].

Beyond medication, digital health tools and telepsychiatry are expanding access to care [73], particularly in rural and underserved areas. These technologies enable remote monitoring, medication management, and psychosocial support, helping to bridge gaps in service delivery.

Given the underutilization of clozapine due to safety concerns and logistical challenges, there is a great need for either dedicated clozapine clinics or at least clozapine-capable clinics (personal communication, Robert Cotes), combined in networks that facilitate learning and dissemination [74]. Clozapine-capable clinics are clinics that serve patients with serious mental illnesses that are able to provide early and competent use of clozapine to any patient who needs clozapine. Leveraging learning health networks can accelerate quality improvement through rapid sharing of best practices and real-world data across these specialized clinics. Such specialized networks would centralize expertise in initiating, titrating clozapine and monitoring its side effects, ensuring timely and safe treatment. In addition, these clinics could provide integrated medical and psychiatric care, addressing the significant medical comorbidities prevalent among this patient population. Recent research has confirmed that clozapine is highly effective and safe when administered within a structured, multidisciplinary care framework [41,75]. The removal of the U.S. REMS for clozapine in 2025 [46] further reduces administrative burdens, making it easier for clinicians to prescribe and patients to access this critical medication. Establishing specialized clozapine clinics (or clozapine-capable clinics) and fostering close collaborations between such specialized clinics would standardize best practices, empower clinicians, and improve patient satisfaction, ultimately improving clinical outcomes and reducing disparities in schizophrenia care.