Clozapine: past, present and future

Clozapine, synthetized over 65 years ago, remains the only antipsychotic approved for treatment‐resistant schizophrenia. Despite its well‐documented efficacy and effectiveness in randomized controlled trials (RCTs) and real‐world studies ¹ , this drug's unclear mechanisms of action, complex side effect profile, and underutilization pose significant challenges for clinical practice. The recent approval of the first M1/M4 muscarinic agonist for schizophrenia has spurred hopes of added efficacy through this mechanism of action for people with insufficient treatment benefits from dopamine receptor antagonists/partial agonists. In this context, it is valuable to reflect on unresolved issues, including clozapine's pharmacologic mechanisms, unique clinical benefits, risks, and barriers to optimal use.

To date, the exact mechanisms underlying clozapine's superior efficacy in treatment‐resistant schizophrenia remain incompletely understood. Unlike other dopamine receptor blocking antipsychotics, which have medium‐strong affinity to dopamine D2 receptors, clozapine has weak D2 receptor affinity, binding more tightly to serotonergic, alpha‐adrenergic, metabotropic glutamatergic, and muscarinic receptors. It also has neuroprotective, antiproliferative and anti‐inflammatory activity.

Clozapine's metabolite, N‐desmethylclozapine, acts as a positive allosteric modulator at muscarinic M1 receptors and as an M4 receptor agonist, raising the possibility that this mechanism of action could contribute to the unique efficacy of the drug. This aspect is particularly relevant, given the above‐mentioned recent approval by the US Food and Drug Administration (FDA) of the M1/M4 receptor agonist xanomeline, paired with the peripherally restricted anticholinergic trospium, for the treatment of schizophrenia ² .

Clozapine offers distinct advantages in managing treatment‐resistant schizophrenia, with demonstrated superiority over other dopamine receptor blocking antipsychotics for positive symptom reduction; reduced relapse/hospitalization risk, suicidal behaviors, substance use and aggressive behavior; increasing functionality, including employment; and reducing mortality risk. However, clozapine's use is limited by significant adverse effects, including agranulocytosis, myocarditis, pneumonia, ileus, weight gain, diabetes, dyslipidemia, and metabolic syndrome, as well as sedation and hypersalivation ³ . The seeming paradox of clozapine's lower risk for all‐cause as well as cardiovascular disease‐related mortality, despite higher risk of cardiometabolic adverse effects versus other antipsychotics, has been addressed by a nationwide within‐subject study ⁴ , indicating that patients taking clozapine also showed greater adherence to statins, antidiabetic medications and antihypertensives. Better psychiatric outcomes could also promote healthy lifestyle behaviors.

There is ongoing debate about when clozapine should be introduced in the treatment algorithm for people with schizophrenia. Current guidelines recommend its introduction after two antipsychotic efficacy failures. However, initiating clozapine after one failed treatment may improve outcomes and reduce delays in effective care, especially as delayed clozapine use has been associated with reduced efficacy. A recent nationwide database study – though presenting some methodological limitations – indicated that, after a first psychosis relapse, a switch to clozapine was associated with the lowest risk of a second psychosis relapse, while a switch to another oral antipsychotic monotherapy was almost as unhelpful in preventing a second relapse as stopping antipsychotics altogether ⁵ . These data, although preliminary, seem to challenge current clinical guidelines and practice of using yet another dopamine receptor blocking antipsychotic, either alone or in combination, after verified failure of treatment with a member of that same pharmacological class, elevating clozapine (or possibly other non‐postsynaptic antidopaminergic agents) to a direct second treatment choice.

Additionally, to mitigate the risk of early (hyperthermia, tachycardia, orthostasis) and potentially severe (myocarditis, pneumonia, agranulocytosis, seizures, ileus) side effects, clozapine's initiation involves slow titration. Recently, ethnicity‐specific differences in tolerability, and dosing as well as titration requirements, have been proposed ³ , raising questions about whether standard protocols should be modified based on ethnic factors.

Obtaining clozapine blood levels can be helpful to inform titration for dose finding. Clozapine is one of the few psychotropic medications with an evidence base supporting measurement‐based care, with an optimal threshold level of >350 (range: 250‐550) ng/ml for efficacy. However, therapeutic blood monitoring is not always/widely available, and clozapine blood levels, when accessible, may take a long time to read out, further complicating clinician use.

Although up to 40% of patients fulfill criteria for treatment‐resistant schizophrenia ⁶ , clozapine – the only antipsychotic with regulatory approval for this condition – continues to be prescribed in less than 10% of patients with schizophrenia worldwide ⁷ . This discrepancy highlights significant barriers, including clinicians’ insufficient training and hesitation, system‐level constraints, and patient or caregiver concerns about side effects or ongoing hematologic monitoring. Educational initiatives aimed at clinicians and patients may help address misconceptions about clozapine. Contact to experienced prescribers can empower clinicians to use clozapine confidently.

The evidence‐based justification for ongoing hematologic monitoring has been called into question, given data that the risk of agranulocytosis in people with normal white counts significantly declines after the first year ³ . Indeed, the FDA has recently decided to discontinue its previously mandated Risk Evaluation and Mitigation Strategy (REMS) program, which required patients to report an absolute neutrophil count blood test prior to pharmacies dispensing clozapine.

Unfortunately, even with clozapine, about 50‐60% of patients respond insufficiently ⁸ . Although electroconvulsive treatment added to clozapine is currently the most evidence‐based treatment option, this is used even less than clozapine. Instead, other psychotropic medications, especially other antipsychotics, are frequently added to clozapine. A meta‐analysis of two nationwide cohorts (Finland and Sweden), which appears in this issue of the journal ⁹ , found in within‐subject analyses that medium‐dose aripiprazole augmentation of clozapine treatment was associated with a 20‐30% risk reduction of hospitalization versus clozapine monotherapy. On the other hand, augmentation with higher doses of aripiprazole, as with high doses of all other antipsychotics, was associated with an increased hospitalization risk.

Improving clozapine utilization will require multifaceted strategies, increasing clinician education on proper initiation, titration, and management of adverse effects, and achieving system‐based reduction of non‐evidence‐based hematological monitoring schedules. Ethnicity‐based dosing and titration schedules ³ require prospective validation.

Since clozapine treatment inevitably increases contact with health care providers due to hematologic exams and, sometimes, therapeutic blood level monitoring, RCTs should compare clozapine with long‐acting injectable antipsychotics, including after antipsychotic treatment failure in patients with a first episode of schizophrenia. Ensuring adherence in the long‐acting antipsychotic arm would help disentangle non‐specific, adherence‐increasing effects of clozapine related to patients’ increased contact with health care providers from potentially specific effects of the drug responsible for its increased effectiveness in real‐world studies.

Moreover, the finding that medium‐dose aripiprazole augmentation of clozapine decreases hospitalization risk in real‐world settings should be followed up by RCTs also investigating symptom reduction and improved functioning.

In patients with treatment‐resistant schizophrenia, head‐to‐head RCTs are needed that compare muscarinic receptor agonists/positive allosteric modulators as monotherapy or augmentation treatment versus continuation of a failed dopamine receptor blocking antipsychotic or switch to another member of this class, or even versus clozapine or augmenting clozapine, as long as excessive cumulative anticholinergic burden can be avoided. Finally, clozapine also has unique efficacy for treatment‐resistant bipolar disorder and other psychiatric conditions, indicating that improving clinicians’ acceptability and confidence in its use could potentially improve outcomes of patients with other severe mental disorders.

Clozapine's unparalleled efficacy in treatment‐resistant schizophrenia, anti‐suicidal and mortality‐reducing effects underscore its importance in psychiatric care. However, its unclear mechanisms of action, underutilization, delayed initiation, and complex safety profile highlight the need for improved education, research and systemic changes. Efforts should focus on expanding access to clozapine for appropriate patients, while increasing exploration of novel pharmacological strategies that could potentially offer similar efficacy with improved tolerability.