Atypical antipsychotics in FAERS: 606,060 adverse-event reports by the numbers

The FDA Adverse Event Reporting System (FAERS) holds 606,060 individual safety reports that name at least one of the thirteen atypical (second-generation) antipsychotics still marketed in the United States — quetiapine, risperidone, clozapine, aripiprazole, olanzapine, paliperidone, brexpiprazole, ziprasidone, cariprazine, lumateperone, lurasidone, asenapine, and iloperidone — in any role, filed between 2004, when the modern openFDA FAERS record begins, and early 2026. Quetiapine leads the class on raw volume with 162,587 reports (26.8 percent of the class total), followed by risperidone (124,360), clozapine (123,134), aripiprazole (119,893), and olanzapine (99,045); the eight remaining agents together account for less than 13 percent. Of the class-level reports, 446,732 — 73.7 percent — carry an FDA seriousness flag, and 68,683 (11.3 percent) record a fatal outcome, the highest death-flag share of any drug class PharmaDossier has cut from FAERS. Clozapine is the structural outlier: 94.6 percent of its 123,134 reports are serious-flagged and 17.8 percent record a fatal outcome, a concentration that reflects a severely-ill, treatment-resistant population under decades of mandated blood monitoring rather than a clean drug-versus-drug ranking. The class signature is visible in the adverse-event families: 50,909 reports in the extrapyramidal and movement-disorder family, 43,975 in the metabolic and weight family, 31,192 blood-dyscrasia reports (the clozapine neutropenia signal), and 11,428 neuroleptic malignant syndrome reports.

This article is a class-level descriptive read of atypical-antipsychotic reporting in FAERS, written for pharmacovigilance, medical-affairs, CNS market-access, and formulary teams who encounter antipsychotic safety numbers in labeling reviews, REMS and risk-management work, step-therapy and prior-authorization design, and metabolic-monitoring policy. Every figure here is computed from the public openFDA FAERS extract (20,328,575 total reports, export dated 2026-06-08). It is not a disproportionality signal analysis, it is not a safety claim, and it is not incidence data. FAERS is a spontaneous-reporting system: it captures what was reported, never what was caused, it has no exposure denominator, and antipsychotic reporting is dominated by a serious-mental-illness population with high baseline medical comorbidity and mortality, in which metabolic events, cardiovascular death, pneumonia, and suicide are common regardless of attribution. Those caveats shape every number below. For the class-wide FAERS methodology and the database aggregate picture, see the companion analysis of 20 million FAERS reports; for the other class cuts, see antiepileptic drugs, statins, proton pump inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, JAK inhibitors, DOACs, and checkpoint inhibitors in FAERS. This article stays on the thirteen marketed atypical antipsychotics.

Methodology, in one paragraph

A report is counted for an agent when the generic or brand name appears as an exact drug-field token in that report — as a suspect, concomitant, or interacting drug — using an exact-token match across the drug_substances, drug_generics, and drug_brands fields (a |-delimited token match, so that the same number is not double-attributed across the class). Because a single report can name several antipsychotics (polypharmacy, or a cross-titration documented on two agents), the per-agent totals sum to more than the 606,060 class-level (union, deduplicated) reports. First-generation (typical) antipsychotics such as haloperidol and chlorpromazine are excluded; this is a second-generation read. A "serious" report is any report the FDA coded as serious. A report counts toward death when either the seriousness field carries a death flag or the outcome field carries a Fatal outcome. Reactions are coded to MedDRA Preferred Terms; reaction counts are case-normalized. The adverse-event families aggregate related Preferred Terms (for example, "extrapyramidal / movement symptoms" combines extrapyramidal disorder, parkinsonism, tremor, akathisia, dystonia, tardive dyskinesia, bradykinesia, and gait disturbance; "blood dyscrasia (clozapine-linked)" combines agranulocytosis, neutropenia, leukopenia, decreased white-blood-cell count, and pancytopenia; "neuroleptic malignant syndrome" combines neuroleptic malignant syndrome, serotonin syndrome, and hyperthermia), and a report contributes once to a family if any term in the family appears. The "any role" counts reported here are intentionally inclusive, so they will exceed suspect-only or differently normalized counts cited elsewhere for the same agent.

The reporting-volume picture, by drug

Three patterns matter for access and medical-affairs teams. First, the top five agents account for the overwhelming share of reporting, and that share tracks market penetration, breadth of approved and off-label use, and time on market — not intrinsic risk. Quetiapine's volume lead reflects two decades as one of the highest-volume psychiatric prescriptions, with schizophrenia, bipolar, and adjunctive-major-depression labels plus extensive off-label use; aripiprazole's reflects its one-time status as the top-selling US prescription drug of any kind. Second, the serious-share band is extraordinarily wide, from 28.3 percent for lumateperone to 94.6 percent for clozapine, and it is driven by indication and monitoring channel, not drug safety. The five newer or lower-volume agents — paliperidone, brexpiprazole, cariprazine, lumateperone, and iloperidone — cluster in the 28-to-50 percent serious range because a larger share of their reports come from outpatient, less-acute settings and post-marketing consumer reporting, whereas clozapine's 94.6 percent serious share is an artifact of a population in which nearly every report is serious-flagged under mandated monitoring. Third, the per-drug death-flag percentages move with population mix: clozapine's 17.8 percent reflects a treatment-resistant-schizophrenia population with among the highest all-cause mortality in medicine, and the small-lumen agents (lurasidone, asenapine) show double-digit death-flag rates on tiny denominators that are statistical noise, not signal. Quoting any single agent's death-flag rate without that population context is quoting a confounded number.

The class-level outcome profile

A report can carry more than one outcome, so these shares sum to more than 100 percent. The Fatal outcome count (48,851) sits below the death-flag measure (68,683) because not every death-flagged report carries a resolved Fatal outcome field. None of these percentages are incidence — the denominator is reports, not exposed patients. Many millions of patients take atypical antipsychotics; the reporting volume here is a small, skewed slice of real-world exposure, concentrated toward the most severe and best-documented events.

The extrapyramidal, metabolic, blood, and NMS footprint

Stripping out the non-specific terms (somnolence, drug ineffective, completed suicide, death, anxiety) that dominate the raw reaction list for any psychiatric class, the label-relevant adverse-event families that define the atypical-antipsychotic safety profile leave a clear footprint:

The footprint maps exactly onto the published disproportionality and meta-analytic literature. The metabolic signal is the most studied: meta-analyses consistently rank clozapine and olanzapine highest for weight gain and metabolic syndrome (in the CATIE trial, olanzapine was associated with roughly 1 kg per month, and a one-year follow-up put olanzapine- and clozapine-associated weight gain at approximately 12 kg, versus 2–3 kg for quetiapine and risperidone and minimal gain for ziprasidone and aripiprazole), with the newer agents cariprazine, brexpiprazole, and lumateperone showing the smallest metabolic effect — a ranking visible in this read's lower serious shares for those three agents. The 2024–2025 FAERS disproportionality literature reinforces the rest: a 2025 Scientific Reports analysis of atypical-antipsychotic rhabdomyolysis reporting found statistically significant reporting odds ratios of 4.02 for olanzapine, 2.76 for ziprasidone, 2.12 for risperidone, 2.00 for aripiprazole, and 1.47 for clozapine; a 2025 age-stratified FAERS study found risperidone carried the highest hyperprolactinaemia signal (adjusted ROR roughly 212) and aripiprazole the highest akathisia signal (adjusted ROR roughly 45), with patients 65 and older more likely to report cardiac, extrapyramidal, and sedative events but less likely to report metabolic events than those under 65; and a 2024 Frontiers in Pharmacology neuroleptic-malignant-syndrome pharmacovigilance study confirmed NMS signals across the class. The descriptive counts here are the reporting backdrop to that risk-ranking literature; the disproportionality studies, not the raw volumes, established the ordering. Beyond the table, two further cardiovascular signals recur in the recent FAERS literature and are worth flagging for risk-management teams. The first is venous thromboembolism and pulmonary embolism: a 2026 Frontiers in Cardiovascular Medicine systematic review and FAERS analysis of olanzapine reported reporting odds ratios of roughly 2.45 for pulmonary embolism and 5.67 for venous embolism, with the underlying literature placing clozapine users at higher venous-thromboembolism and pulmonary-embolism risk than olanzapine users and risperidone at a comparable adjusted hospitalization hazard ratio (1.98) to olanzapine in a nursing-home cohort. The second is clozapine myocarditis and cardiomyopathy, which appear in the same review among the olanzapine/clozapine adverse-event terms not fully captured in the label and which carry an in-label clozapine warning. Neither signal appears as a discrete family in the counts above because thromboembolism and myocarditis terms were not aggregated into the eight families reported here, but both are part of the same cardiovascular reporting burden that sits behind the class's 11.3 percent death-flag share.

Clozapine — the agranulocytosis anchor and the 2025 REMS removal

Clozapine is the agent that built modern antipsychotic risk management, and its FAERS profile (123,134 reports, 94.6 percent serious, 17.8 percent death-flagged, with 31,192 blood-dyscrasia reports class-wide and 11,086 seizure reports) is the reporting echo of four decades of mandated neutrophil monitoring. Clozapine's association with severe neutropenia and agranulocytosis was recognized at approval in 1989; the pre-marketing database put the cumulative one-year agranulocytosis incidence at approximately 1.3 percent (15 cases among 1,743 exposed patients), with the risk greatest in the first months of treatment and potentially fatal if not detected. That risk drove a series of registries and, from 2015, a single shared Clozapine REMS Program requiring prescriber and pharmacy certification, patient enrollment, and absolute-neutrophil-count (ANC) monitoring on a weekly-to-monthly schedule, with documentation before every dispense.

The defining recent regulatory event for the class is the REMS removal. On February 24, 2025, the FDA announced that it no longer expects prescribers, pharmacies, and patients to participate in the Clozapine REMS or to report ANC results before dispensing, following a November 19, 2024 joint meeting of the Drug Safety and Risk Management and Psychopharmacologic Drugs advisory committees at which the agency concluded the REMS was no longer necessary to ensure clozapine's benefits outweighed its risks. Severe-neutropenia information — including the Boxed Warning and a new Medication Guide — remains in the label, and the FDA continues to recommend ANC monitoring at the frequencies described in the prescribing information, but the distribution is no longer REMS-gated. The agency's rationale was that the REMS had never been fully implemented, that it created access barriers for a drug with otherwise limited alternatives in treatment-resistant schizophrenia, and that labeling alone was sufficient. For pharmacovigilance and access teams, the practical consequence is that clozapine prescribing no longer requires REMS enrollment — a workflow simplification that is also likely to shift how and where clozapine adverse-event reports originate over the next several years.

The boxed warning — elderly dementia mortality and suicidality

The atypical antipsychotics carry a class Boxed Warning that is the single most consequential labeling element for formulary and access policy. The 2005 FDA meta-analysis of seventeen placebo-controlled trials (modal duration ten weeks) in elderly patients with dementia-related psychosis — six antipsychotics, 5,377 patients total (3,611 drug, 1,766 placebo), average age 81 — found a 70 percent increased risk of death, with a death rate of about 4.5 percent in the drug arm versus 2.6 percent in placebo over a typical ten-week trial, the deaths predominantly cardiovascular (heart failure, sudden death) or infectious (pneumonia). The boxed warning was extended from the atypicals to all antipsychotics, including the conventional agents, in 2008. A separate suicidality warning applies across the class: antidepressant-style labeling describes an increased risk of suicidal thinking and behavior in children, adolescents, and young adults, and the labels advise monitoring for clinical worsening, agitation, and emergent suicidality. The 68,683 death-flagged class reports and the population-level death context in the outcome table sit behind these warnings; the boxed warning is a placebo-controlled-trial and observational evidence construct, not an inference from the spontaneous-report counts.

The reporting trajectory, by year

The trajectory tracks the class's reporting ecosystem, not a safety trend. The 2009–2012 climb to a ~25,000-report level coincides with the dissemination of the dementia-mortality and metabolic-syndrome guidance and the broadening of second-generation use into adjunctive depression and bipolar maintenance; the sharp 2014-to-2015 step-up (from roughly 22,000 to 40,000) coincides with the October 2015 launch of the single shared Clozapine REMS Program, which generated substantial new prescriber and pharmacy reporting; the post-2015 plateau in the high-30,000s reflects a mature reporting infrastructure and a stable prescribing base dominated by quetiapine, risperidone, aripiprazole, and olanzapine generics. The 2026 figure (8,302) is a partial year through the extract cut-off. The pre-2004 counts are negligible because the modern openFDA FAERS record begins in late 2003.

What this means for pharmacovigilance, medical-affairs, and access teams

• For pharmacovigilance teams, the class's 73.7 percent serious share and 11.3 percent death-flag rate are population effects, not signal. Read serious and death proportions against a serious-mental-illness baseline with high cardiovascular, metabolic, infectious, and suicide mortality; the signals that matter are the disproportionality-documented extrapyramidal, metabolic, blood-dyscrasia, and NMS families, not the headline death counts.
• For medical-affairs and label teams, clozapine is the structural exception that still anchors the class. The 94.6 percent serious share, the 31,192 blood-dyscrasia reports, and the February 2025 REMS removal together define the regulatory posture; any clozapine risk-management or label review must address the post-REMS monitoring framework and the in-label neutropenia language.
• For CNS market-access and formulary teams, the metabolic-ranking literature (olanzapine and clozapine highest; aripiprazole, ziprasidone, lurasidone, cariprazine, brexpiprazole, and lumateperone lowest) is embedded in metabolic-monitoring policy and preferred-agent positioning. Medicaid and commercial formularies routinely tier or require metabolic monitoring for olanzapine and quetiapine, and the newer agents are often preferred where metabolic risk is a concern.
• For risk-management and REMS teams, the clozapine REMS removal is a precedent and a workflow event, not a risk removal. ANC monitoring remains recommended in-label; the change eliminates the certification-and-dispense-gate infrastructure and shifts documentation responsibility back to the prescriber and pharmacy.
• For dossier and evidence teams, per-agent FAERS figures must be anchored with exposure and population context. A quetiapine number in a multi-hundred-million-prescription population is not comparable to a lumateperone or iloperidone number in a fraction of that denominator, and a clozapine serious-share percentage is not comparable to an aripiprazole percentage because the underlying populations differ so sharply; quoting raw volumes or shares without that context invites a misread.

Sources

• US FDA, openFDA FAERS (Adverse Event Reporting System) extract, export dated 2026-06-08 (20,328,575 total reports). Per-drug, class-union, outcome, AE-family, sex, and trajectory aggregates computed by PharmaDossier from the public FAERS extract. https://open.fda.gov/data/faers/
• US FDA. "Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances." 2005 — 17 placebo-controlled trials, 3,611 drug vs 1,766 placebo patients; ~70% increased mortality; ~4.5% drug vs ~2.6% placebo death rate over a typical 10-week trial; deaths largely cardiovascular or infectious. Surfaced in the FDA brexpiprazole (Rexulti) agitation briefing materials. https://www.fda.gov/media/167129/download
• US FDA. "FDA removes risk evaluation and mitigation strategy (REMS) program for the antipsychotic drug Clozapine." February 24, 2025 — REMS eliminated after the November 19, 2024 joint DSaRM/Psychopharmacologic Drugs advisory committee meeting; ANC monitoring remains recommended in-label; severe-neutropenia Boxed Warning retained. https://www.fda.gov/drugs/drug-safety-communications/fda-removes-risk-evaluation-and-mitigation-strategy-rems-program-antipsychotic-drug-clozapine
• US FDA. "Information on Clozapine" and "Clozapine REMS Modification — Frequently Asked Questions." February 24, 2025. https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/information-clozapine
• US FDA. "FDA modifies monitoring for neutropenia associated with clozapine." 2015 — single shared Clozapine REMS Program effective October 12, 2015; ANC-based monitoring; weekly for 6 months, every 2 weeks for months 6–12, monthly after 1 year; benign ethnic neutropenia eligibility. https://www.fda.gov/media/93482/download
• Clozaril (clozapine) prescribing information, Boxed Warning and Warnings — agranulocytosis cumulative 1-year incidence ~1.3% (15/1,743 in pre-marketing database); seizure risk; myocarditis; orthostatic hypotension. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/019758s106lbl.pdf
• Haloperidol (Haldol) and ziprasidone (Geodon) prescribing information, Boxed Warnings — class "Increased Mortality in Elderly Patients with Dementia-Related Psychosis" language; QT prolongation and sudden death (ziprasidone). https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020825s015,017,020919s005,006lbl.pdf
• Yin Y, Jiang J & Jin Y. "Evaluation of atypical antipsychotics associated rhabdomyolysis using the FDA adverse event reporting system database." Scientific Reports 2025 — rhabdomyolysis reporting odds ratios: olanzapine 4.02 (3.72–4.35), ziprasidone 2.76 (2.19–3.49), risperidone 2.12 (1.91–2.35), aripiprazole 2.00 (1.80–2.21), clozapine 1.47 (1.31–1.64). https://www.nature.com/articles/s41598-025-95700-9
• "FAERS Analysis Reveals Significant Age-Related Differences in the Adverse-Event Profiles of Antipsychotics." 2025 — adjusted RORs: risperidone hyperprolactinaemia ~212, aripiprazole akathisia ~45; elderly (≥65) higher cardiac/EPS/sedative, lower metabolic. https://www.dpublication.com/wp-content/uploads/2025/03/401-25.pdf
• Zhang Y, et al. "A real-world pharmacovigilance study of neuroleptic malignant syndrome based on FDA adverse event reporting system." Frontiers in Pharmacology 2024;15:1438661 — NMS disproportionality signals across antipsychotics. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1438661/full
• Zhang X, et al. "Thromboembolic events with olanzapine: a systematic review integrating meta-analysis and FAERS database." Frontiers in Cardiovascular Medicine 2026;13:1710507 — olanzapine pulmonary embolism ROR ~2.45 and venous embolism ROR ~5.67; clozapine VTE/PE risk; risperidone nursing-home VTE hospitalization HR 1.98; olanzapine/clozapine emerging non-label signals (suicidal behavior, QT prolongation, febrile neutropenia, hyponatraemia, myocarditis, aspiration pneumonia). https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2026.1710507/full
• De Hert M, et al. "Metabolic and cardiovascular adverse effects associated with antipsychotic drugs." Nature Reviews Endocrinology 2011;8:114–126 and Pillinger T, et al. "Atypical Antipsychotics and Metabolic Syndrome." Pharmaceuticals (MDPI) 2021;14(3):238 — metabolic-risk ranking: clozapine/olanzapine highest, quetiapine/risperidone/paliperidone intermediate, ziprasidone/lurasidone/aripiprazole lowest; CATIE olanzapine ~1 kg/month; ~12 kg over 1 year for olanzapine/clozapine. https://pmc.ncbi.nlm.nih.gov/articles/PMC8001502/
• US FDA, Drugs@FDA approval records — clozapine (Clozaril, 1989), risperidone (Risperdal, 1993), olanzapine (Zyprexa, 1996), quetiapine (Seroquel, 1997), ziprasidone (Geodon, 2001), aripiprazole (Abilify, 2002), paliperidone (Invega, 2006), asenapine (Saphris, 2009), iloperidone (Fanapt, 2009), lurasidone (Latuda, 2010), brexpiprazole (Rexulti, 2015), cariprazine (Vraylar, 2015), lumateperone (Caplyta, 2019). https://www.accessdata.fda.gov/scripts/cder/daf/