Reversible Clozapine-Induced Antiphospholipid Syndrome

Clozapine has been linked to venous thrombotic events (VTEs), as a dose-independent collateral effect, with a 3-to 27.5-fold increased risk compared to the general population.^1–5 The risk is particularly higher during the first 3 months of treatment.⁶ Several pathophysiological mechanisms, not mutually exclusive, have been proposed for antipsychotic-associated VTE, such as drug-induced sedation, obesity, hyperleptinemia, hyperprolactinemia, hyperhomocysteinemia, enhanced platelet aggregation, and antiphospholipid antibodies.^2,7,8 Prolactin is a potent platelet aggregation coactivator. However, hyperprolactinemia is not expected to ensue with clozapine on account of its low D2 receptor affinity. Conversely, clozapine has a high affinity for the 5-HT_2A receptor; hence, serotonin-induced platelet aggregation may be affected, facilitating thrombosis.⁹ Other risk factors such as elevated homocysteine levels and smoking might also play a role.^2,10 We herein illustrate a case of clozapine-induced antiphospholipid syndrome (APS) complicated by a deep venous thrombosis (DVT) in a patient with no preexisting risk factors.

Case Report

A 68-year-old man, with a prior longstanding diagnosis of schizoaffective disorder, was admitted to our inpatient psychiatric unit for a psychotic episode characterized by disorganized behavior, messianic and ruin delusional ideas, and auditory hallucinations. Hematological and biochemical screening tests were unremarkable. Infectious serologies, comprising HIV, were negative. Computed tomography scan displayed mild chronic microangiopathic cerebral disease. Both vascular risk factors (such as dyslipidemia, cerebrovascular or thromboembolic events, cardiac disease, smoking or drinking habits) and history of venous thromboembolism in first-degree relatives were absent. His body mass index was 25.7 kg/m².

Initial treatment with risperidone, olanzapine, and electroconvulsive therapy was unsuccessful. Clinical improvement was eventually observed with clozapine, slowly titrated up to 150 mg/day, alongside aripiprazole (at 20 mg/day). Physical restraint was never needed. Although some degree of sedation ensued, the patient remained freely mobile.

Three weeks following clozapine commencement, a confusional state emerged. A DVT in the common femoral vein, with extension to the great saphenous vein, was documented by eco-Doppler. Therefore, enoxaparin treatment was started. Further investigational workup revealed increased levels of antiphospholipid antibodies (positive anti-β2-glycoprotein I [β2-GP1] immunoglobulin G [IgG] antibodies; positive lupus anticoagulant, 1.54 [<1.2] dilute Russell’s viper venom time screen ratio; negative anticardiolipin immunoglobulin M/IgG antibodies). Prolactin and homocysteine levels were within normal limits. Factor V Leiden mutation was negative. Malignancy was thoroughly ruled out.

Due to suspicion of clozapine accountability for APS and DVT, clozapine was deprescribed, and aripiprazole dosage was further increased. The patient was discharged in psychopathological remission, with aripiprazole at 30 mg/day and rivaroxaban at 20 mg/day. Six months later, anti-β2-GP1 IgG antibodies had disappeared, while lupus anticoagulant had remained positive.

Discussion

A complete disappearance of anti-β2-GP1 IgG antibodies was documented after clozapine withdrawal. Although these antibodies were negative in the second testing, the repetition of the antiphospholipid antibodies testing was performed much later than the 12-week window required to meet the criteria for APS. Moreover, they are seldom associated with false-positive results. Conversely, the persistence of the lupus anticoagulant should be ascribed to rivaroxaban, since it is accountable for false-positive results.¹¹ Therefore, the diagnosis of clozapine-induced APS was made upon the laboratory finding of the initial positive anti-β2-GP1 IgG antibodies, alongside the assumption that the DVT was attributable to an APS. The clozapine-induced APS eventually remitted after clozapine withdrawal, identically to other drug-induced APS cases.¹² Indeed, the clozapine carrier complex is known to act as an antigen, eliciting APS.^13,14

Psychiatrists should be aware of the dose-independent risk of VTE associated with clozapine and should consider deprescribing whenever suspicion of clozapine-induced APS arises. This case highlights the pertinence of undertaking antiphospholipid antibody monitoring during clozapine treatment. Nevertheless, further research on clozapine-induced APS is warranted to clarify its clinical impact and to recommend tailored guidelines to tackle this issue.

Article Information

Published Online: March 12, 2026. https://doi.org/10.4088/PCC.25cr04042
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(2):25cr04042
Submitted: July 12, 2025; accepted September 22, 2025.
To Cite: Regala J, André R, Reis J. Reversible clozapine-induced antiphospholipid syndrome. Prim Care Companion CNS Disord 2026;28(2):25cr04042.
Author Affiliations: Department of Geriatric Psychiatry, Júlio de Matos Hospital, São José Local Health Unit, Lisbon, Portugal (Regala, Reis); Institute of Anatomy, Lisbon School of Medicine, Lisbon, Portugal (Regala); Department of Psychiatry, Santa Maria Hospital, Santa Maria Local Health Unit, Lisbon, Portugal (André); University Clinic of Psychiatry and Medical Psychology, Lisbon School of Medicine, Lisbon, Portugal (André, Reis).
Corresponding Author: Joana Regala, MD, MSc, Júlio de Matos Psychiatric Hospital -São José Local Health Unit, Av. Do Brasil, Lisbon n° 53 1749-002, Portugal ([email protected]).
Relevant Financial Relationships: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report, and information has been de-identified to protect anonymity.
Acknowledgments: The authors thank Pedrina Sousa, MD (Clinical Immunology Laboratory, São José Hospital, São José Local Health Unit, Lisbon, Portugal), for assisting with clinical and scientific guidance.
ORCID: Joana Regala: https://orcid.org/0000-0001-5534-0326