Evidence-Based Reviews

Rediscovering clozapine: Clinically relevant off-label uses

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Consider the evidence for bipolar disorder, borderline personality disorder, and more. Final of 3 parts.



Clozapine has been available for decades, but relatively little has been published regarding its off-label uses. This data shortage likely is due in part to clozapine’s strict monitoring requirements, and we suspect off-label use is more commonplace than the literature reflects.

Refractory schizophrenia and reduction in suicidal behavior in schizophrenia or schizoaffective disorder are clozapine’s 2 FDA-approved indications. Clozapine also may be prescribed for other indications, and off-label uses have varying degrees of scientific support.

Our goal in “Rediscovering clozapine” has been to deepen clinicians’ appreciation for this unique medication and provide practical clinical guidance for its safe and effective use.1,2 This final segment reviews representative literature regarding clozapine’s off-label use for bipolar disorder and other indications (Table).

Off-label uses of clozapine: Identified published evidence

At this point, clozapine still is generally most appropriate for use in refractory cases, regardless of the primary condition being treated. We suggest, however, that physicians should at least consider, “Why is clozapine NOT appropriate for this refractory patient?”

7 Steps define off-label use
Steps to consider when prescribing medications off-label

Seven steps are useful to consider when prescribing a medication off-label (Figure).3 Off-label prescribing is common in medicine and remains an important component of clinical practice. Sixty percent of antipsychotic prescriptions are written off-label,4 and physicians can prescribe any available medication to any patient for any purpose.

The FDA endorses off-label prescribing: “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.”5 Published case reports and case series provide guidance about the scientific support behind specific off-label indications.

Prescribing off-label based on clinical experience alone is legal, and 1 study reported that 73% of off-label prescriptions written by office-based physicians had little or no scientific support.6 From a medico­legal perspective, prescribing off-label with scientific support is preferred.

Bipolar disorder

Clozapine clearly is established as the most effective antipsychotic for treating refractory schizophrenia. A growing body of evidence supports the off-label use of clozapine for patients with bipolar disorder as well. This literature includes:

  • a randomized, open-label trial of maintenance treatment of refractory bipolar disorder7
  • 2 studies of treatment of acute mania8,9
  • a case series of 3 patients with refractory bipolar disorder and psychotic features who were effectively treated during acute manic episodes with ultra-rapid dose titrations of clozapine.10

In China, clozapine commonly is used to treat bipolar disorder. Results have been positive, and some clinicians there consider clozapine a first-line treatment for this indication.11

In the largest published study of clozapine’s benefits for bipolar disorder, a Danish group presented a retrospective analysis of 326 patients with bipolar disorder (and no history of a schizophrenia-spectrum disorder) treated with clozapine between 1996 and 2007. The study group displayed a significant and clinically relevant reduction in psychiatric hospitalizations, polypharmacy, and self-harm. The authors concluded that clozapine appeared to be an appropriate choice for refractory bipolar disorder and encouraged future investigators to consider randomized controlled studies.12

Major depressive disorder

Published evidence supporting clozapine’s use for refractory unipolar depression is less robust than the evidence for refractory bipolar disorder. One retrospective analysis comparing clozapine treatment for bipolar disorder and unipolar depression concluded that patients with bipolar disorder responded better overall.13

Most case reports involve psychotic depression. One case series discussed clozapine treatment of 3 patients with psychotic depression and reported significant improvement in both depressive and psychotic symptoms.14 Other case reports also described patients with refractory psychotic depression.15,16

We located only 1 case report about using clozapine for depressive symptoms absent psychosis. This case involved a patient who developed recurrent depression, hypersomnia, and behavioral disturbances at age 13 after a viral febrile infection. At age 27, she was hospitalized during an episode and started on low-dose clozapine. After discharge, she remained symptom-free for 30 months on clozapine, 50 to 100 mg/d. Although her symptoms included recurrent depression, her overall clinical picture seemed most consistent with Kleine-Levin syndrome (also known as “Sleeping Beauty” syndrome) rather than a primary mood disorder.17

Borderline personality disorder

Psychotherapy is the mainstay for treating borderline personality disorder (BPD), with pharmacotherapy often added to target symptoms such as anger and impulsivity.18 Some small studies and case series have examined clozapine use for BPD.

An open-label study of 15 inpatients with BPD and psychotic disorder not otherwise specified showed improvement on multiple rating scales with clozapine dosages averaging 250 mg/d.19 In a case series of 22 female inpatients with a primary diagnosis of BPD, clozapine showed beneficial effects in several clinical domains, including symptom severity and frequency of aggressive incidents. The greatest improvement occurred within the first 6 months of treatment.20

Eight patients who continued clozapine after hospital discharge had fewer and shorter subsequent hospitalizations than others with BPD who were not prescribed clozapine at discharge.21 Individual case reports have discussed benefits of clozapine in challenging BPD cases.22-24


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