Clozapine for Treatment-Refractory Behavioral Disturbance in Dementia

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Behavioral and psychological symptoms in dementia significantly contribute to caregiver burden and impose patient hospitalization. The goal of treatment of admitted patients is the rapid remission of symptoms to allow their return to home as soon as possible. Intervention requires an intrusive approach with parenteral treatment and physical restraints, with a negative emotional impact on patients and their families. Despite the large utilization of antipsychotics for behavioral and psychological symptoms, there is no antipsychotic approved by the Food and Drug Administration for agitation in dementia.

Study Question:

To evaluate efficacy and tolerability of clozapine in patients with treatment-resistant agitation associated with dementia.

Study Design:

Cohort study with 337 patients, admitted between January 1, 2012 and December 31, 2016, with dementia according to The Diagnostic and Statistical Manual of Mental Disorders 4th ed. criteria. Clozapine was given in standard titration, starting with 6.25 or 12.5 mg.

Measures and Outcomes:

Efficacy was measured by the need for physical restraints and time to discharge and tolerability by recording all side effects. Data collected included demographics, psychotropics used, physical restraints, length of stay, destination after discharge, and comorbidities.


Of 337 cases, 315 (93.5%) patients received antipsychotics. There were 27 cases treated with clozapine. Before clozapine initiation, haloperidol was given in 16 cases (55.17%, mean = 7.43 mg/d, SD = ±4.01), and the treatment was stopped mainly because of extrapyramidal side effects. Other antipsychotics used were quetiapine (mean dose = 260 mg/d, SD = ±54.77), risperidone (mean dose = 3.3 mg/d, SD = ±0.57), and olanzapine (mean dose = 8.33 mg/d, SD = ±2.88). Mean dose of clozapine was 59.16 mg/d, (SD = ±40.48), ranging from 12.5 to 200 mg/d. There were a lower number of physical restraints after clozapine initiation than before (12 vs. 34, P < 0.05).


Clozapine therapy seemed beneficial in treatment-resistant agitation in patients with dementia. The risk–benefit balance must be well weighed when clozapine is chosen. More studies are needed.

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