The National Institutes of Health estimates that there will be 8.5 million Americans with Alzheimer disease by the year 2030.1 Behavioral and psychological symptoms in dementia significantly contribute to caregiver burden, frequently impose patient hospitalization, and have been associated with adverse outcomes and increased health care costs. These neuropsychiatric symptoms include agitation, aggression, screaming, intrusive behaviors, sexual disinhibition, wandering, night-time disturbance, shadowing, swearing, irritability, and euphoria. These symptoms often occur in patients with Alzheimer disease, Huntington disease, and Parkinson disease.2–4
Increasingly, atypical antipsychotic drugs are prescribed for elderly patients with symptoms of psychosis and behavioral disturbances. Current guidelines recommend using risperidone and olanzapine to treat psychosis in patients with Alzheimer dementia. Quetiapine and clozapine are recommended for the treatment of psychosis in patients with Parkinson disease.4,5
The goal of treatment for behavioral and psychological symptoms of admitted patients with dementia is the rapid remission of symptoms to allow their return to home as soon as possible. Intervention often requires an intrusive approach with parenteral treatment and physical restraints, with a strong negative emotional impact on patients and their families.6 The use of antipsychotics in dementia is reaching high rates despite the warning of deaths provided by the Food and Drug Administration (FDA). In a recent study based on autopsy findings, a direct association between haloperidol use and sudden death in dementia could not be made.7 Other results show that older adults with dementia who take atypical antipsychotics have a similar risk of ischemic stroke compared with those taking typical antipsychotics.8
The Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease trial confirmed that agitation associated with dementia was difficult to treat in 421 outpatients.9
To our knowledge, there are no studies investigating clozapine for the treatment of severe agitation in dementia, excepting case reports.
The project was approved by the Ethics Committee of the Psychiatry and Neurology Hospital, Brasov, Romania, and the research was conducted in accordance with the ethical standards for observational research. Patients or their legal representatives provided written informed consent for anonymous data processing and analysis.
The aim of the study was to evaluate efficacy and tolerability of clozapine in patients with treatment-resistant agitation associated with dementia.
A retrospective chart review of 337 patients, mean age 76.16 ± 9.82 years, 37% men, consecutively admitted to the Psychiatry and Neurology Hospital, Brasov, Romania between January 1, 2012 and December 31, 2016, with the diagnosis of dementia according to the Diagnostic and Statistical Manual of Mental Disorders (4th edition) (DSM-IV) criteria. The main reasons for admission were aggressive behavior, agitation, and psychosis.
Data were collected from charts, covering the period between 2012 and 2016, during routine clinical care in the Psychiatry and Neurology Hospital, Brasov, Romania. This hospital is a public care facility, which covers a population of 400,000. The admission ward is a 120-bed facility with 24-hour service of board-certified psychiatrists. Antipsychotic choice during the admission was however the sole responsibility of the psychiatrist. Clozapine was initiated for severe agitation as a third intention after first- or second-generation antipsychotics. Treatment was given in standard titration, starting with 6.25 or 12.5 mg as a monotherapy without any concomitant medication, except those for medical comorbidities or dementia.
Based on previous experience with clozapine for treatment-resistant schizophrenia and treatment-resistant manic episode in bipolar disorder, clozapine was given as “the last resort” for refractory behavioral disturbance in dementia. Treatment resistance was defined as the lack of or insufficient response to trials of at least 2 antipsychotics given at the recommended doses for behavioral disturbance.
MEASURES AND OUTCOMES
Efficay of clozapine was evaluated by measuring the need for physical restraints and the time to discharge (length of stay). Tolerability was evaluated by recording all side effects and the need for treatment discontinuation because of side effects. We used standard tools for clinical evaluation: Mini-Mental State Examination for cognitive status, the Neuropsychiatric Inventory Questionnaire for behavioral and psychological symptoms, the Clinical Global Impression scale for severity, and the Global Assessment of Functioning scale. Data collected included demographics, education, marital status, reason for admission, all psychotropics used, physical restraints, length of stay, destination before and after discharge, comorbidities, and side effects.
Two-sided tests with alpha 0.05 were used without correction for multiple comparisons because of the purely descriptive nature of the study.
Of 377 cases, 315 (93.5%) patients received antipsychotics. There were 154 (48.8%) cases treated only with haloperidol. In 27 cases, clozapine was indicated as the third treatment option.
Before clozapine initiation, haloperidol was given in 16 cases (55.17%, mean = 7.43 mg/d, SD = ±4.01), and the treatment was stopped because of extrapyramidal side effects or lack of efficacy. Other antipsychotics used before clozapine were quetiapine (n = 5, mean dose = 260 mg/d, SD = ±54.77), risperidone (n = 3, mean dose = 3.3 mg/d, SD = ±0.57), and olanzapine (n = 3, mean dose = 8.33 mg/d, SD = ±2.88). Mean dose of clozapine was 59.16 mg/d (SD = ±40.48), with dose ranging from 12.5 to 200 mg/d.
Concomitant medications used with antipsychotics before clozapine were benzodiazepines (diazepam, lorazepam, and nitrazepam, n = 20), mood stabilizers (valproic acid, n = 16), hypnotics (zopiclone and zolpidem, n = 12), and antidepressants (trazodone, n = 5). Concomitant psychotropic use was lower after clozapine initiation than before (12 vs. 46, P < 0.01).
The side effects of clozapine included drooling (n = 4), constipation (n = 3), and sedation (n = 4). There were no severe adverse events such as seizures, myocarditis, or agranulocytosis during the treatment and no cases of treatment discontinuation because of clozapine-related side effects. Physical restraint was used for all violent and dangerous patients in the emergency department for their own protection and for the protection of others, concomitant with the pharmacological treatment. The number of physical restraint episodes after clozapine initiation was lower than before (12 vs. 34, P < 0.05).
Most patients (21 from 27, 77.7%) were considered “much improved” or “very much improved” after clozapine initiation. The patients were considered “ready to discharge” as soon as they were stable, with no need for restraint or for increasing the antipsychotic dose.
In most cases, clozapine was not given at discharge, and the patients continued with another antipsychotic, mainly because of nonreimbursement of clozapine for dementia. Clinical features of the 27 patients treated with clozapine are shown in Table 1.
The major finding of this study was that clozapine might be a good option in the treatment-refractory behavioral disturbance in dementia. This is the first study with a significant number of patients treated with clozapine for this condition. The use of clozapine on label and off label and the apparent underutilization of clozapine remain a controversial issue in clinical psychiatry.10 Off-label drug use commonly refers to prescribing currently available medication for an indication (disease or symptom) for which it has not received FDA approval.11,12 The mean clozapine dose in our study was higher than the dose reported as efficient in another study13 but lower than those used in 1 case report.14
Use of atypical antipsychotics for the following off-label conditions has been documented in the scientific literature: intellectual disability, attention-deficit hyperactivity disorder, anxiety, dementia, depression, eating disorders, insomnia, obsessive–compulsive disorder, personality disorder, posttraumatic stress disorder, substance use disorders, Tourette syndrome, and autism spectrum disorder. Risperidone, quetiapine, and olanzapine are the most common atypicals prescribed for off-label use.15,16
Off-label use of atypical antipsychotics in various settings increased rapidly after their introduction in the 1990s. All antipsychotic medications carry a black-box warning of increased risk of death compared with placebo in patients with dementia.17 A recent study concluded that the use of atypical antipsychotics decreased in the United States, especially among elderly patients with dementia, after the FDA advisory.
Compared with other population groups, the use of atypical antipsychotics among the elderly has been given more attention, probably because of the widespread use of these drugs in dementia and Alzheimer disease 18 and the fatal risk reported with this use. An update of the off-label use of antipsychotics reported that 25% of the elderly nursing home population received antipsychotics, most often second-generation antipsychotics.19
We prescribed clozapine as “a last resort” to reduce the number of restraints and the total time of restraint, as well as for agitation and violence. Restraint still remains a worldwide overused method in dementia with behavioral and psychological symptoms in the absence of a specific treatment. A review from 2002 found that between 3.4% and 21% (a mean of 10%) of acute care patients were subject to some form of physical restraint during their period of hospitalization20, and more recently, the rate was updated to 44.5%.21 In our study, clozapine significantly reduced the need for restraint in patients with dementia.
There is a lack of data on “patients with refractory dementia,” whereas e the literature on “refractory psychosis” and “refractory mania in bipolar disorder” with well-documented results may be found.22,23 Therapeutic strategies to reduce violence in patients with dementia suffer from a lack of guiding information from randomized studies, and prospective studies are methodologically highly limited because of an inherent selection bias related to informed consent in a predominantly uncooperative study group. Informed consent is a principle that is observed to ensure that patient autonomy is preserved, requiring that competent patients are made aware of and understand enough about the intended benefits and possible risks of the proposed treatment to make an informed decision.24,25
One of the broadest and generally accepted exceptions to the informed consent rule is that a physician is not under a duty of disclosure in cases in which it is reasonably believed that disclosure to the patient would pose a serious threat to the patient's well-being.26
This study has limitations that are inherent to the naturalistic and nonrandomized design. First limitation of the study is the apparent small number of patients treated with clozapine. The second limitation is the retrospective chart review character of the study. Despite those, given the lack of data in the literature, the clinical meaning of the findings is very important for psychiatrists. Further studies are necessary to validate our results.
The group of patients with dementia with treatment-resistant agitation represented one of the most challenging cases in emergency psychiatric units. Comorbid medical conditions and side effects of psychotropic medication even at low doses are factors that must be taken into account. We have to report that clozapine was used as an off-label choice for the treatment of severe agitation in dementia. Controlled clinical trials of clozapine are needed to assess its efficacy and safety in dementia.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
dementia; antipsychotics; clozapine; agitation