Management of Neuropsychiatric Symptoms of Dementia: Spotlight on QTc Prolongation

Neuropsychiatric symptoms (NPS) are common in individuals with dementia, affecting almost 97% of individuals with Alzheimer's disease (AD) over the course of their illness (1). NPS include depression, anxiety, delusions, hallucinations, and sleep changes and are associated with poor quality of life, earlier institutionalization, increased mortality, impaired activities of daily living (ADLs), and patient and caregiver distress (1).

Although the Food and Drug Administration has not approved any medications for the treatment of psychosis in dementia, second-generation antipsychotics are often used when nonpharmacological interventions have failed or when symptoms cause significant impairment (2, 3). Antipsychotics are associated with increased risk of cerebrovascular events in older adults and increased risk of mortality in patients with dementia-related psychosis, resulting in a black box warning. Antipsychotics may prolong QTc interval, increasing the risk of ventricular tachyarrhythmias, including torsades de pointes (TdP) (4). Sertindole and thioridazine have the highest risk of QTc prolongation (Table 1) and were discontinued worldwide following concerns over sudden death from QTc prolongation (4).

Aripiprazole is used off-label for psychosis in dementia, and according to certain studies, it has a lower risk of QTc prolongation (2). We present the case of an elderly female with newly diagnosed dementia and NPS leading to a psychiatric admission and the cautious use of aripiprazole in managing NPS, given her cardiac comorbidities.

Case

An 83-year-old Caucasian female with no psychiatric or neurologic history presented to the emergency department with a 4-month history of depressed mood, insomnia, apathy, and a 1-week history of auditory hallucinations commanding her to stab her sister. Three days prior to presentation, the patient filled her bathtub with the intent of drowning herself to escape these hallucinations, but she aborted the attempt. In the emergency department, the patient denied suicidal and homicidal ideation, but she was worried about acting on the auditory hallucinations and stabbing her sister, with whom she lived.

The patient's medical history was significant for hypertension, diabetes mellitus, dilated cardiomyopathy with implantable defibrillator, and atrial fibrillation. Family history was negative for affective or psychotic disorders, and the patient had no history of substance use. The patient's sister confirmed that the patient had appeared depressed for the past month. The patient's sister and primary care physician both denied past episodes of depression, mania, psychosis, and suicidal ideation or attempts.

On admission, the patient's mental status exam was significant for depressed mood, congruent affect, and auditory hallucinations without overt delusions. The patient was alert and oriented, well related, with reactive mood and linear thought process, without signs or symptoms of delirium. The Montreal Cognitive Assessment (MoCA) score was 22/30, with deficits in executive functioning, working memory, and recall. Her vital signs, hematologic, and biochemical panels were within normal ranges. Initial EKG recorded a ventricular-paced rhythm at 83 bpm with a QTc of 509 ms, and prior EKGs showed QTc ranging between 514 and 545 ms. Neuroimaging was limited to head CT because of the patient's MRI-incompatible cardiac defibrillator, and it showed diffuse parenchymal volume loss greater than expected for the patient's age, without acute changes.

The patient was admitted to the medical floor where additional labs, including B12, folate, and syphilis screening, were unremarkable. A working diagnosis of dementia with psychotic features and mood disorder was made. The severity of the patient's symptoms warranted pharmacological management despite the potential risk of QTc prolongation, and quetiapine 12.5 mg by mouth at bedtime was started, with daily EKG monitoring (5). QTc increased to 523 ms on postadmission day (PAD) 2. Quetiapine was discontinued, and mirtazapine 7.5 mg at bedtime was started for depressive symptoms. The cardiology service was consulted and determined that the patient's QTc of 511 ms was artificially increased by her permanent pacemaker and manually measured it at 430 ms, thereby giving clearance to resume antipsychotics. On PAD 8, risperidone 0.25 mg twice daily was initiated, and mirtazapine was discontinued.

On PAD 10, the patient's QTc increased to 549 ms. Risperidone was discontinued, and aripiprazole 5 mg daily and sertraline 50 mg daily were started due to their lower association with QTc prolongation. The patient's mood and sleep improved, but command auditory hallucinations and intermittent suicidal thoughts remained, necessitating transfer to the inpatient psychiatry unit on PAD 12. The repeat MoCA score was 23/30. Aripiprazole was increased to 5 mg twice daily on PAD 17 (QTc 522 ms), with improved mood, resolution of suicidal ideation, and decreased auditory hallucinations by PAD 29 (QTc 511 ms).

The patient struggled with ADLs and was discharged to a skilled nursing facility. On the basis of deficits in executive functioning, working memory, and recall with preserved anterograde memory, as well as the severity of neuropsychiatric symptoms and functional impairment, the diagnosis was updated to major neurocognitive disorder. The patient's low mood and suicidal thoughts appeared to be in response to distressing command auditory hallucinations, and they improved when her hallucinations decreased. In addition, her mood improved within 2 weeks of initiating low-dose sertraline, making a primary mood disorder less likely.

Discussion

We presented a case of new-onset auditory hallucinations in an elderly female and its management with low-dose aripiprazole. Although the patient had not been diagnosed with dementia previously, testing consistently indicated neurocognitive impairment. NPS can present before cognitive symptoms of dementia become prominent, and the patient's auditory hallucinations were likely NPS of dementia.

The Neuropsychiatric Inventory (NPI) evaluates neuropsychiatric symp​toms common in dementia (6). A meta-analysis of studies using the NPI found that apathy was the most common NPS, followed by depression, aggression, anxiety, sleep disturbances, delusions, hallucinations, and euphoria (7). Up to 41% of patients with dementia may experience hallucinations (7). Although first-line treatment for NPS is nonpharmacological, our patient's hallucinations caused her significant distress and impairment, warranting pharmacological intervention.

The first-generation antipsychotic haloperidol is effective for the positive symptoms of psychosis in dementia at doses up to 1.5 mg daily (3). Because of risks of extrapyramidal effects and cardiotoxicity, it is not preferred at higher doses (3). QTc prolongation depends not only on the medication but also on individual risk factors, including female gender, age >65 years, myocardial hypertrophy, electrolyte disturbances, and rapid infusion of the drug (8). Aripiprazole and oral haloperidol are associated with the lowest risks of QTc prolongation (4, 9) (Table 1). The intravenous (IV) form of haloperidol may prolong QTc significantly more than the oral formulation (10). In a cross-sectional study of 1,017 healthy adults with schizophrenia, IV (but not oral) haloperidol was associated with QTc prolongation (11). However, IV haloperidol is used relatively more frequently in medically ill individuals—who may be at a higher risk of QTc prolongation—and the oral formulation is used more frequently in medically healthy adults with psychosis (10).

Systematic evidence for QTc prolongation with second-generation antipsychotics is limited (10). Aripiprazole may be effective for NPS and may offer a safer side-effect profile related to EPS, weight gain, and anticholinergic and cardiovascular adverse events (2). Our patient was first given quetiapine for hallucinations, which was discontinued because of QTc prolongation, followed by risperidone, which was similarly discontinued. Although QTc interval is only modestly associated with TdP, it is the best available predictor, and medication discontinuation is recommended for QTc >500 ms (8). Our patient had additional risk factors, including female gender, age >65 years, and cardiac comorbidities, leading us to titrate antipsychotics cautiously. Finally, the patient was treated with aripiprazole and showed a reduction in hallucinations and improvement in functioning without QTc prolongation, consistent with published literature (5).

Conclusions

Antipsychotics may be used judiciously for the management of auditory hallucinations in dementia. Physical comorbidities, polypharmacy, and drug interactions may make older individuals more vulnerable to the side effects of antipsychotics. This case illustrates the use of antipsychotics in managing NPS in a patient with cardiac comorbidities and the relatively low risk of aripiprazole for QTc prolongation. Presently, there are few effective treatments for NPS in dementia. Careful use of antipsychotics may be helpful in managing these symptoms.

Key Points/Clinical Pearls