'How I Treat': Agitation Versus Mania In Alzheimer Disease Due to Medication Side Effects Case Presentation

Background: 

Ms Jane Doe is a 83-year-old divorced woman with a 13-year history of progressive neurocognitive impairment who currently lives at home alone.  She is a retired theater talent agent that had to leave the field after a period of homelessness, and diagnosis of bipolar I disorder.   Patient receives care from her daughter and son, who are acting powers of attorney.  She also has some in-home care, and assistance with medication management for parts of the week.  The patient was diagnosed with Alzheimer disease and is seen by providers in memory care.  Neurologists started donepezil, titrated the dose to 10 mg daily, and added memantine 5 mg with a plan to titrate over the next 4 weeks to 10 mg twice daily. 

About 2 weeks ago, the daughter received a change of dosing of the donepezil to 5 mg. Upon inquiring about this, she learned that the refill was an error and that the patient should have been continuing the 10 mg as previously prescribed.   

Presenting Issues: 

Ms Doe presents to the emergency department with family reporting concerns with increased manic behaviors.  The patient is now talking nonsensically, speech is rapid and pressured, and she has not slept in over 5 days.  Family reports that her dose of donepezil was supposed to be at 10 mg daily but was accidentally increased to 15 mg because insurance would not approve the dose. Instead, the patient was given 7.5 mg x 2 tablets.  Ms Doe became increasingly agitated and received 2 IM olanzapine doses, and an IM of lorazepam.  The patient was then admitted to the medical service, with a consultation to psychiatry. 

With initial evaluation patient continues to talk nonsensically, has rapid/pressured speech, A&0 to self only, requiring a sitter.  She does not appear agitated, but requires staff to keep her safe, and to prevent falls.  Family and Hospitalist service are seeking recommendations for possible manic episode.  They are unclear if this was predicated by the donepezil increase, or if this is reemergence of bipolar disorder. 

Medical and Psychiatric History: 

• Alzheimer disease (AD): Diagnosed about 13 years ago; cognitive decline with increasing memory deficits, particularly in short term memory.  Requiring assistance at home from family and home health nurses. 

• Bipolar I: Diagnosed about 20 years ago after patient had experienced a manic episode and became homeless.  Was on treatment for this until about the time the diagnosis was made for AD.  Patient has since been stable with no manic symptoms until recently. 

• Chronic Obstructive Pulmonary Disease (COPD): on medication management.  Working on smoking cessation.  

• Emphysema: Currently on treatment 

• Previous diagnosis of Parkinson disease, however daughter endorses this is no longer considered. 

• Stage 3 chronic kidney disease 

• Medications: Melatonin 2 mg nightly as needed, tiotropium 18 MCG inhale daily, Tylenol 325 mg four times a day as needed for pain, albuterol, inhale 2 puffs into lungs every 4 hours as needed for wheezing, donepezil 10 mg nightly (has been taking 7.5 mg twice daily), lovastatin 20 mg nightly, memantine 10 mg twice daily, and pyridoxine 100 mg by mouth every other day. 

• Prior medication history: haloperidol and lithium had been titrated off given CKD and no manic symptoms in years. 

Assessment of Agitation vs Mania: 

In Alzheimer disease, agitation is a common neuropsychiatric symptom that can manifest in many different ways.  Patients may suffer with symptoms of irritability, aggression, anxiety, or emotional lability.  Also, in bipolar disorder, agitation is also a common neuropsychiatric symptom that can manifest in a similar way. 

An important task with this conundrum is to conduct a good patient history.  Talking with family, getting collateral information, and assessing contributing factors is important. 

In this case, Ms. Doe’s agitation seems primarily linked to her medication change of donepezil.  She had been functioning normally within the context of AD, prior to the adjustment of medication.  She has also not had any breakthrough symptoms of mania except prior to her diagnosis of AD. Case studies have provided evidence that cognitive enhancers, while rare, can precipitate mania/psychotic symptoms in patients.  

Donepezil is an acetylcholinesterase inhibitor used in the mild-to-moderate phases of AD, Lewy body (DLB), and Parkinson disease dementia.  This medication has shown evidence to slow progression of some dementia symptoms and even improve hallucinations and other neuropsychiatric features of dementia. However, psychotic symptoms are also reported as adverse events occurring with donepezil treatment, even though the prescribing information of Aricept (donepezil, reference ID: 4365411), revised in December 2018, states that there are inadequate data to establish a causal relationship between donepezil and mania. 

The most appropriate treatment option would be Option E: All the above.  Given this is a new medication change, we need to make sure we conduct a complete assessment and analysis prior to making recommendations.  A psychiatric consult liaison provider is to make sure we have ruled out other possible contributing factors to an altered mental status. Geriatric patients including patients with AD can have higher incidence of electrolyte imbalances including hyponatremia and can run a higher incident of urinary tract infection or UTI. Where it does seem, the medication may have been the cause of Ms. Does' symptoms, we need to make sure that we have ruled out other possibilities.  

The next step would be collaboration.  Working in psychiatry, and particularly as a consult liaison, we coordinate with all the treatment teams to give the best possible care to our patients. Thís would include talking to our neurologist colleagues about the possibility that a cholinesterase inhibitor may have exacerbated patients' current symptoms. 

 Before we discuss nonpharmacological interventions, it is also crucial to make sure we have a discussion with treatment teams, nursing, and family regarding nonpharmacological strategies to manage agitation and dementia symptoms.  This continues to be the most effective intervention to help patients with the complexities of a major neurocognitive disorder. 

 The last step is medication management. We consider this when the patient continues to show symptoms to where they are putting not only themselves, but others in danger. In this case, I discussed discontinuing the donepezil, after I got back my CBC with Diff, CMP, CK, and UA.  These came back relatively non-concerning, which would point to the possibility of manic-like symptoms and altered mental status due to UTI or electrolyte imbalances.  

 When the patient did not show improvements over the next few days, and the patient continued to be agitated, showing symptoms of mania, I started brexpiprazole.  I didn’t start lithium which would normally be our go-to for mania, due to patient’s CKD stage three, and her CrCL levels were too low currently to safely start this.  To treat multiple aspects which included likely mania, in addition to underlying dementia and agitation, I chose brexpiprazole to target both of those concerns. I started this at a very low dose of 0.25 mg daily. I continued Melatonin at 2 mg nightly to target insomnia, with a backup of low dose trazodone at 25-50 mg as needed for breakthrough insomnia.   

Result: 

Patient calmed significantly the next day after starting the brexpiprazole.  The patient also did not require trazodone for sleep at night as she appeared to sleep well on the melatonin alone.  I continued collaboration with the neurology team so that they could follow up and discuss if it is appropriate to restart the donepezil.  I also worked with social work team, to set up patient with a geriatric psychiatrist to further help with management of bipolar disorder given recent relapse. 

Jonathan Williams, DNP, PMHNP-BC, CARN-AP, is a nurse practitioner with over 9 years of experience in psychiatry. Jonathan has worked in various healthcare settings throughout his psychiatric career, starting at a FQHC in underserved northern Wisconsin in outpatient practice, later transitioning into the inpatient and consult liaison work back with his alma mater, University of Wisconsin Madison. Currently, Jonathan works part time as APP Supervisor for UW AODA and Psychiatric Providers, and back to the ambulatory world working with adults. Jonathan had a love for education, and under the guidance of Andrew Penn, he started to develop lectures and presentations about how cannabis and affects mental health, as well as other important psychiatric questions and innovations. He has recently completed an additional specialty in Addiction Medicine by obtaining his CARN-AP. He aspires to continue deep connection with research to demystify many existing unknowns in psychiatry and mental health treatment. 

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