CGPR: Clinicians often struggle with initiating medications for memory impairment in people with dementia. Can you describe your approach to treatment?

Dr. Mukaetova-Ladinska: Although breaking the news to a patient or relative is challenging, discussing dementia often comes as a relief. A diagnosis helps explain why a patient is experiencing symptoms, and it opens the door to discuss expectations and management. We use a “person-centered approach” that focuses on a patient’s abilities, not their condition. In introducing and adjusting medications, I inform patients about their medication options, including formulations (tablet, liquid, or patch) and their benefits and limitations. 

CGPR: In patients with Alzheimer’s disease, when do you start a cholinesterase inhibitor or memantine?

Dr. Mukaetova-Ladinska: The National Institute for Health and Care Excellence (NICE) guideline for 2018 recommends all three acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine) as options for managing mild to moderate Alzheimer’s disease. They are not approved for mild cognitive impairment. Memantine is recommended for people with moderate or severe Alzheimer’s disease, either alone or as an adjuvant therapy for people already taking a cholinesterase inhibitor. The cumulative evidence shows that the effects of anti-dementia medications on cognition are relevant for at least two years (Farlow MR, Int J Clin Pract Suppl 2002;(127):37–44). A recent study confirmed that all cholinesterase inhibitors decrease long-term cognitive decline and risk of death in people with Alzheimer’s disease, but galantamine was the only anti-dementia medication associated with a significant reduction in the risk of developing severe dementia (Xu H et al, Neurology 2021;96(17):e2220–e2230). Increasing evidence suggests that both cholinesterase inhibitors and memantine may help in the management of behavioral and psychological symptoms of dementia (BPSD).

CGPR: When do you consider the use of cholinesterase inhibitors in non-Alzheimer’s dementia?

Dr. Mukaetova-Ladinska: There is good evidence that cholinesterase inhibitors are effective and safe in people with Lewy body dementia or dementia due to Parkinson’s disease. The NICE guideline recommends the use of cholinesterase inhibitors for the treatment of mixed dementia, but not for vascular dementia alone, nor for frontotemporal dementia, as they may worsen symptoms in the latter. 

CGPR: What side effects do clinicians need to be aware of when initiating these medications?

Dr. Mukaetova-Ladinska: The most frequent side effects of cholinesterase inhibitors are nausea and vomiting, diarrhea, muscle cramps, headaches, dizziness, appetite loss, vivid dreams, nightmares, and skin reddening. With memantine, they are dizziness, drowsiness, constipation, and headaches. Some patients may develop delirium. We can minimize these side effects by initiating at low doses and slowly titrating to the therapeutic dose. Some side effects, like nausea, can be managed by changing the timing or by switching to a transdermal formulation. There are a few serious side effects with anti-dementia medications, including bradycardia, syncope, hypotension, and significant weight loss. 

CGPR: There’s controversy in the field over when it’s appropriate to discontinue dementia medications. What are your thoughts?

Dr. Mukaetova-Ladinska: I would approach the discussion of discontinuation if a patient experiences serious side effects or is in the end stages of dementia. However, we should not stop anti-dementia drugs in patients with moderate dementia simply because the disease appears to be gradually worsening. Discontinuation feels risky, especially in people who are still functioning fairly well and who have been relatively stable. Stopping the medication may worsen a patient’s psychological well-being and physiological state, and it contributes to caregiver stress. There are a range of problems associated with medication discontinuation, including behavioral problems and a higher rate of requiring 24-hour care. 

CGPR: How do you decide which nonpharmacological treatments to start first in the treatment of BPSD?

Dr. Mukaetova-Ladinska: To treat BPSD nonpharmacologically, you have to know the patient with dementia well. Their personality and life experiences will influence their response to treatment. 

CGPR: Which interventions have evidence behind them?

Dr. Mukaetova-Ladinska: The use of lifelike dolls or soft toy animals has been shown to benefit patients with dementia, particularly those with behavioral problems living in residential care. They may care for the “baby” or watch sports with their “grandson” sitting on their lap. Dolls or soft toys promote feelings of relaxation, pleasure, belonging, and responsibility. Sensory stimulation interventions can positively affect behavior, and patients with dementia benefit most when they are provided stimulation on a one-to-one basis. These interventions include music, light therapy, acupressure/reflexology, massage, Snoezelen therapy (a toolbox of equipment to meet different sensory needs), aromatherapy, and gustatory and tactile stimulation. They should be incorporated into daily programs and should not be used on an ad hoc basis, as the cessation of sensory stimulation sessions can have negative withdrawal effects. 

CGPR: What about music and art therapy?

Dr. Mukaetova-Ladinska: “Singing for the brain,” an intervention based on group singing activities, was developed by The Alzheimer’s Society for patients with dementia and their caregivers. Virtual singing services are available for a fee via the internet or over the telephone (for an example, see Ring and Sing: www.store.listenlearnmusic.com/product/ring-and-sing/). This type of musical activity has been found to improve relationships, memory, and mood, as well as acceptance of and coping with a dementia diagnosis. There is also evidence behind art therapy. In a recent systematic review by our group, we identified four outcome domains when using creative art therapies: well-being, quality of life, BPSD, and cognitive function. These interventions incorporate elements of being “in the moment,” and they increase opportunities for communication between patients and their caregivers (Emblad SYM and Mukaetova-Ladinska EB, J Alzheimers Dis Rep 2021;5(1):353–364).

CGPR: Are there any additional interventions that can supplement these therapies?

Dr. Mukaetova-Ladinska: Mobile applications can assist patients with brain training and improve their working memory (Klimova B and Valis M, Front Aging Neurosci 2018;9:436). In instances when technological devices are not applicable, engaging in creative therapies such as knitting, painting, pottery, or basket weaving can structure the day and combat boredom and apathy. I’ve also learned about how to incorporate oxygen therapy, yoga, meditation, Ayurveda, physical activities, and diet into treatment. 

CGPR: When should we choose antipsychotics to treat agitation in patients with dementia?

Dr. Mukaetova-Ladinska: Before starting nonpharmacological or pharmacological treatment, we need to explore the possible reasons for a patient’s distress. A patient should only try an antipsychotic if they are at risk of harming themselves or others, or if they are experiencing agitation, hallucinations, or delusions causing severe distress. Antipsychotics should be used at the lowest effective dose and for the shortest period of time. The patient should be assessed at least every six weeks, and the antipsychotic should be discontinued if it is unhelpful or no longer needed. I speak with patients about adverse effects including sedation, Parkinsonism, an increased risk of infections and falls, and an increased risk of cardiovascular adverse events and death. 

CGPR: What is the evidence for using antidepressants such as SSRIs, mirtazapine, and trazodone to treat agitation in dementia? 

Dr. Mukaetova-Ladinska: Among these medication classes, SSRIs have the best evidence. In a 2011 Cochrane review, sertraline and citalopram were associated with a reduction in symptoms of agitation when compared to placebo in two studies (Seitz DP et al, Cochrane Database Syst Rev 2011;(2):CD008191). Mirtazapine is a commonly used alternative, especially in lower doses. However, in the recent SYMBAD study, mirtazapine failed to show benefit as a treatment for agitation in dementia (Banerjee S et al, Lancet 2021;398(10310):1487–1497). Trazodone is sedating and has a low rate of adverse effects. It may improve agitation, aggressiveness, and compliance with care acceptance, but it has not been associated with a statistically significant benefit for BPSD. It is also cardiotoxic and should be used with caution in older adults with heart arrhythmias or cardiovascular disease. 

CGPR: What about anticonvulsants for agitation?

Dr. Mukaetova-Ladinska: Although anticonvulsants, especially valproate, are still commonly used to treat agitation, the evidence suggests that they are not effective in treating BPSD. A randomized controlled trial and meta-analysis of valproate did not support its use in treating agitation in dementia (Gallagher D and Herrmann N, Drugs 2014;74(15):1747–1755). Furthermore, valproate can aggravate BPSD and can cause confusion and memory impairment. 

CGPR: Is melatonin helpful in patients with BPSD?

Dr. Mukaetova-Ladinska: Altered circadian rhythm can aggravate BPSD in patients with dementia. Melatonin on its own or in combination with light therapy at bedtime may be useful in treating altered night sleep, “sundowning,” or daytime sleepiness. In several randomized controlled studies, melatonin has also been shown to be effective for the treatment of dementia-related behavior disturbances, but not for the treatment of cognitive impairment. 

CGPR: What are your thoughts about scheduled pain protocols in the management of agitation?

Dr. Mukaetova-Ladinska: Pain is one of the major contributors to agitation (Achterberg WP et al, Clin Interv Aging 2013;8:1471–1482). One study showed that agitation, as well as the overall severity of neuropsychiatric symptoms in patients with moderate to severe dementia, improved with paracetamol (acetaminophen) (Husebo BS et al, BMJ 2011;343:d4065). I don’t think that paracetamol is a “cure” for agitation per se; it could be that regulating the pain in study participants contributed to improvement in cognitive performance and BPSD. 

CGPR: Apathy is often mistaken for depression. How do you distinguish between the two? 

Dr. Mukaetova-Ladinska: Apathy is present in nearly half of patients with dementia and becomes more prominent in the later stages. Whereas depression is characterized by the presence of low mood, guilt, early morning awakenings, and so on, people with apathy lack motivation and interest. They may rely on others to suggest and organize activities, or seem detached from events. 

CGPR: How do you approach the management of apathy? Do you trial antidepressants?

Dr. Mukaetova-Ladinska: I prefer nonpharmacological approaches such as arts, reminiscence (revisiting moments of a patient’s past), and cognitive stimulation. People with apathy may benefit from establishing a daily routine consisting of enjoyable and meaningful tasks and activities. Antidepressants do not provide benefits in treating apathy, and in some instances they may worsen it. Emotional blunting is one of the major adverse effects of antidepressants. 

CGPR: What about using memantine or stimulants for apathy?

Dr. Mukaetova-Ladinska: Dopaminergic dysfunction in certain brain areas is an important correlate of apathy in Alzheimer’s disease. Memantine may help with motivation in moderate or severe dementia by stimulating the dopamine receptor, causing a dose-dependent increase in dopamine. However, in mild Alzheimer’s disease, memantine is probably no better than placebo (McShane R et al, Cochrane Database Syst Rev 2019;3(3):CD003154). The NICE guideline does not recommend using stimulants to treat apathy. However, a recent trial suggested that methylphenidate may decrease apathy, although it did not improve quality of life (Mintzer J et al, JAMA 2021;78(11):1324–1332).

CGPR: Antidepressants haven’t performed very well in clinical trials for depression in patients with dementia. What are your thoughts about this? 

Dr. Mukaetova-Ladinska: The 2018 NICE guideline recommends psychological treatments for patients with dementia and mild to moderate depression and/or anxiety. We should not routinely offer antidepressants unless they are indicated for a preexisting severe mental health problem. Antidepressants can be considered in severe depression, or in depression not managed through nonpharmacological means alone. Many antidepressants also have “added benefits,” such as stimulating appetite. Mirtazapine, in particular, seems to be a useful approach to counteract weight loss in Alzheimer’s disease. In advanced dementia, greater neurotransmitter loss may be reflected in serotonergic dysfunction in the gastrointestinal tract, and SSRIs can be helpful in managing symptoms such as constipation. This is important, as constipation is a risk factor for delirium and can worsen cognition in patients with dementia. 

CGPR: Thank you for your time, Dr. Mukaetova-Ladinska.