Do’s and Don’ts of Psychopharmacology in Late Life: Key Challenges and Opportunities

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When working with older individuals with psychiatric symptoms, most clinicians are familiar with the adage “start low and go slow” to guide their prescribing. This refrain has often been augmented with the phrase “but do go” to emphasize the importance of not stopping too early in the titration process. What are the roots of this approach? And, how should it unfold when applied to 3 common psychiatric disorders seen in later life: neurocognitive disorders, depression, and anxiety?

The impact of aging on drug metabolism

The first principle of prescribing any medication in later life is to appreciate important changes in drug metabolism due to aging organ systems. In terms of pharmacokinetics (ie, what the body does to the drug), absorption time is generally stable since decreases in intestinal absorption are offset by increased transit time; distribution varies by type of drug since increased body fat and decreased body water lead to increased volume of distribution for lipophilic drugs and decreased for hydrophilic drugs; bioavailability is increased for many drugs since there is upwards of a 30% reduction in initial hepatic metabolism; and half-lives are often lengthened since renal excretion is slowed by up to 50%.1 In terms of pharmacodynamics (ie, what the drug does to the body), drug response is less predictable due to alterations in receptor sensitivity, neuronal loss, and changes in key cholinergic and serotonergic pathways. In addition, older individuals tend to be more sensitiveto drug effects and may require lower doses, especially with opioids, anesthetics, and benzodiazepines. Some of the most concerning side effects are due to anticholinergic, antihistaminic, extrapyramidal, and sedating properties of medications.

One major guideline for safe prescribing in later life is The Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, also called the Beers List, which was first developed in 1991 by geriatrician Mark Beers, MD. The list highlights medications that pose undue risk for negative outcomes, including falls, injuries, and even death.2 Since 2011, the American Geriatric Society have been revising and updating the list based on both consensus and evidence-based approaches. With these considerations in mind, we can explore several psychiatric conditions frequently seen in older individuals who have multiple comorbid conditions and polypharmacy.

Neurocognitive disorders

There are no cures nor disease-modifying treatments for Alzheimer disease, aside from several experimental agents. Instead, there are 2 categories of medications that are US Food and Drug Administration-approved to improve its symptoms. These include 3 acetylcholinesterase inhibitors (AChEIs) that are indicated for mild-to-severe Alzheimer such as donepezil, rivastigmine, and galantamine; and 1 NMDA (glutamate) receptor antagonist called memantine for moderate-to-severe Alzheimer. There is also evidence that these agents can improve symptoms in Lewy body dementia and vascular dementia.

Here are several key do’s and don’ts to keep in mind when prescribing these medications:

- Do keep expectations modest; the goal is symptomatic improvement and not curing the disease.

- Don’t promise disease slowing, but educate patients and caregivers about realistic expectations and side effects.

- Do start with the lowest dose and titrate slowly, per guidelines.

- Don’t combine multiple acetylcholinesterase inhibitors.

- Do combine acetylcholinesterase inhibitors with memantine as the disease progresses into moderate and advanced stages.

- Do monitor closely for important side effects of AChEIs such as nausea, vomiting, diarrhea, nightmares, or slowed heart rate; and sedation, dizziness or confusion with memantine use.

- Do start early. The later in the disease course you initiate use of cognitive enhancers, the less benefit you may see. Remember that studies have shown significant symptomatic benefit even in moderate-to-severe disease states.

Late-life depression

Treating older individuals with depression poses unique challenges and considerations. Various forms of late-life depression affect 9% to 18% of individuals older than 55, and these rates increase significantly after the age of 85, especially for individuals in nursing homes and hospitals. On the other hand, the more serious and specific diagnosis of major depressive disorder is less prevalent than in younger individuals, with rates of 2% versus 6% to 7%.³

Depression can have significant impacts on our bodies by accelerating brain aging and increasing the risk for medical conditions such as diabetes mellitus, cancer, neurocognitive disorders, and both cardiovascular and cerebrovascular disease and events. Risk factors associated with late-life depression include female gender, chronic medical illness, neurocognitive impairment, functional impairment, social isolation, and major life stresses. In many older individuals, depression may present with less mood-related symptoms and more physical or functional complaints and social issues, including fatigue, weight loss, pain, social isolation, resistance, agitation, self-neglect, and substance use. Up to 30% of older individuals with depression may have impairment in executive dysfunction, often due to vascular damage to frontolimbic white matter tracts. This “depression executive dysfunction syndrome,”as described by George S. Alexopoulos, MD, is notable for a poorer response to antidepressants and cognitive-behavioral therapy, earlier relapse, and a greater risk for recurrence.⁴

In terms of selecting an antidepressant for older individuals, there is no favored agent based on multiple studies and meta-analyses, but they all work better than placebo.⁵ In general, individuals older than 55 years have slightly lower response rates and higher relapse rates compared to younger individuals.⁶

Augmentation strategies that have shown efficacy for late-life depression include the use of antipsychotics, lithium, and methylphenidate. The addition of acetylcholinesterase inhibitors may help improve cognitive deficits, but they have not been shown to be helpful for depressive symptoms. Although antidepressants can improve depression and quality of life associated with medical illnesses, they do not clearly improve the medical conditions themselves. The exception of this is post-myocardial infarct depression, for which they may reduce the risk of recurrent cardiac events, procedures, and overall mortality.⁷

Late-life anxiety disorders

Anxiety disorders are very common conditions in late life, affecting 1.2% to 28% of older patients depending on the subtype of disorder; generalized anxiety disorder and phobias are the most common. Higher rates are seen in chronic obstructive pulmonary disease, diabetes, depression, Alzheimer disease, and Parkinson disease. Antidepressants are first-line treatments, with both selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors most commonly used.⁸

Benzodiazepine use in older patients is often necessary but must be managed carefully. On the one hand, they work quickly and effectively, and at low doses there is little risk of dose escalation or addiction. In general, there is a low risk of drug-drug interactions except with alcohol or other sedative-hypnotics. The purported risk of dementia associated with benzodiazepine use has limited evidence; even if true, it is less of a priority when working with older adults suffering from acute anxiety, especially when they may already have neurocognitive impairment.⁹ There is good reason for caution, however, given their concerning risk-to-benefit ratio, especially when prescribed by non-specialists. In older patients, benzodiazepine use is associated with an increased risk of falls with fractures, excess sedation, cognitive deficits, and motor vehicle accidents, and an overall elevated mortality rate.¹⁰

Here are several important suggestions for safer benzodiazepine use:

- Don’t use in individuals who have a history of unsteady gait, falls, or who are already on multiple medications affecting the central nervous system.

- Don’t combine with other benzodiazepines or sedative-hypnotics.

- Don’t use when there is active alcohol or other substance abuse.

- Don’t use long-term use, escalate doses unnecessarily, or abruptly withdraw the medication.

- Do use antidepressants as the pharmacologic base for anxiety disorders, with benzodiazepines as short-term options for severe symptoms.

- Do use cognitive behavioral therapy, sleep hygiene, and other forms of psychotherapy.

- Do remember that lorazepam and temazepam have no active metabolites since they are metabolized by conjugation only.

Benzodiazepines can be helpful in the short run for acute anxiety and panic while waiting for the more enduring antidepressant to take effect. Thereafter, they are best used only on an as-needed basis and always with close supervision. Individuals with Alzheimer disease and other neurocognitive disorders will be especially vulnerable to side effects of confusion and sedation. In some circumstances, low dose antipsychotics and trazodone can substitute for benzodiazepines, but only under the careful management of a geriatric psychiatrist or other specialist.

Dr Agronin is a geriatric psychiatrist and senior vice president for Behavioral Health and the chief medical officer for MIND Institute at Miami Jewish Health. His discussed these issues during his “The Top Dos and Don’ts in the Psychopharmacologic Treatment of Geriatric Patients: Focus on Dementia and Late-Life Depression and Anxiety” presentation at Virtual Psych Congress 2020.

References

1. Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab. 2011;12(7):601-610.

2. American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694.

3. Kok RM, Reynolds CF. Management of depression in older adults: a review. JAMA. 2017;317(20):2114-2122.

4. Alexopoulos GS. Mechanisms and treatment of late-life depression. Transl Psychiatry. 2019;9(1):188.

5. Cipriani A, Furukawa TA, Salantiet G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366.

6. Tedeschini E, Levkovitz Y, Lovieno N, et al. Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. J Clin Psychiatry. 2011;72(12):1660-1668.

7. Kim JM, Stewart R, Yong-Seong L, et al. Effect of escitalopram vs placebo treatment for depression on long-term cardiac outcomes in patients with acute coronary syndrome: a randomized clinical trial. JAMA. 2018;320(4):350-358.

8. Crocco EA, Jaramillo S, Cruz-Ortiz C, Camfield K. Pharmacological management of anxiety disorders in the elderly. Curr Treat Options Psychiatry. 2017;4(1):33-46.

9. Salzman C, Shader RI. Benzodiazepine use and risk for Alzheimer disease. J Clin Psychopharmacol. 2015;35(1):1-3.

10. Markota M, Rummans TA, Bostwick JM, Lapid MI. Benzodiazepine use in older adults: dangers, management, and alternative therapies. Mayo Clin Proc. 2016;91(11):1632-1639.