Consider Impact of Certain Medications on Brain Function
Pharmacists can identify drugs that cause problems, guide selection, and recommend treatment strategies.
The CDC’s healthy brain initiative aims to improve “understanding of brain health as a central part of public health practice”1 through education to health care providers and patients. The Pharmacy Times® Cognitive Health Focus series offers pharmacists information to help them actively participate as members of the health care team in addressing brain health. The previous article in the series discussed how pharmacists can help optimize patients’ modifiable risk factors, including nutrition and physical activity, to improve cognitive health.2 This article highlights medications that both cause and treat cognitive issues and summarizes the use of brain health supplements.
MEDICATIONS THAT TREAT COGNITIVE ISSUES
Practitioners can identify cognitive issues through performance-based screening tools, such as Mini-Cog and Mini-Mental State Examination, and technology, such as Cognivue Thrive.3,4 Cognitive issues such as dementia and associated behavioral and neuropsychiatric symptoms (eg, depression and hallucinations) are often treated with pharmacological therapies.5,6 Medications such as acetylcholinesterase inhibitors (AChEIs; eg, donepezil, galantamine, and rivastigmine) and N-methyl-D-aspartate receptor antagonists such as memantine are considered for the treatment of dementia.7 The choice of AChEI is based primarily on clinician and patient preference because of limited head-to-head comparison studies, and when compared with a placebo, all AChEIs demonstrated effectiveness.8,9 Atypical antipsychotics such as aripiprazole and risperidone are frequently prescribed for psychotic symptoms of dementia, such as hallucinations, as these medications are associated with extrapyramidal adverse effects less than typical antipsychotics are.5,10,11 Risperidone treating agitation and aggression in patients with dementia, and it has been approved for these indications internationally.12,13 However, atypical antipsychotics are not without substantial risk to older adults.11
Depression is prevalent in dementia and is linked to a faster decline in memory.14 Although about 30% of patients typically do not respond to antidepressant therapy, practitioners frequently chose pharmacological aid either alone or alongside nonpharmacological therapies such as sensory-stimulation therapies.15 Selective serotonin reuptake inhibitors (SSRIs) such as citalopram and sertraline are considered first-line options for the treatment of depression, especially in older adults, because of their considerable safety profile compared with other classes of antidepressants (eg, tricyclic antidepres- sants).16,17 However, of the SSRIs, paroxetine is not recommended in older adults because of its high anticholinergic burden (ACB).18 Regardless of the medication they choose to treat the cognitive issue, clinicians must be mindful of intrinsic factors, such as genetics, as well as extrinsic factors, such as concomitant medications, that may alter the medication’s effectiveness and safety.19-21 Both pharmacogenetic variation and coadministration with certain medications, such as cytochrome P450 (CYP) inhibitors or inducers, can increase patient risk for adverse drug events (ADEs) or subtherapeutic or supratherapeutic response.19-22 For example, aripiprazole, donepezil, and sertraline are medications that are metabolized by CYP2D6 and are affected by CYP2D6 genetic variants and by coadministration with CYP2D6 inhibitors such as amiodarone.19,23-25
MEDICATIONS THAT CAUSE COGNITIVE ISSUES
As mentioned, otherwise appropriate medications, such as antidepressants with anticholinergic properties, can be associated with ADEs such as cognitive impairment.26 Often these ADEs are avoidable, and the risk of harm can ultimately outweigh the benefit of using the medication(s). For example, anticholinergic medications block the mechanism of action (MOA) of the naturally occurring acetylcholine molecule by competing for muscarinic receptor sites.27 Because acetylcholine is required for adequate neurotransmission, anticholinergic effects will modulate functions at the effector site, resulting in a decrease of secretions in various organ systems either centrally, as in the central nervous system, or peripherally.28 Additionally, differences exist in the propensities of individual medications to cause anticholinergic effects. The ACB of a medication ranges from no adverse effects (eg, aspirin) to mild adverse effects (metoprolol), prominent adverse effects (paroxetine), and primary adverse effects (diphenhydramine).29 For each medication on a patient’s regimen, practitioners must evaluate both the measure of ACB and the duration of patient exposure.
Pharmacodynamic drug interactions are also a concern for patients being treated for cognitive issues. Specifically, concomitant use of medications with anticholinergic properties may lead to an additive ACB effect. Additionally, caution is warranted if clinicians are coprescribing anticholinergic medications with AChEIs, as anticholinergic medications decrease acetylcholine, whereas AChEIs increase acetylcholine, so therapeutic failure may result. For patients with cognitive issues, practitioners must review medication regimens for risks related to total ACB and competing MOA. Evaluation of concomitant medications and physiological factors can help clinicians explain and prevent ADEs before they occur.
Finally, advanced age is associated with altered acetylcholine function and transmission because of decreased acetylcholine uptake and release, fewer nicotinic and muscarinic receptors, and insufficient axonal transport. As a result, older adults are more susceptible to common ACB effects, such as blurred vision, constipation, dry eyes, and xerostomia, as well as longer-term ADEs, such as cognitive impairment, dental caries, and glaucoma. The treatment of ADEs may lead to a prescribing cascade. For example, a report of constipation leads to laxatives, of dry eyes leads to ocular lubricants, and of dry mouth leads to prescribing of mouthwashes. Before adding medications, evaluate the root cause of the ADE and mitigate as appropriate. Pharmacists can leverage medication decision support tools, such as MedWise Medication Risk Mitigation Matrix, to identify medication-related problems and risks, including but not limited to simultaneous, multidrug interactions, drug-gene interactions, and cumulative ACB.30
BRAIN HEALTH SUPPLEMENTS
Because of the challenges in treating cognitive impairment, many health care providers and patients turn to nonpharmacological options to either augment or replace prescription medications. Nonprescription medications, such as brain health supplements and vitamins, are often self-administered without clinical oversight.31
Some OTC medications may be beneficial for cognitive health. Fish oil and turmeric may reduce inflammation, whereas folic acid and vitamin B12 are thought to facilitate synthesis of the neurotransmitters dopamine and serotonin.32-34 Brain health supplements and vitamins are topics of high interest for many patients, who often receive conflicting information from family members, friends, and the internet regarding the efficacy and safety of the active ingredients in brain health supplements and vitamins in prevention and treatment.35 Many consumers of nonprescription medications are unaware of the potential harm associated with exceeding the recommended daily dose, inappropriately combining nonprescription and prescription medications, or taking multiple products with the same active ingredient, which increase the risk for possibly dangerous ADEs and drug-drug interactions.36 Pharmacists are key resources for assessing clinical data and evidence and helping patients interpret medication information and package labeling, to help ensure safe and effective use.
Pharmacists are well equipped to conduct thorough medication therapy reviews, which include brain health supplements and vitamins, to avoid or mitigate any potential medication therapy problems. As the most accessible health care professionals, pharmacists can serve as a resource for patients in the early identification of cognitive impairment from day-to-day interactions. Many community pharmacies continue to build their clinical service offerings, and the incorporation of assessment tools and medication safety technology can increase the quality of care they offer to patients with needs related to cognitive impairment. Pharmacists are uniquely positioned to identify medications that can cause cognitive problems, guide medication selection for cognitive health, and recommend appropriate strategies for treating cognitive issues.
The following individuals contributed to this article: Jacques Turgeon, PhD, BPharm, chief scientific officer at Tabula Rasa HealthCare in Moorestown, New Jersey, and CEO of its TRHC Precision Pharmacotherapy Research and Development Institute; Charles Dushman, consultant at Cognivue of Victor, New York; and Dana Filippoli, MBE, MPH, communications consultant at Tabula Rasa HealthCare.
- Healthy brain initiative. CDC. Updated July 30, 2020. Accessed September 21, 2020. https://www.cdc.gov/aging/healthybrain/index.htm
- Campbell KM. Pharmacists may be first to recognize deterioration. Pharmacy Times®. September 24, 2020. Accessed October 19, 2020. https://www.pharmacytimes.com/publications/issue/2020/Septembe2020/pharmacists-may-be-first-to-recognize-deterioration
- Galvin JE, Sadowsky CH; NINCDS-ADRDA. Practical guidelines for the recognition and diagnosis of dementia. J Am Board Fam Med. 2012;25(3):367-382. doi:10.3122/jabfm.2012.03.100181
- Cahn-Hidalgo D, Estes PW, Benabou R. Validity, reliability, and psychometric properties of a computerized, cognitive assessment test (Cognivue). World J Psychiatry. 2020;10(1):1-11. doi:10.5498/wjp.v10.i1.1
- Liperoti R, Pedone C, Corsonello A. Antipsychotics for the treatment of behavioral and psychological symptoms of dementia (BPSD). Curr Neuropharmacol. 2008;6(2):117-124. doi:10.2174/157015908784533860
- Dyer SM, Harrison SL, Laver K, Whitehead C, Crotty M. An overview of systematic reviews of pharmacological and non-pharmacological interventions for the treatment of behavioral and psychological symptoms of dementia. Int Psychogeriatr. 2018;30(3):295-309. doi:10.1017/S1041610217002344
- Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease. National Institute for Health and Care Excellence. March 23, 2011. Accessed November 18, 2020. https://www.nice.org.uk/guidance/ta217/resources/donepezil-galantamine-rivastigmine-and-memantine-for-the-treatment-of-alzheimers-disease-pdf-82600254699973#:~:text=There%20is%20no%20cure%20for,available%20specifically%20for%20Alzheimer's%20disease
- Campbell NL, Perkins AJ, Gao S, et al. Adherence and tolerability of Alzheimer's disease medications: a pragmatic randomized trial. J Am Geriatr Soc. 2017;65(7):1497-1504. doi:10.1111/jgs.14827
- Cui CC, Sun Y, Wang XY, Zhang Y, Xing Y. The effect of anti-dementia drugs on Alzheimer disease-induced cognitive impairment: a network meta-analysis. Medicine (Baltimore). 2019;98(27):e16091. doi:10.1097/MD.0000000000016091
- Matos A, Bain KT, Bankes DL, et al. Cytochrome P450 (CYP450) interactions involving atypical antipsychotics are common in community-dwelling older adults treated for behavioral and psychological symptoms of dementia. Pharmacy (Basel). 2020;8(2):63. doi:10.3390/pharmacy8020063
- Gareri P, De Fazio P, Manfredi VGL, De Sarro G. Use and safety of antipsychotics in behavioral disorders in elderly people with dementia. J Clin Psychopharmacol. 2014;34(1):109-123. doi:10.1097/JCP.0b013e3182a6096e
- Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173(5):543-546. doi:10.1176/appi.ajp.2015.173501
- Yunusa I, El Helou ML. The use of risperidone in behavioral and psychological symptoms of dementia: a review of pharmacology, clinical evidence, regulatory approvals, and off-label use. Front Pharmacol. 2020;11:596. doi:10.3389/fphar.2020.00596
- Kuring JK, Mathias JL, Ward L. Prevalence of depression, anxiety and PTSD in people with dementia: a systematic review and meta-analysis. Neuropsychol Rev. 2018;28(4):393-416. doi:10.1007/s11065-018-9396-2
- Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-388. doi:10.2147/PPA.S29716
- Rodda J, Walker Z, Carter J. Depression in older adults. BMJ. 2011;343:d5219. doi:10.1136/bmj.d5219
- Taylor WD. Should antidepressant medication be used in the elderly? Expert Rev Neurother. 2015;15(9):961-963. doi:10.1586/14737175.2015.1070671
- 2019 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. doi:10.1111/jgs.15767
- Cacabelos R. Pharmacogenetic considerations when prescribing cholinesterase inhibitors for the treatment of Alzheimer’s disease. Expert Opin Drug Metab Toxicol. 2020;16(8):673-701. doi:10.1080/17425255.2020.1779700
- Pasqualetti G, Tognini S, Calsolaro V, Polini A, Monzani F. Potential drug-drug interactions in Alzheimer patients with behavioral symptoms. Clin Interv Aging. 2015;10:1457-1466. doi:10.2147/CIA.S87466
- Zhong Y, Zheng X, Miao Y, Wan L, Yan H, Wang B. Effect of CYP2D6*10 and APOE polymorphisms on the efficacy of donepezil in patients with Alzheimer’s disease. Am J Med Sci. 2013;345(3):222-226. doi:10.1097/MAJ.0b013e318255a8f9
- Sönnerstam E, Sjölander M, Lövheim H, Gustafsson M. Clinically relevant drug-drug interactions among elderly people with dementia. Eur J Clin Pharmacol. 2018;74(10):1351-1360. doi:10.1007/s00228-018-2514-5
- Kirschbaum KM, Möller MJ, Malevani J, et al. Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects. World J Biol Psychiatry. 2008;9(3):212-218. doi:10.1080/15622970701361255
- Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98(2):127-134. doi:10.1002/cpt.147
- English BA, Dortch M, Ereshefsky L, Jhee S. Clinically significant psychotropic drug-drug interactions in the primary care setting. Curr Psychiatry Rep. 2012;14(4):376-390. doi:10.1007/s11920-012-0284-9
- Heath L, Gray SL, Boudreau DM, et al. Cumulative antidepressant use and risk of dementia in a prospective cohort study. J Am Geriatr Soc. 2018;66(10):1948-1955. doi:10.1111/jgs.15508
- West T, Pruchnicki MC, Porter K, Emptage R. Evaluation of anticholinergic burden of medications in older adults. J Am Pharm Assoc (2003). 2013;53(5):496-504. doi:10.1331/JAPhA.2013.12138
- Campbell N, Boustani M, Limbil T, et al. The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging. 2009;4:225-233. doi:10.2147/cia.s5358
- Rudd KM, Raehl CL, Bond CA, Abbruscato TJ, Stenhouse AC. Methods for assessing drug-related anticholinergic activity. Pharmacotherapy. 2005;25(11):1592-1601. doi:10.1592/phco.2005.25.11.1592
- Bankes DL, Amin NS, Bardolia C, Awadalla MS, Knowlton CH, Bain KT. Medication-related problems encountered in the Program of All-Inclusive Care for the Elderly: an observational study. J Am Pharm Assoc (2003). 2020;60(2):319-327. doi:10.1016/j.japh.2019.10.012
- Statistics on OTC use. Consumer Healthcare Products Association. Accessed September 21, 2020. https://www.chpa.org/marketstats.aspx#:~:text=Research%20shows%20that%2081%20percent,otherwise%20would%20not%20seek%20treatment
- Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical use of curcumin in depression: a meta-analysis. J Am Med Dir Assoc. 2017;18(6):503-508. doi:10.1016/j.jamda.2016.12.071
- Burhani MD, Rasenick MM. Fish oil and depression: the skinny on fats. J Integr Neurosci. 2017;16(s1):S115-S124. doi:10.3233/JIN-170072
- Kennedy DO. B vitamins and the brain: mechanisms, dose and efficacy—a review. Nutrients. 2016;8(2):68. doi:10.3390/nu8020068
- Global Council on Brain Health. AARP. Accessed November 20, 2020. https://www.GlobalCouncilOnBrainHealth.org
- A call to action: protecting U.S. citizens from inappropriate medication use. Institute for Safe Medication Practices. 2007. Accessed September 21, 2020. https://forms.ismp.org/pressroom/viewpoints/CommunityPharmacy.pdf