|Ahead of print
|Pharmacological management of behavioral and psychological symptoms of dementia: Brief review
Shobit Garg1, Deepak Goel2, Sai Tikka Krishna3
1 Associate Professor, Department of Psychiatry, S.G.R.R. University, Dehradun, Uttarakhand, India
2 Associate Professor, Department of Neurology, Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India
3 Associate Professor, Department of Psychiatry, AIIMS, Bibinagar, Hyderabad, Telangana, India
Click here for correspondence address and email
|Date of Submission||10-Feb-2021|
|Date of Acceptance||15-Apr-2021|
|Date of Web Publication||23-Nov-2021|
Behavioral and psychological symptoms of dementia (BPSD) are the main reason for medical attention in dementia patients. Most of the time caregivers get attentive toward dementia only after BPSD. The patient's quality of life is dependent on severity and burden of psychological symptoms. Most common BPSD manifestations are agitation/aggression, depression, psychosis, and social disinhibition. We are presenting the current biological understanding and brief review of pharmacological treatment of BPSD. The current review is based on PUBMED search with the following key words “Neuro-cognitive Disorders” AND “BPSD” AND “Pharmacological Treatment,” “Antipsychotics,” “Antidepressants,” “Mood Stabilizers,” “Benzodiazepines,” “Cognitive Enhancer,” “Antihypertensive.” We have selected all reviews, systemic reviews, meta-analysis, and randomized trials on pharmacotherapy in BPSD from 2002 to 2021. Brief review on BPSD will help to fill the knowledge gap of clinical decision on pharmacotherapy in BPSD patients. It is not a systemic review but only brief view point or commentary/summary on evidence-based pharmacotherapy in BPSD.
Keywords: Agitation in dementia, dementia with behavior disorder, drugs in dementia
| Introduction|| |
Behavioral and psychological symptom of dementia (BPSD) is a challenge for the caregivers and clinician following dementia patient. Selection of pharmacological treatment is not universal and should be individualized on overall pattern of dementia. Through this brief review, we are presenting summary on evidence-based selection of pharmacotherapy in BPSD patients. Current brief review on pharmacological treatment of BPSD is based on PUBMED search with the following keywords “Neuro-cognitive Disorders” AND “BPSD” AND “Pharmacological Treatment,” “Antipsychotics,” “Antidepressants,” “Mood Stabilizers,” “Benzodiazepines,” “Cognitive Enhancer,” and “Antihypertensive.” Brief review on the topic was done just to fill the knowledge gap of clinical decision on BPSD patients. It is not a systemic review but only brief view point or commentary/summary on evidence-based pharmacotherapy in BPSD.
We have selected all full length articles on reviews, systemic reviews, meta-analysis, and randomized trials from 2002 to 2021. Among 95 articles (all reviews, systemic reviews, meta-analysis, guidelines, and randomized controlled trial), 45 were published between the years 2016 and 2021, and 50 were between the years 2002 and 2015. One latest systemic review published on all types of therapies (pharmacological and nonpharmacological) in BPSD was in the year 2016 was taken as baseline and out of 45 articles on treatment of BPSD (2016–2021), 21 were on various nonpharmacological treatments (music, acupuncture, occupational therapy, interventional psychiatry, etc.). Among 24 remaining articles, three were on Chinese or Japanese Herbs, and rests 21 were on pharmacological treatment of BPSD. Our current brief review is based on various evidences and opinion published in these articles. Our aim was to view the available evidence base so as to implicate its applicability in the current context.
Behavioral and psychological symptoms of dementia (BPSD) are prevalent in more than 80% of probands at different stages of their illness. BPSD is associated with impaired quality of life, higher rates of institutionalization, and inflated cost of care. This functional burden is accentuated by fact that only 10% of psychotropic usages are appropriate in the context of BPSD (PROPER I-study). More specifically, this treatment gap in BPSD could be even wider because of lack of naturalistic studies not taking into account our region's transcultural differences, different pharmacogenetics, and diverse background. The issue is compounded further by a lack of updated clinical practice guidelines addressing BPSD, till a recent one by Shaji et al.
| Clinical Presentation|| |
BPSD as per consensus statement by Finkel et al. has replaced the term “behavioral disturbances” in dementia or neuropsychiatry symptoms in dementia and comprises different clusters of (1) psychosis (delusion, hallucination, agitation, or aggression); (2) anxiety and depression; (3) apathy or disinhibition (social or sexual); (4) motor disturbances (nonpurposive motor activities); and (5) sleep disorders (night time behavior disorders or sun-downing). One of the most commonly recognized BPSD in dementia is HIDA domain (hyperactivity-Impulsivity-Irritability-Disinhibition-Aggression-Agitation). Psychosis as the most severe phenotype of BPSD has been defined by various criteria such as Jest and Finkel, Lyketsos, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. However, Fischer et al. recently proposed the most comprehensive criteria for psychosis in dementia taking into the account the staging (preclinical/prodromal), grading (mild/moderate/severe), and duration (at least 4 weeks).
Although BPSD symptoms are not specific for the etiological diagnosis of dementia, few symptoms are particularly common in specific subtype of dementia, as depression is known to be more common in vascular dementia, hallucinations are more common with dementia of Lewy bodies, and behavioral issues in frontotemporal dementia (FTD) are more common than Alzheimer disease. Therefore, specific patterns of BPSD can indicate specific subtypes of dementia.
| Pathophysiological Aspect|| |
Structural, functional imaging and other biomarker studies lead to better understanding of neural network associated with BPSD. Three main circuits involved in BPSD are dorsolateral circuit (executive functions), prefrontal basal-ganglia circuit (motivation), and orbitofrontal circuit (social behavior). Apathy is associated with medial frontal dysfunction; depression with low metabolism in frontal-parietal cortex; and aggression with abnormalities in cingulate gurus and insular cortex. Other than these cortical circuits, ascending monoaminergic systems (AMS) of brain stem plays an important role in behavior physiology, like in depression AMS is suppressed, and deficit in cholinergic transmission is associated with agitation. Various other bio-psycho-social factors associated with BPSD are medical illnesses, drugs, unmet needs, preexisting personality or psychiatric illness, caregiver response, and environment.
Serotonergic system had been extensively reviewed in BPSD patients and biogenic serotonin had been proposed as neurotransmitter as well as neuromodulator for behavioral problems in dementia.
Brain histaminergic system has been recently explored in various neurocognitive disorders including BPSD and neuroinflammation of microglia can be option for targeted therapy.
| Pharmacological Treatment Strategies|| |
Overall, this comprehensive and operational criterion would assist in early identification, biomarker research, and placement of effective treatment strategies. Primary recommended first line treatment for any BPSD is nonpharmacological. Various nonpharmacological strategies are reminiscence therapy, music therapy, validation therapy, simulated presence therapy, aromatherapy, snoezelen, acupuncture, light therapy, and cognitive rehabilitation. However, moderate-to-severe intensity BPSD including psychosis needs pharmacological intervention. Before initiating drugs, the clinician has to be mindful of the simple clinical scenarios in BPSD probands such as pain (e.g., toothache), constipation (or dehydration), delirium (e.g., due to electrolyte imbalance), environmental factors (like deprivation), interpersonal factors, anticholinergic drugs (e.g., urological drugs), etc.
The most important pharmacological treatment of BPSD is based on antipsychotics and other psychotropic agents such as antidepressants, mood stabilizers, cognitive enhancers, and miscellaneous agents such as prazocin.
| Antipsychotics|| |
A total of 21 studies (year 2002–2016) on antipsychotics were included in latest systemic review on antipsychotics in BPSD. It is important to know in the initial step that antipsychotics not have been approved for routine clinical use in dementia patients due to associated multiple complications and black box warning, still it is the most common agents prescribed in BPSD. Expectedly, antipsychotic dosages should be initiated at a low dose and is to be titrated up to the minimum effective dose as per tolerance. All second-generation antipsychotics (SGA) have shown modest efficacy in BPSD as compared to first-generation antipsychotics (FGA).,, Majority of papers on Alzheimer's and mixed dementia showed that risperidone (best evidence), aripiprazole, olanzapine, and quetiapine are being commonly utilized. Risperidone (0.5 mg/day titrated to a maximum dose of 2 mg/day) though not Food and Drug Administration approved for this indication has attained approval in the UK (up to 6 weeks) and Canada., Quetiapine (25 mg/day titrated to maximum dose of 200 mg/day) has shown to differentially improve agitation than psychosis. In Lewy body dementia More Details, unlike quetiapine, olanzapine (5 mg/day) has shown efficacy in psychotic symptoms. Other SGA such as clozpine, asenapine, paliperidone, and ziprasidone have been rarely used with a lack of controlled data in BPSD.
Not explicitly mentioned in Indian guidelines, SGA should be ideally continued for not more than 4 months and should be tapered off with postdiscontinuation period of observation of 4 months (for rebound symptoms). Moreover, an adequate trial of each antipsychotic in BPSD context is not more than 4 weeks. Discontinuation phase has been relatively safer with minimal rebound symptoms (as per metanalyses). However, concerns have been raised lately to higher relapse rates of the hallucinatory phenomenon after SGA discontinuation.
The network meta-analysis on comparative effectiveness and safety of atypical antipsychotics in treatment of BPSD published in the year 2019 (17 studies and 5373 patients) concluded that single most effective and safe treatment option does not exists and clinicians should individualized the prescribed atypical antipsychotic medication.
Lack of early response to antipsychotics in BPSD can be a good indicator of pharmaco-resistance in future and alternative methods should be adopted in these patients.
| Evidences on Adverse Effects of Antipsychotics|| |
Citing plethora of side effects, haloperidol should not be considered as first line in BPSD and especially in the absence of delirium. Number needed to Harm (for mortality) of haloperidol, risperidone, olanzapine, and quetiapine is 26, 27, 40, and 50, respectively. Other side effects due to off targets by SGA in BPSD are falls, fractures, cardiometabolic, and extra pyramidal side. Most common symptom in BPSD is agitation and aggression; thus, the most common pharmacotherapy is in the form of antipsychotic medications. The most common side effect associated with antipsychotic is the development of extrapyramidal features (bradykinesia, rigidity, and tremors). The extrapyramidal side effects of antipsychotic medication can be augmented by poly-pharmacotherapy, frequently used in dementia patients. Among anti-Alzheimer's drugs, donapazil and galantamine and among antidepressant medication, selective serotonin reuptake inhibitors (SSRI) can synergistically augment the extrapyramidal complication of antipsychotics, while drugs such as memantine (NMDA antagonists) and mirtazepine (alpha 2, 5-HT2, and 5-HT3 antagonist) can improve extrapyramidal complication.
The prevalence of cerebrovascular adverse events is less than previously estimated (odds ratio = 1.31) but is still highest for risperidone among the SGAs. One meta-analysis done to address the issue of cerebrovascular accident (CVA) in patients with BPSD using antipsychotics and SGAs were found safer as compared to FGAs and were not associated with high risk of CVA.
| Antidepressants|| |
Between 2002 and 2016, 13 articles on antidepressant in BPSD were analyzed by Preuss et al. Among antidepressants, tricyclic antidepressants are not recommended due to side effect burden in elderly. Among selective serotonin reuptake inhibitors (SSRIs), citalopram (not available in India) has shown efficacy in reducing agitation (CitAD trial), but safety concerns have been raised due to QTc prolongation. Another SSRI sertraline has shown some therapeutic benefits in BPSD. Trazodone, a serotonin receptor antagonist and reuptake inhibitor, citing minimal anticholinergic and significant sedating profile, has the potential role in BPSD. Trazodone has also shown promise in reducing agitation in FTD and as a PRN (pro re nata, when necessary) drug(25 mg every hour till 150 mg/day) for intermittent agitation in dementia. Other antidepressants such as escitalopram, buspirone, and mirtazapine have been poorly studied. With all available evidences (not strong), citalopram and mitazepine could be better choices as compare to others SSRI in terms of managing agitation and associated lesser side effects.
| Mood Stabilizers|| |
Only three articles were published on anticovulsant in BPSD during 2002–2016 and last systemic review on anticonvulsants in BPSD was published in the year 2008., Among mood stabilizers, carbamazapine (barring CYP3A4 drug interactions) holds promise when compared with valproate (ineffective in lower and side effects with higher dosages), lamotrigine, and gabapentine. Currently, with the exception of carbamazepine, other mood stabilizers had little support of evidences. Other antiepileptic drugs such as gabapentin and pregabalin can be chosen for BPSD when carbamazepine cannot be given or tolerated by the patients.
| Cognitive Enhancer|| |
Total 12 studies were included in systemic review by Preuss et al. 2016, on cognitive enhancer between the duration of 2002 and 2016. Among cognitive enhancers, acetylcholine esterase inhibitors (AChEI) such as donepezil, rivastigmine, and galantamine and NMDA uncompetitive antagonists such as memantine have shown slow insidious benefits in BPSD (over 6 months). The combination (AChEI and memantine) has shown superior efficacy over monotherapy in a recent meta-analysis.
| Benzodiazepines|| |
Only two articles were eligible on benzodiazepines in BPSD during 2002–2016. One systemic review summarized findings of five randomized controlled trials on benzodiazepines in BPSD. Benzodiazepines are not recommended due to side effects such as falls, cognitive deficits, sedation, and paradoxical agitation but exceptionally lorazepam can be utilized as a PRN drug (0.5 mg every 4 h as needed, maximum 2 mg/24 h). Citing limited therapeutic options tailor made for BPSD, there are several ongoing trials of novel molecules. Relative deficiency of melatonin is associated with consequences of dementia and sun downing. Recently, melatonin administration has shown to be associated with better neurobehavioral outcome, better sleep quality, lesser sun downing, and better overall quality of life.
| Miscellaneous|| |
Antihypertensive agents such as prazosin due to alpha-adrenoceptor blocking actions have shown benefits in agitation in Alzheimer's dementia (dose between 1 mg and 6 mg/day) with additional benefits in associated REM sleep behavioral disorder.
Pain might be one important factor behind BPSD and six studies including three randomized controlled trials had shown benefit of analgesics in patients of BPSD.
| Evidences of Complementary Alternative Medicine in Bpsd|| |
Ginkgo Biloba extract has been reviewed (4 trials and 1628 patients) and found that 22–24-week therapy improves BPSD symptoms and reduces caregiver distress.
The systemic review (2006) had identified many herbs and herbal formulations for therapeutic effects on Alzheimer's disease. Melissa officinalis, salivia officinalis, Yi-Gan–San, BDW (Ba Wei De Huang Wan), and Ginkgo Biloba were five preparation found useful in agitation.
| Conclusion|| |
To summarize, there has been a lack of evidence-driven algorithms for BPSD and none from our region leading to complications such as poor outcomes, prolonged institutionalization, polypharmacy, and inflated caregiver burden. Hence, with current evidence base, we can define native approach or algorithm giving attention to the type (nonpharmacological vs. nonpharmacological), dose, and duration (of each trial) of treatment for different clusters of BPSD. We also need naturalistic and longitudinal data to generate evidence for the same.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Preuss UW, Wong JW, Koller G. Treatment of behavioral and psychological symptoms of dementia: A systemic review. Psychiatr Pol 2016;50:679-715.
Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: Results from the cardiovascular health study. JAMA 2002;288:1475-83.
van der Spek K, Gerritsen DL, Smalbrugge M, Nelissen-Vrancken MH, Wetzels RB, Smeets CH, et al.
Only 10% of the psychotropic drug use for neuropsychiatric symptoms in patients with dementia is fully appropriate. The PROPER I-study. Int Psychogeriatr 2016;28:1589-95.
Shaji KS, Sivakumar PT, Rao GP, Paul N. Clinical practice guidelines for management of dementia. Indian J Psychiatry 2018;60 Suppl S3:312-28.
Finkel SI, Costa e Silva J, Cohen G, Miller S, Sartorius N. Behavioral and psychological signs and symptoms of dementia: A consensus statement on current knowledge and implications for research and treatment. Int Psychogeriatr 1996;8 Suppl 3:497-500.
Keszycki RM, Fisher DW, Dong H. The hyperactivity-impulsivity-irritability-disinhibition-aggression-agitation domain in Alzheimer's disease: Current management and future direction. Front Pharmacol 2019;10:1109. [doi: 10.3389/fphar. 2019.01109].
Fischer CE, Ismail Z, Youakim JM, Creese B, Kumar S, Nuñez N, et al.
Revisiting criteria for psychosis in Alzheimer's disease and related dementias: Toward better phenotypic classification and biomarker research. J Alzheimers Dis 2020;73:1143-56.
Kales HC, Gitlin LN, Lyketsos CG. Assessment and management of behavioral and psychological symptoms of dementia. BMJ 2015;350:h369.
Chakraborty S, Lennon JC, Malkaram SA, Zeng Y, Fisher DW, Dong H. Serotonergic system, cognition, and BPSD in Alzheimer's disease. Neurosci Lett 2019;704:36-44.
Eissa N, Sadeq A, Sasse A, Sadek B. Role of inflammation in autism spectrum disorder and the emergence of brain Histaminergic system. Lesson also for BPSD. Front Pharmacol 2020;11:886.
Reus VI, Fochtmann LJ, Eyler AE, Hilty DM, Horvitz-Lennon M, Jibson MD, et al.
The American Psychiatric Association Practice Guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Focus (Am Psychiatr Publ) 2017;15:81-4.
Tible OP, Riese F, Savaskan E, Gunten AV. Best practices in the management of behavioral and psychological symptoms of dementia. Ther Adv Neurol Disord 2017;10:297-309.
Tampi RR, Tampi DJ, Balachandran S, Srinivasan S. Antipsychotic use in dementia: A systematic review of benefits and risks from meta-analyses. Ther Adv Chronic Dis 2016;7:229-45.
Davies SJ, Burhan AM, Kim D, Gerretsen P, Graff-Guerrero A, Woo VL, et al.
Sequential drug treatment algorithm for agitation and aggression in Alzheimer's and mixed dementia. J Psychopharmacol 2018;32:509-23.
Yunusa I, El Helou ML. The use of resperidone in behavioral and psychological symptoms of dementia. A review of pharmacology, clinical evidence, regulatory approval and off-lable use. Front Pharmacol 2020;11:596.
Stinton C, McKeith I, Taylor J, Lafortune L, Mark E, Mioshi E, et al
. Pharmacological management of lewy body dementia: A systematic review and meta-analysis. Am J Psychiatry 2015;172:731-42.
Masopust J, Protopopová D, Vališ M, Pavelek Z, Klímová B. Treatment of behavioral and psychological symptoms of dementias with psychopharmaceuticals: A review. Neuropsychiatr Dis Treat 2018;14:1211-20.
Yunusa I, Alsumali A, Garba AE, Regestein QR, Eguale T. Assessment of reported comparative effectiveness and safety of atypical antipsychotics in the treatment of behavioral and psychological symptoms of dementia: A network meta-analysis. JAMA Netw Open 2019;2:e190828.
Yoshida K, Roberts R, Suzuki T, Lebowitz B, Reeves S, Howard R, et al
. Lack of early improvement with antipsychotics is a marker of subsequent nonresponse in behavioral nd psychological symptoms of dementia: Analysis of CAITE-AD data. Am J Getiatr Psychiatry 2017;25:708-16.
Maust DT, Kim HM, Seyfried LS, Chiang C, Kavanagh J, Schneider LS, et al.
Antipsychotics, other psychotropics, and the risk of death in patients with dementia: Number needed to harm. JAMA Psychiatry 2015;72:438-45.
Ohno Y, Kunisawa N, Shimizu S. Antipsychotic treatment of behavioral and psychological symptoms of dementia (BPSD): Management of extrapyramidal side effects. Front Pharmacol 2019;10:1045.
Hsu WT, Esmaily-Fard A, Lai CC, Zala D, Lee SH, Chang SS, et al.
Antipsychotics and the risk of cerebrovascular accident: A systematic review and meta-analysis of observational studies. J Am Med Dir Assoc 2017;18:692-9.
Rao A, Suliman A, Story G, Vuik S, Aylin P, Darzi A. Meta-analysis of population-based studies comparing risk of cerebrovascular accident associated with first- and second-generation antipsychotic prescribing in dementia. Int J Methods Psychiatr Res 2016;25:289-98.
Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, et al.
Effect of citalopram on agitation in Alzheimer disease: The CitAD randomized clinical trial. JAMA 2014;311:682-91.
Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: A randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004;17:355-9.
Wang F, Feng TY, Yang S, Preter M, Zhou JN, Wang XP. Drug therapy for behavioral and psychological symptoms of dementia. Curr Neuropharmacol 2016;14:307-13.
Pinheiro D. Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD). Encephale 2008;34:409-15.
Supasitthumrong T, Bolea-Alamanac BM, Asmer S, Woo VL, Abdool PS, Davies SJ. Gabapentin and Pregabalin to treat aggressivity in dementia: A systemic review and illustrative case report. Br J Clin Pharmacol 2019;85:690-703.
Lin CH, Lane HY. The role of N-Methyl-D-aspartate receptor neurotransmission and precision medicine in behavioral and psychological symptoms of dementia. Front Pharmacol 2019;10:540.
Chen R, Chan PT, Chu H, Lin YC, Chang PC, Chen CY, et al.
Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta-analysis. PLoS One 2017;12:e0183586.
Tampi RR, Tampi DJ. Efficacy and tolerability of benzodiazepines for the treatment of behavioral and psychological symptoms of dementia: A systematic review of randomized controlled trials. Am J Alzheimers Dis Other Demen 2014;29:565-74.
Ooms S, Ju YE. Treatment of sleep disorders in dementia. Curr Treat Options Neurol 2016;18:40.
Brusco LI, Márquez M, Cardinali DP. Monozygotic twins with Alzheimer's disease treated with melatonin: Case report. J Pineal Res 1998;25:260-3.
Tampi RR, Hassel C, Joshi P, Tampi DJ. Analgesic in the management of behavioral ans psychological symptoms of dementia: A perspective review. Drug Context 2017;6:212508.
Savaskan E, Mueller H, Hoerr R, von Gunten A, Gauthier S. Treatment effects of Ginkgo Biloba extract EGb 761® on the spectrum of behavioral and psychological symptoms of dementia: Meta-analysis of randomized controlled trials. Int Psychogeriatr 2018;30:285-93.
Dos Santos-Neto LL, De Vilhena Toledo MA, Medeiros-Souza P, De Souza GA. The use of herbal medicine in Alzheimer's disease: A systematic review. Evid Based Complement Alternat Med 2006;3:441-5.
Department of Neurology, Himalayan Institute of Medical Sciences, Dehradun - 248 001, Uttarakhand
Source of Support: None, Conflict of Interest: None
| Article Access Statistics|
| Viewed||59 |
| PDF Downloaded||2 |