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Liu Y, Aquili L, Wong KH, Lu Z, Lim LW. Past, present, and future of serotonin-targeting therapeutics for Alzheimer's disease: Perspectives from DNA methylation. Ageing Res Rev 2025; 108:102755. [PMID: 40239871 DOI: 10.1016/j.arr.2025.102755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 03/02/2025] [Accepted: 04/13/2025] [Indexed: 04/18/2025]
Abstract
With population aging, Alzheimer's disease (AD) is becoming increasingly prevalent, causing great health and economic burdens worldwide. Despite decades of research, there are still no effective disease-modifying treatments for AD, highlighting the urgent need for more in-depth understanding of the disease-causing mechanisms. The brain serotonin (5-HT) neurotransmission system undergoes structural and functional changes in aging and AD, which contributes to cognitive decline and comorbid mood disturbances. This review discusses the critical involvement of the brain 5-HT system in aging and AD. Existing findings on the changes in projection fiber innervation and receptor/transporter expression in AD are reviewed. Preclinical and clinical progress on the development of 5-HT-modulating drugs for AD and the obstacles faced by these development efforts are discussed. Epigenetic control of the brain 5-HT system and the potential of modulating 5-HT transmission via DNA methylation are also examined.
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Affiliation(s)
- Yanzhi Liu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
| | - Luca Aquili
- Department of Biosciences and Bioinformatics, and Suzhou Municipal Key Laboratory of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China; School of Management, Ritsumeikan Asia Pacific University, Beppu, Oita, Japan.
| | - Kah Hui Wong
- Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
| | - Zhiliang Lu
- Department of Biosciences and Bioinformatics, and Suzhou Municipal Key Laboratory of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China.
| | - Lee Wei Lim
- Department of Biosciences and Bioinformatics, and Suzhou Municipal Key Laboratory of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China.
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2
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Rajji TK, Baksh SN, Shade DM, Ismail Z, Burhan AM, Okhravi HR, Padala PR, Rosenberg PB, Schneider LS, Porsteinsson AP, Lyketsos CG. Escitalopram for agitation in Alzheimer's dementia: a randomized controlled phase 3 trial. Nat Med 2025; 31:1586-1591. [PMID: 40133524 DOI: 10.1038/s41591-025-03569-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 02/04/2025] [Indexed: 03/27/2025]
Abstract
Citalopram is effective in treating agitation in Alzheimer's dementia (AD), but it is associated with cognitive and cardiac risks, likely due to its R-enantiomer. Escitalopram, the S-enantiomer, may be an alternative. In this double-masked randomized (1:1) placebo-controlled trial, we assessed the efficacy and safety of escitalopram in treating agitation in AD after failure of a psychosocial intervention (PSI). Assessments occurred at enrollment, post-PSI (baseline) and at 3, 6, 9 and 12 weeks post-baseline. Settings were 27 community-based centers. The target randomization sample was 392 participants. Participants were adults with AD, a Mini-Mental State Examination Telephone score of 3-20 and significant agitation. PSI non-responders received escitalopram (up to 15 mg per day) or placebo for 12 weeks while continuing PSI. The outcome was the proportion of participants with clinically significant improvement in agitation from baseline at 12 weeks. In total, 173 participants were randomized (84 escitalopram versus 89 placebo; mean ± s.d. age = 78.4 ± 8.7 years; 90 men (52.0%); 127 White (73.4%)). The unadjusted risk difference at 12 weeks was 0.08 (95% confidence interval: -0.21, 0.06). Drug-related QT interval prolongation was observed. Although the randomized sample was smaller than planned, escitalopram was not effective in treating agitation in AD and was associated with cardiac conduction delays. Clinicians need to be cautious in recommending escitalopram as an alternative to citalopram for this condition. ClincialTrials.gov identifier: NCT03108846 .
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Affiliation(s)
- Tarek K Rajji
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
- Department of Psychiatry and Toronto Dementia Research Alliance, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Sheriza N Baksh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - David M Shade
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Zahinoor Ismail
- Departments of Psychiatry, Clinical Neurosciences and Community Health Sciences, Hotchkiss Brain Institute and O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
| | - Amer M Burhan
- Department of Psychiatry and Toronto Dementia Research Alliance, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Ontario Shores Centre for Mental Health Sciences, Whitby, Ontario, Canada
| | - Hamid R Okhravi
- Department of Medicine, Lawrence J. Goldrich Institute for Integrated Neuro-Health, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA, USA
| | - Prasad R Padala
- Central Arkansas Veterans Healthcare System and College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Paul B Rosenberg
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
| | - Lon S Schneider
- Department of Psychiatry and the Behavioral Sciences and Department of Neurology, University of Southern California Keck School of Medicine and the University of Southern California Leonard Davis School of Gerontology, Los Angeles, CA, USA
| | - Anton P Porsteinsson
- Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Constantine G Lyketsos
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
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Dong M, Liu C, Luo H, Su D, Li G, Xu F, Song M, Zhang Y. Efficacy and tolerability of antidepressants monotherapy for behavioral and psychological symptoms of dementia: A meta-analysis of randomized controlled trials. J Psychiatr Res 2025; 181:417-424. [PMID: 39662328 DOI: 10.1016/j.jpsychires.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 12/01/2024] [Accepted: 12/02/2024] [Indexed: 12/13/2024]
Abstract
Behavioral and psychological symptoms of dementia (BPSD) are common and difficult to manage. Although experimental data suggest that antidepressants may reduce BPSD, the results are inconclusive. To evaluate the efficacy and tolerability of antidepressants monotherapy for treating BPSD. We searched 10 cross-disciplinary electronic databases from inception to October 2023.Randomized controlled trials (RCTs) comparing antidepressants versus placebo for treating BPSD were included. The primary outcome was change in total neuropsychiatric symptom scale scores. Secondary outcomes included changes on agitation and psychosis subscale scores, change in total score of Mini-mental State Examination (MMSE). Tolerability outcomes included incidences and discontinuations due to adverse events. Finally, 8 RCTs including 676 patients were identified. We found a small beneficial effect of antidepressants on overall BPSD However, when trials with potential high-dose citalopram were excluded, no improvement was observed. No significant effects were detected on agitation and cognition. Currently there is no clear evidence of a beneficial effect of currently available antidepressants on overall BPSD and in particular agitation. Notably, clinician should be cautious of the potential risk of arrhythmias, dizziness and diarrhea when prescribing an antidepressant.
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Affiliation(s)
- Meng Dong
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing, China
| | - Chang Liu
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing, China
| | - Haiyan Luo
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing, China
| | - Dongyun Su
- Department of Neurology, The First People's Hospital of Longquanyi District No. 669 Donglang Road, Longquanyi District, Longquanyi District Chengdu, China
| | - Gongbo Li
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing, China
| | - Fenghua Xu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, China
| | - Min Song
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing, China.
| | - Yuqing Zhang
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing, China.
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Lee HH, Chinnameyyappan A, Feldman OJ, Marotta G, Survilla K, Lanctôt KL. Behavioral and Psychological Symptoms (BPSD) in Alzheimer's Disease (AD): Development and Treatment. Curr Top Behav Neurosci 2025; 69:245-273. [PMID: 39853561 DOI: 10.1007/7854_2024_566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Behavioral and psychological symptoms of dementia (BPSD), such as agitation, apathy, and psychosis, are highly prevalent and have a significant impact on patients and their care partners. The neurobiology of BPSD involves a complex interplay of structural brain changes and alterations in the neurotransmitter system. Various genetic and plasma biomarkers have also been studied. Research in BPSD has been limited by heterogeneity in the diagnostic criteria and assessment tools. As such, there have been ongoing efforts to develop a gold-standard assessment tool and diagnostic criteria. Current practice guidelines recommend nonpharmacological therapies as first-line treatments. Pharmacological options are often used when there is an insufficient response to nonpharmacological strategies, but there can be serious adverse effects with existing pharmacological agents. This has resulted in growing efforts to develop novel therapeutics with more favorable tolerability profiles, with some showing promising results. Other biological therapies, such as neurostimulation, have also demonstrated positive results. As our understanding of BPSD evolves, ongoing research efforts in treatment of BPSD are warranted in order to enhance the quality of life for patients and their care partners.
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Affiliation(s)
- Hyewon H Lee
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
| | | | - Oriel J Feldman
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - Giovanni Marotta
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
- Division of Geriatric Medicine, University of Toronto, Toronto, ON, Canada
| | - Kate Survilla
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Krista L Lanctôt
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
- Bernick Chair in Geriatric Psychopharmacology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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Peng S, Schaper FLWVJ, Cohen-Zimerman S, Miller GN, Jiang J, Rouhl RPW, Temel Y, Siddiqi SH, Grafman J, Fox MD, Cohen AL. Mapping Lesion-Related Human Aggression to a Common Brain Network. Biol Psychiatry 2024:S0006-3223(24)01627-5. [PMID: 39369761 PMCID: PMC11968440 DOI: 10.1016/j.biopsych.2024.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 09/07/2024] [Accepted: 09/27/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Aggression exacts a significant toll on human societies and is highly prevalent among neuropsychiatric patients. The neural mechanisms of aggression are unclear and treatment options are limited. METHODS Using a recently validated lesion network mapping technique, we derived an aggression-associated network by analyzing data from 182 patients who had experienced penetrating head injuries during their service in the Vietnam War. To test whether damage to this lesion-derived network would increase the risk of aggression-related neuropsychiatric symptoms, we used the Harvard Lesion Repository (N = 852). To explore potential therapeutic relevance of this network, we used an independent deep brain stimulation dataset of 25 patients with epilepsy, in which irritability and aggression are known potential side effects. RESULTS We found that lesions associated with aggression occurred in many different brain locations but were characterized by a specific brain network defined by functional connectivity to a hub region in the right prefrontal cortex. This network involves positive connectivity to the ventromedial prefrontal cortex, dorsolateral prefrontal cortex, frontal pole, posterior cingulate cortex, anterior cingulate cortex, temporal-parietal junction, and lateral temporal lobe and negative connectivity to the amygdala, hippocampus, insula, and visual cortex. Among all 24 neuropsychiatric symptoms included in the Harvard Lesion Repository, criminality demonstrated the most alignment with our aggression-associated network. Deep brain stimulation site connectivity to this same network was associated with increased irritability. CONCLUSIONS We conclude that brain lesions associated with aggression map to a specific human brain circuit, and the functionally connected regions in this circuit provide testable targets for therapeutic neuromodulation.
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Affiliation(s)
- Shaoling Peng
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Frederic L W V J Schaper
- Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Shira Cohen-Zimerman
- Cognitive Neuroscience Laboratory, Brain Injury Research, Shirley Ryan Ability Lab, Chicago, Illinois; Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Gillian N Miller
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jing Jiang
- Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Rob P W Rouhl
- Department of Neurology and School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands; Academic Center for Epileptology Kempenhaeghe/Maastricht University Medical Center, Heeze & Maastricht, the Netherlands
| | - Yasin Temel
- Department of Neurosurgery and School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Shan H Siddiqi
- Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jordan Grafman
- Cognitive Neuroscience Laboratory, Brain Injury Research, Shirley Ryan Ability Lab, Chicago, Illinois; Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Psychiatry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, Illinois
| | - Michael D Fox
- Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Alexander L Cohen
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
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Mercier C, Rollason V, Eshmawey M, Mendes A, Frisoni GB. The treatment of behavioural and psychological symptoms in dementia: pragmatic recommendations. Psychogeriatrics 2024; 24:968-982. [PMID: 38638077 DOI: 10.1111/psyg.13116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/20/2024] [Accepted: 03/19/2024] [Indexed: 04/20/2024]
Abstract
Behavioural and psychological symptoms of dementia (BPSD) are a clinical challenge for the lack of a sound taxonomy, frequent presentation with comorbid BPSD, lack of specific pharmacologic interventions, poor base of methodologically sound evidence with randomized clinical trials, contamination from the treatment of behavioural disturbances of young and adult psychiatric conditions, and small efficacy window of psychotropic drugs. We present here a treatment workflow based on a concept-driven literature review based on the notions that (i) the aetiology of BPSD can be mainly neurobiological (so-called 'primary' symptoms) or mainly environmental and functional ('secondary' symptoms) and that this drives treatment; (ii) the clinical efficacy of psychotropic drugs is driven by their specific profile of receptor affinity; (iii) drug treatment should follow the rules of 'start low-go slow, prescribe and revise'. This article argues in support of the distinction between primary and secondary BPSD, as well as their characteristics, which until now have been just sketchily described in the literature. It also offers comprehensive and pragmatic clinician-oriented recommendations for the treatment of BPSD.
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Affiliation(s)
- Camille Mercier
- Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland
- Memory Center, Department of Rehabilitation and Geriatrics, University Hospitals of Geneva, Geneva, Switzerland
| | - Victoria Rollason
- Department of Acute Medicine, Clinical Pharmacology and Toxicology Service, University Hospitals of Geneva, Geneva, Switzerland
| | - Mohamed Eshmawey
- Department of Psychiatry, Geriatric Psychiatry Service, University Hospitals of Geneva, Geneva, Switzerland
| | - Aline Mendes
- Geriatrics and Rehabilitation Department, Department of Rehabilitation and Geriatrics, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland
| | - Giovanni B Frisoni
- Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland
- Memory Center, Department of Rehabilitation and Geriatrics, University Hospitals of Geneva, Geneva, Switzerland
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Antonsdottir IM, Creese B, Klei L, DeMichele‐Sweet MAA, Weamer EA, Garcia‐Gonzalez P, Marquie M, Boada M, Alarcón‐Martín E, Valero S, NIA‐LOAD Family Based Study Consortium, Alzheimer's Disease Genetics Consortium (ADGC), AddNeuroMed Consortium, Liu Y, Hooli B, Aarsland D, Selbaek G, Bergh S, Rongve A, Saltvedt I, Skjellegrind HK, Engdahl B, Andreassen OA, Borroni B, Mecocci P, Wedatilake Y, Mayeux R, Foroud T, Ruiz A, Lopez OL, Kamboh MI, Ballard C, Devlin B, Lyketsos C, Sweet RA. Genetic associations with psychosis and affective disturbance in Alzheimer's disease. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2024; 10:e12472. [PMID: 38784964 PMCID: PMC11114588 DOI: 10.1002/trc2.12472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 11/01/2023] [Accepted: 01/30/2024] [Indexed: 05/25/2024]
Abstract
INTRODUCTION Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHODS Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.
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Del Rosario Hernández T, Gore SV, Kreiling JA, Creton R. Drug repurposing for neurodegenerative diseases using Zebrafish behavioral profiles. Biomed Pharmacother 2024; 171:116096. [PMID: 38185043 PMCID: PMC10922774 DOI: 10.1016/j.biopha.2023.116096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/18/2023] [Accepted: 12/26/2023] [Indexed: 01/09/2024] Open
Abstract
Drug repurposing can accelerate drug development while reducing the cost and risk of toxicity typically associated with de novo drug design. Several disorders lacking pharmacological solutions and exhibiting poor results in clinical trials - such as Alzheimer's disease (AD) - could benefit from a cost-effective approach to finding new therapeutics. We previously developed a neural network model, Z-LaP Tracker, capable of quantifying behaviors in zebrafish larvae relevant to cognitive function, including activity, reactivity, swimming patterns, and optomotor response in the presence of visual and acoustic stimuli. Using this model, we performed a high-throughput screening of FDA-approved drugs to identify compounds that affect zebrafish larval behavior in a manner consistent with the distinct behavior induced by calcineurin inhibitors. Cyclosporine (CsA) and other calcineurin inhibitors have garnered interest for their potential role in the prevention of AD. We generated behavioral profiles suitable for cluster analysis, through which we identified 64 candidate therapeutics for neurodegenerative disorders.
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Affiliation(s)
| | - Sayali V Gore
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
| | - Jill A Kreiling
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
| | - Robbert Creton
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
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9
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Hernández TDR, Gore SV, Kreiling JA, Creton R. Finding Drug Repurposing Candidates for Neurodegenerative Diseases using Zebrafish Behavioral Profiles. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.12.557235. [PMID: 37745452 PMCID: PMC10515830 DOI: 10.1101/2023.09.12.557235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Drug repurposing can accelerate drug development while reducing the cost and risk of toxicity typically associated with de novo drug design. Several disorders lacking pharmacological solutions and exhibiting poor results in clinical trials - such as Alzheimer's disease (AD) - could benefit from a cost-effective approach to finding new therapeutics. We previously developed a neural network model, Z-LaP Tracker, capable of quantifying behaviors in zebrafish larvae relevant to cognitive function, including activity, reactivity, swimming patterns, and optomotor response in the presence of visual and acoustic stimuli. Using this model, we performed a high-throughput screening of FDA-approved drugs to identify compounds that affect zebrafish larval behavior in a manner consistent with the distinct behavior induced by calcineurin inhibitors. Cyclosporine (CsA) and other calcineurin inhibitors have garnered interest for their potential role in the prevention of AD. We generated behavioral profiles suitable for cluster analysis, through which we identified 64 candidate therapeutics for neurodegenerative disorders.
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Affiliation(s)
- Thaís Del Rosario Hernández
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
| | - Sayali V Gore
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
| | - Jill A Kreiling
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
| | - Robbert Creton
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA
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Fan P, Zeng L, Ding Y, Kofler J, Silverstein J, Krivinko J, Sweet RA, Wang L. Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease. CPT Pharmacometrics Syst Pharmacol 2023; 12:1119-1131. [PMID: 37128639 PMCID: PMC10431054 DOI: 10.1002/psp4.12979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 05/03/2023] Open
Abstract
Psychotic symptoms are reported as one of the most common complications of Alzheimer's disease (AD), in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in patients with AD and with psychosis (AD+P) and themselves increase mortality. Recent studies suggested the use and beneficial effects of antidepressants among patients with AD+P. This motivates our rationale for exploring their potential as a novel combination therapy option among these patients. We included electronic medical records of 10,260 patients with AD in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. A protein-protein interaction network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. A combined score was developed to measure the potential synergetic effect against AD+P. Our survival analyses showed that the co-administration of antidepressants with antipsychotics have a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar Signed Jaccard Index (SJI) scores to AD+P. Eight drug pairs, including some popular recommendations like aripiprazole/sertraline, showed higher than average scores which suggest their potential in treating AD+P via strong synergetic effects. Our proposed combinations of antipsychotic and antidepressant therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.
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Affiliation(s)
- Peihao Fan
- Computational Chemical Genomics Screening Center, Department of Pharmaceutical Sciences/School of PharmacyUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Lang Zeng
- Graduate School of Public HealthUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Ying Ding
- Graduate School of Public HealthUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Julia Kofler
- Division of Neuropathology, Department of PathologyUniversity of Pittsburgh Medical CenterPittsburghPennsylvaniaUSA
| | - Jonathan Silverstein
- Department of Biomedical Informatics, School of MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Joshua Krivinko
- Department of Psychiatry, School of MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Robert A. Sweet
- Department of Psychiatry, School of MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
- Alzheimer Disease Research CenterUniversity of Pittsburgh Medical CenterPittsburghPennsylvaniaUSA
| | - Lirong Wang
- Computational Chemical Genomics Screening Center, Department of Pharmaceutical Sciences/School of PharmacyUniversity of PittsburghPittsburghPennsylvaniaUSA
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Abstract
OBJECTIVES Administration of antidepressant drugs - principally selective serotonin reuptake inhibitors (SSRIs) - may induce clinically significant 'apathy' which can affect treatment outcomes adversely. We aimed to review all relevant previous reports. METHODS We performed a PUBMED search of English-language studies, combining terms concerning psychopathology (e.g. apathy) and classes of antidepressants (e.g. SSRI). RESULTS According to certain inclusion (e.g. use of DSM/ICD diagnostic criteria) and exclusion (e.g. presence of a clinical condition that may induce apathy) criteria, 50 articles were eligible for review. Together, they suggest that administration of antidepressants - usually SSRIs - can induce an apathy syndrome or emotional blunting, i.e. a decrease in emotional responsiveness, to circumstances which would have triggered intense mood reactions prior to pharmacotherapy. The reported prevalence of antidepressant-induced apathy ranges between 5.8 and 50%, and for SSRIs ranges between 20 and 92%. Antidepressant-induced apathy emerges independently of diagnosis, age, and treatment outcome and appears dose-dependent and reversible. The main treatment strategy is dose reduction, though some data suggest the usefulness of treatment with olanzapine, bupropion, agomelatine or amisulpride, or the methylphenidate-modafinil-olanzapine combination. CONCLUSION Antidepressant-induced apathy needs careful clinical attention. Further systematic research is needed to investigate the prevalence, course, aetiology, and treatment of this important clinical condition.
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Affiliation(s)
- Vasilios G Masdrakis
- Department of Psychiatry, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Manolis Markianos
- Department of Psychiatry, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - David S Baldwin
- University Department of Psychiatry, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- University Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
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Theleritis C, Siarkos K, Politis A, Smyrnis N, Papageorgiou C, Politis AM. A Systematic Review of Pharmacological Interventions for Apathy in Aging Neurocognitive Disorders. Brain Sci 2023; 13:1061. [PMID: 37508993 PMCID: PMC10377475 DOI: 10.3390/brainsci13071061] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/05/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
OBJECTIVE Apathy, a frequent neuropsychiatric symptom in aging neurocognitive disorders, has been associated with cognitive decline and functional disability. Therefore, timely provision of pharmacological interventions for apathy is greatly needed. DESIGN A systematical literature review of existing studies was conducted up to 30 May 2023 in several databases (PubMed, PsychInfo, Cochrane, Google Scholar, etc.) that included randomized controlled trials (RCTs) and meta-analyses assessing pharmacological treatments for apathy in aging neurocognitive disorders. The quality of the studies was appraised. RESULTS In patients with Alzheimer's Disease (AD), donepezil, galantamine, rivastigmine, methylphenidate, and gingko biloba were proven efficacious for apathy, while rivastigmine, cognitive enhancer IRL752 and piribedil were found to be beneficial in patients with Parkinson's Disease (PD) and agomelatine in patients with Frontotemporal Dementia (FD). The extensive proportion of RCTs in which apathy was used as a secondary outcome measure, along with the considerable methodological heterogeneity, did not allow the evaluation of group effects. CONCLUSIONS Pharmacological interventions for apathy in aging neurocognitive disorders are complex and under-investigated. The continuation of systematic research efforts and the provision of individualized treatment for patients suffering from these disorders is vital.
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Affiliation(s)
- Christos Theleritis
- First Department of Psychiatry, National and Kapodistrian University of Athens, Eginition Hospital, 74 Vas. Sofias Ave., 11528 Athens, Greece
| | - Kostas Siarkos
- First Department of Psychiatry, National and Kapodistrian University of Athens, Eginition Hospital, 74 Vas. Sofias Ave., 11528 Athens, Greece
| | - Anastasios Politis
- Second Department of Neurosurgery, National and Kapodistrian University of Athens, Attikon Hospital, 1 Rimini Str., 12462 Athens, Greece
| | - Nikolaos Smyrnis
- Second Department of Psychiatry, National and Kapodistrian University of Athens, Attikon Hospital, 1 Rimini Str., 12462 Athens, Greece
| | - Charalabos Papageorgiou
- First Department of Psychiatry, National and Kapodistrian University of Athens, Eginition Hospital, 74 Vas. Sofias Ave., 11528 Athens, Greece
| | - Antonios M Politis
- First Department of Psychiatry, National and Kapodistrian University of Athens, Eginition Hospital, 74 Vas. Sofias Ave., 11528 Athens, Greece
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21218, USA
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13
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Fan P, Zeng L, Ding Y, Kofler J, Silverstein J, Krivinko J, Sweet RA, Wang L. Combination of Antidepressants and Antipsychotics as A Novel Treatment Option for Psychosis in Alzheimer's Disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.01.24.23284970. [PMID: 36747620 PMCID: PMC9901071 DOI: 10.1101/2023.01.24.23284970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Background Psychotic symptoms are reported as one of the most common complications of Alzheimer's disease (AD), affecting approximately half of AD patients, in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in AD patients with psychosis (AD+P) and themselves increase mortality. A recent genome-wide meta-analysis and early clinical trials suggest the use and beneficial effects of antidepressants among AD+P patients. This motivates our rationale for exploring their potential as a novel combination therapy option amongst these patients. Methods We included University of Pittsburgh Medical Center (UPMC) electronic medical records (EMRs) of 10,260 AD patients from January 2004 and October 2019 in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. To provide more valuable insights on the hidden mechanisms of the combinatorial therapy, a protein-protein interaction (PPI) network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. An indicator score combining the measurements on the separation between drugs and the proximity between the drugs and AD+P was used to measure the effect of an antipsychotic-antidepressant drug pair against AD+P. Results Our survival analyses replicated that antipsychotic usage is strongly associated with increased mortality in AD patients while the co-administration of antidepressants with antipsychotics showed a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar proximity scores to AD+P. Eight drug pairs, including some popular recommendations like Aripiprazole/Sertraline and other pairs not reported previously like Iloperidone/Maprotiline showed higher than average indicator scores which suggest their potential in treating AD+P via strong synergetic effects as seen in our study. Conclusion Our proposed combinations of antipsychotics and antidepressants therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.
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14
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Chen K, Li H, Yang L, Jiang Y, Wang Q, Zhang J, He J. Comparative efficacy and safety of antidepressant therapy for the agitation of dementia: A systematic review and network meta-analysis. Front Aging Neurosci 2023; 15:1103039. [PMID: 36936502 PMCID: PMC10020338 DOI: 10.3389/fnagi.2023.1103039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 02/13/2023] [Indexed: 03/06/2023] Open
Abstract
Background Dementia is a clinical syndrome commonly seen in the elderly individuals. With the prevalence of dementia, the incidence of neuropsychiatric symptoms in dementia patients is increasing annually. Agitation, as one of the neuropsychiatric symptoms, has a serious impact on the quality of life of patients with dementia. Several antidepressant drugs have been shown to be effective for treating agitated behavior symptoms in patients with dementia, but there are no direct comparisons among those drugs. Therefore, we carried out a network meta-analysis (NMA) to examine the efficacy and safety of those antidepressant drugs. Methods We searched eight databases (PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, China National Knowledge Infrastructure, VIP Database and China biomedical literature service) from their inception to 6 November 2022. Randomized controlled trials (RCTs) reporting the efficacy and safety of antidepressant drugs in treating agitated behavior symptoms in patients with dementia were included in our analysis. The quality assessment was carried out by two researchers individually and the analysis was based on the frequency method. Results Twelve articles with 1,146 participants were included in our analysis. Based on the outcome of the agitation score, treatment with citalopram (standardized mean difference, SMD = -0.44, 95% confidence interval, 95% CI = -0.72 to -0.16) showed significant benefits over the placebo group. Treatment with trazodone (odds ratio, OR = 4.58, 95% CI = 1.12-18.69) was associated with a higher risk of total adverse events compared with a placebo treatment. Conclusion Among the antidepressant drugs included in this study, treatment with citalopram was probably the only optimal intervention, when considering the improvement from baseline to the end of the intervention, and there was not a statistically significant difference in safety when compared with a placebo treatment. Systematic review registration https://www.crd.york.ac.uk/prospero/#recordDetails, identifier: PROSPERO, CRD42022320932.
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Affiliation(s)
- Kaili Chen
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Haiqi Li
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Le Yang
- Department of Endocrinology, Jilin Province People's Hospital, Changchun, China
| | - Yan Jiang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qiaoli Wang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiao Zhang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinting He
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Jinting He
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15
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Fischer CE, Namasivayam A, Crawford-Holland L, Hakobyan N, Schweizer TA, Munoz DG, Pollock BG. Psychotic Disorders in the Elderly: Diagnosis, Epidemiology, and Treatment. Psychiatr Clin North Am 2022; 45:691-705. [PMID: 36396273 DOI: 10.1016/j.psc.2022.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
This review covers the latest advances in our understanding of psychosis in the elderly population with respect to diagnosis, epidemiology, and treatment. Major topics of discussion include late life psychiatric disorders such as schizophrenia, schizoaffective disorder, and delusional disorder as well as dementia-related psychosis. Clinical differences between early-onset and late-onset disorders are reviewed in terms of prevalence, symptomatology, and approach to treatment. Newly revised research and clinical criteria for dementia-related psychosis are referenced. The evidence base for emerging therapies including citalopram and pimavanserin in relation to conventional therapies such as atypical antipsychotics are discussed..
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Affiliation(s)
- Corinne E Fischer
- Keenan Research Centre for Biomedical Science, Room 17044 cc wing, St. Michaels Hospital, #30 Bond St., Toronto, Ontario, M5B1W8, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
| | - Andrew Namasivayam
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Lucas Crawford-Holland
- Keenan Research Centre for Biomedical Science, Room 17044 cc wing, St. Michaels Hospital, #30 Bond St., Toronto, Ontario, M5B1W8, Canada
| | - Narek Hakobyan
- Keenan Research Centre for Biomedical Science, Room 17044 cc wing, St. Michaels Hospital, #30 Bond St., Toronto, Ontario, M5B1W8, Canada
| | - Tom A Schweizer
- Keenan Research Centre for Biomedical Science, Room 17044 cc wing, St. Michaels Hospital, #30 Bond St., Toronto, Ontario, M5B1W8, Canada; St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; Department of Neurosurgery, University of Toronto, Toronto, Canada
| | - David G Munoz
- Keenan Research Centre for Biomedical Science, Room 17044 cc wing, St. Michaels Hospital, #30 Bond St., Toronto, Ontario, M5B1W8, Canada; St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Bruce G Pollock
- Division of Geriatric Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8, Canada; Toronto Dementia Research Alliance, University of Toronto, Toronto, Ontario, Canada
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16
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Agüera-Ortiz L, Babulal GM, Bruneau MA, Creese B, D'Antonio F, Fischer CE, Gatchel JR, Ismail Z, Kumar S, McGeown WJ, Mortby ME, Nuñez NA, de Oliveira FF, Pereiro AX, Ravona-Springer R, Rouse HJ, Wang H, Lanctôt KL. Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions. J Alzheimers Dis 2022; 88:1203-1228. [PMID: 35786651 PMCID: PMC9484097 DOI: 10.3233/jad-215483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.
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Affiliation(s)
- Luis Agüera-Ortiz
- Department of Psychiatry, Instituto de Investigación Sanitaria (imas12), Hospital Universitario 12 de Octubre, & Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain
| | - Ganesh M Babulal
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.,Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.,Department of Psychology, Faculty of Humanities, University of Johannesburg, South Africa
| | - Marie-Andrée Bruneau
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal, Quebec, Canada.,Geriatric Institute of Montreal Research Center, Montreal, Quebec, Canada
| | - Byron Creese
- Medical School, College of Medicine and Health, University of Exeter, UK
| | | | - Corinne E Fischer
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.,University of Toronto, Department of Psychiatry, Toronto, Ontario, Canada
| | - Jennifer R Gatchel
- Harvard Medical School; Massachusetts General Hospital, Boston MA, USA.,McLean Hospital, Belmont MA, USA
| | - Zahinoor Ismail
- Hotchkiss Brain Institute & O'Brien Institute for Public Health, University of Calgary, Calgary, Canada
| | - Sanjeev Kumar
- Adult Neurodevelopmental and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - William J McGeown
- School of Psychological Sciences and Health, University of Strathclyde, Glasgow, UK
| | - Moyra E Mortby
- School of Psychology, University of New South Wales, Sydney, Australia & Neuroscience Research Australia, Sydney, Australia
| | - Nicolas A Nuñez
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - Fabricio F de Oliveira
- Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Arturo X Pereiro
- Facultade de Psicoloxía, Universidade de Santiago de Compostela, Spain
| | - Ramit Ravona-Springer
- Sheba Medical Center, Tel Hashomer, Israel & Sackler School of Medicine, Tel Aviv University, Israel
| | - Hillary J Rouse
- School of Aging Studies, University of South Florida, Tampa, FL, USA.,SiteRx, New York, NY, USA
| | - Huali Wang
- Dementia Care and Research Center, Peking University Institute of Mental Health; National & Clinical Research Center for Mental Disorders, Beijing, China
| | - Krista L Lanctôt
- Hurvitz Brain Sciences Program, Sunnybrook Research Institute and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada
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17
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Qasim HS, Simpson MD. A Narrative Review of Studies Comparing Efficacy and Safety of Citalopram with Atypical Antipsychotics for Agitation in Behavioral and Psychological Symptoms of Dementia (BPSD). PHARMACY 2022; 10:pharmacy10030061. [PMID: 35736776 PMCID: PMC9228736 DOI: 10.3390/pharmacy10030061] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/14/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Psychomotor agitation as part of the behavioral and psychological symptoms of dementia (BPSD) is one of the common issues found in aged care facilities. The current inadequate management strategies lead to poor functional and medical outcomes. Psychotropic interventions are the current preferred treatment method, but should these medications be the prescribers’ first preference? This review aims to compare pharmacological interventions for psychomotor agitation, judging them according to their effectuality and justifiability profiles. This is to be achieved by retrieving information from Randomized Control Trials (RCTs) and systematic reviews. Objectives: This review evaluates evidence from RCTs, systematic reviews, and meta-analyses of BPSD patients who have taken agitation treatments. Assessing the efficacy of citalopram, other selective serotonin reuptake inhibitors (SSRIs) and antipsychotic treatments were compared to each other for the purpose of improving agitation outcomes and lowering patient side effects. Methods: This review includes RCT that compared citalopram with one or more atypical antipsychotics or with a placebo, along with systematic reviews comparing citalopram (SSRI) with antipsychotics such as quetiapine, olanzapine, and risperidone. Studies were extracted by searching and accessing databases, such as PubMed, OVID, and Cochrane with restrictions of date from 2000 to 2021 and published in the English language. Conclusion: There are still a limited number of studies including SSRIs for the treatment of agitation in BPSD. SSRIs such as citalopram were associated with a reduction in the symptoms of agitation, and lower risk of adverse effects when compared to antipsychotics. Future studies are required to assess the long-term safety and efficacy of SSRI treatments for agitation in BPSD.
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18
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Rashid N, Wetmore JB, Irfan M, Peng Y, Abler V. Medicare claims analysis of agents used to manage dementia-related psychosis: a treatment pattern study. Int Clin Psychopharmacol 2022; 37:84-91. [PMID: 35357330 PMCID: PMC8969840 DOI: 10.1097/yic.0000000000000401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 02/15/2022] [Indexed: 11/25/2022]
Abstract
Currently, no agents are approved in the USA to treat dementia-related psychosis. After failure of a nonpharmacologic approach to treatment, antipsychotics or divalproex is often prescribed. We characterized existing treatment patterns in patients with dementia-related psychosis. Medicare claims data from 2008 to 2016 were used to identify patients with dementia-related psychosis. The agents and associated dosages prescribed, time to first use, and patterns of use were evaluated for agents prescribed to treat dementia-related psychosis. In total, 49 509 patients were identified as having dementia-related psychosis. Over three-quarters (76.8%) received an antipsychotic or divalproex. The most prescribed first-line agents were quetiapine (30.5%), risperidone (19.5%), and divalproex (11.2%). More than 80% of patients received a low dose of an agent, and 65.5% switched or discontinued their first-line treatment during a mean follow-up period of 1.8 years. In the absence of US FDA-approved therapies to treat dementia-related psychosis, treatment after behavioral intervention involves frequent use of low-dose antipsychotics or divalproex. The high rate of treatment switching or discontinuation is consistent with current treatment guidelines and suggests a need for an improved, standardized pharmacological approach to treat dementia-related psychosis.
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Affiliation(s)
- Nazia Rashid
- Acadia Pharmaceuticals Inc., San Diego, California
| | - James B. Wetmore
- Division of Nephrology, Hennepin County Medical Center
- Chronic Disease Research Group, Hennepin Healthcare Research Institute
| | - Muna Irfan
- Department of Neurology, University of Minnesota and Veterans Affairs Medical Center, Minneapolis, Minnesota, USA
| | - Yi Peng
- Chronic Disease Research Group, Hennepin Healthcare Research Institute
| | - Victor Abler
- Acadia Pharmaceuticals Inc., San Diego, California
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19
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Moskaliuk VS, Kozhemyakina RV, Bazovkina DV, Terenina E, Khomenko TM, Volcho KP, Salakhutdinov NF, Kulikov AV, Naumenko VS, Kulikova E. On an association between fear-induced aggression and striatal-enriched protein tyrosine phosphatase (STEP) in the brain of Norway rats. Pharmacotherapy 2022; 147:112667. [DOI: 10.1016/j.biopha.2022.112667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/14/2022] [Accepted: 01/24/2022] [Indexed: 11/28/2022]
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20
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Azhar L, Kusumo RW, Marotta G, Lanctôt KL, Herrmann N. Pharmacological Management of Apathy in Dementia. CNS Drugs 2022; 36:143-165. [PMID: 35006557 DOI: 10.1007/s40263-021-00883-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2021] [Indexed: 12/11/2022]
Abstract
Apathy is a highly prevalent symptom of dementia. Despite its association with faster cognitive and functional decline, decreased quality of life and increased mortality, no therapies are currently approved to treat apathy. The objective of this review was to summarize the drugs that have been studied for apathy treatment in patients with dementia (specifically Alzheimer's disease [AD], Huntington's disease [HD] and Parkinson's disease [PD] dementia; dementia with Lewy bodies [DLB]; vascular dementia [VaD]; and frontotemporal dementia [FTD]) based on their putative mechanisms of action. A search for relevant studies was performed using ClinicalTrials.gov and PubMed. Eligible studies were randomized controlled trials that were available in English and included at least one drug intervention and an apathy measure scale. A total of 52 studies that included patients with AD (n = 33 studies), PD (n = 5), HD (n = 1), DLB (n = 1), FTD (n = 3), VaD (n = 1), VaD and AD (n = 4), VaD and mixed dementia (n = 1), and AD, VaD and mixed dementia (n = 3) were eligible for inclusion. These studies showed that methylphenidate, olanzapine, cholinesterase inhibitors, choline alphoscerate, citalopram, memantine, and mibampator are the only beneficial drugs in AD-related apathy. For PD-related apathy, only methylphenidate, rotigotine and rivastigmine showed benefits. Regarding FTD- and DLB-related apathy, initial studies with agomelatine and rivastigmine showed benefits, respectively. As for HD- and only-VaD-related apathy, no drugs demonstrated benefits. With regards to mixed populations, memantine, galantamine and gingko biloba showed effects on apathy in the AD plus VaD populations and nimodipine in the VaD plus mixed dementia populations. Of the drugs with positive results, some are already prescribed to patients with dementia to target other symptoms, some have characteristics-such as medical contraindications (e.g., cardiovascular) and adverse effects (e.g., gastrointestinal disturbances)-that limit their clinical use and some require further study. Future studies should investigate apathy as a primary outcome, making use of appropriate sample sizes and study durations to ensure durability of results. There should also be a consensus on using scales with high test/retest and interrater reliabilities to limit the inconsistencies between clinical trials. In conclusion, there are currently no US FDA-approved drugs that target apathy in dementia, so there is an ongoing need for the development of such drugs.
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Affiliation(s)
- Laiba Azhar
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Raphael W Kusumo
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Giovanni Marotta
- Geriatric Medicine Division, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Krista L Lanctôt
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Nathan Herrmann
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada.
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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21
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Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials. Am J Geriatr Psychiatry 2022; 30:119-147. [PMID: 34315645 DOI: 10.1016/j.jagp.2021.06.016] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/25/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022]
Abstract
Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.
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22
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Mühlbauer V, Möhler R, Dichter MN, Zuidema SU, Köpke S, Luijendijk HJ. Antipsychotics for agitation and psychosis in people with Alzheimer's disease and vascular dementia. Cochrane Database Syst Rev 2021; 12:CD013304. [PMID: 34918337 PMCID: PMC8678509 DOI: 10.1002/14651858.cd013304.pub2] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Typical and atypical antipsychotics are widely used to treat agitation and psychosis in dementia. However, whether or not they are beneficial is uncertain. Some trials have yielded negative results and effectiveness may be outweighed by harms. OBJECTIVES To assess the efficacy and safety of antipsychotics for the treatment of agitation and psychosis in people with Alzheimer's disease and vascular dementia. SEARCH METHODS We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid Sp), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov and the World Health Organization's meta-register, and the International Clinical Trials Registry Portal on 7 January 2021. Two review authors independently screened the title and abstract of the hits, and two review authors assessed the full text of studies that got through this screening. SELECTION CRITERIA We included randomised, placebo-controlled, parallel-arm trials comparing the effects of antipsychotics and placebo for the treatment of agitation or psychosis in people with dementia due to Alzheimer's disease or vascular dementia, or both, irrespective of age, severity of cognitive impairment, and setting. (The majority of) participants had to have clinically significant agitation (including aggression) or psychosis or both at baseline. We excluded studies about antipsychotics that are no longer available in the USA or EU, or that are used for emergency short-term sedation. We also excluded head-to-head trials and antipsychotic withdrawal trials. DATA COLLECTION AND ANALYSIS The primary outcomes were (1) reduction in agitation or psychosis in participants with agitation or psychosis, respectively at baseline, and (2) the number of participants with adverse events: somnolence, extrapyramidal symptoms, any adverse event, any serious adverse event (SAE), and death. Two review authors independently extracted the necessary data and assessed risk of bias with the Cochrane risk of bias tool. We calculated the pooled effect on agitation and psychosis for typical and atypical antipsychotics separately, and the pooled risk of adverse effects independent of the target symptom (agitation or psychosis). We used RevMan Web for the analyses. MAIN RESULTS The search yielded 8233 separate hits. After assessing the full-text of 35 studies, we included 24 trials that met the eligibility criteria. Six trials tested a typical antipsychotic, four for agitation and two for psychosis. Twenty trials tested an atypical antipsychotic, eight for agitation and 12 for psychosis. Two trials tested both drug types. Seventeen of 26 comparisons were performed in patients with Alzheimer's disease specifically. The other nine comparisons also included patients with vascular dementia or mixed dementia. Together, the studies included 6090 participants (12 to 652 per study). The trials were performed in institutionalised, hospitalised and community-dwelling patients, or a combination of those. For typical antipsychotics (e.g. haloperidol, thiothixene), we are uncertain whether these drugs improve agitation compared with placebo (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.57 to -0.15, 4 studies, n = 361); very low-certainty evidence, but typical antipsychotics may improve psychosis slightly (SMD -0.29, 95% CI -0.55 to -0.03, 2studies, n= 240; low-certainty evidence) compared with placebo. These drugs probably increase the risk of somnolence (risk ratio (RR) 2.62, 95% CI 1.51 to 4.56, 3 studies, n = 466; moderate-certainty evidence) and increase extrapyramidal symptoms (RR 2.26, 95% CI 1.58 to 3.23, 3 studies, n = 467; high-certainty) evidence. There was no evidence regarding the risk of any adverse event. The risks of SAEs (RR 1.32, 95% CI 0.65 to 2.66, 1 study, n = 193) and death (RR 1.46, 95% CI 0.54 to 4.00, 6 studies, n = 578) may be increased slightly, but these estimates were very imprecise, and the certainty was low. The effect estimates for haloperidol from five trials were in line with those of the drug class. Atypical antipsychotics (e.g. risperidone, olanzapine, aripiprazole, quetiapine) probably reduce agitation slightly (SMD -0.21, 95% CI -0.30 to -0.12, 7 studies, n = 1971; moderate-certainty evidence), but probably have a negligible effect on psychosis (SMD -0.11, 95% CI -0.18 to -0.03, 12 studies, n = 3364; moderate-certainty evidence). These drugs increase the risk of somnolence (RR 1.93, 95% CI 1.57 to 2.39, 13 studies, n - 3878; high-certainty evidence) and are probably also associated with slightly increased risk of extrapyramidal symptoms (RR 1.39, 95% CI 1.14 to 1.68, 15 studies, n = 4180; moderate-certainty evidence), serious adverse events (RR 1.32, 95% CI 1.09 to 1.61, 15 studies, n= 4316; moderate-certainty evidence) and death (RR 1.36, 95% CI 0.90 to 2.05, 17 studies, n= 5032; moderate-certainty evidence), although the latter estimate was imprecise. The drugs probably have a negligible effect on the risk of any adverse event (RR 1.05, 95% CI 1.02 to 1.09, 11 studies, n = 2785; moderate-certainty evidence). The findings from seven trials for risperidone were in line with those for the drug class. AUTHORS' CONCLUSIONS There is some evidence that typical antipsychotics might decrease agitation and psychosis slightly in patients with dementia. Atypical antipsychotics reduce agitation in dementia slightly, but their effect on psychosis in dementia is negligible. The apparent effectiveness of the drugs seen in daily practice may be explained by a favourable natural course of the symptoms, as observed in the placebo groups. Both drug classes increase the risk of somnolence and other adverse events. If antipsychotics are considered for sedation in patients with severe and dangerous symptoms, this should be discussed openly with the patient and legal representative.
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Affiliation(s)
- Viktoria Mühlbauer
- DigiHealth Institute, Neu-Ulm University of Applied Sciences, Neu-Ulm, Germany
| | - Ralph Möhler
- Institute for Health Services Research and Health Economics, Centre for Health and Society, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
| | - Martin N Dichter
- German Center for Neurodegenerative Diseases (DZNE), Witten, Germany
| | - Sytse U Zuidema
- Department of General Practice and Elderly Care Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Sascha Köpke
- Institute of Nursing Science, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hendrika J Luijendijk
- Department of General Practice and Elderly Care Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Scuteri D, Corasaniti MT, Tonin P, Nicotera P, Bagetta G. New trends in pharmacological control of neuropsychiatric symptoms of dementia. Curr Opin Pharmacol 2021; 61:69-76. [PMID: 34634603 DOI: 10.1016/j.coph.2021.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 01/15/2023]
Abstract
Abnormal neuronal and synaptic plasticity occurs in Alzheimer's disease (AD) and depression. The latter, particularly late-life, has been recognized as fundamental in the identification of at-risk prodromal stages of AD. The lack of disease-modifying drugs and the off-label use of antipsychotics and antidepressants for neuropsychiatric symptoms (NPSs) have caused a season of therapeutic inappropriateness. To date, the wealth of clinical trials investigating drugs, diverse for structure and mechanism of action, has failed to provide a cure for all the spectrums of NPSs. Psychedelics in microdosing afford promotion of neurogenesis and synaptic plasticity and, recently, have been considered a revolution for the management of depression endowed with faster action and an improved side effect profile than antidepressants. In the current scenario, therefore, the rapid-acting antidepressant esketamine could represent the first-in-class for treatment of NPSs, and this deserves to be demonstrated with an open-label clinical trial.
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Affiliation(s)
- Damiana Scuteri
- Pharmacotechnology Documentation and Transfer Unit, Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; Regional Center for Serious Brain Injuries, S. Anna Institute, Crotone, Italy
| | | | - Paolo Tonin
- Regional Center for Serious Brain Injuries, S. Anna Institute, Crotone, Italy
| | | | - Giacinto Bagetta
- Pharmacotechnology Documentation and Transfer Unit, Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
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Closing the gap: unmet needs of individuals with impulsive aggressive behavior observed in children and adolescents. CNS Spectr 2021; 26:448-456. [PMID: 32228725 DOI: 10.1017/s1092852920001224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Impulsive aggressive (IA, or impulsive aggression) behavior describes an aggregate set of maladaptive, aggressive behaviors occurring across multiple neuropsychiatric disorders. IA is reactive, eruptive, sudden, and unplanned; it provides information about the severity, but not the nature, of its associated primary disorder. IA in children and adolescents is of serious clinical concern for patients, families, and physicians, given the detrimental impact pediatric IA can have on development. Currently, the ability to properly identify, monitor, and treat IA behavior across clinical populations is hindered by two major roadblocks: (1) the lack of an assessment tool designed for and sensitive to the set of behaviors comprising IA, and (2) the absence of a treatment indicated for IA symptomatology. In this review, we discuss the clinical gaps in the approach to monitoring and treating IA behavior, and highlight emerging solutions that may improve clinical outcomes in patients with IA.
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DeMichele-Sweet MAA, Klei L, Creese B, Harwood JC, Weamer EA, McClain L, Sims R, Hernandez I, Moreno-Grau S, Tárraga L, Boada M, Alarcón-Martín E, Valero S, Liu Y, Hooli B, Aarsland D, Selbaek G, Bergh S, Rongve A, Saltvedt I, Skjellegrind HK, Engdahl B, Stordal E, Andreassen OA, Djurovic S, Athanasiu L, Seripa D, Borroni B, Albani D, Forloni G, Mecocci P, Serretti A, De Ronchi D, Politis A, Williams J, Mayeux R, Foroud T, Ruiz A, Ballard C, Holmans P, Lopez OL, Kamboh MI, Devlin B, Sweet RA. Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol Psychiatry 2021; 26:5797-5811. [PMID: 34112972 PMCID: PMC8660923 DOI: 10.1038/s41380-021-01152-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 04/15/2021] [Accepted: 04/29/2021] [Indexed: 11/09/2022]
Abstract
Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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Affiliation(s)
| | - Lambertus Klei
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Byron Creese
- University of Exeter Medical School, College of Medicine and Health, Exeter, UK
- Norwegian, Exeter and King's College Consortium for Genetics of Neuropsychiatric Symptoms in Dementia, Exeter, UK
| | - Janet C Harwood
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
| | - Elise A Weamer
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Lora McClain
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rebecca Sims
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
| | - Isabel Hernandez
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Sonia Moreno-Grau
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Lluís Tárraga
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Mercè Boada
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Emilio Alarcón-Martín
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Sergi Valero
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Yushi Liu
- Global Statistical Science, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Basavaraj Hooli
- Neurodegeneration Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Dag Aarsland
- Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London and Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
| | - Geir Selbaek
- Norwegian National Advisory Unit in Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
- Department Geriatric Medicine, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Sverre Bergh
- Research Centre of Age-related Functional Decline and Disease, Innlandet Hospital Trust, Pb 68, Ottestad, Norway
| | - Arvid Rongve
- Department of Research and Innovation, Helse Fonna, Haugesund and Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway
| | - Ingvild Saltvedt
- Geriatric Department, St. Olav Hospital, University Hospital of Trondheim, Trondheim, Norway
- Department of Neuromedicine and Movement science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Håvard K Skjellegrind
- HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Levanger, Norway
- Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Bo Engdahl
- Norwegian Institute of Public Health, Oslo, Norway
| | - Eystein Stordal
- Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ole A Andreassen
- NORMENT Centre, Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Oslo, Norway
| | - Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Lavinia Athanasiu
- NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Davide Seripa
- Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy
| | - Barbara Borroni
- Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Diego Albani
- Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Gianluigi Forloni
- Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Patrizia Mecocci
- Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessandro Serretti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Diana De Ronchi
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Antonis Politis
- 1st Department of Psychiatry, Eginition Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Julie Williams
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
- UK Dementia Research Institute @ Cardiff, School of Medicine, Cardiff University, Cardiff, UK
| | - Richard Mayeux
- Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, USA
| | - Tatiana Foroud
- Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Agustin Ruiz
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | | | - Peter Holmans
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Oscar L Lopez
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - M Ilyas Kamboh
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bernie Devlin
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert A Sweet
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
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Wang YJ, Gong WG, Ren QG, Zhang ZJ. Escitalopram Alleviates Alzheimer's Disease-Type Tau Pathologies in the Aged P301L Tau Transgenic Mice. J Alzheimers Dis 2021; 77:807-819. [PMID: 32741828 DOI: 10.3233/jad-200401] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer's disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. OBJECTIVE In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. METHODS Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. RESULTS Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. CONCLUSION The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway.
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Affiliation(s)
- Yan-Juan Wang
- Department of Neurology, ZhongDa Hospital, Neuropsychiatric Institute, Medical School of Southeast University, Nanjing, China
| | - Wei-Gang Gong
- Department of Neurology, ZhongDa Hospital, Neuropsychiatric Institute, Medical School of Southeast University, Nanjing, China
| | - Qing-Guo Ren
- Department of Neurology, ZhongDa Hospital, Neuropsychiatric Institute, Medical School of Southeast University, Nanjing, China
| | - Zhi-Jun Zhang
- Department of Neurology, ZhongDa Hospital, Neuropsychiatric Institute, Medical School of Southeast University, Nanjing, China
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Hsu TW, Stubbs B, Liang CS, Chen TY, Yeh TC, Pan CC, Chu CS. Efficacy of serotonergic antidepressant treatment for the neuropsychiatric symptoms and agitation in dementia: A systematic review and meta-analysis. Ageing Res Rev 2021; 69:101362. [PMID: 34000464 DOI: 10.1016/j.arr.2021.101362] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Serotonergic dysfunction may be involved in the etiology of overall neuropsychiatric symptoms (NPS) and agitation in patients with dementia; therefore, we aim to perform a systematic review and meta-analysis to investigate the efficacy of serotonergic antidepressants in such populations. METHODS We systematically searched PubMed, Medline, Embase, and Cochrane Library to obtain randomized controlled trials (RCTs) from the date of their inception until December 11, 2020 to examine the effect of serotonergic antidepressants on the outcomes of interest in patients with dementia. Data were pooled using a random-effects model. Co-primary outcomes were mean changes in overall NPS and agitation as a specific symptom of NPS. Secondary outcomes were mean changes in depressive symptoms, cognition, and care burden. RESULTS Fourteen randomized controlled trials were eligible (n = 1,374; mean age = 76.8 years; mean proportion of female = 61.9 %). Serotonergic antidepressants significantly reduced the overall NPS (k = 12, n = 1276, Hedges' g = -0.49, 95 % confidence intervals [CIs] = -0.74 to -0.24, p < 0.001) and agitation severity (k = 9, n = 749, Hedges' g = -0.28, 95 % CIs = -0.43 to -0.14, p < 0.001), both with small effect size in patients with dementia. For secondary outcome, serotonergic antidepressants also significantly improved depressive symptoms, cognition, and care burden with small to very small effect sizes (depressive symptoms, k = 8, n = 938, Hedges' g = -0.32, 95 % CIs = -0.49 to -0.15, p < 0.001;cognition, k = 6, n = 983, Hedges' g = 0.15, 95 % CIs = 0.002 to 0.29, p = 0.046; care burden, k = 7, n = 961, Hedges' g = -0.24, 95 % CIs = -0.41 to -0.07, p = 0.005). Subgroup analysis showed that both selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs significant reduced agitation and depressive symptoms (For agitation, SSRIs, k = 6, n = 605, Hedges' g = -0.25, 95 % CIs = -0.41 to -0.09, p=0.002; non-SSRIs, k = 3, n = 144, Hedges' g = -0.41, 95 % CIs = -0.74 to -0.08, p = 0.016; For depression, SSRIs, k = 6, n = 736, Hedges' g = -0.29, 95 % CIs = -0.48 to -0.09, p=0.004; non-SSRIs, k = 343, n = 144, Hedges' g = -0.43, 95 % CIs = -0.78 to -0.09, p = 0.016), whereas only SSRIs reduced overall NPS (k = 9, n = 1109, Hedges' g = -0.49, 95 % CIs = -0.78 to -0.20, p = 0.001) and care burden (k = 5, n = 740, Hedges' g = -0.29, 95 % CIs = -0.50 to -0.08, p=0.007). CONCLUSION The present meta-analysis indicates that serotonergic antidepressants effectively alleviate overall NPS, agitation, depressive symptoms, and care burden, and improve cognitive function.
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Affiliation(s)
- Tien-Wei Hsu
- Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Brendon Stubbs
- Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK; Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK; Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK
| | - Chih-Sung Liang
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Tien-Yu Chen
- Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Ta-Chuan Yeh
- Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; Department of Psychiatry, Penghu Branch, Tri-Service General Hospital, Penghu, Taiwan
| | - Chih-Chuan Pan
- Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Che-Sheng Chu
- Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Non-invasive Neuromodulation Consortium for Mental Disorders, Society of Psychophysiology, Taipei, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Atypical antipsychotics in the treatment of psychotic symptoms in Alzheimer's disease: a systematic review. Int Clin Psychopharmacol 2021; 36:169-180. [PMID: 33902085 DOI: 10.1097/yic.0000000000000358] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
With the advancement of Alzheimer's disease as well as other types of dementia, in addition to the cognitive decline, psychiatric symptoms have been outlined, including psychotic symptoms. The aim of the study is to review the available results on the antipsychotic treatment of Alzheimer's disease associated psychotic symptoms. The main objective of the study is to evaluate the efficacy of the treatment. The second objective is to assess the tolerability of this treatment. Double-blind, randomized, placebo-controlled trials, which took place over the course of at least 4 weeks, have been searched. Studies that compared one atypical antipsychotic to placebo, as well as more atypical antipsychotics, compared one to another, have been taken into account. In total 17 studies have been selected. The efficacy of the atypical antipsychotics has proven to be significant in most studies. Moreover, antipsychotic medication, such as risperidone, aripiprazole, olanzapine, quetiapine and pimavanserin, has been well tolerated. Atypical antipsychotics are the treatment of choice for psychotic symptoms in dementia. Despite the consistent results present in the literature up to this point, various antipsychotics remain insufficiently studied and would need more generous sample sizes for their outcomes to be substantiated.
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Abstract
Aggressive behavior is one of the most disturbing symptoms of Alzheimer disease and other progressive neurodegenerative dementias. Development of strategies for management of aggressive behaviors in people with dementia is hindered by a lack of recognition that aggression is not a uniform behavioral construct. It is possible to distinguish 2 types of aggression: reactive or impulsive aggression and proactive or premeditated aggression. Research concerning aggressive behaviors in people with dementia is hindered by scales describing behavioral symptoms of dementia which do not distinguish between reactive and proactive aggressions because they do not consider the factors leading to these behaviors. Reactive aggression is caused by lack of understanding, leading to rejection of care, while proactive aggression could be caused by a psychopathic personality, hallucinations or delusions, and other determinants. It is difficult to underestimate the importance of distinguishing reactive and proactive aggressions in people with dementia because there are different strategies that can be used for management of these behaviors. For reactive aggression, delayed treatment, distraction, improved communication, and change in treatment strategy is useful, while antipsychotic medication may be needed for treatment of proactive aggression. Dementia is increasing the risk of both types of aggressions and antidepressant treatment can be helpful. Most importantly, persons exhibiting reactive aggression should not be labeled "aggressors" because this behavior could be caused by unmet persons' needs, pain and poor communication with care providers.
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Affiliation(s)
- Ladislav Volicer
- School of Aging Studies, 7831University of South Florida, Tampa, FL, USA.,3rd Medical Faculty, Charles University, Prague, Czech Republic
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Carrarini C, Russo M, Dono F, Barbone F, Rispoli MG, Ferri L, Di Pietro M, Digiovanni A, Ajdinaj P, Speranza R, Granzotto A, Frazzini V, Thomas A, Pilotto A, Padovani A, Onofrj M, Sensi SL, Bonanni L. Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions. Front Neurol 2021; 12:644317. [PMID: 33935943 PMCID: PMC8085397 DOI: 10.3389/fneur.2021.644317] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 03/12/2021] [Indexed: 01/11/2023] Open
Abstract
Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.
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Affiliation(s)
- Claudia Carrarini
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Mirella Russo
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Fedele Dono
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Filomena Barbone
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Marianna G Rispoli
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Laura Ferri
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Martina Di Pietro
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Anna Digiovanni
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Paola Ajdinaj
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Rino Speranza
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Alberto Granzotto
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Institute for Mind Impairments and Neurological Disorders-iMIND, University of California, Irvine, Irvine, CA, United States
| | - Valerio Frazzini
- Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Institut du Cerveau et de la Moelle épinière, ICM, INSERM UMRS 1127, CNRS UMR 7225, Pitié Salpêtrière Hospital, Paris, France.,AP-HP, GH Pitie-Salpêtrière-Charles Foix, Epilepsy Unit and Neurophysiology Department, Paris, France
| | - Astrid Thomas
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Andrea Pilotto
- Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Parkinson's Disease Rehabilitation Centre, FERB ONLUS-S. Isidoro Hospital, Trescore Balneario, Italy
| | - Alessandro Padovani
- Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Marco Onofrj
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Stefano L Sensi
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Laura Bonanni
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
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The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on management of behavioral and psychological symptoms in dementia. Psychiatry Res 2021; 295:113641. [PMID: 33340800 DOI: 10.1016/j.psychres.2020.113641] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/09/2020] [Indexed: 12/27/2022]
Abstract
Geriatric patients with dementia frequently present with agitation, aggression, psychosis, and other behavioral and psychological symptoms of dementia (BPSD). We present an update of our previously published algorithms for the use of psychopharmacologic agents in these patients taking into account more recent studies and findings in meta-analyses, reviews, and other published algorithms. We propose three algorithms: BPSD in an emergent, urgent, and non-urgent setting. In the emergent setting when intramuscular (IM) administration is necessary, the first-line recommendation is for olanzapine (since IM aripiprazole, previously favored, is no longer available) and haloperidol injection is the second choice, followed by possible consideration of an IM benzodiazepine. In the urgent setting, the first line would be oral second-generation antipsychotics (SGAs) aripiprazole and risperidone. Perhaps next could be then prazosin, and lastly electroconvulsive therapy is a consideration. There are risks associated with these agents, and adverse effects can be severe. Dosing strategies, discontinuation considerations, and side effects are discussed. In the non-emergent setting, medications are proposed for use in the following order: trazodone, donepezil and memantine, antidepressants such as escitalopram and sertraline, SGAs, prazosin, and carbamazepine. Other options with less support but potential future promise are discussed.
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Gerlach LB, Kales HC. Pharmacological Management of Neuropsychiatric Symptoms of Dementia. CURRENT TREATMENT OPTIONS IN PSYCHIATRY 2020; 7:489-507. [PMID: 33344107 PMCID: PMC7742723 DOI: 10.1007/s40501-020-00233-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE Neuropsychiatric symptoms are universal across all stages and types of dementia and can cause significant challenges for patients and caregivers. While there are currently no approved medications for treatment of neuropsychiatric symptoms of dementia, a variety of psychotropic medications such as antipsychotics, benzodiazepines, anticonvulsants, and antidepressants are used off-label to treat these symptoms. This systematic review evaluated the available evidence for effectiveness and tolerability of pharmacologic treatments in addressing behavioral disturbances in dementia. RECENT FINDINGS Inclusion criteria were placebo-controlled, randomized controlled clinical trials (RCTs) or meta-analyses; a total of 38 studies and 3 meta-analyses representing an additional 27 RCTs met the inclusion criteria. Of the medication classes evaluated, atypical antipsychotics had the greatest available evidence for use, however, the treatment effect size was modest. Nine trials of antidepressants were included; 3 trials supported use in dementia. Eight trials of anticonvulsants were included; only one showed benefit. For benzodiazepines, 2 RCTs were included; only one trial of lorazepam showed improvement. Six trials of melatonin agonists were included; none showed efficacy outside of improved sleep measures. Evidence for effectiveness of pimavanserin and dextromethorphan-quinidine was limited to one study each, both of which showed benefit. SUMMARY Despite the widespread off-label use of psychotropic medications for treatment of neuropsychiatric symptoms in dementia, there are relatively few RCTs to evaluate their use with treatment effect sizes absent or modest for most medication classes. Of the medication classes reviewed, atypical antipsychotics have the best evidence for effectiveness, however, the overall magnitude of treatment effect is modest and must be balanced with risk of serious adverse events including death.
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Affiliation(s)
- Lauren B. Gerlach
- Department of Psychiatry, University of Michigan, Ann Arbor, MI
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI
| | - Helen C. Kales
- Department of Psychiatry, University of California, Davis, CA
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Bateman DR, Gill S, Hu S, Foster ED, Ruthirakuhan MT, Sellek AF, Mortby ME, Matušková V, Ng KP, Tarawneh RM, Freund-Levi Y, Kumar S, Gauthier S, Rosenberg PB, Ferreira de Oliveira F, Devanand DP, Ballard C, Ismail Z. Agitation and impulsivity in mid and late life as possible risk markers for incident dementia. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2020; 6:e12016. [PMID: 32995467 PMCID: PMC7507499 DOI: 10.1002/trc2.12016] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 02/17/2020] [Indexed: 12/14/2022]
Abstract
To identify knowledge gaps regarding new-onset agitation and impulsivity prior to onset of cognitive impairment or dementia the International Society to Advance Alzheimer's Research and Treatment Neuropsychiatric Syndromes (NPS) Professional Interest Area conducted a scoping review. Extending a series of reviews exploring the pre-dementia risk syndrome Mild Behavioral Impairment (MBI), we focused on late-onset agitation and impulsivity (the MBI impulse dyscontrol domain) and risk of incident cognitive decline and dementia. This scoping review of agitation and impulsivity pre-dementia syndromes summarizes the current biomedical literature in terms of epidemiology, diagnosis and measurement, neurobiology, neuroimaging, biomarkers, course and prognosis, treatment, and ongoing clinical trials. Validations for pre-dementia scales such as the MBI Checklist, and incorporation into longitudinal and intervention trials, are needed to better understand impulse dyscontrol as a risk factor for mild cognitive impairment and dementia.
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Affiliation(s)
- Daniel R Bateman
- Department of Psychiatry Indiana University School of Medicine Indianapolis Indiana
- Indiana University Center for Aging Research Regenstrief Institute Indianapolis Indiana
| | - Sascha Gill
- Department of Clinical Neurosciences; and the Ron and Rene Ward Centre for Healthy Brain Aging Research; Hotchkiss Brain Institute University of Calgary Calgary Alberta Canada
| | - Sophie Hu
- Community Health Sciences, and O'Brien Institute for Public Health University of Calgary Calgary Alberta Canada
| | - Erin D Foster
- Ruth Lilly Medical Library Indiana University School of Medicine Indianapolis Indiana
- University of California Berkeley Berkeley CA
| | - Myuri T Ruthirakuhan
- Hurvitz Brain Sciences Research Program Sunnybrook Research Institute Toronto Ontario Canada
- Department of Pharmacology and Toxicology University of Toronto Ontario Canada
| | | | - Moyra E Mortby
- School of Psychology University of New South Wales Sydney New South Wales Australia
- Neuroscience Research Australia University of New South Wales Sydney New South Wales Australia
| | - Veronika Matušková
- International Clinical Research Center St. Anne's University Hospital Brno Brno Czech Republic
- Memory Disorders Clinic, Department of Neurology, 2nd Faculty of Medicine Charles University in Prague and Motol University Hospital Prague Czech Republic
| | - Kok Pin Ng
- Department of Neurology National Neuroscience Institute Singapore Singapore
| | - Rawan M Tarawneh
- Department of Neurology, College of Medicine The Ohio State University Columbus Ohio USA
| | - Yvonne Freund-Levi
- Center for Alzheimer Research, Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society Karolinska Institute Stockholm Sweden
- School of Medical Sciences Örebro University Örebro Sweden
| | - Sanjeev Kumar
- Centre for Addiction and Mental Health Toronto Ontario Canada
- Department of Psychiatry University of Toronto Ontario Canada
| | - Serge Gauthier
- McGill Center for Studies in Aging McGill University Montreal Quebec Canada
| | - Paul B Rosenberg
- Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral, Sciences Johns Hopkins University School of Medicine Baltimore Maryland
| | - Fabricio Ferreira de Oliveira
- Department of Neurology and Neurosurgery, Escola Paulista de Medicina Federal University of São Paulo (UNIFESP), São Paulo São Paulo Brazil
| | - D P Devanand
- New York State Psychiatric Institute and Department of Psychiatry and Department of Psychiatry, College of Physicians and Surgeons Columbia University New York New York
| | - Clive Ballard
- College of Medicine and Health The University of Exeter Exeter UK
| | - Zahinoor Ismail
- Department of Clinical Neurosciences; and the Ron and Rene Ward Centre for Healthy Brain Aging Research; Hotchkiss Brain Institute University of Calgary Calgary Alberta Canada
- Community Health Sciences, and O'Brien Institute for Public Health University of Calgary Calgary Alberta Canada
- Department of Psychiatry, and the Mathison Centre for Mental Health Research & Education Cumming School of Medicine, University of Calgary Calgary Alberta Canada
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Hulshof TA, Zuidema SU, Janus SIM, Luijendijk HJ. Large Sample Size Fallacy in Trials About Antipsychotics for Neuropsychiatric Symptoms in Dementia. Front Pharmacol 2020; 10:1701. [PMID: 32153391 PMCID: PMC7047221 DOI: 10.3389/fphar.2019.01701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/31/2019] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND A typical antipsychotics for neuropsychiatric symptoms in dementia have been tested in much larger trials than the older conventional drugs. The advantage of larger sample sizes is that negative findings become less likely and the effect estimates more precise. However, as sample sizes increase, the trials also get more expensive and time consuming while exposing more patients to drugs with unknown safety profiles. Moreover, a large sample size might yield a statistically significant effect that is not necessarily clinically relevant. OBJECTIVE To assess (1) the variation in sample size and sample size calculations of antipsychotic trials in dementia, (2) the size of reported treatment effects and related statistical significance, and (3) general study characteristics that might be related to sample size. STUDY DESIGN AND SETTING We performed a meta-epidemiological study of randomized trials that tested antipsychotics for neuropsychiatric symptoms in dementia. The trials compared conventional or atypical antipsychotics with placebo or another antipsychotic. Two reviewers independently extracted sample size, sample size calculations, reported treatment effects with p-values, and general study characteristics (drug type, trial duration, type of funding). We calculated a reference sample size of 83 and 433 per study group for the placebo-controlled and head-to-head trials respectively. RESULTS We identified 33 placebo-controlled trials, and 18 head-to-head trials. Only 14 (42%) and 2 (11%), respectively, reported a sample size calculation. The average sample size per arm was 34 (range 6-179) in placebo-controlled trials testing conventional drugs, 107 (8-237) in such trials testing atypical drugs, and 104 (95-115) in such trials testing both drug types; it was 31 (10-88) in head-to-head trials. Thirteen out of 18 trials with sample sizes larger than required (72%) reported a statistically significant treatment effect, of which two (15%) were clinically relevant. None of the head-to-head trials reported a statistically significant treatment effect, even though some suggested non-inferiority. In placebo-controlled trials of atypical drugs, longer trial duration (>6 weeks) and commercial funding were associated with higher sample size. CONCLUSION Sample size calculations were poorly reported in antipsychotic trials for dementia. Placebo-controlled trials of atypical antipsychotics showed large sample size fallacy while head-to-head trials were massively underpowered.
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Affiliation(s)
| | | | | | - Hendrika J. Luijendijk
- University Medical Center Groningen, Department of General Practice, University of Groningen, Groningen, Netherlands
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Marcinkowska M, Śniecikowska J, Fajkis N, Paśko P, Franczyk W, Kołaczkowski M. Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates. CNS Drugs 2020; 34:243-268. [PMID: 32052375 PMCID: PMC7048860 DOI: 10.1007/s40263-020-00707-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation, and depression. Atypical antipsychotics are commonly prescribed off-label to manage certain symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated with their use in elderly patients. Moreover, these compounds display a limited clinical efficacy, mostly owing to the fact that they were developed to treat schizophrenia, a disease characterized by neurobiological deficits. Thus, to improve clinical efficacy, it has been suggested that patients with dementia should be treated with exclusively designed and developed drugs that interact with pharmacologically relevant targets. Within this context, numerous studies have suggested druggable targets that might achieve therapeutically acceptable pharmacological profiles. Based on this, several different drug candidates have been proposed that are being investigated in clinical trials for behavioral and psychological symptoms of dementia. We highlight the recent advances toward the development of therapeutic agents for dementia-related psychosis and agitation/aggression and discuss the relationship between the relevant biological targets and their etiology. In addition, we review the compounds that are in the early stage of development (discovery or preclinical phase) and those that are currently being investigated in clinical trials for dementia-related psychosis and agitation/aggression. We also discuss the mechanism of action of these compounds and their pharmacological utility in patients with dementia.
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Affiliation(s)
- Monika Marcinkowska
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688, Poland.
| | - Joanna Śniecikowska
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland ,Adamed Pharma S.A., Czosnow, Poland
| | - Nikola Fajkis
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland
| | - Paweł Paśko
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland
| | - Weronika Franczyk
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland
| | - Marcin Kołaczkowski
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland ,Adamed Pharma S.A., Czosnow, Poland
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Hulshof TA, Zuidema SU, Gispen-de Wied CC, Luijendijk HJ. Run-in periods and clinical outcomes of antipsychotics in dementia: A meta-epidemiological study of placebo-controlled trials. Pharmacoepidemiol Drug Saf 2019; 29:125-133. [PMID: 31730266 PMCID: PMC7027584 DOI: 10.1002/pds.4903] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/06/2019] [Accepted: 09/09/2019] [Indexed: 01/03/2023]
Abstract
Purpose Run‐in periods are used to identify placebo‐responders and washout. Our aim was to assess the association of run‐in periods with clinical outcomes of antipsychotics in dementia. Methods We searched randomized placebo‐controlled trials of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia in electronic sources and references of selected articles. We extracted (a) the presence of a run‐in period, use of placebo/investigated drug during run‐in (versus washout only), and run‐in duration (1 week or more) and (b) the reduction in NPS, number of participants with somnolence, extrapyramidal symptoms (EPS), and deaths per treatment group. We pooled clinical outcomes comparing antipsychotic and placebo groups in trials with and without run‐in. Results We identified 35 trials. Twenty‐nine trials used run‐in. The pooled standardized mean difference in the reduction of NPS was −0.170 (95% CI, −0.227 to −0.112) in trials with run‐in and −0.142 (95% CI, −0.331 to 0.047) in trials without run‐in. The pooled odds ratio for somnolence was 2.8 (95% CI, 2.3‐3.5) in trials with run‐in and 3.5 (95% CI, 1.2‐10.7) in trials without run‐in; for EPS, these ORs were 1.8 (95% CI, 1.4‐2.2) and 2.0 (95% CI, 1.3‐3.1) respectively, and for mortality 1.4 (95% CI, 1.0‐2.0) and 1.6 (95% CI, 0.7‐3.4). The use of placebo/investigated drug during run‐in and run‐in duration did not affect the estimates in a consistent way. Conclusions The use of run‐in in trials might have led to overestimated efficacy and especially underestimated risks of side effects of antipsychotics compared with placebo for NPS in dementia.
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Affiliation(s)
- Tessa A Hulshof
- Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Sytse U Zuidema
- Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Hendrika J Luijendijk
- Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, Groningen, The Netherlands
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Theleritis CG, Siarkos KT, Politis AM. Unmet Needs in Pharmacological Treatment of Apathy in Alzheimer's Disease: A Systematic Review. Front Pharmacol 2019; 10:1108. [PMID: 31680942 PMCID: PMC6797825 DOI: 10.3389/fphar.2019.01108] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 08/29/2019] [Indexed: 01/15/2023] Open
Abstract
Background: Apathy is one of the most prevalent neuropsychiatric symptoms encountered in Alzheimer’s disease (AD) and may be an early sign in the development of dementia persisting over the disease course. It has been associated with poor disease outcome, impaired daily functioning, and significant caregiver distress. Early diagnosis and timely treatment of apathy in AD are of great importance. However, approved agents for apathy are still missing. Methods: Within this context, we conducted an extensive electronic search in the databases included in the National Library of Medicine, PsychInfo, and Google Scholar for studies that have investigated the effect of pharmacological treatments in apathy in AD. There were no limitations regarding study design and all care settings were considered for inclusion. Structured measures for level of evidence and study quality were employed to evaluate the results. Results: A total of 1,607 records were identified; 1,483 records remained after the removal of duplicates and were screened; 166 full-text articles were selected and assessed for eligibility and a remaining 90 unique studies and relevant reviews were included in the qualitative synthesis. Acetylcholinesterase inhibitors, gingko biloba, and methylphenidate were found to be successful in reducing apathy in patients with AD. Methodological heterogeneity in the studies and the small amount of studies where apathy was the primary outcome are limiting factors to assess for group effects. Conclusions: Pharmacological treatment of apathy in AD is an underexplored field. Standardized and systematic efforts are needed to establish a possible treatment benefit. Elucidating the pathophysiology of apathy and its components or subtypes will inform disease models and mechanistic drug studies that can quantify a benefit from specific agents for specific AD groups.
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Affiliation(s)
- Christos G Theleritis
- Division of Geriatric Psychiatry, First Department of Psychiatry, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas T Siarkos
- Division of Geriatric Psychiatry, First Department of Psychiatry, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios M Politis
- Division of Geriatric Psychiatry, First Department of Psychiatry, National and Kapodistrian University of Athens, Athens, Greece.,Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States
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Ehrhardt S, Porsteinsson AP, Munro CA, Rosenberg PB, Pollock BG, Devanand DP, Mintzer J, Rajji TK, Ismail Z, Schneider LS, Baksh SN, Drye LT, Avramopoulos D, Shade DM, Lyketsos CG. Escitalopram for agitation in Alzheimer's disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial. Alzheimers Dement 2019; 15:1427-1436. [PMID: 31587995 DOI: 10.1016/j.jalz.2019.06.4946] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 06/16/2019] [Accepted: 06/24/2019] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. METHODS S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC). DISCUSSION S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846).
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Affiliation(s)
- Stephan Ehrhardt
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
| | - Anton P Porsteinsson
- Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Cynthia A Munro
- Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
| | - Paul B Rosenberg
- Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
| | - Bruce G Pollock
- Campbell Family Research Institute and Division of Adult Neurodevelopment and Geriatric Psychiatry, CAMH, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Davangere P Devanand
- Division of Geriatric Psychiatry, New York State Psychiatric Institute and College of Physicians and Surgeons of Columbia University, New York, NY, USA
| | - Jacobo Mintzer
- Roper St. Francis Research and Innovation Center, Charleston, SC, USA; Medical University of South Carolina, College of Health Professionals and Ralph H Johnson VA Medical Center, Charleston, SC, USA
| | - Tarek K Rajji
- Campbell Family Research Institute and Division of Adult Neurodevelopment and Geriatric Psychiatry, CAMH, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Zahinoor Ismail
- Department of Psychiatry, Hotchkiss Brain Institute and O'Brien Institute for Public Health, University of Calgary, Calgary, AB, Canada; Department of Clinical Neurosciences, Hotchkiss Brain Institute and O'Brien Institute for Public Health, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Hotchkiss Brain Institute and O'Brien Institute for Public Health, University of Calgary, Calgary, AB, Canada
| | - Lon S Schneider
- Departments of Psychiatry and the Behavioral Sciences and Neurology, University of Southern California Keck School of Medicine and the University of Southern California Leonard Davis School of Gerontology, Los Angeles, CA, USA; Department of Neurology, University of Southern California Keck School of Medicine and the University of Southern California Leonard Davis School of Gerontology, Los Angeles, CA, USA
| | - Sheriza N Baksh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Lea T Drye
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Dimitri Avramopoulos
- Department of Psychiatry and Behavioral Sciences, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David M Shade
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Constantine G Lyketsos
- Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
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Aga VM. When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram. Am J Geriatr Psychiatry 2019; 27:1099-1107. [PMID: 31288974 DOI: 10.1016/j.jagp.2019.04.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/14/2019] [Accepted: 04/24/2019] [Indexed: 01/30/2023]
Abstract
Agitation is a common neuropsychiatric symptom (NPS) in the early and middle stages of Alzheimer's disease (AD) dementia, which is difficult to treat and causes much distress. The U.S. Food and Drug Administration (U.S. FDA) issued black box warnings against the use of antipsychotics in dementia in 2005 and 2008 due to the increased risk of morbidity and mortality, resulting in the reduction in antipsychotic use for treating dementia-related NPS and spurring the quest for safer and more effective pharmacological options. The data favoring the use of citalopram for treating agitation in AD dementia is particularly compelling, and this may be a class effect for all selective serotonin reuptake inhibitors. However, concerns about the cardiac side-effects of citalopram have limited its widespread use for this indication. In this article, available efficacy and safety data for the use of citalopram and escitalopram in treating agitation in AD dementia is reviewed, using a composite case to illustrate key points. Practical recommendations are made to facilitate the use of these medications in routine clinical practice, risk mitigation strategies are discussed and salient issues for future clinical research are emphasized.
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Affiliation(s)
- Vimal M Aga
- Layton Aging and Alzheimer's Disease Center, Oregon Health and Science University (OHSU), Portland, OR.
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40
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Vredeveld EJ, Hulshof TA, Zuidema SU, Luijendijk HJ. Subjective Versus Objective Outcomes of Antipsychotics for the Treatment of Neuropsychiatric Symptoms Associated with Dementia. CNS Drugs 2019; 33:933-942. [PMID: 31473979 PMCID: PMC6776492 DOI: 10.1007/s40263-019-00654-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Knowledge about treatment status can influence effects measured in trials when subjective scales are used. OBJECTIVE The aim of this study was to compare subjective outcomes with objective outcomes of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia. METHODS We performed a meta-epidemiological study of 38 randomized, placebo-controlled trials. For effectiveness, we used change in NPS and response rate as subjective outcomes, while overall dropout and additional psychotropic use were used as objective outcomes. For side effects, extrapyramidal symptoms (EPS) and somnolence were used as subjective outcomes, while dropout due to adverse events, medication use for EPS, and participants falling were used as objective outcomes. RESULTS Conventional antipsychotics reduced NPS more than placebo (standardized mean difference [SMD] - 0.36, 95% confidence interval [CI] - 0.49 to - 0.23), as did atypical antipsychotics (SMD - 0.14, 95% CI - 0.19 to - 0.08). Response rates in the drug groups were also higher. Overall dropout did not differ between conventional antipsychotics and placebo (odds ratio [OR] 1.03, 95% CI 0.77-1.37) or atypical antipsychotics and placebo (OR 1.01, 95% CI 0.89-1.14). Furthermore, additional psychotropic use did not differ. The risk of EPS was higher for conventional (OR 2.93, 95% CI 2.04-4.22) and atypical antipsychotics (OR 1.52, 95% CI 1.23-1.88) versus placebo, as was the risk of somnolence and dropout due to adverse events, but medication use for EPS, as well as risk of falls, was not. CONCLUSIONS The effectiveness of antipsychotics for NPS in dementia based on subjective scales was not confirmed using objective outcomes, in contrast to the increased risk of side effects.
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Affiliation(s)
- Eline J Vredeveld
- Department of General Practice and Elderly Care Medicine, University Medical Centre Groningen, University of Groningen, PO Box 196, 9700 AD, Groningen, The Netherlands
| | - Tessa A Hulshof
- Department of General Practice and Elderly Care Medicine, University Medical Centre Groningen, University of Groningen, PO Box 196, 9700 AD, Groningen, The Netherlands
| | - Sytse U Zuidema
- Department of General Practice and Elderly Care Medicine, University Medical Centre Groningen, University of Groningen, PO Box 196, 9700 AD, Groningen, The Netherlands
| | - Hendrika J Luijendijk
- Department of General Practice and Elderly Care Medicine, University Medical Centre Groningen, University of Groningen, PO Box 196, 9700 AD, Groningen, The Netherlands.
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41
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Current Agents in Development for Treating Behavioral and Psychological Symptoms Associated with Dementia. Drugs Aging 2019; 36:589-605. [PMID: 30957198 DOI: 10.1007/s40266-019-00668-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Behavioral and psychological symptoms associated with dementia are highly prevalent and are associated with an increased risk of institutionalization and mortality. Current pharmacological treatments for these symptoms include cholinesterase inhibitors, antipsychotics, and selective serotonin reuptake inhibitors. When used for treating behavioral and psychological symptoms associated with dementia, they are associated with limited efficacy and/or serious adverse events. As such, there has been extensive research into novel agents with varying mechanisms of action targeting behavioral and psychological symptoms associated with dementia. In this article, we present the results of a comprehensive literature search and review that evaluates current agents that have completed or are currently in clinical trials for treating behavioral and psychological symptoms associated with dementia as a primary outcome. We highlight novel agents from miscellaneous drug classes, such as dextromethorphan/quinidine, bupropion/dextromethorphan, lumateperone, deudextromethorphan/quinidine, methylphenidate and scyllo-inositol, and drugs from various therapeutic classes (including atypical antipsychotics, selective serotonin reuptake inhibitors, and cannabinoids) that have demonstrated promising results and were generally well tolerated. Future research with large appropriately powered studies using validated outcome measures for behavioral and psychological symptoms associated with dementia should be conducted to further establish the clinical utility of these agents.
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42
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McCarrell JL, Bailey TA, Duncan NA, Covington LP, Clifford KM, Hall RG, Blaszczyk AT. A review of citalopram dose restrictions in the treatment of neuropsychiatric disorders in older adults. Ment Health Clin 2019; 9:280-286. [PMID: 31293848 PMCID: PMC6607952 DOI: 10.9740/mhc.2019.07.280] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Introduction Neuropsychiatric disorders affect millions of older adults. Despite this, there are relatively few older adults included in clinical trials evaluating treatments for psychiatric disorders. Citalopram has been evaluated in older adults with neuropsychiatric disorders and has largely been found beneficial, making the 2011 US Food and Drug Administration (FDA) safety advisory on citalopram extremely impactful. Methods A literature search was completed using the PubMed database. Results were limited to clinical trials conducted in older adults that were published in English. Results Review of the literature confirms the efficacy of citalopram in depression, anxiety, depression associated with Parkinson disease, and behavioral and psychological symptoms of dementia. Additionally, no adverse cardiac outcomes have been described related to citalopram. Discussion The FDA's evidence for applying this safety advisory to citalopram is minimal and largely based on surrogate markers, such as the QTc interval rather than clinical and safety outcomes. Citalopram is known to increase the QTc, but this increase has not been linked to adverse cardiac outcomes. The evidence for efficacy and against adverse outcomes suggests that a reevaluation of the dosing restrictions in older adults with neuropsychiatric disorders is needed.
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Avedisova AS, Guekht AB, Zakharova KV, Akzhigitov RG. [The efficacy of pharmacological approaches to therapy of the apathy syndrome in dementia disorders (the review)]. Zh Nevrol Psikhiatr Im S S Korsakova 2019; 118:126-133. [PMID: 29863706 DOI: 10.17116/jnevro201811841126-133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The article presents a literature review of psychopharmacological methods of treatment of the apathy syndrome, which is common in neurocognitive disorders. The review provides recommendations for the management of such patients, taking into account evidence-based medicine.
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Affiliation(s)
- A S Avedisova
- Serbsky Federal Medical Research Centre for Psychiatry and Narcology, Moscow, Russia, Soloviev Scientific and Practical Center of Psychoneurology, Moscow, Russia
| | - A B Guekht
- Serbsky Federal Medical Research Centre for Psychiatry and Narcology, Moscow, Russia, Soloviev Scientific and Practical Center of Psychoneurology, Moscow, Russia
| | - K V Zakharova
- Serbsky Federal Medical Research Centre for Psychiatry and Narcology, Moscow, Russia, Soloviev Scientific and Practical Center of Psychoneurology, Moscow, Russia
| | - R G Akzhigitov
- Serbsky Federal Medical Research Centre for Psychiatry and Narcology, Moscow, Russia, Soloviev Scientific and Practical Center of Psychoneurology, Moscow, Russia
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Supasitthumrong T, Bolea-Alamanac BM, Asmer S, Woo VL, Abdool PS, Davies SJC. Gabapentin and pregabalin to treat aggressivity in dementia: a systematic review and illustrative case report. Br J Clin Pharmacol 2019; 85:690-703. [PMID: 30575088 DOI: 10.1111/bcp.13844] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 12/12/2018] [Accepted: 12/13/2018] [Indexed: 12/12/2022] Open
Abstract
AIMS The prevalence of dementia is rising as life expectancy increases globally. Behavioural and psychological symptoms of dementia (BPSD), including agitation and aggression, are common, presenting a challenge to clinicians and caregivers. METHODS Following PRISMA guidelines, we systematically reviewed evidence for gabapentin and pregabalin against BPSD symptoms of agitation or aggression in any dementia, using six databases (Pubmed, CINHL, PsychINFO, HealthStar, Embase, and Web of Science). Complementing this formal systematic review, an illustrative case of a patient with BPSD in mixed Alzheimer's/vascular dementia, who appeared to derive benefits in terms of symptom control and functioning from the introduction of gabapentin titrated up to 3600 mg day-1 alongside other interventions, is presented. RESULTS Twenty-four relevant articles were identified in the systematic review. There were no randomized trials. Fifteen papers were original case series/case reports of patients treated with these compounds, encompassing 87 patients given gabapentin and six given pregabalin. In 12 of 15 papers, drug treatment was effective in the majority of cases. The remaining nine papers were solely reviews, of which two were described as systematic but predated PRISMA guidelines. Preliminary low-grade evidence based on case series and case reviews suggests possible benefit of gabapentin and pregabalin in patients with BPSD in Alzheimer's disease. These benefits cannot be confirmed until well-powered randomized controlled trials are undertaken. Evidence in frontotemporal dementia is lacking. CONCLUSION Gabapentin and pregabalin could be considered for BPSD when medications having stronger evidence bases (risperidone, other antipsychotics, carbamazepine and citalopram) have been ineffective or present unacceptable risks of adverse outcomes.
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Affiliation(s)
- Thitiporn Supasitthumrong
- Geriatric Mental Health Service, Centre for Addiction and Mental Health, Toronto, Canada.,Department of Psychiatry, University of Toronto, Toronto, Canada.,Department of Psychiatry, Faculty of Medicine, King Chulalongkorn University, Bangkok, Thailand
| | - Blanca M Bolea-Alamanac
- Department of Psychiatry, University of Toronto, Toronto, Canada.,General Systems Division, Centre for Addiction and Mental Health, University of Toronto, Canada
| | - Selim Asmer
- Geriatric Mental Health Service, Centre for Addiction and Mental Health, Toronto, Canada
| | - Vincent L Woo
- Department of Psychiatry, University of Toronto, Toronto, Canada.,Specialized Geriatrics Program, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada
| | - Petal S Abdool
- Geriatric Mental Health Service, Centre for Addiction and Mental Health, Toronto, Canada.,Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Simon J C Davies
- Geriatric Mental Health Service, Centre for Addiction and Mental Health, Toronto, Canada.,Department of Psychiatry, University of Toronto, Toronto, Canada
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D’Onofrio G, Panza F, Sancarlo D, Lauriola M, Dagostino MP, Paroni G, Lozupone M, Mangiacotti A, Bisceglia P, Gravina C, Urbano M, Addante F, Paris F, Cascavilla L, Greco A, Seripa D. Hydroxytryptamine transporter gene-linked polymorphic region (5HTTLPR) is associated with delusions in Alzheimer's disease. Transl Neurodegener 2019; 8:4. [PMID: 30733861 PMCID: PMC6357440 DOI: 10.1186/s40035-019-0144-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 01/14/2019] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Serotoninergic pathways underlying delusion symptoms in Alzheimer's disease (AD) have not been fully clarified. 5-Hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is a variable number tandem repeats in the promoter region of serotonin transporter encoding-gene affecting transcription. METHODS We investigated the association of 5-HTTLPR with delusions in a total of 257 consecutive patients clinically diagnosed as AD according to the National Institute on Aging-Alzheimer's Association criteria. All participants underwent a comprehensive evaluation with a standardized comprehensive geriatric assessment and Neuropsychiatric Inventory. RESULTS Delusion symptoms were observed in 171 patients (66.54%). In respect to AD patients without delusions, AD patients with delusions showed a low prevalence of S-plus carriers (5-HTTLPR-L/S + 5-HTTLPR-S/S genotypes) [p < 0.001; odds ratio (OR) = 0.240, 95% confidence interval (CI) = 0.121-0.471]. Logistic regression analysis adjusted for the apolipoprotein E polymorphism showed that in AD patients with delusions the presence of an 5-HTTLPR-S allele may reduce disease duration (p = 0.005; OR = 0.680, 95% CI = 0.522-0.886) and increase aberrant motor activity (p = 0.013; OR = 2.257, 95% CI = 1.195-4.260). The present findings suggested that 5-HTTLPR might be associated with delusions in AD. S-plus carriers might be associated with protective effect against delusions in AD. CONCLUSIONS More studies on wider samples of high selected demented patients are needed to confirm our results. However, the present findings suggested that a genetic factor related to serotonin metabolism might exert a protective role on the clinical expression of neuropsychiatric clusters in AD with important implications regarding mechanisms underlying delusions and their possible treatment across the AD and dementia spectrum.
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Affiliation(s)
- Grazia D’Onofrio
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Francesco Panza
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
- Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
- Department of Clinical Research in Neurology, University of Bari Aldo Moro, Pia Fondazione Cardinale G. Panico, Tricase, Lecce, Italy
| | - Daniele Sancarlo
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Michele Lauriola
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Mariangela P. Dagostino
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Giulia Paroni
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Madia Lozupone
- Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Antonio Mangiacotti
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Paola Bisceglia
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Carolina Gravina
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Maria Urbano
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Filomena Addante
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Francesco Paris
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Leandro Cascavilla
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Antonio Greco
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
| | - Davide Seripa
- Fondazione Casa Sollievo della Sofferenza, Department of Medical Sciences, Geriatrics Unit, San Giovanni Rotondo (FG) Foggia, Italy
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Mathys M. Pharmacologic management of behavioral and psychological symptoms of major neurocognitive disorder. Ment Health Clin 2018; 8:284-293. [PMID: 30397570 PMCID: PMC6213893 DOI: 10.9740/mhc.2018.11.284] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Behavioral and psychological symptoms of dementia (BPSD) occur in approximately 80% of patients who receive a diagnosis of major neurocognitive disorder. Nonpharmacologic strategies are the first-line treatment for BPSD. However, psychotropic medications are often necessary when nonpharmacologic methods are not effective in treating symptoms that are distressing or are causing behaviors that are dangerous to the patient or the patient's caregivers. The article provides a review of evidence-based recommendations for the use of antipsychotics, cognitive enhancers, and serotonin reuptake inhibitors for the treatment of BPSD. Different pharmacologic approaches are demonstrated through 2 patient cases in which nonpharmacologic management was not effective. The severity of BPSD must be weighed against the risks and benefits of pharmacologic intervention in order to implement an optimal medication regimen.
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Affiliation(s)
- Monica Mathys
- (Corresponding author) Associate Professor of Pharmacy Practice, Clinical Pharmacy Specialist-Mental Health, Texas Tech University Health Sciences Center, Dallas, Texas,
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47
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Smeets C, Zuidema S, Hulshof T, Smalbrugge M, Gerritsen D, Koopmans R, Luijendijk H. Efficacy of antipsychotics in dementia depended on the definition of patients and outcomes: a meta-epidemiological study. J Clin Epidemiol 2018; 101:17-27. [DOI: 10.1016/j.jclinepi.2018.05.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/27/2018] [Accepted: 05/14/2018] [Indexed: 10/16/2022]
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Heldt JP, Zito MF, Seroussi A, Wilson SP, Schneider PL, Strouse TB, Cheung EH. A Medical Incapacity Hold Policy Reduces Inappropriate Use of Involuntary Psychiatric Holds While Protecting Patients From Harm. PSYCHOSOMATICS 2018; 60:37-46. [PMID: 30064729 DOI: 10.1016/j.psym.2018.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 11/28/2022]
Abstract
BACKGROUND The use of involuntary psychiatric holds (IPH) to detain patients who lack the capacity to make health care decisions due to nonpsychiatric conditions is common. While this practice prevents patient harm, it also deprives civil liberties, risks liability for false imprisonment, and may hinder disposition. Medical incapacity hold (MIH) policies, which establish institutional criteria and processes for detaining patients who lack capacity but do not meet criteria for an IPH, provide a potential solution. METHODS A retrospective chart review was conducted on adult medical/surgical inpatients placed on an IPH or MIH over the 1-year periods before and after implementation of a MIH policy at an academic medical center. The primary outcome was frequency of IPH utilization in patients who did not qualify for an IPH as determined by 2 independent physician reviewers. A Cohen's kappa was calculated to determine inter-rater reliability. Differences in patient demographics and outcomes were compared using a Student's t-test, Wilcoxon rank-sum test, and Pearson chi-square test (α = 0.05). RESULTS The Cohen's kappa was 0.72 indicating substantial agreement. Seventy MIHs were placed after implementation (mean duration 4.3 days). Before MIH implementation, 17.6% of IPHs were placed on non-qualifying patients, which decreased to 3.9% following MIH implementation (p < 0.01). The average length of stay for patients on an IPH or MIH did not change following MIH implementation. No instances of patient elopement, grievances, or litigation were found. CONCLUSION MIH policies benefit both patients lacking capacity and the health care systems seeking to protect them while avoiding inappropriate use of IPHs.
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Affiliation(s)
- Jonathan P Heldt
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Psychiatry, Los Angeles, CA.
| | - Michael F Zito
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Psychiatry, Los Angeles, CA
| | - Ariel Seroussi
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Psychiatry, Los Angeles, CA
| | - Sharlena P Wilson
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Psychiatry, Los Angeles, CA
| | - Paul L Schneider
- VA Greater Los Angeles Healthcare System, Psychiatry, Los Angeles, CA
| | - Thomas B Strouse
- University of California Los Angeles David Geffen School of Medicine, Psychiatry, Los Angeles, CA
| | - Erick H Cheung
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Psychiatry, Los Angeles, CA
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Kongpakwattana K, Sawangjit R, Tawankanjanachot I, Bell JS, Hilmer SN, Chaiyakunapruk N. Pharmacological treatments for alleviating agitation in dementia: a systematic review and network meta-analysis. Br J Clin Pharmacol 2018; 84:1445-1456. [PMID: 29637593 PMCID: PMC6005613 DOI: 10.1111/bcp.13604] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 12/18/2022] Open
Abstract
AIMS To determine the most efficacious and acceptable treatments of agitation in dementia. METHODS MEDLINE, EMBASE, PsycINFO, CENTRAL and clinicaltrials.gov were searched up to 7 February 2017. Two independent reviewers selected randomized controlled trials (RCTs) of treatments to alleviate agitation in people with all-types dementia. Data were extracted using standardized forms and study quality was assessed using the revised Cochrane Risk of Bias Tool for RCTs. Data were pooled using meta-analysis. The primary outcome, efficacy, was 8-week response rates defined as a 50% reduction in baseline agitation score. The secondary outcome was treatment acceptability defined as treatment continuation for 8 weeks. RESULTS Thirty-six RCTs comprising 5585 participants (30.9% male; mean ± standard deviation age, 81.8 ± 4.9 years) were included. Dextromethorphan/quinidine [odds ratio (OR) 3.04; 95% confidence interval (CI), 1.63-5.66], risperidone (OR 1.96; 95% CI, 1.49-2.59) and selective serotonin reuptake inhibitors as a class (OR 1.61; 95% CI, 1.02-2.53) were found to be significantly more efficacious than placebo. Haloperidol appeared less efficacious than nearly all comparators. Most treatments had noninferior treatment continuation compared to placebo, except oxcarbazepine, which was inferior. Findings were supported by subgroup and sensitivity analyses. CONCLUSIONS Risperidone, serotonin reuptake inhibitors as a class and dextromethorphan/quinidine demonstrated evidence of efficacy for agitation in dementia, although findings for dextromethorphan/quinidine were based on a single RCT. Our findings do not support prescribing haloperidol due to lack of efficacy, or oxcarbazepine due to lack of acceptability. The decision to prescribe should be based on comprehensive consideration of the benefits and risks, including those not evaluated in this meta-analysis.
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Affiliation(s)
| | - Ratree Sawangjit
- Clinical Trials and Evidence Base Syntheses Research Unit (CTEBs RU), Department of Clinical Pharmacy, Faculty of PharmacyMahasarakham UniversityMahasarakhamThailand
| | - Itthipol Tawankanjanachot
- Department of Psychiatry, King Chulalongkorn Memorial Hospital, Faculty of MedicineChulalongkorn UniversityBangkokThailand
| | - J. Simon Bell
- Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical SciencesMonash UniversityAustralia
| | - Sarah N. Hilmer
- Kolling Institute of Medical ResearchRoyal North Shore Hospital and University of SydneySt LeonardsNSWAustralia
| | - Nathorn Chaiyakunapruk
- School of PharmacyMonash University MalaysiaSelangorMalaysia
- Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical SciencesNaresuan UniversityPhitsanulokThailand
- Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well‐being Cluster, Global Asia in the 21st Century (GA21) PlatformMonash University MalaysiaBandar SunwaySelangorMalaysia
- School of PharmacyUniversity of WisconsinMadisonUSA
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50
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Creese B, Da Silva MV, Johar I, Ballard C. The modern role of antipsychotics for the treatment of agitation and psychosis in Alzheimer's disease. Expert Rev Neurother 2018; 18:461-467. [PMID: 29764230 DOI: 10.1080/14737175.2018.1476140] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Antipsychotics have long been the mainstay of treatment for agitation and psychosis in Alzheimer's disease. Despite their current use successive studies have shown that they only confer a modest benefit which must be balanced against their well-established serious side effects (extrapyramidal symptoms, stroke, accelerated cognitive decline and mortality). Areas covered: This review outlines the current guidance on antipsychotic usage and the evidence of their continued usage against a backdrop of emerging pharmacological treatments and an increasing emphasis on the importance of non-pharmacological interventions. Expert commentary: The current justification for antipsychotic use in the context of the changing landscape of prescribing and provide a view on the most promising alternative candidates to this class of drug are appraised.
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Affiliation(s)
- Byron Creese
- a University of Exeter Medical School , University of Exeter , UK
| | | | - Iskandar Johar
- b Department of Old Age Psychiatry , Institute of Psychiatry, Psychology and Neuroscience, King's College London , UK
| | - Clive Ballard
- a University of Exeter Medical School , University of Exeter , UK
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