Myuri Ruthirakuhan

Pharmacological Management of Agitation and Aggression in Alzheimer’s Disease: A Review of Current and Novel Treatments

Agitation and aggression are common neuropsychiatric symptoms of Alzheimers disease and are highly prevalent in people with dementia. When pharmacological intervention becomes necessary, current clinical practice guidelines recommend antipsychotics, cholinesterase inhibitors, and some antidepressants. However, those interventions have modest to low efficacy, and those with the highest demonstrated efficacy have significant safety concerns. As a result, current research is focusing on novel compounds that have different mechanisms of action and that may have a better balance of efficacy over safety. The purpose of this review is to evaluate novel pharmacological therapies for the management of agitation and aggression in AD patients. We performed a comprehensive literature search to identify recent novel drugs that are not included in most clinical practice guidelines or are currently undergoing clinical trials for the treatment of agitation and/or aggression in AD. This review suggests that novel treatments, such as cannabinoids, lithium, non-steroidal anti-inflammatory drugs, analgesics, narcotics, and newer antiepileptic drugs, may provide a safer alternative treatment option for the management of agitation and aggression in AD and requires further study in order to clarify their risks and benefits.

Beyond immunotherapy: new approaches for disease modifying treatments for early Alzheimer’s disease

ABSTRACT Introduction: Current pharmacological recommendations for the treatment of Alzheimer’s disease (AD) include the cholinesterase inhibitors and the N-methyl-D-aspartate antagonist, memantine. However, these medications only manage symptoms of AD, and do not target Aβ plaques and neurofibrillary tangles. As such, there is a need to develop effective and safe disease modifying treatments that directly target AD pathology and alter the course of AD progression. Areas covered: This review evaluates ongoing phase 2 and 3 clinical trials, as well as those completed or published over the past five years. Studies for this review were obtained from clinicaltrials.gov, alzforum.org/therapeutics, and PubMed. Keywords and search criteria included: phase 2, or 3 trials related to Alzheimer’s disease, mild cognitive impairment, amyloid-beta and tau. Immunotherapies for AD have not been included as this is beyond the scope of this review. Expert opinion: A substantial number of trials investigating disease modifying drugs in AD target amyloid-beta and tau pathology. However, many of these trials have relatively short treatment duration and do not include combined assessment of biomarkers and clinical outcomes. Future investigations are recommended to include biomarker assessments and clinical outcomes over a minimum treatment duration of 18 months in order to establish disease-modifying effects.

INVESTIGATING BIOMARKERS OF AGITATION IN MODERATE-TO-SEVERE ALZHEIMER’S DISEASE PATIENTS ENROLLED IN A RANDOMIZED CONTROLLED TRIAL WITH NABILONE

neuropathological AD lesions leading to their inclusion into AD criteria. However, these biomarkers are costly and invasive and new simple biomarkers are needed. Several studies have established a link between morphological and functional changes occurring in the monoaminergic ascending system and the physiopathology of AD. Noradrenaline (NA)-containing neurons in the locus coerulus (LC) are the main source of noradrenergic inputs to numerous regions throughout the brain. Due to its widespread efferent inervation, the LC projection system plays a pivotal regulatory role in processes such as stress and maintenance of cognitive performance. Gannon et al. have reported that a significant loss and damage of noradrenergic neurons in LC occurs in AD. Furthermore, O’Bryant et al. have suggested an important contribution of noradrenergic LC dysfunction in AD pathogenesis. In this work we present our preliminary results demonstrating that the simultaneous quantitation of 3 catecholamines (CAs) could be a potential new plasma AD biomarkers.Methods:In this retrospective study, we quantified epinephrine, norepinephrine (NE) and dopamine (DA) levels in plasma from patients investigated for neurocognitive disorders (NC), other neurological diseases without dementia (CON), and healthy controls (HC) (Montpellier, Paris). All diagnoses were performed according to current diagnostic criteria including neurological examination, neuropsychological tests, brain MRI and CSF biomarkers. CAs quantifications were performed by HPLC coupled with electrochemical detection. A mathematical model was developed to discriminate AD from other neurocognitive diseases, CON and HC. Results: Plasma from 202 participants, including 30 AD, were analyzed. A distinctive CAs signature in AD patients was observed comparatively to NC and CON groups. Significant lower levels in epinephrine and NE were observed, whereas DA was increased. A positive correlation between MMSE score and noradrenaline concentrations was observed. This method displays a good discrimination power regarding AD patients with 80 % in sensitivity and 97 % in specificity. Conclusions:Mathematical scores based on plasma CAs quantitation allowed us to clearly distinguish AD patients from NC and CON. Large prospective studies are needed to confirm that CAs are blood biomarkers for the screening of AD. 1. Simic G, Stanic G,Mladinov M, Jovanov-Milosevic N, Kostovic I, Hof PR. Does Alzheimer’s disease begin in the brainstem?: Annotation. Neuropathol Appl Neurobiol. 2009;35(6):532-554. https://doi.org/10.1111/j. l365-2990.2009.01038.x. 2. Trillo L, Das D, Hsieh W, et al. Ascending monoaminergic systems alterations in Alzheimer’s disease. Translating basic science into clinical care. Neurosci Biobehav Rev. 2013;37(8):1363-1379. https://doi.org/10.1016/j.neubiorev. 2013.05.008. 3. Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009;10(3):211-223. https:// doi.org/10.1038/nrn2573. 4. Gannon M, Che P, Chen Y, Jiao K, Roberson ED, Wang Q. Noradrenergic dysfunction in Alzheimer’s disease. Front Neurosci. 2015;9(JUN):1-12. https://doi.org/10.3389/ fnins.2015.00220. 5. O’Bryant SE, Edwards M, Johnson L, et al. A blood screening test for Alzheimer’s disease. Alzheimer’s Dement Diagnosis, Assess Dis Monit. 2016;3:83-90. https://doi.org/10.1016/ J.DADM.2016.06.004. P3-250 INVESTIGATING BIOMARKERS OF AGITATION IN MODERATE-TO-SEVERE ALZHEIMER’S DISEASE PATIENTS ENROLLED IN A RANDOMIZED CONTROLLED TRIALWITH NABILONE Myuri Ruthirakuhan, Nathan Herrmann, Ana C. Andreazza, Nicolaas Paul L. G. Verhoeff, Damien Gallagher, Sandra E. Black, Krista L. Lanctot, Sunnybrook Research Institute, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; Neuropsychopharmacology Research Group, Toronto, ON, Canada; Baycrest Hospital, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Contact e-mail: rutmyuri@sri.utoronto.ca

NABILONE SIGNIFICANTLY IMPROVES AGITATION/AGGRESSION IN PATIENTS WITH MODERATE-TO-SEVERE AD: PRELIMINARY RESULTS OF A PLACEBO-CONTROLLED, DOUBLE-BLIND, CROSS-OVER TRIAL

is maintained. The primary hypothesis is that the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) will decrease more on lithium than placebo. The secondary hypothesis is that there will be a greater number of responders on lithium than placebo. Change in NPI psychosis scores on lithium compared to placebo will be explored. Treatment Emergent Symptom Scale (TESS) scores and emergent adverse events will be used to assess tolerability. Exploratory outcomes include change in serum brainderived neurotrophic factor (BDNF) levels and two genetic markers as potential predictors of response to lithium: a specific SNP on intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus. Results:Trial Design; blinded study is in progress. Conclusions:This study will provide initial data on three potential roles for low-dose lithium in clinical practice: (1) first-line treatment; (2) adjunct treatment in partial responders; (3) second-line agent after non-response or intolerability to other medications. The results of this Phase II trial will determine the potential of a large-scale Phase III clinical trial of lithium in these patients.

Pharmacotherapy of Dementia

Alzheimer’s disease (AD), the most common form of dementia, is a progressive and debilitating condition that causes deterioration in cognition and function, as well as disturbances in behavior. Currently available treatments for AD (donepezil, rivastigmine, galantamine, and memantine) are symptomatic and do not prevent the progression of the disease. These therapies demonstrate modest but consistent benefit for cognition, global status, functional ability, and behavioral disturbances or neuropsychiatric symptoms. The search for disease-modifying interventions has focused largely on compounds targeting the amyloid-β pathway. Current efforts are also geared toward other disease hallmarks such as tau pathology, neuroinflammation, and mitochondrial dysfunction. Given the negative results of disease-modifying drug candidates for mild-tomoderate AD patients, a large number of trials are focusing on the early or S.A. Chau • C.S. Liu • M. Ruthirakuhan Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program Sunnybrook Research Institute, Toronto, ON, Canada K.L. Lanctôt Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program Sunnybrook Research Institute, Toronto, ON, Canada Department of Psychiatry, University of Toronto, Toronto, ON, Canada N. Herrmann (*) Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program Sunnybrook Research Institute, Toronto, ON, Canada Department of Psychiatry, University of Toronto, Toronto, ON, Canada Division of Geriatric Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada e-mail: Nathan.Herrmann@sunnybrook.ca # Springer Nature Singapore Pte Ltd. 2016 H. Chiu et al. (eds.), Mental Health and Illness of the Elderly, Mental Health and Illness Worldwide 2, DOI 10.1007/978-981-10-0370-7_20-1 1 prodromal stages of the disease. Neuropsychiatric symptoms, including apathy, depression, agitation and aggression, sleeping disorders and insomnia, and psychotic symptoms, are prevalent in dementia and have a negative impact on both quality of life and caregiver burden. Pharmacological management of specific neuropsychiatric symptoms is also a focus of clinical trials. Given that AD patients are frailer and have more comorbid illnesses, the prescription of psychotropic medications, particularly those of questionable benefit, should be done with careful consideration. In this chapter, we critically examine evidence of the safety and efficacy of currently approved drugs and emerging pharmacotherapies in AD.

Cannabinoids for the treatment of neuropsychiatric symptoms, pain and weight loss in dementia

Purpose of review Efficacious treatment for neuropsychiatric symptoms (NPS), pain and weight loss for dementia patients is desperately needed. This review presents an up-to-date look at the literature investigating the use of cannabinoid for these symptoms in dementia. Recent findings We searched electronically for publications regarding cannabinoid use in dementia, with a focus on Alzheimers disease. Seven studies and one case report have been conducted to examine the use of cannabinoids for the treatment of NPS of dementia, and three of these trials reported on the effect of cannabinoids on weight. Five studies reported decreased agitation or improvements in sleep with cannabinoid use. One crossover trial found that cannabinoids positively impacted weight, whereas a chart review study found no impact on weight with cannabinoids, but an increase in food intake. There were no trials examining the use of cannabinoids for pain in dementia. Summary Findings from trials with small sample sizes and various clinical populations suggest that cannabinoid use may be well tolerated and effective for treatment of NPS such as agitation as well as weight and pain management in patients with dementia. Additional studies are necessary to further elucidate the relative risks and benefits of this treatment.

A RANDOMIZED, PLACEBO-CONTROLLED, CROSS-OVER TRIAL INVESTIGATING NABILONE AS A TREATMENT FOR AGITATION IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER'S DISEASE: BLINDED, INTERIM SAFETY RESULTS

P4-003 A RANDOMIZED, PLACEBO-CONTROLLED, CROSS-OVER TRIAL INVESTIGATING NABILONE AS A TREATMENT FOR AGITATION IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE: BLINDED, INTERIM SAFETY RESULTS Myuri Ruthirakuhan, Nathan Herrmann, Eleenor H. Abraham, Chelsea Sherman, Nicolaas Paul L. G. Verhoeff, Alex Kiss, Sandra E. Black, Ana C. Andreazza, Krista L. Lanctot, Sunnybrook Research Institute, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; Neuropsychopharmacology Research Group, Toronto, ON, Canada; Baycrest Hospital, Toronto, ON, Canada. Contact e-mail: rutmyuri@sri.utoronto.ca

Predictors of worsening following cholinesterase inhibitor discontinuation trial in institutionalized persons with moderate to severe Alzheimer's disease: Results of a double-blind, placebo controlled trial

participants were prevented from viewing the start point from any point by carefully chosen locations. The angle deviation from the correct response at each point was recorded and analyzed. Results:The angle deviation showed difference among three groups at point 3 (p1⁄40.017), point 4 (p1⁄40.000) and point 5 (p1⁄40.000). Post hoc analysis showed that the performance of PI differentiates AD from non-AD at point 4 and point 5. It also showed that the angle deviations at point 4 are correlated with all components of the QuENA, namely landmark agnosia, egocentric disorientation, heading disorientation and inattention, while that at point 5 with components of landmark agnosia and heading disorientation. No correlation was found between the perfusion deficit and angle deviation at any point. Conclusions: The relationship between the brain dysfunction and the performance of PI is more complex as previously thought. More in-depth design and careful interpretation are in need to develop a new tool for helping diagnosis of the MCI and monitoring the progress of AD.