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Pathogenesis and Personalized Interventions for Pharmacological Treatment-Resistant Neuropsychiatric Symptoms in Alzheimer’s Disease

• Alzheimer's disease is the most common form of dementia and is characterized by cognitive impairment and neuropsychiatric symptoms (NPSs).

• NPSs worsen patients' prognoses, resulting in a shorter life span, earlier institutionalization, more severe caregiver burden, and increased socio-economic burden.

• Recent treatment guidelines for NPSs have recommended non-pharmacological treatments as the first line of therapy, followed by pharmacological treatments.

• Pharmacological treatment for urgent NPSs can be difficult because of a lack of efficacy or an intolerance, requiring multiple changes in psychotropic prescriptions.

• Structural deterioration in elderly people with dementia may cause a functional vulnerability affecting the pharmacological response.

• Other causative factors might include awkward psychosocial interpersonal relations between patients and their caregiver, resulting in distressful vicious circles.

• Overlapping NPS sub-symptoms can also blur the prioritization of targeted symptoms.

• Consistent neurocognitive reductions cause a primary apathy state and a secondary distorted ideation or perception of present objects, leading to reactions that cannot be treated pharmacologically.

• Non-pharmacological interventions for the treatment of NPSs may be relatively weak alternatives to pharmacological treatments for urgent NPSs that can result in harmful behaviors to the patient and to others.

• Elucidating the pathogeneses of NPSs that are difficult to treat pharmacologically may be helpful to clinicians and caregivers during discussions regarding long-term care plans and treatment strategies, possibly improving patient prognosis, including the quality of life (QOL), and mortality in patients with AD.

• The present review defines treatment-resistant NPSs in AD and discusses the pathogenesis and comprehensive solutions based on three major hypothetical pathophysiological viewpoints: (1) biology, (2) psychosociology, and (3) neurocognition.

• The complex hypothetical pathogenesis of symptoms that are difficult to treat pharmacologically will be considered from these three viewpoints, and future perspectives regarding treatment strategies and solutions for these elusive issues will be discussed.

• Pharmacological treatment difficulties in patients with mental disorders have been discussed and defined in previous reports, but those concerning NPSs in patients with dementia have not yet been described in detail.Pharmacological Treatment-Resistant Neuropsychiatric Symptoms in Alzheimer's Disease: A Theoretical Review

• There are three categories of treatment-resistant neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD): pharmacological, non-pharmacological, and mixed.

• Pharmacological treatment-resistant NPSs in AD (p-TRENS-AD) refers to sub-symptoms such as psychosis, aggressiveness, and depression that are likely to respond poorly to pharmacological treatment or for which pharmacological treatment is likely to be intolerable to the patient, resulting in a need to switch to multiple psychotropics.

• The definition of p-TRENS-AD overlaps with sub-symptoms that are unlikely to respond to a pharmacological approach, such as wandering, perseverative shouting, and some sexually inappropriate behaviors.

• The pathogenesis of p-TRENS-AD is complex and involves biological factors (such as pharmacokinetics, metabolism, pharmacogenomics, and neuropharmacology), psychosocial factors (such as severe caregiver burden and demographic factors), and neurocognitive factors (such as rapid cognitive decline and poor self-awareness).

• Age-related alterations in peripheral pharmacokinetics reduce drug clearance, contributing to undesirable adverse effects arising from elevated blood concentrations.

• Treatment discontinuation in AD is influenced by undesirable adverse effects and a lack of efficacy, and treatment must often be switched to an alternative medication.

• The efficacy of a selective serotonin reuptake inhibitor (SSRI) or a serotonin noradrenalin reuptake inhibitor (SNRI) has been shown for the treatment of aggressiveness in AD.

• The decreases in cholinergic function in AD are significantly correlated with aggressive behavior, suggesting a reciprocal role of the cholinergic systems via monoaminergic neuronal activation.

• Severe caregiver burden and housemate type, racial type, educational level, sex, marital status, and comorbid sub-symptoms are psychosocial or demographic factors that influence NPSs in AD.

• The theoretical neuropharmacological mechanism of psychosis in AD is subtly different from that for schizophrenia mainly because of the relevance of the monoaminergic neurocircuitry.

• The DRS or LC is involved in the control of the sleep-wake cycle, which means that its impairment may cause diurnal (circadian) rhythm disorders including wake-sleep cycle disturbances in patients with AD.

• The above findings suggest that pharmacokinetic alterations arising from the therapeutic window within the brain, pharmacogenomic phenotypes, and monoaminergic-cholinergic system alterations may influence the unstable treatment response to selected antipsychotics or antidepressants in elderly people with AD, leading to treatment discontinuation or a need to switch prescriptions.Factors influencing the emergence of neuropsychiatric symptoms in Alzheimer's disease

• Severe caregiver burden is significantly associated with some neuropsychiatric symptom sub-symptoms.

• Comprehensive non-pharmacological interventions for cohabitant caregivers can contribute to a reduction in the severity of neuropsychiatric symptoms in patients with dementia.

• Racial type and educational level may be interactive factors in economic matters connected to receiving care or medical services and financial support.

• Gender differences in patients with Alzheimer's disease significantly influence the presence of a cohabitant and marital status, which may be associated with various lifestyle changes relevant to loneliness.

• Serious life events, including bereavement, may lead to loneliness or depressive symptoms in elderly widows.

• Intrafamily psychological conflict can cause severe caregiver burdens resulting in dysphoria in the patient, creating a "distressful vicious circle" between the caregiver and the patient.

• Various other neuropsychiatric sub-symptoms may hinder clinicians from focusing on targeted symptoms.

• Pharmacological treatments should prioritize antidepressants, rather than antipsychotics, for patients with Alzheimer's disease.

• A lack of recent autobiographical memory and preserved remote personal episodic memory in patients with Alzheimer's disease may cause distorted interpretations of objects present in reality, leading to delusional misidentifications.

• Rapid neurocognitive reduction through a certain duration has been significantly associated with some neuropsychiatric symptom sub-symptoms during the long-term course of Alzheimer's disease.

• Self-awareness of cognitive symptoms and neuropsychiatric symptoms may influence the prognostic treatment response, since poor self-awareness can lead to refusal of care.

• Clinicians should identify landmarks caused by differences between Alzheimer's disease and dementia with Lewy bodies from a neurocognitive viewpoint to determine each disease treatment strategy over a long-term course.Strategies for Treating Treatment-Resistant Neuropsychiatric Symptoms in Alzheimer's Disease

• Patients with Alzheimer's disease (AD) may experience treatment-resistant neuropsychiatric symptoms (p-TRENS-AD) due to various factors, including biology, psychosociology, and neurocognition.

• Pharmacokinetic and pharmacogenomic factors, such as the passage of drugs across the blood-brain barrier or monoaminergic receptor availability, can affect clinical pharmacological effects in AD patients.

• Metabolic factors of the CYP system can indirectly affect drug-drug interactions among prescribed medicines and psychotropics, potentially leading to adverse effects or lack of efficacy.

• Neuropharmacological alterations in the monoaminergic or cholinergic system due to neurodegeneration and aging can influence treatment responses in elderly AD patients.

• Psychosocial and demographic factors associated with neuropsychiatric symptom (NPS) emergence can lead to treatment resistance, and the significant association between NPS severity and caregiver burden can exacerbate symptoms.

• Comorbid sub-symptoms can cause delays in starting interventions for the true causative factor, leading to treatment resistance.

• Neurocognitive impairment in AD patients can cause secondary affective reactions or actions based on misidentified convictions, such as preserved self-awareness leading to pessimistic ideation and misidentification or confusion reflecting a distorted interpretation of present objects.

• A preserved self-awareness of cognitive symptoms in mild AD patients can cause pessimistic ideation concerning the future, leading to depressive symptoms and an extreme underestimation of one's symptoms, potentially causing suicidal behavior.

• Interpersonal interventions and non-pharmacological interventions, such as music therapy and behavioral management techniques, can reduce the severity of NPSs in dementia as a first-line approach.

• Patient relocation to specialized care units with appropriate facilities and specialized staff who can perform "behavioral management techniques" may be considered for patients with wandering or inappropriate behaviors for which optimal pharmacological treatments have not been determined.

• Augmentation of antidepressant therapy with lower doses of an atypical antipsychotic, dopamine compounds, lithium, or thyroid hormone may be helpful for treating depressive mood in patients with psychosis.

• Neuromodulation, including modified electric convulsive therapy, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation, may be effective alternative treatments for apathy or depression in AD patients. Clinicians should select safe treatment options bearing in mind the time-dependent pattern of NPS improvement and early clinical predictors of future prognosis.